Bastion of Reason

Biofuels and Co-Localization

2012-02-10T08:02:00.000-08:00

Years ago biofuel was viewed as the next step in reducing transport based emissions, but during recent years the principle feed source for biofuels, foods like corn, beats and sugar cane, have taken a beating with regards to how effective they are at actually reducing emissions. Currently very few individuals continue to believe that food-based feed sources should be pursued for expansion (of course this reality has not prevented the agricultural lobby from pushing for ethanol quotas from corn and other food sources). The loss of momentum for food-based sources appeared to open the door for algae feed sources to carry the biofuel banner. However, research has suggested that costs and environmental damage associated with algae feed sources could also eliminate its viability as a transportation alternative.1

To combat these detriments some within the algae biofuel community have suggested that co-localization is a necessary step to ensuring both profitability as well as the environmental footprint. Co-localization is viewed as important to the algae-based biofuel sector because while algae only requires water, CO2 and an energy source (typically sunlight) as inputs to produce the oils necessary for biofuels, efficiency rates are viewed as too low for large-scale production. Depending on the exact methodology of production adding additional elements like phosphorous and/or nitrogen increase yield rates. The process of co-localization is designed to take advantage of waste products from other industries like CO2 from coal plants, nitrogen run-off from certain agricultural process or wastewater from water treatment facilities and divert those elements to algae biofuel production at a reduced cost. Not only does this recycling reduce costs by lowering input costs it also reduces environmental waste as most of these byproducts from their associated industries are toxic and freely disrupt the local environment. Initially such a system design seems very effective and should be utilized whenever possible, however, there is an important consideration that must be taken into account, one which typically seems to be ignored in most analysis.

One must not forget that the original purpose of producing biofuels is to provide an alternative to oil or (if ever possible natural gas) as a transportation energy source in order to reduce carbon emissions. The reduction of transportation carbon emissions is only a part of the equation other emission reductions will be required to ensure the relevance of the transport reductions. Taking this reality into account demands that co-localization not only addresses the present, but also the future. For example while co-localization within a coal plant may appear attractive, the coal plant will need to be retired much earlier versus its natural time-derived retirement. Therefore, if production of the algae biofuel comes to rely on the byproduct feed from a coal plant or other heavy emission generating industry as an input stream the closure of said plant would create a production shortfall. This production shortfall would increase biofuel costs to both the company and the public as well as create inefficiencies in the transport infrastructure. Thus, individuals need to take into consideration the timeline associated with the elimination of the input providing industry.

The value of co-localizing heavily decreases if improper longevities are calculated both from a standpoint of corporate profits and societal efficiency. Therefore, it may be more practical for proponents of co-localizing to actually construct ‘biofuel parks’ that incorporate both biofuel culturing/processing centers along with a secondary industry built over a similar timeframe that would have an associated longevity period. While the initial capital costs would be higher it would guarantee both present and future synergy. Overall it is important that those individuals looking to reduce costs through co-localizing algae-based biofuel production take into consideration how those other facilities will change with time.

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1. Clarens, et, Al. "Environmental Life Cycle Comparison of Algae to Other Bioenergy Feedstocks." Environmental Science & Technology. 434-924-7966.

Cooperation vs. Competition

2012-01-30T08:56:00.000-08:00

One of the important questions of the future is the application of cooperation vs. competition in society. While competition has been widely praised, it is largely a myth that competition is good for the species as a whole. Competition, like fear, is only useful in an illogical and idle society that cannot reasonably identify way to advance society and evolve as individuals. Cooperation is better able to harness differing viewpoints and strategies to create scenarios where groups of individuals become greater than the sum of their parts and are able to accomplish things otherwise unattainable.

Competition is imbedded into our society because it is one of the principle tenants of capitalism. It is not necessarily a bad thing for it can act as a driving force for technological advancement and as a means to control overzealous profiteers. Unfortunately these benefits of competition are only benefits in the context of a fragmented society. For instance in a society where people are self-motivated and have the necessary foresight to reasonably prepare for potential problems competition loses its benefits vs. the application of cooperation. When cooperating with another individual and/or group the primary goal is to create a situation where all parties benefit in a greater capacity than either side would benefit if operating alone. This benefit typically embodies either an increase in capital acquisition (increasing profit or lowering costs) or the development of a new product or technique.

The act of cooperation eliminates the need to utilize competition to control profiteers because all sides are benefiting from the partnership and continuation of the partnership will create greater long-term gain than any potential short-term gain created from deviation. Most entities that engage in cooperation will typically have multiple dealings with one another, thus creating the avenue for greater mutual gain. Unfortunately human nature tends to avoid viewing future interactions in favor for present interaction, thus making cooperation a potentially dangerous investment if parties do not consider the long-term benefits. Therefore, to further neutralize short-term gain constructs, one side can punish those looking for only short-term gain by ending the relationship and collaborating with another party or in multiple groups networks simply remove the offending network. In such a strategy one isolates the offending party weakening them to the point where their ‘competitive’ mindset ceases to be useful.

For instance take the popular Prisoner's Dilemma scenario. Recalling the situation two suspects are in separate rooms being questioned regarding their involvement in a particular crime. Each suspect has one of two options: claim innocence or guilt. If both claim to be innocent then both receive 3 years in jail. If both claim to be guilty then both receive 1 year in jail. If one claims innocence and the other claims guilt then the one declaring innocence goes free and the one declaring guilt goes to jail for 10 years.

When viewing the Prisoner's Dilemma using Nash Equilibriums, a compellation component to capitalism frequently used in global trade where each participant strives for the best individual outcome assuming that all other participating individuals are doing the same, each prisoner should pled innocent because the best that can happen is gaining freedom and the worst that can happen is 3 years in jail. In a Nash Equilibrium example if a prisoner pleads guilty the best outcome is 1 year in jail and the worst outcome is 10 years in jail, initially pleading guilty clearly appears inferior to claiming innocence. Of course under Nash Equilibriums each prisoner will receive 3 years in jail because both will claim innocence. Unfortunately for the prisoners if each plead guilty they would only receive 1 year in jail, a 67% reduction in their Nashian sentence. So if the prisoners would adjust their strategy from taking an action that is solely in the best interest for themselves to taking an action that is in the best interest for the group both prisoners come out ahead.

The biggest problem with cooperation in the Prisoner's Dilemma is that both prisoners have to accept 1 year in jail because it would be easy for one prisoner to screw over the other prisoner and stick him with a 10-year sentence while obtaining freedom for himself. Of course this problem would not be a concern if both prisoners act in a logical fashion and abide by their previous cooperation agreement. Overall that is the key to cooperation, especially in situations where repeated interaction is improbable, is to have faith in the other individuals/groups remembering that everybody gains more when everybody looks out for one another rather than going at it alone.

Another example utilizing competition versus cooperation is an example that can be called the cash question. Consider the situation where two individuals are walking down the street (Person A and Person B) when another individual approaches them and offers Person A a choice; this individual would give Person A 5 dollars and Person B 3 dollars or he would give Person A 11 dollars and steal 4 dollars from Person B. What should Person A do? Competition indicates that the second selection should be made where cooperation indicates that the first selection should be made. If each of these situations were made in a vacuum it would be difficult to argue against the second option if one excluded any morality issues (taking money from another individual to increase your level of gain). However, when dealing with people in real life rarely is a situation like this conducted in a vacuum. Each decision one makes bolsters an aspect of your personality where other individuals will either respond positively or negatively to the new aspect and may change their overall opinion of an individual’s character.

From an interpersonal psychological issue when both participants gain, the non-active participant will have greater respect for the active participant and should be more likely to select a mutually beneficial option when he/she is the active participant. Remember it is likely that there will be multiple times when similar situations arise, not in the same context, but similar gain-gain vs. gain-lose outcomes. In this situations Person A will not always be making the selection. Therefore, because these situations do not occur in a vacuum the long-term gain is enhanced when considering less short-term gain. For instance if the situation arose 10 times with each participant selecting 5 times and each participant selecting the same choice as the last participant if parties compete with each other the overall gain for both participants would be + 35 dollars. If parties choose to cooperate the overall gain for both participants would be + 40 dollars. Of course one could try to sneak in a couple of short-term decisions in attempt to maximize their gain, but such a tactic would more than likely not go unpunished over multiple selections and result is greater loss for both parties.

Of course it is easy to cooperate with another party if gains are greater when working together than working apart. What is to be done if one side can gain more by shunning not only cooperation, but hurting another party? One could point out that if the net gain in the first option is greater than the net gain in the second option after one full turn in the above game, it would make financial sense to select the first option (assume the payoff was not 11 dollars, but instead 13 dollars). Unfortunately this is true, but somewhat dishonorable to punish the second individual solely because you want to acquire more even if you are not in competition with the second individual. The nature of human greed is the principle element that needs to be combated when striving for more cooperative relationships between humans over the present strategy of competition.

Initially it is difficult to comprehend why people are greedy for it appears to be in the best interest of individuals to support others around them in order to build a stronger community. The continuing relevance of greed can be rationalized in one of two ways. First, when human beings first evolved they were typically divided into a vast number of nomadic tribes with sparse populations. Although these individuals were in groups, the group existed primarily as a safety mechanism, protection from other nomadic tribes and wild animals in line with the old saying "Safety in Numbers". The irony of the situation was that looking at group dynamics, most tribe members acquired material and resources for themselves and their mates instead of distributing among the group in order to make the entire tribe stronger, a strategy that would go further in protecting all members. The reason behind such behavior was to improve their standing/power within the group. So the nature of greed could be thought of as evolutionary because even at an early age humans tended to hoard resources for purposes of increasing power instead of freely distributing them among their fellow members.

The second reason for developing greed through the accumulation and eventual hoarding of resources could be derived from mating dynamics for it is common behavior that in early human history females looked to mate with males who they believed could provide the most stable environment for raising young and provide the necessary support for survival. An important factor in providing this level of security comes from resource acquisition where in some way one could state that the number of resources one has is proportional to the ability provide these desired characteristics. Therefore, if one shared resources with the community, that particular individual would lose some level of attraction to the available females while enhancing the attractiveness of other males.

The above reasoning may help to explain the evolutionary rational behind male greed, but what about females? Females are a little more difficult to characterize because the roles assigned to them by society have only recently changed. For instance in the early years of nomadic tribes the principle role of females entailed raising children and once-in-a-while foraging for food. Back then there was little time to acquire resources for survival because other less able entities (children) were dependent on these females for survival, thus part of the reason females sought out males with large amounts of resources. In modern times, although females are still largely regarded as the primary caregiver in the family community, they now are not stereotypically tied to such a role. Therefore, now the acquisition of resources by one's own hand is a legitimate reality. So now females do not need to rely largely on the resources acquired by males in order to support a family and can now use resources to enhance social status and standing.

The nature of greed does have an evolutionary tinge, but the origins of these tendencies stem from a disjointed social structure. Now there is a more cohesive social structure and community where cooperation is easier and more beneficial. Although the evolutionary tendencies towards mating may remain, they should not be principally responsible for the level of greed that still seems to persist in society. The reason for greed can then be characterized by the first ‘evolutionary’ element, simple vanity and insecurity disguised as self-confidence and self-worth.

Unfortunately in modern society many people are not strong enough to stand on their own two feet when it comes to creating a level of positive and healthy self-worth and confidence. In essence certain people need to regard themselves as better than other people to feel good about themselves. Realistically as long as people hold this attitude a classless society can never exist because people will always be striving to prove to themselves that they are better than someone else and competition will continue to suppress genuine cooperation. One of the best ways in the current society to move up in social structure or class is to acquire more material possessions than most people and to acquire material possessions one needs money, thus greed and acquisition of money becomes a top priority.

What can be done about this psychological deficiency that catalyzes greed? In an ideal world one could recommend that the sense of emptiness and despair produced by feelings of inadequacy can be remedied by encouraging strong relationships between individuals and developing significant and realistic goals to accomplish. One could assume that this strategy would create a sense of meaning in life eliminating the drive to accumulate wealth as a means to establish meaning and worthiness. Unfortunately this does not appear to be the case else more people in this world would be happy and there would be fewer detrimental actions. So why does this strategy not work? Two options are available to explain this circumstance. First, individuals are not aware of the potential of this strategy to eliminate their emptiness. Second, the strategy is unsuccessful for a particular individual because he/she believes that amassing material objects is a faster and more thorough way to obtain self-worth. Neither reason is acceptable because the status quo is unacceptable, thus it must change.

A Brief Discussion about Leadership

2012-01-27T07:54:00.000-08:00

It can be said that the world is divided into leaders and followers. There are significant differences between good followers and bad followers, but the general understanding of a follower is well defined and accepted. Creating a consensus on what actions and characteristics typically define a leader is more difficult for there are a variety of opinions regarding essential leadership traits. Leaders are largely defined by their actions in groups and how those actions influence the dynamics of a group. One of the key attributes of a good leader is the optimization of the work environment, both from a personnel and a resource perspective.

Focusing first on the personnel aspect. It is not a leader’s job to promote harmony in the group; while harmony would be nice, the primary obligation of a leader is to make sure that Person A and Person B do their respective jobs. This duty can be more difficult if Person A and Person B do not like each other, but have to work together because their skills and expertise will produce better results. Thus it is a leader’s job to ensure that the disharmony and dislike between Person A and Person B does not interfere with their job performance. What happens if either Person A or Person B allows his/her personal feelings to influence performance? Such a situation is unfortunately complicated because the easiest solution is to remove the individual that is deemed less important (assume Person A for this scenario) from the team and bring in an individual with similar skills (Person A’). Using this strategy the job the released person was responsible for and the remaining individual (Person B) should increase in efficiency with little lost time or resources.

There are two obstacles with the easiest solution: it is frequently only useful in the short-term and it is questionable whether or not a Person A’ exists at the company in question. Person A was assigned to that particular team for a reason, more than likely because he/she was the best individual with the particular skill set, so if Person A’ even exists he/she will be inferior in skill at some significant level else Person A’ would have been assigned to the team in the first place. Therefore, the benefit of Person A’s dismissal must be weighed against the time and resources lost versus the gain of a productive Person A over the Person A’. In short the leader has to consider many cost-benefit questions on a theoretical level as noted below:

- What is the difference in skill level between Person A and Person A’ under normal working conditions?
- Are there skills and/or knowledge that Person A has that Person A’ does not? If so how relevant are they to the task at hand and how long would it take Person A’ to close the gap?
- What is the production drop-off from Person A when working with Person B and visa-versa?
- What would be the production change in both Person A’ and Person B when working together?
- What would be the time and resource expenditure when attempting to reconcile the differences between Person A and Person B?
- How many more projects would it be useful to have Person A and Person B work together (for skill set purposes)?

So although a leader is not obligated to play psychologist between Person A and Person B, he/she might have to for the benefit of the current project or future projects. Clearly the best way to neutralize these ill feelings would be to keep Person A and Person B segregated from each other. If they have to work together it is best to make it clear to both of them that the primary goal is the success of the project, how they feel about each other is irrelevant as success benefits both while failure would hurt both. This approach is necessary in most instances because typically when two people do not like each other to the point that it hurts productivity, that dislike is deep seated and the leader does not the time or resources to understand its origins and whatever may rectify it.

One of the more interesting questions regarding optimization of performance in a group is should the leader lead by example or act through delegation of duties? Leading by example seems to be the buzz phrase for leadership as it is frequently uttered in the business, political and entertainment world. The chief strength of leading by example is characterized by an increase in drive and motivation of other team members for witnessing the leader work directly ‘in the trenches’ to accomplish the goal typically enhances their own will to accomplish the goal.

An interesting element to this motivation enhancement is not any potential increase in motivate, but ensuring no decrease in motivation. Naturally any individual on a team should be instinctively motivated to accomplish the goal regardless of outside factors; however, in certain instances a weak and idle leader can foster deterioration in both confidence and willingness to work amongst team members creating an environment of inefficiency, jealousy and possible strife. Many people will attest that it is difficult to follow a leader who does not appear to do anything. Therefore, avoiding this drop-off in productivity is the primary issue for a leader to take an active role in achieving the goal.

Two main concerns stem from this type of leadership strategy. First, a strong and effective leader can instill complacency in other members of the team. Some individuals may allow a strong leader to perform much of the work either because they are just lazy or lack confidence in their own ability. With this potential outcome it is important for a leader to ensure that other team members are consistently being prodded for their input and are given significant tasks with realistic timetables.

If the leader can take on extra work it is appropriate to do so as long as all other team members have significantly important roles in the progression of the project. Realistically such a strategy should frequently be implemented, but as a neutralizing factor it should merely act as a backup plan as team members should be naturally motivated to succeed and such motivation should not diminish in the presence of a motivated and strong leader. A leader undertaking additional roles is important, but must be tempered with reason for if a leader over-extends in duty, it will have a negative effect in all areas of performance. Over-extension is the second potential drawback of direct active leadership for a leader can misinterpret his/her own superiority and skill based on position or preliminary results, which could accelerate parts of the project before they are ready. Such rapid movement can easily lead to wasted time, resources and damaged confidence among team members, especially if the leader participates in portions of the project outside his/her area of expertise.

Unlike a leader that leads by example who can simply take over the team and literally 'will' it to success, a leader who delegates needs to subtly control the direction of development and how each portion of the project advances. When teams are comprised of confident and competent members, delegation leadership is easy, just make sure everyone stays out of each other's way and slowly funnel information into the overall objective. When teams are comprised of less confident and/or competent individuals, delegation leadership becomes harder because the leader needs to identify relevant yet manageable goals for these members to ensure efficient progress. The main positive in this strategy is that delegation leadership has a tendency to improve the quality of a team faster than leadership by example because the probability of growth by each individual member is greater.

After considering the natural characteristics of the leader, a delegation strategy seems to be superior in situations where a solution will create a large number of new questions that will need to be answered by the same group. The delegation strategy creates a strong and more prepared team to solve the additional problems as long as they remain in the skill sets of those within the team. Leadership by example seems to be superior when striving for an isolated solution that needs to be attained in an accelerated fashion because team unity after the fact is not very important.

Overall the leader must be aware of when to apply one strategy versus the other for maximum results. Maximizing results should be a matter of personal pride for the leader because most people will tend not to care or criticize either strategy as long as the project moves forward in a positive way, but maximum output at lowest cost should always be the goal.

Climate Reporting in the Media

2012-01-09T08:05:00.000-08:00

Recently climate blogs like Climate Progress and The Daily Climate have lamented the drop in reporting on climate related issues including what they perceive either as an unwillingness or inability to ‘connect the dots’ linking global warming to extreme weather events. The glaring problem with this lamentation is its lack of focus. What exactly do the administrators and commenters on these websites want and how do they propose to accomplish their desires? Initially one could conclude that they want more general stories about global warming, but how would those stories be presented? One option, as they suggest, could be to make a connection between extreme weather events and global warming. However, would this be appropriate?

While only an ignorant individual would conclude that the occurrence probability of extreme weather is unrelated to global warming, the problem with ‘tying’ global warming to extreme weather is that it is scientifically irresponsible to associate the actual occurrence of a given extreme weather event to global warming. Basically one cannot say that the only reason flood x or drought y occurred was solely due to global warming as providing definitive scientific proof for such a claim is nearly impossible. Unfortunately depending on changes in probabilistic magnitudes to associate global warming influence with extreme weather is confusing not just at a lay level, but also at a purely scientific level due to uncertainty.

Based on these elements it seems unlikely that any increase in climate reporting can develop correlations between global warming and a single specific extreme weather event. Therefore, within the confines of extreme weather events expansion of reporting on global warming appears limited to general analysis pieces explaining that the probability of occurrence and magnitude of extreme weather events increases by some unknown variable which increases as the planet warms. Unfortunately these information analysis pieces will more than likely not significantly increase the number of climate related issues discussed in the mainstream media because such a topic changes little with time. Thus multiple presentations of this information over a consistent short timeframe could result in most readers tuning out the information as ‘exactly the same as 5 days ago’ or ‘exactly the same as a report in publication y a week ago’. A number of individuals believe that a similar psychological attitude has handicapped the ability to properly respect the magnitude of detrimental consequences to global warming as a form of ‘doom saying’.

It is difficult to conclude that these individuals are lamenting about a lack of coverage regarding individual climate-related events because such reporting is reactive not proactive. Basically it is difficult to report on a hurricane that has not happened yet. For the most part most media organizations do a respectable job covering single climate based events and as discussed above it is impossible to associate the 100% occurrence of a given event with current climate conditions, thus media organizations cannot do so despite what their detractors may want.

Some could argue that the lack of coverage involves too many lulls for ongoing events. One example could be the 2010-2011 drought in Texas and other parts of the Southwest United States. In some context the drought become so commonplace and part of the general environment that it was no longer interesting to report on in the national media. Therefore, almost by default individuals could start to consider the drought conditions as the new normal despite that fact that they shouldn’t accept that as inevitable. Such a mindset is similar to the frog accepting a slowly and continuously warming frying pan not reacting and escaping until it is too late. While most climate stories are not ‘sexy’, heck it could not be surprising if ‘Jerry Sandusky’ has been mentioned more in the last four months than ‘global warming’ has been mentioned in the last 3 years, it does appear important for media organizations to continue to address the non-normal climate conditions to avoid a general malaise of acceptance.

Unfortunately amid all of the lamentation little productive information is being given with regards to how the media should correct itself. The only refrain is ‘more coverage, more coverage’, but suggestions on how to effectively accomplish this goal are few. While some may argue that blanket coverage (more regardless of quality as long as it acknowledges the reality of global warming and its dangers) is suitable because eventually enough of it should convince people, this strategy is probably not effective. First off as previously mentioned simply increasing the amount of climate stores could result in individuals ‘tuning out’ the stories limiting their effectiveness on combating malaise.

Some would argue that this ‘blanket’ strategy is the same general strategy used by global warming deniers to try to tip public sentiment in their favor and while true there are other factors at work. The strength of the denier argument is in the controversy they create. People inherently are distrustful of ‘guarantees’, especially when they are negative. The guarantee that global warming is real and it will be seriously detrimental allow a better acceptance environment for deniers to make inaccurate to crazy claims about how it is not true. Another advantage for the deniers in this ‘blanket’ strategy is the ability to better maintain variety in the attack. Deniers can challenge various aspects of global warming consequences using different ‘theories’ so other individuals do not become bored. For those trying to demonstrate the validity of global warming this variety is not so widely available as the same 5-6 topics dominate in global warming consequence prediction.

Instead of attempting ‘blanket’ coverage an organized information campaign on specific topics could be a better strategy. In this situation the media outlet would devote a specific amount of time to a given component of global warming over the course of a specific timeframe. For example a newspaper may decide to discuss ocean acidification where they devote a page two space once a day for a week. One of the important elements to such a strategy is to maximize the probability that individuals understand what they are reading. Thus the Monday and Tuesday stories would need to focus on more background information pertaining to the particular topic.

An immediate problem to executing the above strategy would be a lack of interest. As previously mentioned climate science and environmental issues are not sexy or typically short-term dynamic thus providing an incentive would be useful to encourage readership. One strategy to develop incentive would involve having a mini-quiz at the end of the week where individuals who answered 80% of the questions correctly would be entered into a contest to win some form of prize. The medium for the contest would be via the Internet or mail order through the U.S. post office. Environmental organizations could help sponsor these prizes if necessary.

On a related side note while the media can be criticized for not effectively addressing their role in fight the acceptance of a new normal most in the environmental community seem not to go far enough either. The environmental community should not only be pushing the media to lay the groundwork for climate understanding to combat malaise and legitimatize genuine importance, but also to provide a debating forum for solutions. Unfortunately a number of individuals in the environmental community do not want this debate. Most simply want the application of their ‘pet’ solutions and are unwilling to address whether or not those solutions are viable.

For example proponents of solar and wind deployment continuously shy away from addressing possible cost overruns due to lack of storage and intermittence in an energy infrastructure that no longer utilizes fossil fuels. Instead they foolishly or dishonestly report ‘grid parody’ prices for wind and solar relative to fossil fuels in the modern fossil fuel based energy infrastructure, numbers that do not make sense because if wind and solar are going to be a solution they must be incorporated into an infrastructure that does not utilize fossil fuels. In addition these same proponents avoid the question of a possible rare earth shortage which will disallow the economic development of a principally wind/solar energy infrastructure. Thus not only must the attitude of the media change with regards to covering climate issues, but so too must the attitudes of those who claim to be its champions.

Digressing back to the media aspect, the issue that environmentalists should be discussing is not necessarily quantity, but quality and how to deliver that quality. The goal of the media pertaining to climate issues is two-fold: provide enough information over a suitable number of intervals to combat malaise/mitigation of importance and provide that information in a way that actually allow individuals to intelligently participate in discussions regarding solving climate related problems. One possible strategy to aid in accomplishing these goals, which the media has thoroughly been lacking, would be to devote constant time to a given aspect of global warming with quizzes and prizes to increase interest and aid learning and retention. However, some could argue that the ‘blanket’ strategy is still an option. If so those making this argument need to address how to evade the concerns discussed above. Overall regardless of what strategies are utilized the environmental community needs to better outline in specific detail how the mainstream media should present climate information over just complaining about the lack of it.

The Flaw of the Flat Tax

2011-12-30T08:07:00.000-08:00

Paying both federal and state income taxes can be an exasperating and depressing experience. It is easy to understand this dissatisfaction, especially because individuals do not know the precise destination of their tax dollars, instead watching the money vanish into a black hole riddled with waste and misappropriation. Unfortunately the black hole is not even the worst part of the tax system, yet few people seem to either realize the real problems in the tax system or care enough to do something about it.

One of the more popular suggested tax reforms is the elimination of the progressive tax system in favor of a flat tax system where all taxpayers would pay the same percentage of income. Proponents of the flat tax system sing its praises for its simplicity, what they believe as fairness and its ability to acquire more revenue for the federal government than the current progressive system due to a perceived elimination of a vast number of deductions and tax shelter tricks. However, proponents of the flat tax are either misinformed or trying to create a greater advantage for themselves with little concern for others.

Despite numerous studies concluding that flat taxes provide insufficient funds relative to the existing progressive tax system from a methodological standpoint comparing revenue gains from a flat tax system to the current progressive system is silly because the current system is so riddled with immorality and waste that almost any reform will give the appearance of a short-term increase in revenue with favorable assumptions. Therefore, if one were to be reasonable the flat tax system would need to be compared to other reforms in the progressive system and other new systems to gauge the legitimacy of its revenue collection superiority. Simply comparing one reform against the current system without comparing it against other possible reforms diminishes the authenticity of such an analysis. Such a mindset is also questionable in that it is irrational to conclude that there is only one possible alternative to an existing system or solution without careful analysis.

With regards to fairness it is easy to see why proponents of a flat tax system believe such a system is fairer to all parties than the current progressive system. The common flat tax and tax cut battle cry has frequently been ‘why should those that make more money be penalized?’ under the typically bias mindset that those who make a lot of money work harder than those who make less money. Most flat tax supporters appear to believe that the progressive tax system punishes ambition and success, which in turn may discourage individuals from being successful because the more successful they are the less they get. Of course any practical analysis instantly characterizes that complaint as complete and utter bull because first it is irrational to believe that an individual will be less motivated to acquire financial resources simply because they will have to pay more in taxes. Anyone given a choice between pursuing a career where he/she would make 25,000 dollars a year and pay 4,500 in taxes versus make 100,000 dollars and pay 34,000 dollars, would obviously selection the latter option. No reasonable person would elect to only make 20,500 dollars a year instead of 66,000 dollars a year to either ‘stick it to the man’ or because paying 34,000 dollars instead of 4,500 dollars to the government is so distressing that making a net of 45,500 dollars more is immaterial.

Proponents of a flat tax would contend that the above statement misses the point. The very fact that the disparity exists in the tax system at all is what is unfair. If these individuals feel so strongly about ‘rooting’ out unfairness then they should start promoting a communistic economic system. Capitalism is fraught with inequalities and unfairness for gone are the days where individuals can consistently achieve financial success by simply studying hard and working hard. There is indeed still the rare case where an individual pulls him/herself out of poverty to make it big, but in the modernized capitalistic system who you know and what resources you possess have a much more pronounced effect on your success than any drive to work hard. A majority of the individuals that have wealth today definitely took advantage of some of the unfair elements of capitalism to amass their fortunes. How funny it is that most individuals complain about unfair elements that are to their disadvantage, yet say nothing about unfair elements that are to their advantage.

Unfairness in capitalism and the role of the progressive and flat tax is best illustrated in an example. Consider two participants running a 400-meter dash, Runner A and Runner B where Runner A gets to start 100 meters ahead of Runner B (think of this as better connections and greater access to resources largely due to parental connections). The gun is fired, the participants run the race to the best of their ability and Runner A wins easily. Suppose then the timers elect to remove 5 seconds off of Runner B’s time closing the difference between the two times, yet still maintaining an easy victory for Runner A. Those that support a flat tax would cry foul about removing 5 seconds from Runner B’s time, but would remain silent about Runner A’s 100 meter head-start. Replacing the progressive tax with a flat tax would simply be removing one unfair element that favors the poor further stacking the deck in favor of the rich and well connected.

A more conspiracy theorist view of the flat tax could label the system itself as a fiendish negotiating tactic by the super rich. Perhaps one day the masses will realize the actual disparity in the tax rate between those who make 35,000 dollars a year versus those who make 1,000,000 dollars a year is not in their favor, but the favor of the million dollar earner due to government neutering of the IRS and tax loopholes for the rich. Such realization will result in a demand to close tax loopholes for both the individual and corporations reestablishing the genuine rate as outlined in the progressive system.

With this eventual understanding that some perceive to be inevitable, one could believe that the flat tax is just a preemptive strike to neutralize progressive tax reform. In essence although the flat tax would result in an increase in tax payment from net effective rate of the mid-teen (what most well-connected wealthy individuals pay) to something like 20% it would dramatically reduce the probability of reform within the progressive system itself that could result in a rate increase from mid-teens to 39% or even higher. So by giving up something like 4-5 percent points, the biggest benefactors of a flat tax save themselves a 20-30 percent point increase at some point in the future.

Finally the importance of the assigned tax rate in the flat tax itself deserves analysis. If the rate is too low, then the government will not be able to recoup the necessary capital required to effectively run programs for the benefit of its citizens, which would lead to the loss of certain programs or increased national debt either element would negatively affect the economy. If the rate is too high, then those in the lower portion of tax bracket in the progressive system will end up paying more and those in the higher portions of the tax bracket may end up paying less and that hardly seems to emulate the ‘fairness’ of the system, the less you make the more you pay. This single statement has deduced the reality behind the flat tax. Inherently in its purest ‘on paper’ form the flat tax is fair, but the current practice of capitalism is not. The insertion of a flat tax into an unfair system of much greater magnitude corrupts any authenticity in the flat tax. So while a flat tax may be fair in isolation, in the current economic system of the United States, it is unfair and unwarranted.

Death Penalty Logic?

2011-12-30T08:00:00.000-08:00

Since 1973 the death penalty has regained its previously controversial place in society. The controversial nature of the death penalty is somewhat confusing in light of looking at the benefits of death penalty opposed to its detriments. A critical first question when evaluating the merits of the death penalty involves defining the purpose of the death penalty. One commonly citied goal for the death penalty is that of a deterrent, a means to prevent future actions which would warrant the death of the perpetrator. Although in theory this goal may seem logical and noble as preventing crime is always preferable to reacting to crime, no hard proof has ever been produced demonstrating a long-term reduction in homicides directly associated with the reemergence of the death penalty. So the goal of using the death penalty as a deterrent does not appear to be working,

If validating the death penalty through its use as a deterrent is not applicable in reality altering its goal to that of a tool for vengeance seems like the next logical step. The question of whether the death penalty actually serves as a positive psychological tool for the families of the victim is essential to judging the validity of this death penalty goal and purpose. Overall it is a troubling thought to think that families actually receive some level of satisfaction when the criminal is put to death over sentencing the criminal to permanent incarceration, but for the sake of argument consider for a moment that this reaction is indeed the case.

Why is it that the ‘vengeance’ mentality demands the ‘eye for an eye’ treatment in this situation? Although ‘ an eye for an eye’ can be regarded as an appropriate reaction, the concern is that some have come to believe that it is the only appropriate response available, which is not correct. Clearly a single action has many different reactions of differing severities. It is unrealistic to believe that only one specific response among a multitude of possible responses is appropriate instead there are a number of different options for redress and justice.

Why do some individuals look upon a lifetime of imprisonment as inappropriate? One of the worst things you can do to an individual is restrict or remove freedom. Although one could argue that the worst thing that can happen to an individual is the loss of his/her life, with suicide rates greater than zero clearly other individuals believe that living in certain circumstances are worse than death. From a psychological perspective restricting the freedom of an individual for the rest of his/her life appears to be an appropriate response for the vengeance seeking individual set on inflicting a significant level of suffering to the criminal as redress for the crime. For certain individuals one could regard life imprisonment as a worse punishment than death for certain individuals.

In regards to what comforts death offers a family over life imprisonment, any significant difference seems rare as both death and life imprisonment remove the ability of the individual to repeat the action against an individual that the family would regard as important or even society in general. The death itself may not be as tragic an event for the criminal as desired because of acceptance of the inevitable.

Also the numerous appeals and legal hurdles rightly involved in an execution typically provides delays of multiple years, which could inflict undue psychological damage on those who want to see a particular individual die, a case of deferred justice. In the end realistically very little is gained when electing to execute an individual over the punishment of life imprisonment for the sake of vengeance alone. Instead by electing to utilize an unnecessary and potentially savage response over one that is appropriate in its own right society could lose another shred of its humanity.

If deterrence and vengeance as reasonable motivating factors for utilizing the death penalty are eliminated, what makes the death penalty useful? Despite its flaws, the death penalty is remarkably effective as a bargaining chip for prosecutors when negotiating plea agreements with eligible criminals in question. The fear provided by the death penalty may not work as an effective deterrent in the prevention of certain crimes, but is effective in neutralizing the vigor in which a criminal may desire a trial. Whether or not this is actually a good thing is debatable. In a logical and perfect world one would conclude that only an individual that is actually guilty of a crime would plead guilty, but unfortunately due to fear and psychological trauma that ideal is not always achieved as individuals not guilty of the crimes they are accused of have pled guilty to lesser offenses or been found guilty by a jury.

So the death penalty may be a great negotiating tool only because of its greatest flaw, its finality. Clearly individuals in the past and more than likely in the present have been killed for crimes in which they have later been exonerated. Therefore, an individual that is not guilty may believe that pleading guilty to avoid the death penalty might be the only way to eventually prove his/her innocence of the accused crime and still have a life to live when this innocence is recognized. The fact that this psychological belief even exists demonstrates a great failure of the criminal justice system.

By stripping the death penalty of a worthy and significant purpose, the proverbial ‘death penalty horse’ has been shot and killed, but just to be thorough it is time to pick up a stick and commence wailing on it. Even if the death penalty did have a worthwhile purpose there would still exist multiple fronts in which opponents could attack both its philosophical existence (even when excluding moral arguments) and its execution (no pun intended). The primary goal of the prison system in general seems to be rehabilitation not punishment. The use of the death penalty displaces that goal for it is impossible for one to become a productive member of society if one is dead. It could be argued that the same failure occurs when an individual is sentenced to life without parole, but such a belief is in error.

Although an individual sentenced to life without parole will never be able to reemerge into society as a changed individual, if the individual is indeed rehabilitated he/she can instruct other individuals within jail and in society on what mistakes to avoid and provide other information and experiences that could better both the prison society and non-prison society. In response to those that believe certain individuals cannot be rehabilitated, the only way to be sure of such a position is to never give those individuals a chance.

Also when looking at life in prison versus the death penalty from a simple economic argument, the death penalty losses out as in every state that has studied the economic differences between death and life in prison has concluded that executions cost significantly more money mostly due to the required appeals that come with a death sentence to limit the possibility that a not-guilty individual is being put to death. Finally with regards to individuals who are deemed too violent for general population, solitary confinement is always available.

Overall opposition to the death penalty could be driven by any underlying concern for the sanctity of human life, but elements of practicality, efficiency and accuracy also play important roles.

Progress at Durban?

2011-12-14T07:57:00.000-08:00

The two sides of contrast in the COP-17 agreement at Durban seem to divide on the perspective of goal advancement. Assume for a moment that the necessary emission reductions and other necessary strategies (leaning more towards various geo-engineering applications) can be akin to society collecting 10 fireflies in a jar. Suppose the consequence to not collecting these fireflies in a certain time frame is death.

The group who believes that Durban is a success could argue that Durban captured one firefly, finally the ‘developing’ nations like China and India acknowledge that they will need to cut emissions in consort with the developed nations not after. These individuals could also argue that those who view Durban as a failure are being unreasonable, assuming that a vast majority, if not all, of the fireflies could be captured in a single swipe of the jar. The ‘Durban was a success’ crowd believes that the best strategy for capturing all ten fireflies is to capture one firefly at a time and because Durban seems to have done just that it should be considered a success.

The ‘Durban was a failure’ crowd believes this mindset is foolish. This criticism flows one of two ways. First, society has not collected 10 fireflies yet and until that happens nothing else should be viewed as a success. Overall while understandable, this mindset is rather counterproductive and unrealistic because no rational person would conclude that such a dramatic shift in human society could occur in a single element short-time frame.

Second, even if you could argue that Durban was a success based on both the U.S., China, India, etc. actually agreeing, despite no binding elements, to reduce emissions within a global carbon scheme the problem is timing. Assume that both China and the U.S. actually live up to this pledge, a critic could state that why should people be happy about capturing one firefly, a firefly that has been evading the jar for over ten years since Kyoto. Does society really have the luxury of spending an average of ten years capturing each one of the remaining nine fireflies?

A critic could argue that perhaps it is time for a new strategy to capture these fireflies, one that does not involve aimlessly running around wildly swinging a jar (global climate conferences). Recall that a number of individuals believed that this ‘Durban’ firefly was captured in Bali in 2007 and the final details from Bali were supposed to be addressed in Copenhagen in 2009, all interested parties know how that turned out.

The biggest telling point in the above criticism is that with no binding elements in the agreement the proverbial can has simply been kicked down the street until the next conference, something society has been doing for the last decade. Without binding elements that could penalize non-participating or non-complying countries such emission agreements are equal to having a sizable hole in the jar where whether or not any fireflies remain captive is at the discretion of the firefly not society. When it is in the interest of the firefly to be free it is difficult to consider the possibility that it will voluntarily restrict itself for the sake of others.

Revisiting Campaign Finance Reform

2011-11-25T08:18:00.000-08:00

The original question in Citizens United v. Federal Election Commission revolved around whether or not the FEC could use the McCain-Feingold Act (a.k.a. Bipartisan Campaign Reform Act) to prevent groups from distributing political advertisements within 30 or 60 days from a specific type of election. However, while this narrow element was the original nature of the case, the majority in the case expanded the breadth of the ruling to justify whether or not money expenditure in an election could be considered an extension of free speech and if corporations could use it for the direct purpose of supporting the election or defeat of a given candidate.

The somewhat sad reasoning in Citizens is that Justice Kennedy in the majority opinion seems to suggest that there is no way to distinguish between media (who was not restricted the McCain-Feingold Act) and other non-media corporation, even though governments and its agencies had been doing just that for years leading up to this case. The real question stemming from Citizens is what is the obligation of the United States to the Constitution when the consequences to possibility not upholding an aspect of it could be disastrous?

One of the chief problems with Citizens is the rationality that money is a form of speech and the First Amendment should protect its use. The underlying problem in the application of such a belief is that there is no inherent limit to the distribution of money. In this regard society tiers the importance of an individual’s speech by how much money he/she has. This scenario creates an unequal weight on speech that is not inherent to the accuracy of the speech. The point of the First Amendment was to ensure all speech because all speech was viewed as equal based on the premise of equal weight within reason. The tiered environment created by money destroys the assumed ‘equal weight’ environment, which ‘housed’ the First Amendment. The court in First Nat. Bank of Boston v. Bellotti did not properly appreciate this understanding.

Now one could argue that the ‘influence’ of newspapers and other print media, which received an exception before Citizens, also destroyed this environment. Such an argument is not correct. Newspapers offered the option of readers commenting on inaccuracies or perceived impartialities through the ‘letters to the editor’ section reducing the argument weight relative to the opinion produced by the paper. This option is not available for print insert, television or radio advertisements, the principle mediums of action by those who ‘demonstrate their speech’ with money.

Based on the entry costs associated with these mediums there is little to no opportunity for the average citizen to counter inaccurate information given by these ‘speechmakers’. In addition these ‘speechmakers’ can repetitively engage in this speech tapping into a very large audience. This lack of correction as a means to control weight is important because most of these advertisements are ripe with inaccurate and/or misleading information because to those producing them the point is not to win an election fairly, honestly and/or morally, the point is to win by any means necessary.

Another problem is that individuals and media outlets have an inherent ceiling to the influence they can exhibit in a political environment. Basically the maximum weight of their argument is reasonably capped. Individuals engage in direct speech (i.e. soapbox) are clearly limited by time and resources so their message(s) rarely carry lasting influence. Newspapers only produce one paper per day, which heavily restricts the content that it can devote to attacking/praising a given candidate(s) or the total influence it has as numerous papers would have to devote large percentages of space to a given candidate to generate lasting influence.

Television stations have a greater theoretical ceiling having the ability to disseminate content all 24 hours in a day, but face a ‘feasibility’ ceiling in that devoting too much aired content to attacking/praising a given candidate(s) will drive away undecided and ‘independent’ viewers allowing the station in question to only retain individuals devoted to loving/hating that given candidate/policy in a pre-conceived way. The tiered structure of ‘money speech’ has a much larger ceiling as advertisements of support/ridicule can appear in many different mediums generating huge levels of exposure (dwarfing those of newspapers and single television stations) with a much lower probability of turning off individuals who the advertisements are meant to influence.

Therefore, these advantages make ‘money speech’ much more valuable than ‘conventional speech’ and the more money one has the more ‘money speech’ one can make. Some try to make the argument that many people can ‘pool’ their money into collective organizations which would represent their interests with more ‘money speech’ than these individuals could muster on their own. Unfortunately due to the incredible imbalance in the current economic system the only organizations of this nature that could compete with corporate interests acting as a potential counterbalance are worker unions.

However, individuals who oppose the existence of these unions, because they do not agree with their political positions, are continuously attacking these institutions in various states in effort to destroy them. The systematic attempt to eliminate these established ‘common man’ money pools and the inability of other pools to generate equalizing amounts of money to compete with corporate interests heavily damages the validity of the pooled money argument. It is reasonable to suggest that the largest corporations will always have dramatically more ‘money speech’ than common citizens or smaller companies.

Those who argue that the point of Citizens was to liberate the ‘money speech’ for small businesses are either naïve or purposely misleading their audience. Available ‘money speech’ for small businesses only matters if that business agrees with the position of a larger business and if this is the case then there is little point for the small business to contribute because of vast percentage of the ‘speech’ on that given topic will be made by the larger business because it has more to gain or lose from influencing policy. If the smaller business disagrees with the larger business in a matter of policy there is no reasonable expectation that the smaller business will be able to utilize the ‘advantage’ of its ‘money speech’ to defeat the opinion of the larger business. In fact lack of viable restrictions on ‘money speech’ actually weakens the power of the speech for the small business relative to large business regardless of which business is actually right.

Interestingly the characterization of money as speech changes an intangible element to a tangible one, which actually strengthens the argument for regulating this type of speech. The original point of Citizens (from the petitioner’s viewpoint) argument was that it was not fair that their organization was restricted from releasing a political advertisement based on a specific time deadline, a deadline which did not apply to media organizations. The argument was that this deadline was a complete restriction of their organization’s ‘speech’. One could see the potential validity of their argument in that their ‘speech’ was being restricted in its entirety by the deadline. However, while the First Amendment disallows a government entity (federal, state or local) the ability to restrict an individual from speaking at all (outside of very specific situations), it does not restrict that same government entity from applying restrictions to certain types of speech.

A similar vein can be seen within the Second Amendment in that even if one argues that the rights of private citizens not in a government sponsored militia to bear arms are supported by the Second Amendment, an argument that is nearly impossible to make logically, government can still restrict the types of arms one can own legally. For example just because the Second Amendment states one can bear arms does not mean that the government has to allow an individual the right to own a nuclear bomb. Thus the right to bear arms is not universally protected in all forms. The same logic can be applied to the First Amendment in the form of ‘money speech’. Based on that precedent the government could place a ceiling on how much money a ‘person’ could spend in a given election cycle (just not donate to a given candidate, but actually spend be it independently or through some subsidiary).

One could argue that such ceilings were addressed in Buckley v. Valeo, but the reasoning in Buckley is incredibly naïve when addressing the ceilings relative to the improbability of corruption: “[the] absence of pre-arrangement and coordination…alleviates the danger that expenditures will be given as a quid pro quo for improper commitments from the candidate.” Perhaps one could hold on to such illusions in 1976 when the Buckley ruling was made, but with changes in technology as well as existing anecdotal evidence over the last 30 years it is extremely difficult to view such a reasoning as valid in 2009 (when Citizens was ruled) or 2011.

Another interesting association between the First Amendment and money can also generate allowable government restriction. The spirit of the First Amendment was designed to protect differing opinions, but not opinions that were deterministically false, there is a reason libel and slander laws exist. Normally deterministically false statements are of little consequence because of the small scale in which they occur; however, within each election cycle based on what is at stake due to how the decisions legislators make influence the well-being of the general public the importance of deterministically false speech in the election environment, regardless of intent, is significantly magnified. Therefore, it should be the prerogative of a government agency to penalize and restrict individuals or groups making clearly false, ambiguous or misleading ‘money speech’ in an election environment within proper jurisdictions.

Some want to argue that these types of restrictions are not necessary largely because voters are intelligent actors and money invested in election cycles only has a muted influence on which candidate a voter votes for. This reasoning seems to fall short of viability on two points. First, if such a statement were accurate then why are hundreds of millions of dollars spent in each major Federal election cycle; clearly the individuals/groups spending this money have conducted numerous studies to identify the best and most efficient means to spend the money as ‘speech’. Therefore, it is difficult to accept the reasoning that all of this money and time would be spent on an endeavor that had little to no influence.

Second, the belief that general voters intelligently analyze candidate platforms and logically determine whether those platforms are valid and will be effective at solving problems is naïve. Most voters do not either have the time, the experience or the desire to undertake such a task, especially because of the general lack of specificity offered by candidates on their platform (most simply give general stock answers to questions or flat out lie). Thus, without this in-depth analysis most voters rely on media outlets and advertisements to ‘inform’ them regarding political platforms and opinions. Overall ‘money speech’ clearly plays a significant role in politics with regards to influencing voting trends and habits and to argue otherwise is simply foolish.

When considering the manner of speech itself a distinction must be drawn regarding subjectivity. There are two types of elected official: legislative and judicial (note that this categorization is different from branches of government of which there are three). These two categories are divided by the roles they play in crafting the law. The legislative category is responsible for creating, debating and passing/failing perspective legislation (the President is also a part of this category) where the judicial category is responsible for determining whether two separate laws contradict and how to resolve that contradiction and address criminal sentencing.

Between these two categories the legislative one has a much greater level of subjectivity relative to how to solve a given problem. The purpose of passing new laws is to solve a problem in society, yet due to imperfect knowledge and boundary conditions the analysis ability to determine whether or not a given solution is successful is not purely determinate. An extremely simple example of this process is determining a solution for x + y = 7. In this situation there are numerous solutions to the problem regardless of methodology.

However, the general openness of the legislative category does not exist for the judicial category. Determining if a given piece of legislation is constitutional, in conflict with another piece of legislation or if a defendant is guilty, etc. are much more restrictive due to existing logic and boundary conditions. For example for this category instead of x + y = 7 the problem is x + y = 7 where x > 3 and y is positive. Basically the level of subjectivity is much smaller and there are fewer viable possibilities for x and y.

The general point of speech in the election of an individual who will take a legislative role, regardless of type, is to demonstrate support for a particular idea or group of ideas that embodies the candidate. It can be argued that another rationality is to exhibit support for certain personal characteristics of the candidate, which could allow him/her to better work with other legislators to come to a deal. This situation is different for a judicial election because the limited options eliminate the second rationality for speech support. Judges do not negotiate with other judges in a quid-pro-quo manner similar to politicians. The first opinion is also significantly hindered by the limited number of correct options due to sentencing guidelines, logic and legal precedent. Therefore, speech in support or opposition against judicial candidates can only effectively be given as a measure of how effective a judge is at upholding the law on an analytical basis.

Unfortunately most of the ‘money speech’ in judicial elections is based around fear and bias largely driven by an attempt to seat like-minded individuals regardless of whether or not the legal opinions of the candidate in question are correct. This lack of respect for the legal system is troubling and actually could allow for the restriction of support/detraction speech in judicial elections due to Brandenburg v. Ohio.

Brandenburg v. Ohio largely addressed the issue of ‘clear and present danger’ exception to the First Amendment, which was first validated in Schenck v. United States. Originally the ‘clear and present danger’ exception was clarified under the ‘bad tendency’ test in Whitney v. California where if the speech has a tendency to cause sedition or lawlessness it could be constitutionally prohibited. However, Brandenburg created a new standard for the exception through a three-pronged test, which limited its application restricting government ability to restrict speech. The three elements that make up the test are intent, imminence and likelihood. When individuals devote ‘money speech’ to the defeat of a sitting judge who has not demonstrate malfeasance it can be argued that such ‘speech’ is meets the three elements of the Brandenburg test.

Arguing that a judge that has a reputation for ruling correctly legally and logically should be replaced in an election demonstrates intent in that supporters of the challenger believe that the challenger will rule differently than the sitting judge. However, if the sitting judge has ruled correctly then these supporters are supporting a candidate who will rule incorrectly, a candidate that intends to break the law by improperly evaluating it. Likelihood occurs because judges do not summarily rule on the constitutionality of an issue randomly and spontaneously, typically a petitioner must bring a suit, which challenges the standing of a given law. Therefore, if an individual is bringing a suit and is successful it stands to reason that the likelihood of that individual acting upon that new ruling is very high.

The only questionable element is imminence, but similar to likelihood it stands to reason that if an individual is bringing a suit against a particular law that if it is overturned that petitioner will act upon the law as soon as possible (a near immediate effect). Therefore, it appears possible that the government would be authorized to disallow ‘money speech’ in an election against a standing incumbent judge who has not demonstrated malfeasance.

Note that ‘money speech’ would be targeted in the above example over general speech because of the breadth of contact. The ‘danger’ in a judicial election is an individual taking the bench who will make judgments that are incorrect solely due to personal or professional motivations. Only ‘money speech’ has the ability to influence enough people to elect the judicial candidate who will be inappropriate for the job. There is little reason to suspect that general speech will be able to create a sufficient level of influence. Also note that the ability of the government to restrict ‘money speech’ only applies to judicial elections with an incumbent as there is not existing record to judge for two competing non-incumbents.

One exception that could be discussed regarding an incumbent re-election is past action within the sentencing range. While the judicial rulings on guilt and constitutionality are rather firm, the most subjective aspect of a judge’s role is sentencing. Some individuals may disagree with a judge who assigns penalties on the higher edge of the guidelines (5 years instead of 3 years for a 3-5 guideline crime) or visa-versa. In these situations if ‘money speech’ can demonstrate specific instances of such behavior through explicit citations then it would be difficult to eliminate ‘money speech’ made in opposition of that premise on the basis of the Brandenburg test.

One may try to argue that ‘money speech’ should never be restricted in elections based on the sole element of personal opinion regarding likeability. Basically ‘money speech’ could be used simply to exclaim to the public that candidate A is a ‘good guy’ and individual or organization A likes him. The problem with this mindset is that it is very unlikely that an individual or organization would spend thousands to tens of thousands of dollars in ‘money speech’ driven only by a personal like for the given candidate, there will be an ulterior motive.

Overall while the rationality in that completely restricting the ability of an individual or organization to participate in the political process through purchasing advertisement may seem logical, the First Amendment also does not guarantee unlimited speech in an environment when all individuals do not have the same opportunity for speech. Therefore, this realization logically, and more than likely legally, gives the government the ability to place a ceiling on the total ability of individuals to ‘speak’ in these types of environments. For example the government could set a ceiling on the amount of money that a given individual or corporation could spend in an election cycle to 20,000 dollars. Also based on the general differences between those who make the law and those who enforce punishment and interpret the law monetary speech restrictions in judicial elections could be even more strict, possibly even disallowed. While some believe that the ruling in Citizens significantly curtailed the government’s ability to restrict corporate money in political activities, any interpretation that the government is unable to apply monetary caps to corporations or individuals for political activities is unethical and logically wrong.

Intestinal Bacteria and Obesity

2011-11-16T08:09:00.000-08:00

Some important biochemical interactions and responses to obesity have previously been discussed here.

In recent years explanations for the sudden rise in obesity have ranged from a further unbalanced internal biological energy balance to environmental pollution. Another accompanying explanation that is gaining support is that the type of bacteria residing in an individual’s intestinal tract is important relative to what foods an individual consumes. There is widespread belief that particular bacteria types drive certain metabolic rates and processes that have a significant effect on weight loss vs. weight retention.

The digestive process can be broken down into three stages after chewing. First, the food enters the stomach and is rendered into chyme by hydrochloric acid. Second, the chyme goes into the small intestine where a vast majority of the nutrient absorption occurs through osmosis, active transport and diffusion to nearby capillaries and eventual transport to the blood stream. Third, the indigestible and unabsorbed material passes through the large intestine where some of the indigestible material is processed (usually fermentation) by appropriate intestinal bacteria, water is reabsorbed and remaining material is packaged for excretion. It is this third element that is of particular interest here.

The human intestinal “metagenome” consists of trillions of microbes that provide enhanced metabolic capabilities due to absent enzyme inclusion (polysaccharide metabolization), protection against pathogens (indirect mucosal defense and luminal colonization competition), immune system support and aids gastrointestinal development and maintenance through interaction with epithelial cells.1-5 The two major elements which drive the specific populations of the metagenome in a given individual are genetics and diet. At the moment there is little that can be done regarding genetics, but the influence of diet is prevalent and that influence begins as early as infancy.1 In fact there is reason to believe that this “metagenome” is most influenced within the first few years of life and can have significant effect on immunity development.6,7

A vast majority of intestinal bacteria belong to one of two phylum of bacteria: Firmicutes and Bacteroidetes. Among these two phylum the bacteria in the intestinal with the largest populations are thought to be (in no particular order) genera Bacteroides (bact.), Clostridium (firm.), Bifidobacterium (bact.), Peptostreptococcus (firm.) and Ruminococcus (firm.) with minor populations of Escherichia (proteo), Lactobacillus (firm), Enterobacter (proteo) and Enterococcus (firm) with various methanogens.3,8,9. The parentheses identify the phylum type for the particular bacteria. It must be emphasized that specifics regarding exact populations are still far and few between relative to the specific genus which make up the Firmicutes and Bacteroidetes phylums for they contain 250 and 20 genera respectively;10 however, it is thought that Ruminococcus makes up a significant percentage of the Firmicutes phylum. On a side note Firmicutes bacteria are typically gram-positive (outside a very small few which have pseudo membrane walls) and Bacteroidetes bacteria are typically gram-negative.

Not surprisingly various intestinal bacteria populations are not evenly distributed throughout the digestive system, but each specific bacteria group has some environmental niche, notable is that higher bacterial populations are found in the lower portion of the intestinal tract vs. the upper portion. Also the upper portion has a large percentage of aerobic bacteria vs. the lower portion having a large percentage of anaerobic bacteria with the terminal ileum as the transition zone.7,11

The principle reason why intestinal bacteria have perked interest in the obesity ‘epidemic’ originated from an experiment in mice which demonstrated that intestinal bacteria play an important role in energy metabolism and weight changes. The study involved using a set of control mice and axenic mice (note that axenic mice are mice without any significant amounts of intestinal bacteria i.e. germ-free mice). Under normal conditions the axenic mice, controlled for age and background, weighted about 40% less than the control mice. However, after colonizing intestinal microflora (from the distal section) derived from the control mice within the axenic mice, the weight of the axenic mice increased by 60% over a short period of time.12 The inclusion of the microflora is thought to influence weight gain through three mechanisms: increases in intestinal glucose absorption, energy extraction from indigestible foods and concomitant higher glycemia and insulinemia.12,13

Changes in the suggested mechanisms from above are though to occur through influence on the action of two signaling proteins: carbohydrate response element-binding protein (ChREBP) and liver sterol response element-binding protein type-1 (SREBP-1) which in turn influence intestinal fasting-induced adipocyte factor [Fiaf; a.k.a. (angiopoietin-like protein 4)].14 When Fiaf is expressed it inhibits lipoprotein lipase activity, which increases the probability that fatty acids are released from triacylglycerols; these fatty acids can then be absorbed by muscles and adipose tissues to be used as energy (basically the fatty acids are consumed). If Fiaf is not expressed then lipoprotein lipase activity increases, increasing the probability of more fat synthesis. Germ-free mice seem to avoid obesity due to excess food consumption, commonly called diet-induced obesity, through three independent mechanisms: increased levels of Fiaf, increased levels of adenosine monophosphate activated protein kinase and reduced food consumption.14

Since the original study more studies have demonstrated differing intestinal bacteria populations in individuals of various weights. Most studies have developed support for a similar pattern between the obese and the non-obese in that more obese mice have a higher population of Firmicutes over Bacteroidetes.15-18 However, other studies have demonstrated no changes with populations in these bacteria or even the reverse with Bacteroidetes at higher population than Firmicutes.19,20 Thus the principle question becomes: do bacteria x protect against obesity in some way or are they simply preferentially selected in non-obese individuals vs. bacteria x which are preferentially selected in obese individuals?

Associate these elements with the fact that the Firmicutes/Bacteroidetes ratio drops when obese individuals lose weight (assuming no dramatic increase in fiber consumption) and Firmicutes population could be tied to fat, possibly through lipid production and storage. One study did demonstrate specific enzymatic activity in obese individuals associated with gram positive bacteria (Firmicutes) over gram negative bacteria (Bacteroidetes).21,22

The problem with fully determining the role of the Firmicutes/Bacteroidetes relationship is the contrasting results. For example some studies report that Bacteroidetes population increases from 3% to 15% with a hypocaloric diet in obese individuals where the Firmicutes population does not undergo significant changes.13,19 If this case is accurate it indicates that Firmicutes growth is not augmented by increased calories/fat, but instead Bacteroidetes growth is inhibited by those elements in some way. However, others report a decrease in Firmicutes population with weight loss and a decrease in Bacteroidetes (50% reduction) in obese individuals vs. non-obese.19

The issue with the Firmicutes/Bacteroidetes ratio may not be the change in the ratio, but instead the change in absolute population. For example in obese individuals what drives the change in the ratio, a decrease in Bacteroidetes population, an increase in Firmicutes population or do both change in general consort with each other? For example if an increase in the Firmicutes population is the dominating factor then it could be possible that Firmicutes responds to non-insoluble fiber elements. However, if a decrease in the Bacteroidetes population is the dominating factor then it could be possible that Bacteroidetes reduces fat absorption.

Other results have shown that axenic mice gain more weight when colonized with microbiota from obese mice opposed to lean mice.15 This result leads to the question of whether Firmicutes are able to extract more energy from a conventional diet over Bacteroidetes or do Firmicutes drive greater amounts of fat storage over Bacteroidetes? The second possibility sees support in that decreases in Bifidobacterium in mice fed a high fat diet also correlated to an increase in lipid polysaccharide (LPS) concentrations.23

The ‘battle’ between Firmicutes and Bacteroidetes begins at birth. The most influential element in early childhood appears to be the duration of time an infant spends consuming breast milk over solid foods and formulas.1 Based on comparisons of Firmicutes and Bacteroidetes populations between infants who consume breast milk and infants who consume formula, infants that consume breast milk longer have lower Firmicutes/Bacteroidetes ratios and seem to have lower probabilities for future obesity1,24-26 (E/A, Gillman et al. 2001, Kalies et al. 2005, Mayer-Davis et al. 2006). Examination of different populations of infants between Africa and Europe supported this conclusion of higher Bacteroidetes populations and lower Firmicutes populations in children breastfeed longer. The rationality behind the difference between African and European children is that Africa infants had to be breastfeed for additional time due to financial limitation or resource availability regarding formula.

One of the major reasons for this developmental difference seems to be the population growth of Lactobacilli and Bifidobacteria in breastfeed infants vs. formula feed infants, which fail to develop these two types of bacteria in significant proportions.27-29 The colonization of Bifidobacteria is thought to be especially important in the maturation of the intestinal lining and localized lymphoid tissue and delayed Bifidobacterial colonization increases the probability of a variety of gastrointestinal and/or allergic conditions.30-32

Originally it was thought that the bacteria present in breast milk was from skin contaminates, but recent testing has developed support for the idea that the bacteria is, not surprisingly, derived from the maternal intestine and follows the entero-mammary pathway to the mammary gland.33 Also no Bifidobacteria has ever been isolated from skin samples from women who have Bifidobacteria in their breast milk.30 The derivation of these bacterium from the mother’s own intestinal system may provide insight into why obese mothers have children that are pre-disposed to becoming obese and why fit mothers have children that have resistance against obesity as those bacteria populations heavily influence the populations in the infants.

Another important association between intestinal bacteria and obesity is the role of interspecies hydrogen transfer from hydrogen producing bacterium to hydrogen consuming methanogens. Non-obese individuals have very small methanogen-based intestinal populations whereas obese individuals have larger populations.10 This population shift has also been associated with genetically homogeneous obese mice (ob+/ob+) over heterogeneous mice (ob+/ob-) and homogeneous non-obese (ob-/ob-).15 The association with genetically obese mice over mice that have become obese through food consumption supports the notion that methanogen population influences weight over methanogen bacteria being selected for based on weight. Basically the methanogen population of bacteria expands first before one gains significant weight. The importance behind this relationship is best demonstrated by understanding the biochemical process involved in the formation of fatty acids in the body.

Methanogens like Methanobrevibacter smithii enhance fermentation efficiency by removing excess free hydrogen and formate in the colon. A reduced concentration of hydrogen leads to an increased rate of conversion of insoluble fibers into short-chain fatty acids.10 Proprionate, acetate, butyrate and formate are the most common SCFAs formed and absorbed across the intestinal epithelium providing a significant portion of the energy for intestinal epithelial cells promoting survival, differentiation and proliferation ensuring effective stomach lining.3,10,34 Butyric acid is also utilized by the colonocytes.35 Formate also can be directly used by hydrogenotrophic methanogens and propionate and lactate can be fermented to acetate and H2.10

The Methanobrevibacter smithii population in non-obese individuals is very small on an absolute level whereas the population in obese individuals is much higher (gastric). This result is supported by metagenomic study which identified more Archaea gene fragments in ob+/ob+ mice over leaner heterogeneous ob+/- or ob-/ob- mice.15 Overall the population of Archaea bacteria in the gut, largely associated to Methanobrevibacter smithii, is tied to obesity with the key factor being availability of free hydrogen. If there is a lot of free hydrogen then there is a higher probability for a lot of Archaea, otherwise there is a very low population of Archaea because there is a limited ‘food source’.

Interestingly anorexic individuals also see an increase in Methanogen bacteria (Methanobrevibacter) over non-obese healthy individuals.21 This increase in anorexic individuals seems to make sense as fermentation rates probably increase in effort to maximize energy optimization from food intake due to reduced food consumption. Increased fermentation rates would increase H2 concentrations resulting in increased Methanogen populations.

Other investigators have looked at how receptor interaction with intestinal microbes influences weight. A promising avenue of research is Toll-like receptor (TLR) 5, a transmembrane protein expressed in the intestinal mucosa that recognizes bacterial flagellin.35 Analysis of TLR5 knockout mice vs. controls demonstrates a 20% greater body mass in the knockouts, a weight which corresponds to an increase in visceral fat.35 This additional body mass is thought to occur through greater food consumption (knockout mice consume 10% more food than controls), which seems to lead to greater fat deposit formation. However, despite this increased food consumption there were no significant changes in short-chain fatty acid concentrations between knockouts and controls.35 Also due to mixed results it is difficult to draw any conclusions regarding differing influences on orexigenic or anorexic hormones between knockouts and control.35

Elimination of intestinal bacteria through broad spectrum antibiotic treatment supported the contention that intestinal bacteria and TLR5 had an interactive relationship in controlling an individual’s weight as germfree TLR5 knockout mice did not suffer from the same weight gain as their TLR5 knockout non-germ free kin.35 The implantation of the microbiota from a TLR5 knockout mouse into a previously germ-free non-knockout mouse lead to the development of a similar phenotype to the TLR5 knockout in the germ-free mouse.35 This result suggests that there are certain bacteria that interact with TLR5 because despite the non-knockouts having the necessary receptors they still develop attributes similar the knockouts, thus the microbiota of the knockouts do not appear to have the required bacteria for activation. This lacking makes sense because without TLR5 receptors it stands to reason that bacteria, which activate TLR5, would be selected against.

Based on the information above it appears that activation of TLR5 somehow reduces weight gain. This result occurs either through interaction between TLR5 and orexigenic and anorexic hormones (which would influence appetite) or involves the reduction in fat deposit synthesis from soluble elements. Due to the results from germfree knockouts and the mixed hormone results, the second possibility seems viable. For example interaction between Bacteroidetes and TLR5 could lead to the inhibition of lipoprotein lipase activity (possibility through increased expression of Fiaf). This action would result in less fat storage and less overall weight gain.

If the above contention were true this action of changing Fiaf expression probably has a positive feedback effect in lean individuals and a negative feedback effect in obese individuals. For example as individuals lose weight the Bacteroidetes population increases which would lead to more TLR5 activation and less fat storage. However, as individuals gain weight Bacteroidetes population decreases which would lead to less TLR5 activation and increase the probability for greater fat storage.

One of the big remaining questions is how do the populations of Bacteroidetes and Firmicutes change to influence weight changes? One possibility is that while both Bacteroidetes and Firmicutes assist in fermentation perhaps Bacteroidetes are more responsive to complex sugars and other complex carbohydrates and Firmicutes are more responsive to simple sugars. Usually obese individuals consume lots of fat and simple sugars which are converted more easily to fat. The consumption of these types of foods select for Firmicutes over Bacteroidetes. When an individual loses weight it typically involves changes in the diet largely a reduction the amount of simple sugars and fats. This change could lead to a reduction in Firmicutes and due to less competition from the Firmicutes a corresponding increase in Bacteroidetes.

Another possibility for the increase in Bacteroidetes is that weight loss (excluding surgical intervention) involves a large amount of exercise. This additional exercise would lead to larger demands for energy consumption both in currently stored fat and newly consumed food. Such a change should reduce the amount of fat storage possibly involving the increased expression of TLR5 which could increase the population of Bacteroidetes if Bacteroidetes do indeed activate TLR5.

Overall it certainly appears that Firmicutes and Bacteroidetes play an important role in controlling weight. This influence seems to stem from two different mechanisms: overall food consumption and the extraction of energy from that food and probability of fat storage vs. fat consumption. While the exact mechanisms have not been discovered, Bacteroidetes appears to favor lean bodies and Firmicutes appears to favor obese bodies. Whether or not there is an evolutionary element is unclear. Beastfeeding also appears to be an important early element in driving either a lean or obese future. Due to potential feedback elements associated with fat content and intestinal bacteria populations like Firmicutes doping individuals with Bacteroidetes like Bifidobacteria may seem like a good idea, but the best option for weight loss involves the old stable tactics of high quality diet with insoluble fibers and exercise.

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17. Armougom, F and Raoult, D. “Use of pyrosequencing and DNA barcodes to monitor variations in Firmicutes and Bacteroidetes communities in the gut microbiota of obese humans.” BMC Genomics. 9:576, 2008.

18. Guo, X, et, Al. “Real-time PCR quantification of the predominant bacterial divisions in the distal gut of Meishan and Landrace pigs.” Anaerobe. 2008. 14:224-228.

19. Ley, R, et, Al. “Microbial ecology: Human gut microbes associated with obesity.” Nature. 2006. 444:1022–1023.

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21. Armougom, F, et, Al. “Monitoring Bacterial Community of Human Gut Microbiota Reveals an Increase in Lactobacillus in Obese Patients and Methanogens in Anorexic Patients.” PLoS ONE. 2009. 4(9):e7125.

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23. Cani, P, et, Al. “Selective increases of bifidobacteria in gut microflora improves high-fat diet-induced diabetes in mice through a mechanism associated with endotoxemia.” Diabetologia. 2007. 50(11):2374–83.

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A Qualitative Discussion Regarding the Development of an Air Capture Complex

2011-11-11T07:30:00.000-08:00

The reality of the situation involving global warming is that both reduction in carbon emissions and carbon emission remediation will be required to significantly reduce detrimental damage to the environment, damage that will influence the future survival rate of humanity. For carbon emission remediation two elements take precedence: effectiveness and speed. Effectiveness is rather self-explanatory; if the process is unable to remove more CO2 from the air than is added over the lifecycle of the process then such a remediation strategy is not worth exploring. Speed is necessary because there is already a dangerous amount of CO2 in the atmosphere and the rate of carbon mitigation is not proceeding nearly fast enough relative to the capacity of natural sinks to remove CO2.

Therefore, although there are other more cost-effective ambient air capture techniques, which involve more natural processes (planting trees or synthesizing bio-char), these processes are significantly slower than technological methods. Speed is important, not just on a general level, because also a feedback level for during the process of removing the necessary CO2 the now more acidic ocean could lose a significant amount of its sink capacity has it begins out-gassing previously absorbed CO2 back into the atmosphere due to the change in the concentration gradient, thus the process must be fast enough to accommodate any further reduced sink capacity. Also the threat of some permafrost melt will also increase atmospheric CO2 concentrations which will need to be effectively managed beyond mitigation of directly derived human emissions.

Most economists are troubled by the calculated theoretical (no large scale system has been empirically tested yet) costs of technology driven air capture ($400-600 dollars per ton of CO2) and they should be, but as explained here the options available to the global community to address global warming consequences are quite small. Realistically due to the deficiencies of natural sinks there are only two choices: rapidly deploy both emission reduction programs and direct air capture technology or prepare to live in a much harsher environment which should reduce life expectancy. The reason for the parameters of the first choice is that natural sinks (land and ocean) will be unable to remove enough CO2 from the atmosphere, even in a scenario of rapid emission reduction because there is already too much CO2 and other greenhouse gases in the atmosphere, to avoid significant detrimental environmental effects.

However, these air capture unit must be efficient, otherwise they will lose their speed advantage over augmenting natural sources. Therefore, there are some important operational issues that must be addressed before deployment. The first major issue is water use. Regardless of the system, the chemical reaction utilized to absorb CO2 from the atmosphere requires the use of water. In most situations the water is supposed to act as a catalyst, but due to the open-air nature of the reaction system a significant percentage of the water (how much is heavily based on overall process design) is absorbed into the atmosphere becoming water vapor making water recovery more difficult.

Another important consideration is that most of the costs associated with air capture relate to gross costs per ton of CO2 captured because the estimates do not take into consideration what energy source is utilized to power the capture unit. A general background regarding where energy in most system designs is utilized can be found here. If a trace emission source is utilized (nuclear, geothermal, wind or solar) then the gross cost can be reasonably estimated as 90-99% efficient (thus the net cost will be 1.01-1.1 times more than the gross cost). However, if a fossil fuel source is utilized then the net cost will be higher than the gross cost (largely dependent on the exact fuel mix), but most of the time at least 1.3-1.5 times. Not only does the use of a fossil fuel energy source increase per unit costs and overall long-term costs, but it also reduces the overall speed of CO2 removal making technology air capture less attractive vs. natural sources. Therefore, it is important that all air capture units be powered by trace emission sources.

The final consideration is developing an endpoint for the captured CO2. A number of air capture developers have dreamt to using the captured CO2 as a marketed product either to enhance oil recovery, in a methane or hydrocarbon based fuel or in commercial industry (soda, etc.). Unfortunately the first two options add CO2 back to the atmosphere, just another means of disrupting the overall extraction efficiency of these units making them less desirable relative to expanding natural sources. The commercial option is incredibly insufficient at utilizing a vast majority of the CO2 that needs to be captured (gigatons of CO2). The best means to address this glut of CO2 appears to be sequestering it underground.

With all of these additional considerations to take into account it is not wise to simply build these air capture units at random. These units clearly need to be constructed in an orderly and cohesive manner perhaps even in a localized autonomous network. This network needs to contain a water source, a power source and a means of utilizing the captured CO2 in addition to having recycling pathways for all necessary materials used in the selected air capture reactions.

The most important element in such an air capture complex is selecting a power source. Recalling that volumetric speed is one of the principle elements behind the need for technology air capture the selected power source will need to be reliable and have as little downtime (intermittence) as possible. This requirement limits the viability of using wind or solar power as those energy methodologies cannot reliably power this proposed complex 24 hours 7 days a week.

Now one could argue that wind or solar would be appropriate with storage, but the general lack of storage options and empirical track record hurts the viability of this response. For example Solar Tres uses molten nitrate salt as a storage medium, but it is difficult to conclude that enough storage could be generated on a consistent basis to generate the 24-7 operational period. Remember energy can only stored if it is in excess, which will not be true most of the time if the solar panels are already providing power to various elements in the complex. Pumped hydro shares the same problem, as well as limiting the location for the complex because of its required topography. Also the addition of a storage medium would increase the cost associated with capture.

Without being able to rely on solar or wind power due to consistency concerns, viable energy options fall to nuclear power and geothermal. Nuclear power in a conventional plant is a little tricky because the provided power would be too much for the needs of the complex, thus if nuclear power was used in this way it would have to come from an outside plant, brought in by transmission lines. Another nuclear option may be to utilize a small modular unit design for a given complex.

Geothermal power is an attractive option when considering an Enhanced Geothermal Systems (EGS) model, but not a conventional model. A conventional geothermal model is similar to utilizing a pumped hydro storage system in that it limits where the complex can be constructed. An EGS model is also attractive as a secondary means to utilize some of the captured CO2 as a supercritical fluid in the system itself. So it appears that from the perspective of the complex itself the best power sources in decreasing order of effectiveness are EGS > Nuclear > Solar > Wind.

There are two main strategies for developing a water source: desalination or atmospheric capture of water vapor. The advantage of an air capture complex is that both of these strategies can be utilized because the air capture unit itself does not rely on natural wind patterns, but creates its own direct air flow to drive ambient air into the reaction section. The only boundary condition for the unit is tied to the power source utilized. This flexibility advantage is useful because the air capture complex requires a system to provide the initial water and would be heavily aided by a system which recycles water (reduces loss from air absorption).

Therefore, the complex could be constructed near a source of salt water, use desalination to provide in the initial water supply and utilize atmospheric water condensers to limit the amount of water required from desalination after the initial reactant amount. Note that tapping a continuous water source (such as desalination) may not be necessary as long as a sufficient amount of water is made available at the beginning of the process until the atmospheric collectors can successfully begin the recycling process, it just appears to be an easier overall strategy.

Desalination use has always involved two major concerns: the energy required for the process itself and determining an endpoint for the brine. The energy requirement is not a significant issue if using one of the two best-fit energy sources for the complex. Under normal circumstances the brine is a very significant issue that has environmental repercussions as returning it to the sea (standard practice) is through to have serious detrimental effects in the localized region where it is returned. Other than injecting it back into the source, effective ideas to address the leftover brine are far and few between.

Similar to the absorbed CO2, the total raw amount of salt from the brine, which would be generated from such a desalination project, is so large that using it in commercial endeavors does not appear viable. Some have proposed ammoniating the brine and using it to increase the volume of CO2 capture. The concern with that strategy is providing the necessary ammonium to react with the brine to create a consistent and worthwhile reactant volume. Another option that has been floated is incorporating the brine into a set of molten salts that would be used in either nuclear power reactors or batteries. However, the viability of such an idea is still questionable.

It is understandable that if the economic impact of developing such a complex was quantitatively calculated that it would be high; however, the nature of the complex is that all of these elements will be required in the future based on the current environmental-use path humans have embarked upon, thus the cost is not based on luxury, but necessity. The idea behind such a complex is actually to lower costs by tying many of the air capture units into the same required operational elements, thus making the technology air capture strategy more economical, saving money for investment in other environmentally necessary avenues like emission reduction. Overall while the manifestation of such a complex may not be exactly as described in this blog post, the reality is that such a complex will be needed in one form or another.

The figure below is a crude visual representation regarding what the complex may look like without mileage delineations between units as such an element needs to be modeled to maximize the efficiency of each given operational unit.

Third Party Voting in the 2012 Presidential Election

2011-11-09T08:01:00.000-08:00

The mindset that individuals should vote for a third party candidate over Obama due to the failings of Obama to live up to his campaign promises, especially with respect to the environment is foolish. The irrationality of this mindset is demonstrated in two parts.

The first element involves the value of single issue voting. Third party candidacy largely distinguishes itself through a strong differing opinion on a single political issue, be it in the realm of the economy, environment, judiciary, foreign affairs, etc. However, the problem with focusing on a single issue, for both the candidate and the voter, is that rarely is an issue an island unto itself. Therefore, one must analyze the entire policy platform put forth by the third party candidate to see if there are contradictions, which would eliminate the usefulness of the single-issue position. Unfortunately for most supporters third party candidates can rarely be characterized as ‘exactly like that major party candidate except on this one issue’.

Also due to the emotion and intensity that can encompass these single issues and their adherents, most single-issue voters erroneously convince themselves that there are more individuals who think as they do and will act on this single issue than there actually are, warping the probability of success. One reason for this mindset is most single-issue voters frequent environments that act as echo chambers of sort for their opinion on a particular issue catalyzing the belief that more people share the belief in question with a similar level of commitment and passion.

Another aspect to the emotional element of single issue voting is respect and the lack thereof between certain groups and a given political party. For example one psychological aspect that has grown in the environmental movement is that they feel neglected, that Democrats ignore them due to a belief that environmentalists will always fall in line and vote Democrat because the alternative (Republican) is worse. The almost comical nature of this element is that some believe that not voting for Obama will ‘show him that I matter’.

Such a belief is foolish because the 2012 election can realistically only play out one of two ways: 1. Obama wins despite reduced support from environmentalists; in this scenario Obama, and perhaps the Democratic Party, could view the power structure of environmentalists with less respect because he still won even with reduced support; 2. Obama loses; so what lesson did Obama learn that can actually be applied in the future? He may lament having neglected environmentalists (from an ego standpoint), but how is that relevant if he is not going to run for President (or for that matter any political office) again, thus the ‘lessoned learned’ cannot be applied because he will no longer be in a position to apply it.

The sad thing is that this neglect that environmentalists feel is self-inflicted as they have yet to produce a viable alternative to give Democrats pause, a real power vacuum threat. The Green Party is a complete joke and realistically has done more to damage the environment than to benefit it (the 2000 election springs to mind). Even if the idea is just to ‘teach the Democratic Party a lesson’ not necessarily Obama, without a viable political party to oppose both the Democrats and Republicans, all individuals who feel that their vote is being ‘taken for granted’ will essentially either continue to cast a ‘taken for granted’ vote or will instead cast a ‘thrown away vote’.

The previous paragraph flows well into the second element, a lack of preparation and organization required for victory. Pertaining to the most viable scenario as stated above, third party candidacy in the 2012 Presidential Election, what candidate is a serious challenger to both the Democratic and Republican nominees? Winning the Presidency demands name recognition, money and logistical support. What third party candidate has these attributes in such capacity to rival the engines of the two major political parties? A secondary influencing factor is the non-democratic nature of a Presidential election where whether or not a vote counts is determined by where you live.

The Electoral College, a relic from a bygone era, complicates voting for POTUS by heavily penalizing those individuals that do not have the above three elements. The best example of this detriment was seen in 1992 where Ross Perot garnered 18.9% of the total popular vote, yet received 0 electoral votes. Therefore, due to the role of the Electoral College in the process of electing the POTUS, Mr. Perot was no closer to winning the presidency at 18.9% of the popular vote versus had he received 0.4% of the popular vote. Do those who wish to challenge Obama and the Republican candidate in the 2012 election with a third party candidate actually believe that they could generate a better result than that of 1992 in the current environment? If so, what leads them to draw such a conclusion and does objective analysis destroy that ‘rationality’ behind the conclusion?

The simple unassailable fact is that this late in the game there is little reason to believe in the election of an individual not from one of the two major political parties. Some third party voters attempt to make a stand on the grounds of morality. This intent is largely seen as a strategy against those who claim to be voting for a particular candidate who they classify as ‘the lesser of two evils’. Such a classification signifies that the voter is not in agreement with that individual’s platform, but is instead concerned about his/her opponent’s platform. Third party voters believe that these individuals are doing a disservice to themselves and to their country by not treating their limited access to power (typically voting for representatives once every two years) with more respect; basically these voters should be voting for the candidate they want to vote for and will perform well, not a candidate that may not do the job well, but has major party backing. The ‘moral’ third-party voters believe that a vote for the ‘lesser of two evils’ is still a vote for evil.

The problem with the morality argument is it is an abstraction. The mindset that one was not a coward and upheld his/her morals when voting is of little rational comfort if ‘the greater of two evils’ wins the election and begins to systematically lead policy completely away from those morals. Only one of incredible arrogance (or stupidity) would consider such a scenario a victory. In short these third party voters seem to neglect the reality that within this ‘classification’ mindset, evil is going to win the election, thus do you want less evil or more evil?

If third party supporters truly want to make headway they need to start in the non-presidential election cycles. Nominating candidates for the U.S. House of Representatives and Senate through the argument that both major political parties have failed to advance this country in a positive direction thus new ideas and perspectives are required to achieve such a goal. The process of electing these individuals will be easier during non-presidential years due to a smaller voter turnout as well as less money being spent in the political arena. Then after these individuals have demonstrated some measure of success over the two years between elections, supporters should use these successes as a means to introduce the advantage to having a POTUS from the given third party of choice.

Overall in the current environment any individual choosing to vote for a third party candidate because he/she does not believe in Obama is acting akin to the unfortunate reality associated with third party candidates, ‘throwing their vote away’; when one’s only power in the U.S. ‘democracy’ comes once every two years, why waste it sending a message that does not have enough volume to be heard?

A Change in the Supreme Court Environment

2011-10-28T08:03:00.000-07:00

When the U.S. Constitution was crafted one of the key components was to ensure that no branch of the government garnered too much power. A neutral judiciary was an essential element to this power balance. The original intended purpose of the judiciary was to have control over whether or not the passage and/or enforcement of a specific law violated the Constitution, a role officially ascribed in Marbury v. Madison. In the vein of judicial view, the personal viewpoints of the judiciary were to remain as muted as possible instead only ruling on how the law and the Constitution interact. While rooting out personal opinion entirely is unrealistic because perception and interpretation is influenced by personal opinion, personal opinion should not be the principle driver in determining how a justice rules in a given court case.

Unfortunately the 21st century has given way to neutral and objective interpretation inviting personal beliefs and abstraction into the judiciary, especially in the U.S. Supreme Court. Too often does the selection of a U.S. Supreme Court justice revolve around political affiliation over legal record and qualification. Also members of Congress affiliated with a political party different to that of the President almost automatically oppose any candidate that is offered for confirmation to the U.S. Supreme Court; this opposition is frequently derived not because they believe that the nominated individual is unqualified, but because they disagree with the way the nominee will rule when on the court as those rulings will be contrary to their own personal and/or political beliefs.

That viewpoint highlights the problem. If the nominated justice would rule properly, then the member of Congress should have no problem with the ruling even if it conflicts with his/her personal beliefs because the Constitution is bigger than any one individual. If the nominated justice would rule improperly, believing his/her viewpoint to be bigger than the Constitution then the individual should never have been nominated in the first place and the President should be condemned for it. Thus the question is why does it appear that U.S. Supreme Court justices are following their personal opinions over the law?

The law is fairly similar to math in its application, heck almost everything is similar to math, but especially the law in that there are very few correct solutions/interpretations, with one usually being superior in accuracy over the others. For example a typical court case can be equated to math by breaking it down into an equation. In one case: X + Y = 7 where X and Y are not negative and are integers. Clearly in this situation X and Y only have a limited number of solutions, but there are multiple solutions. However, rarely do given court cases exist in a vacuum, there is precedent and other legal realities that need to be considered. When properly interpreted these other elements apply other required conditions to the equations such as X > 3.

With the additional condition(s) most other solutions become incorrect and typically only a few of the possible solutions to the equation remain valid, solutions that typically do not differ significantly from one another. With such a deterministic-type flow it is difficult to rationalize why justices would come to an incorrect solution. Of course one or two may decide differently by interpreting the precedent as X = 3 instead of X > 3. However, 5-4 decisions, especially when the same groups of individuals find themselves on the same side of the issue almost all of the time, challenge this differing interpretation condition. How is it that with all of the possibilities and the different ways to coming to a given solution the same two groups almost always end up on the same side of a given issue when 5-4 decisions are rendered?

That uniformity of frequency is the problem with the modern 5-4 decision. Suppose you have nine justices A, B, C, D, E, F, G, H and I. 5-4 decisions would not be viewed as a significant problem if the variance of determination routinely differed between cases. For example in case 1 justices A, B, C, F and H form the majority decision, in case 2 justices A, E, C, G and I form the majority decision and in case 3 justices B, F, G, H and I form the majority decision. In this scenario the majority decision is formed by a variety of justices, there are no ‘groups’.

However, a problem arises if instead in case 1 justices A, B, C, D and E make the majority decision, in case 2 justices E, F, G, H and I make the majority decision and in case 3 justices A, B, C, D and E make the majority decision and so on and so forth. This ‘group-think’ mentality creates a dangerous precedence where the same individuals view the law in the same way, which significantly limits the perception that these individuals are actually looking at the law and not relying on other elements of their personalities and belief structures to lead them to conclusions about how to rule on a given case.

The sad state of affairs is that the 5-4 decision in the modern U.S. Supreme Court, due to this group-think mentality, appear to be have political beliefs as the driving force over actual legal principle. Unfortunately the vitriol of the partisan political climate has torn away the necessary impartiality of the court tainting their decisions. To neutralize this improper behavior a simple majority is no longer a proper means to determine a legal precedent. Instead 6 votes not only 5 must be in favor of a writ in order to validate it. Under this new proposal if the court rules 5-4 on a given case it would be akin to if the Supreme Court never heard the case in the first place, no opinions (majority or minority) would be issued and the ruling of the lower appellate court would stand.

Such a step may seem too extreme, for although the final decision made by a justice can only fall into one of two categories there can be multiple reasons behind the final decision expressed in multiple opinions. In this situation the opinion can be properly viewed as the methodology and the decision as the result where logical and thorough methodology will lead to the correct result and improper and illogical methodology will commonly lead to the incorrect result.

The concern for methodology is limited to the rare case where the incorrect methodology leads to the correct result. An incorrect methodology should always be a concern because even if a correct result is attained once, there is the distinct possibility that an incorrect result will be attained for a future case using the same flawed reasoning. Therefore, it really does not matter that x justices may have y differing opinions/interpretations that lead to the same result beyond the fact that they are wrong and understanding the reason may result in its correction. It is like one person saying 2 + 2 = 7, another saying 2 + 2 = 9 and a third saying 2 + 2 = 19. It does not matter how close someone is to the right answer or really the logic behind how they got the answer, the only thing that matters is that all three answers are wrong.

There are two possible major lingering problems from making this 5-4 decision nullification change. First, a 5-4 nullifier could give too much power to the Appellate courts, especially if the Supreme Court continues to judge based on politics and not the law, but in the end that would be the Supreme Court's fault. Second, should such a decision nullify previous 5-4 decisions when applicable? Clearly it would be impossible to impose any retroactive enforcement on time sensitive rulings like Bush v. Gore from 2000, but what about a case like Kelo v. New London from 2006? One problem stemming from retroactive enforcement is when does one initiate the reversal? One option would be starting in 2000 the time when a number of people believe hyperpartisan began to significantly influence the court.

Another lesser concern may be that the precedent that is being used to decide a present day case was unduly influenced by a personal and political opinion of a past justice, thus contaminating that piece of precedence. Thus if present-day justices need to work from previously tainted rulings without the ability to use their own interpretations to correct those rulings the system will forever be flawed and wrong. The above statement is true, but has no merit against the 5-4 policy proposed because then all of the justices should be able to recognize the error in that precedence during the deliberation of the case where that precedence is relevant.

Overall it appears that regardless of tradition it is now appropriate to begin to think about changing the dynamic of the Supreme Court with respect to narrow 5-4 majority decisions and their justification.

The Correct Contextual Economic Argument for Direct Air Capture

2011-10-17T07:07:00.000-07:00

The topic of direct air capture (DAC) has previously been discussed here, here and here.

Since the last time DAC was discussed on this blog it has received more attention including a report issued by American Physical Society. Unfortunately, yet not surprisingly, most of these discussions have focused on the economics of developing and deploying such a system over technical/feasibility discussions. Most would argue that the economic element is critically important in the modern capitalistic world as almost all decisions revolve around economics and affordability. Also efforts to reduce costs should aid in the technical development of the overall process. While both these statements are true, the problem is that most of the economic analysis is not being conducting from the proper perspective.

For example most estimates place the cost of removing 1 ton of CO2 from the atmosphere, regardless of specific design, between $450-600. Relate this cost back to the fact that CO2 has traded in the European Trading Scheme rather consistently at $20-30 per ton (meaning that it costs $20-30 dollars for a participant to emit 1 ton of CO2) and clearly application of current DAC models is too expensive.

Compounding the problem is that it is reasonable to conclude that these estimates only calculate the costs associated with capturing 1 gross ton of CO2 because these estimates do not include the CO2 emitted to provide the energy required to capture the CO2 from the atmosphere, thus the costs now are even higher than those stated above. Overall most DAC proponents agree that this cost is too high and believe that through the additions of carbon taxes and trade programs and reductions in technical and development costs due to scale up will lower these costs significantly. Also proponents believe that finding a marketplace for the captured carbon will also narrow the cost gap.

This desire for a marketplace is where the economic argument begins to breakdown relative to the environmental nature of DAC. The principle rationality behind pursuing DAC is to reduce the amount of CO2 in the atmosphere in order to lessen the detrimental effects of global warming, not make money. Unfortunately the two most cited methods for making money from a DAC system are in contradiction to this principle rationality. The first means of ‘funding’ DAC is to use the captured CO2 in enhanced oil recovery (EOR). The problem with this strategy is obvious. The point of recovering more oil is to burn it in some industrial process or use it for transportation. Thus there is no significant decrease in atmospheric CO2. With the most optimistic scenario such a system could be viewed as a CO2 neutral. Unfortunately such a system then simply wastes energy (energy that is used to extract the CO2 and the oil) and further pollutes the environment (recall that refining and burning oil releases other pollutants in addition to CO2).

The second means of ‘funding’ DAC is to use the captured CO2 as a basis for a ‘carbon neutral’ hydrocarbon or biologically-based fuel. Earlier in the thought process the idea was to create a hydrocarbon-based fuel, but that idea was complicated because such a process typically required high purity streams of CO2 and hydrogen (most sources of hydrogen are currently drawn from fossil fuel combustion). Now this idea has evolved into using CO2 as a highly concentrated feedstock for algae and extracting bio-fuel from the algae. However, the problem with this strategy is the same as using the CO2 for EOR, at its best as long as the fuel produced by the algae is being consumed and the end-products released into the atmosphere, it is another closed CO2 neutral system.

Also again like above, due to the other externalities (infrastructure and transportation of inputs and outputs) involved, the overall system should add CO2 and other greenhouse gases to the atmosphere. Also the fuel issue is somewhat irrelevant as well because of the advent of electrical vehicles which could be powered in the future by electricity from trace emission sources (nuclear, solar, geothermal, etc.). If society did not have the technology required to transition away from fossil fuels to electrical vehicles for another couple of decades such a carbon neutral fuel idea may be applicable, but that is not the case. Thus, such a closed loop carbon neutral system seems to have no real benefit and only results in wasted energy and resources.

The waste is especially pertinent to trace emission energy generation if that generation comes from either wind or solar due to limited economically available amounts of various rare earths. Basically if only a certain number of solar panels could be created then there is no reason to waste any by attaching them to a closed-loop system which provides no net benefit. The same argument can be made for water as current DAC designs demand significant water consumption. Other ideas surrounding funding are extremely small potatoes like selling the captured CO2 to beverage companies. Clearly there is a market for pure CO2 to beverage companies, but not a 7-gigatons of CO2 per year market.

So if there is no viable market for captured CO2 that is also in accordance to the principle reason for establishing a DAC network, then what is economic argument? The response is adjusting how one looks at the economic issue. The economics of DAC is not profitability, but prevention. For example does Person A eat broccoli on a regular basis because Person B pays them a sum of money to do so? No, Person A either consumes broccoli because they like it or because it is a healthy food. There is reason to believe that the consistent consumption of broccoli will result in reduced probability of various diseases and ailments in the future relative to a person who does not consume broccoli (all other elements being accounted for). Thus, any economic benefit to consuming broccoli is derived from lower future costs associated with healthcare and perhaps a reduction in lost wages due to less work missed versus immediate short-term payment.

No reasonable person disputes the fact that global warming will increase the probability and severity of future extreme weather events and will also change general weather patterns which will result in environments receiving much more or much less rainfall leading to an increase in flooding or drought probability. After simply looking at the overall economic damage associated with extreme weather events and floods/droughts in 2010 and 2011 alone a reasonable person would come to the conclusion that it is important to lessen the probability impacts of global warming as much as possible.

Also such a reduction would result in the savings of billions of dollars in the short-term (10-20 years from now) and trillions of dollars in the long-term (20-50 years from now). Therefore, similar to the broccoli example, the above prevention model is how proponents of the DAC should sell their technology instead of trying to make it short-term profitable. The profitability comes from the money saved in the future by reducing the probability of extreme weather associated with global warming.

Based on this mindset proponents and designers of DAC systems should not be looking towards venture capitalists to fund the development and deployment of DAC systems as acquiring the necessary funds (billions of dollars) will be nearly impossible, unless said venture capitalists are young and have large stockholdings in insurance companies. In a just world every major company in the world would have to pay into a ‘carbon remediation and mitigation’ fund as a consequence to their past actions resulting in a significant percentage of the total amount of human-derived CO2 emitted in the atmosphere. Money from this fund could then be used to reduce human-derived emissions as well as fund DAC.

Unfortunately it is quite obvious that the world is not just; therefore, the argument of self-preservation must be applied and governments must bear the burden of development, a difficult reality due to the general financial crisis that currently exists. From a self-preservation standpoint China and India probably should be first in line with funding because both countries are high on the list of ‘going to have their environments significantly and detrimentally changed due to global warming’, costing them trillions in future economic damages.

Overall the whole point of pursuing DAC is to reduce the probability of detrimental effects from global warming by reducing the amount of CO2 in the atmosphere. The sheer amount of CO2 that needs to be removed from the atmosphere is tremendous, so much that no CO2 market could be created to absorb anywhere near the amount that needs to be removed. So those looking to try to justify developing DAC under a ‘money in the pocket now’ economic model should fail unless one abandons the point of pursuing DAC in the first place, which then calls into question why one pursues DAC at all. Therefore, proponents must argue not from a viewpoint of how the captured CO2 will be utilized, but from the viewpoint of how much money will be saved when embarking on the program vs. failing to do so when discussing the economics of CO2.

Discussion of the Inherent Nature of the Sugar/Fat Tax

2011-10-12T07:05:00.001-07:00

In recent years the question of whether or not society has a duty to the health of her citizens has arisen taking the form of the implementation of a ‘sin’ tax against unhealthy food and drink. The tax can typically take two forms: first, a flat fee assigned to a group of products (all sodas for example regardless of overall sugar content) or a progressive fee assigned to a given product based on sugar or fat content over a certain baseline amount. Most of these types of taxes fall into the former category. Not surprisingly regardless of category manufacturers and suppliers of products which would fall under this tax do not want it and incessantly lobby against implementation of such policy.

The principle argument made by these suppliers is that the populace should reject government implementing policy which creates favoritism among existing choices. Of course the suppliers use more buzz and emotional language like ‘keep the government from restricting your food freedom’ or ‘the government thinks you are too stupid to make sound nutritional decisions’.

The interesting thing about this mindset is that it is wrong. Government already constantly, through the use of various subsidies and taxes in a number of industries, create this ‘distortion of choice’ that food suppliers are so concerned about when talking about a fat tax, but could care less about when talking about oil subsidies. With regards to the ‘too stupid’ attack angle, with over 33% of the U.S. population obese and another 33% classified as overweight and the basic biochemical understanding that a significant portion of weight is determined by one’s energy balance, it can easily be argued that yes most people appear to be lacking in the ability to effectively manage their own nutrition.

Despite these realities food suppliers would counter-argue that unlike smoking and alcohol government still should not be involved with food consumption favoritism because it is an individual’s decision; whether or not an individual is obese does not affect society as second-hand smoke or drunk driving do, instead only the individual in question is affected. This argument is foolish because obesity rates certainly influence society largely via the economy through work productivity rates and healthcare costs. With Medicare and Medicaid participation in a percentage of these healthcare costs clearly it is in the prerogative of the government to act. While one obese individual may not provide any significant influence, numerous obese individuals do and numerous is the scenario that society is currently facing.

The final strategy that suppliers use to combat the fat/sugar tax is to use a form of divide and conquer. These suppliers cite that the supporters of these types of taxes come from one of two camps. The first camp encompasses individuals who genuinely want to make society healthier and have determined that one way to accomplish that goal is to increase the cost of less nutritious options. The second camp encompasses individuals, typically lawmakers (according to the suppliers), who are looking for additional revenue streams. Suppliers seek to create division between these two groups by citing that if people reduce consumption of their products due to the higher costs due to extra taxes, then the revenue stream anticipated by the second group will shrink. Basically suppliers try to make the argument that if one group gets what it wants the other group will not get want it wants.

The inherent logic of this proposal is flawed because there is no significant ‘investment’ cost in creating the tax. For example suppose person A invested in project A for 5 dollars after an analysis concludes that person A should receive 100 dollars from the project. Would person A regret investing if the return was only 35 dollars? Of course not; person A may be disappointed that the return was not what was originally anticipated, but to regret making an investment which results in a 30 dollar profit with little associated opportunity cost is foolish.

This situation is akin to a fat tax, there is little investment cost thus regardless of how much is acquired due to the probability of reduced consumption lowing actual revenues whatever revenue is acquired will still be meaningful. However, this analysis does demand that lawmakers look at this issue through a logical mindset, which may be asking too much based on the behavior of lawmakers in the past.

The supplier analysis conveniently excludes the savings that will develop on Medicare and Medicaid from healthier individuals having to take less medication due to chronic health problems. Also the concern that individuals will simply move from one unhealthy food item to another is only applicable under narrow product specific taxes. For example such behavior could be expected if a soda tax is implemented with students drinking more fruit juice (which is mostly sugar), energy drinks, coffee and water. However, if the tax is applied (either progressively or flatly) in a broad way in the way a sugar/fat tax should be this concern is mitigated.

There are two immediate moral concerns with a sugar/fat tax. One concern is that these types of taxes are inherently unfair to healthy individuals. Individuals who properly manage their weight and health are punished by such a policy if they ever wish to ‘reward’ themselves for completing a workout or some other accomplishment. It is the not the fault of these individuals that other individuals cannot maintain a healthy weight and yet they face the same penalty when purchasing certain foods.

Another concern is how ‘food deserts’ would respond to such policy. Regrettably there are still a number of areas in the United States where food choice is scarce. In most of these regions the majority of available food is of lower quality and nutritional value, foods that would be more likely to fall under these types of fat/sugar taxes. Thus in these areas such a tax would put undue burden on these individuals who do not have a viable choice to select a healthier dining option.

Another real problem with the sugar/fax tax is a lack of public support. The campaign of taxation demonization in general has heavily crippled any public support for taxes which may influence those respondents. In general support for taxes boils down to whether or not that tax will affect the particular individual usually regardless of what benefits are derived from it. Additional taxes on millionaires have drawn large public support because they do not affect most of the public; however, most polling data on sugar/fat taxes have revealed significant resistance to implementation.

Recall that relying on polling data to make any decision is stupid because polls almost never have large enough sample sizes to properly represent the public. Although polling data should not be trusted, it seems reasonable to suggest that general attitudes will demonstrate resistance to sugar/fat taxes generally based on consumption patterns and most people consume the targeted type(s) of products. Therefore, the large-scale application of these taxes is unlikely outside of strong government actors willing to go against ‘popular’ opinion and certain elements in the business community.

The ironic aspect of the sugar/fax tax debate is that unhealthy foods already have an inherent tax associated with their consumption, that being poorer health. However, most individuals do not have the foresight to associate numerous choices characterized with little consequence in the present has having a significant influence on the future until too late. Thus the shortening of lifespan due to obesity typically ‘sneaks’ up on a person more than anything and it is frequently eliminated through cognitive dissidence. While the psychological element of health is muted individually, the inherent near-term financial tax of these foods is masked by the lack of transparency and price separation in the healthcare insurance industry. Basically how insurance companies ‘score’ their customers through the underwriting process creates an environment where it is difficult to understand the significance of compounding food decisions.

For example when one applies for health insurance as an individual, they agree in principle to a given rate which can be changed after an ‘independent’ underwriting of the applying individual. This underwriting is undertaken to determine the financial ‘risks’ associated with insuring that particular individual. After the process, if the applicant is still acceptable for coverage, the applicant is quoted a final price for the policy which he/she can either accept or decline. However, over the course of this process the applicant is not given information to why any change was made (if one was made) in the premium payment rate. Not providing this information leaves the applicant wondering about the rationality of the change, due to weight, cholesterol, smoking, family history, etc.

One step forward from this concern would be if health insurance companies could provide a detailed ‘invoice’ of sorts analyzing what aspects of an individual’s health profile were influential in producing a given premium price. In addition a benchmark range list could be provided showing price addition/subtraction relative to other values for given health indicators.

For example suppose an applicant’s blood pressure is 150/110, a higher than recommended value. The invoice would state that such a blood pressure cost the applicant 45 dollars a month towards the overall premium. However, supplemental material in the invoice would indicate that if blood pressure were 120/80 instead the associated cost towards the premium from blood pressure would only be 29 dollars a month. Providing information in such a format would allow applicants to see in full detail how aspects of their health influenced the direct financial cost of purchasing health insurance. Note how this issue of transparency is different from the more popularly known push for transparency in the insurance industry where insurance companies need to reveal the rationality behind sudden changes in premiums for large groups of customers.

This system would also need to have significant divergence between different health indicators to be truly effective. For example if a healthy individual paid 1,000 dollars a year in health insurance costs and an obese individual paid 1,200 dollars a year it can be reasoned that the transparency of such a system will do little to drive the obese individual to change his/her eating habits, especially when that 200 dollars is spread over 12 months. Therefore, it is important that health insurance premiums, which have risen significantly in the last few decades, are lowered for healthier individuals.

It can be argued that creating this significant gap between non-obese and obese individuals is appropriate because it represents a risk-associated interest in the insurance industry as obese individuals have a higher probability of needing medical attention. Note that with the high costs associated with health insurance premiums, it is not advisable that health insurance companies raise premium prices for the obese, instead the decrease for non-obese individuals is appropriate to create a sufficient separation and incentive.

The transparency in underwriting method outlined above may draw criticism from the health insurance industry. Some may argue there is too much additional work required to create such ‘personalized’ invoices. Without associated genetic screening, which is not included in this invoice because individuals can do little to positively change their existing genetics, this argument is reaching. The bulk of the invoice is either based in a flat ranged price based on existing parameters that are created by the insurance companies which exist in almost a form letter format or information provided by the applicant that is scored anyways, thus any concern of ‘more work’ is unfounded (in theory). Basically the insurance company simply needs to make a master list and then apply it to all individuals.

Some may argue that the transparency opens up how different prices are offered to different races, ethnicities or sexes. This should not be a concern at all because either a company has scientific evidence to back treating a male with 140/100 blood pressure different from a woman with the same blood pressure or they are being bias and that bias should be brought to light. Finally some may argue that the transparency is unfair because it could expose the company to competition. Such a concern is insulting as an industry which cites capitalism as the reason it should be allowed to make millions of dollars in profit a year would deny one of the principle tenets of capitalism when it does not suit them.

A genuine concern about this method is the reaction of employers. What type of legal ramifications will exist, if any, when employers who still provide health insurance elect to fire certain individuals because of the additional costs those employees are adding to the company? Could people sue for discrimination or would that reason be countered by the fact that weight is a controllable element which is affecting the profit potential of the company in question?

The final element is a continuation in nutrition education must be undertaken so individuals realize what foods can be consumed frequently, what foods consumed on occasion and what foods should be eliminated from the diet. Obviously without the proper education linking certain unhealthy food options to an increased probability of gaining weight and perspective additional health problems such a transparency program in the health insurance industry would be less effective.

Overall while a sugar/fat tax looks to establish a direct means to reduce unhealthy food consumption, such policy has met with resistance from the general public and industry. One alternative option is to create more transparency in providing health insurance. Health insurance is a large financial investment and to see a direct comparison of how premium costs affect individuals of poor health vs. healthy individuals could provide significant incentive for an individual to become healthier. It stands to reason that this strategy may be superior to a sugar/fat tax (for those who have health insurance at least) because of the magnitude of the premium difference in a single setting vs. the ‘nickel and dime’ nature of the tax. A sugar/fat tax could be a useful element in the fight against obesity, but society needs to investigate other means as well because at this moment there is still no ‘silver’ bullet.

The Israeli-Palestinian Question

2011-09-30T08:44:00.001-07:00

One issue that few people seem to discuss is how should future generations be affected by the actions of past generations on their environment. Not surprisingly this issue is at the forefront in any Israeli/Palestinian peace negotiation, but not considered at the forefront by the players. Past sins largely involve whether or not to allow for the formation of an independent Arab Palestinian state. The popular sentiment appears to be to allow for such a decision, but is this the correct course of action?

The first important element in this question is understanding the events that drove the creation of Israel vs. an Arab state. The original Mandate for Palestine, which encompassed the area now known as Israel and Jordan, was created in 1920 and agreed to unanimously by the League of Nations in 1922 establishing the British as a magistrate for the region. In the Mandate the British had included an objective for the establishment of a Jewish National Homeland in accordance to the Balfour Declaration in 1917. Also further support of the British commitment at the time to create a Jewish National Home was demonstrated by making the national home for the Jewish people an article of the Law of Nations, by incorporating the wording of the Balfour Declaration. However, the British had a problem in while the Balfour Declaration could be interpreted that the British intended to turn the area of Palestine into a Jewish National Homeland, two years prior they also had promised the Arabs independence in certain areas of the Ottoman Empire in exchange for revolting against the Ottomans, an arrangement stipulated in the McMahon–Hussein Correspondence.

The McMahon-Hussein Correspondence was the first of many problems for the British in the Palestine region regarding the question of a Jewish National Homeland largely due to its lack of explicit terms. The initial rationality behind the correspondence was British concern that Arabs in territories under their control in the Middle East would side with the Ottoman Empire during WWI. Therefore, as a means to avoid the complications of such a shift in allegiance, McMahon promised Hussein bin Ali control of Arab lands with the exception of ‘portions of Syria lying to the west of the districts of Damascus, Homs, Hama and Aleppo’ if they would rebel against the Ottoman as well as refrain from rebelling in British territories. Palestine lies to the Southwest of these areas and was not explicitly mentioned. Unfortunately it is difficult to know what Hussein was thinking because he never explicitly asked about Palestine at the time either, one can only assume that he assumed that Palestine would have an opportunity for independence.

Soon before approval of the British Mandate for Palestine by the League of Nations (July 24, 1922), the Churchill White Paper was released (June 3, 1922). The Churchill White Paper is important because it stated that it was not the intent of the British government to covert Palestine as a whole into a Jewish National Home, but that such a Home should be founded “in Palestine.” However, it also stated that the British had included Palestine (more specifically the vilayet of Beirut and Sanjak of Jerusalem) in the McMahon-Hussein exception, thus Palestine should not have expected any guarantees to its independence.

One rationality for the White Paper could be not only clarification in an attempt to end all of the various interpretations and contradictions in the previous seven years of agreements and treaties (especially the troublesome Sykes-Picot agreement), but also a means to explain to the Jews the formation of Transjordan east of the Jordan River. One could argue that this initial split in territory, which resulted in Transjordan receiving 77% of the land in question (Palestine) was adequate compromise to satisfy both promises. Side Note: in September 1922, the British officially communicated with the League of Nations that Transjordan would be excluded from any discussions regarding a Jewish National Homeland. Unfortunately this White Paper did not appear to make any claims regarding how much of the land west of the Jordan River would be made available to a Jewish National Home. Due to the lack of clarity on this point, not surprisingly most Jews believed that area west of the Jordan river to the Mediterranean sea was still ‘promised’ for a Jewish National Homeland, that the formation of Transjordan signified the part of Palestine that they were not receiving regarding the White Paper statement that not all of Palestine would become part of the Home. Some actually cried foul to the formation of Transjordan believing the Jewish people should receive all of Palestine.

On a side note some argue that Lord Curzon’s statements in a Eastern Committee of the Cabinet meeting stating that “… Palestine was included in the areas as to which Great Britain pledged itself that they should be Arab and independent in the future…” is of relevance, but these comments were made on December 5, 1918 and can be regarded as only his opinion, Lord Curzon was not Secretary of State for Foreign Affairs yet. Secondary note: for the purposes of this blog post the area of Palestine west of the Jordan river will now be referred to as Palestine, excluding Transjordan.

In the beginning (through the 1920s) the level of Jewish migration to Palestine was sparse largely due to difficult conditions in the region, little foreign aid to foster development and British driven Jewish immigration quotas initiated by Arab resistance to Jewish immigration. These quotas were typically tied to the perceived economic capacity of Palestine to absorb immigrants without damaging the local economy, thus the quotas only applied to poor Jews as rich Jews (assets of 500 pounds or more) were allowed to enter without counting against the quota. Also some levels of strife in the early 1920s was reported by High Commissioner, Herbert Samuel while he attempted to establish self-governing institutions in Palestine as Arab leadership refused to cooperate with any institution that involved Jewish participation.

However, migration rates changed significantly in the 1930s largely attributed to the rise of Adolf Hitler and with him a dramatic increase in anti-Semitism in Europe. Not willing to accept the migration of these Jewish individuals, a bout of Arab nationalism lead to the Arab riots of 1936-1939. Other elements which contributed to the Arab riots could have been the Jewish economic sector in Palestine surpassing the Arab sector in total productivity and the death of Sheikh Izz ad-Din al-Qassam, at British and Jewish hands, founder of the Black Hand an anti-Zionist and anti-British militant organization.

Due to the riots the British Peel Commission was formed in 1937. As a means to appease the surrounding Arab countries while still affirming the Balfour declaration the Peel Commission proposed to further divide the land west of the Jordan River creating independent Jewish and Arab states. Arab leadership both in Palestine and in the neighboring countries rejected this proposal. What is interesting about this rejection is that under the Peel Plan Arabs would have received approximately 83% of the land, with 15% going to the Jewish state and 2% would have fallen under international administration.

After the rejection of the Peel Plan British support for the potential Jewish National Homeland underwent a significant shift exemplified in the following staff memo: “No solution of the Palestine problem should be proposed which would alienate the Arab states. If one of the two communities had to be antagonised, it was preferable, from the purely military angle, that a solution should be found which did not involve the continuing hostility of the Arabs; for in the that event our difficulties would not be confined to Palestine, but would extend throughout the whole of the Middle East”. This belief was predicated on the belief that Jewish support was either guaranteed or unimportant if Britain had to go to war with Hitler, but Arab support was not thought to be guaranteed, thus must be bolstered.

The lack of foresight provided by the British through this entire incident would be comical if so many people were not so negatively affected by it. In some context one could regard the situation as an interesting aspect of bait-and-switch against the Jewish people. Propose a homeland and then later do almost everything one can short of direct military intervention to deny that homeland or mitigate its significance and size as much as possible. Side note: in February 1939 the British staged the St. James Conference as a last-ditch effort to negotiate an agreement between the Jews and Arabs, but the Arab delegation is reported to have refused to meet with the Jews, to recognize their authority or even use the same entrances to the main conference hall. Not surprisingly the conference failed.

The release of the 1939 White Paper (MacDonald White Paper) officially confirmed the change in British attitude regarding Jews in Palestine and the British commitment to suppressing a Jewish National Homeland largely by heavily restricting Jewish immigration to Palestine and land ownership/land transfers in Palestine. Per Jewish immigration a total limit of 75,000 was set for the five-year period of 1940-1944 (this quota was broken down into a yearly quota of 10,000 with a supplemental quota of 25,000 to cover ‘emergencies’). The quota was enforced through an official certificate system. The creation of the White Paper of 1939 is interesting because the British had, for all intensive purposes, already lost support of the Arabs in Palestine and the anti-Jewish position of the paper lost support of the Jews, so now everybody in Palestine was dissatisfied with the British.

The Jewish regarded the 1939 White Paper as a betrayal and their response was two-fold. First, they began planning strategies to circumvent the quotas through a program of illegal immigration called Aliyah Bet. The British countered this program by cracking down both in raids and blockading entrances to Palestine both on land and sea. Captured Jews were held in Cyprus and stripped of their citizenship, thus they had no official standing for exchange or release. Interestingly enough so many Jews were captured that British officials eventually started releasing them for fear of a violent uprising in Cyprus.

Second, the Jewish Lehi (Fighters for the Freedom of Israel) began staging violent actions against British targets in Palestine. The most famous action taken against the British was the assassination of Lord Moyne in Cairo in 1944. The violent action taken against the British was not condoned by the ‘mainstream’ Jewish leadership which continued to try to negotiate more favorable conditions from the British. Interestingly enough some believe that the formation of the Jewish Lehi bolstered the combat readiness of the Jews to the point where if these immigration quotas had not existed the future of Israel may have been much shorter.

Meanwhile after the League of Nations fell apart, the end of WWII created a greater level of sympathy for the Jewish people leading to the United Nations reconfirmed the original mandate with U.N. Charter’s Article 80 which was later supported by the International Court of Justice. Despite this inclusion the problem of co-existence between the growing Jewish population and the existing Arab population still remained. In 1946 the Grady-Morrison Committee tried to argue that the demand for a Jewish State went beyond the obligations of both the Balfour Declaration and the original British Mandate for Palestine. However, this abandonment of a Jewish state was rejected and the decision to address the division between Jews and Arabs culminated in U.N. Resolution 181, known also as the U.N. 1947 Partition Resolution. Side note: in 1945 at the behest of the British the Arab League was formed to manage and coordinate policy between the Arab states in the Middle East.

Anyone looking at the territory distribution between the proposed Arab state and the Israeli state under U.N. Resolution 181 can only laugh at its discontinuity. While the intentions of the plan seem to make sense, due to the lack of large amounts of paperwork pertaining to private land ownership complicated by Ottoman restrictions on land ownership, it was thought best to divide the land into existing settlement majorities. Of course based on the requisite demand for farmland and other resources this distribution of territory did not stand much of a chance for success even if the Jewish Agency (the representatives for the Jewish in Palestine), the Palestinian Arabs (through the Arab Higher Committee) and the Arab League approved it. One could theorize that perhaps the Arab states may have accepted U.N. Resolution 181 if the distribution were more continuous, but based on existing attitudes at the time that theory does not appear to have a high probability of validity.

While not happy about how the land was distributed the Jewish Agency agreed to the partition, some believing that agreement was necessary to further legitimacy of the Jewish National Homeland. All of the neighboring Arab powers (Iraq, Iran, Egypt, Lebenon, Syria) rejected the partition plan and voted against U.N. Resolution 181 in the General Assembly. There were rumors, which were later confirmed, that if it had a vote Transjordan would have accepted the partition, but under the intention of later annexing the West Bank portion of the new Arab state (only because Abdullah realized he could not annex all of Palestine). The Arab rejection could be argued to exist in two parts: intransigence due to the desire not to have any Jewish state in Palestine and disagreement with how fair the overall agreement was pertaining to the land divisions as a whole and the resources distribution.

The chief complaint of fairness was that 56% of the land was being given to the Jewish state despite only approximately (by the best estimates of the time) 33% of the population being Jewish. In addition the current demographics of the Jewish state would have a 55% Jewish majority and a 45% Arab minority, thus many Arabs would have to consider migration as a Jewish majority governorship was thought not to appeal to most Arabs. Incidentally this Jewish over Arab or Arab over Jewish ‘dominance’ is the rationality the Grady-Morrison Committee used to suggest that there be no Jewish or Arab state in Palestine. Overall these population numbers changed slightly because of the initial inclusion of members of the Bedouins which would have made Arabs the majority in the Jewish state, thus revisions were made which assigned Beersheba to the proposed Arab state and further parts of the Judean Desert to the Jewish state to avoid this population problem.

The interesting thing about the partition plan is that both sides, Jewish and Arab, heavily complained that the other side was getting unfair favorable treatment. The funny thing about the Arab citation of only receiving 42% of the land versus what would become Israel receiving 56% and the remaining 2% being under U.N. administration) is that a majority of the land received by Israel included the Negev and Judean Deserts, so Arabs claim they were concerned that the Jewish state was getting a lot of desert which could not effectively be cultivated at the time. The unfairness of the partition is an interesting issue because under the partition plan the Jewish state ending up losing 87% of the land that they originally be should have been given to them under the Balfour Declaration.

Another note is that one could only guess what the Jewish population in Palestine would have been had the British not been placing severe immigration quotas on Jewish entry, especially from 1940-1944 during the Holocaust. In fact the 1939 White Paper basically stated that the intent of the immigration restriction policy was to ensure a Jewish population in Palestine of only 33%, which is what it was when U.N. Resolution 181 was proposed in 1947.

The Arab rejection due to unfairness loses significant credibility when thinking back to the rejection of the Peel Plan as well as the frequent claims made by the neighboring Arab powers that the Jewish state should not exist. In fact during a group of meetings in November and December 1947, the Arab League adopted a series of resolutions aimed at a military solution to the Palestinian question. Also on the day of their invasion of Israel in 1948 the Arab League issued a statement documenting their motivations for the invasion: “the only solution of the Palestine problem is the establishment of a unitary Palestinian State, in accordance with democratic principles, whereby its inhabitants will enjoy complete equality before the law, [and whereby] minorities will be assured of all the guarantees recognised in democratic constitutional countries…”; basically proclaiming a United State of Palestine for Arabs instead of the two-state solution proposed by the U.N. Thus it is difficult to take seriously a ‘lack of fairness due to land partitioning’ as the primary motive for Arab rejection of U.N. Resolution 181 unless one argues that any land given to the Jews was viewed as unacceptable/unfair.

This mindset was further illustrated by Azzam Pasha, the General Secretary of the Arab League, who was thought to have said, although whether or not true is debated, “This will be a war of extermination and a momentous massacre which will be spoken of like the Mongolian massacres and the Crusades.” Six days later Azzam then also stated (no one questions this statement), “We are fighting for an Arab Palestine. Whatever the outcome the Arabs will stick to their offer of equal citizenship for Jews in Arab Palestine and let them be as Jewish as they like. In areas where they predominate they will have complete autonomy.”

The interesting thing is that the second part of that statement about complete autonomy is basically what the partition plan tried to accomplish. So was Azzam suggesting a form of ‘Don’t ask, don’t tell’ for the Jewish state? In areas where you Jews are the majority you can govern yourselves like an official state, just don’t tell anyone because we don’t want you to be recognized as an official state. Realistically this attitude interpretation may be generous because other communications from Arabs in this time period give the impression of ‘we don’t care if there are Jews in Palestine as long as they do not have any power or an independent state.’

Despite the Palestinian Arab and Arab League rejection of U.N. Resolution 181it passed the General Assembly on November 29, 1947; on May 14, 1948 the temporary legislature of Israel declared statehood one day before the British Mandate over Palestine officially lapsed. That night and during the next morning Egypt, Iraq, Lebanon and Syria invaded Israel starting the Arab-Israeli War of 1948. It should be noted that Lebanon involvement in the war was ‘token’ due to an arrangement reached earlier by the Jewish Agency and the Lebanese government. Transjordan originally planned not to participate in the attack based on a previously reached non-aggression agreement with Jewish leaders in exchange for the ability to annex areas of the West Bank, but other Arab leaders basically shamed Abdullah into violating that agreement.

During the 1948 War, the British also continued their support for the neighboring Arab nations. Basically this mindset in some respects coalesced with the Arab mindset that Israel needed to be destroyed because the Arabs had clearly demonstrated that the very existence of Israel alienated them. This goal was especially prevalent in the diplomatic region with the British continuously arguing after each cease-fire that the areas controlled by the Arabs should belong to the respective Arab occupier.

After numerous cease-fires, which were commonly violated by the Arab powers, violations supported by the British, the war concluded in the early-mid 1949 when Israel signed four separate armistices, Egypt on February 24, Lebanon on March 23, Jordan on April 3 and Syria on July 20. After the conclusion of the war Jordan claimed the West Bank and East Jerusalem, Egypt claimed the Gaza Strip and Israel claimed all of the original land it thought it received after the 1922 redistribution decision outside of the aforementioned areas. Side note: the 1956 war is of little relevance to the above issue so it will not be discussed.

The realities of the 1967 war are controversial. In general it is not disputed that Israel commenced the primary attacks against Egypt; however, the circumstances that lead to the attack are important. In mid May 1967 Nasser began massing troops in the Sinai Peninsula on Israel’s border, expelled the United Nations Emergency Force (UNEF) from Gaza and Sinai and mobilized at Sharm el-Sheikh overlooking Straits of Tiran. Despite Israeli declarations that closing the Straits of Tiran would be akin to declaring war on Israel, Nasser declared the Straits closed to Israeli vessels on May 22. On June 1, 1967 Iraq began deploying troops and armored vehicles into Jordan. So from an Israeli perspective when Nasser closed the Straits he in essence declared war on Israel. Future actions by Egypt and the other Arab neighbors (Jordan, Syria and Iraq) along with the history between Israel and their Arab neighbors did nothing to dissuade Israeli concerns of multiple attacks on multiple fronts. Based on these conditions it is understandable why Israel launched a pre-emptive strike against the strongest Arab prospective participant, Egypt.

With respect to attacks against Syria and Jordan both initiated action against Israel; Jordan did so despite communication from Israel for a non-aggression pact. Some would argue that the defense pact Jordan signed with Egypt was the motivating factor for the attack by Jordan. The potential problem with that statement is that Jordan commenced operations against Israel on the morning of June 5 which was similar to when Israel commenced operations against Egypt. Therefore, Jordan had only hours to respond to the Israeli aggression amid confusion on the battlefront where both sides (Israel and Egypt) reported being attacked and Egypt reported to Jordan that they were actively bombing Israel (which was not true as most of Egypt’s air force was wiped out in the very early stages of the war).

From a logical perspective if the Arab countries, especially Egypt, took actions leading Israel to be concerned for its imminent safety the initial strike can be understood and the blame can even be attributed to those Arab countries because it is illogical to presume that Israel should only fight a defensive war when its existence is at stake. However, one credible issue may be that while it was appropriate for Israel to attack Egypt in a pre-emptive way progressing the action from destroying the Arab threat to invading and taking Arab territory cannot be justified. The problem with this contention is that Israel should not be expected to engage in a mobius strip based defense/pre-emptive attack strategy. Basically suppose Israel neutralizes the Arab forces in 1967, but does not take any territory to create an additional militarized buffer region between Tel Aviv, West Jerusalem and other key Israeli cities. It stands to reason that Israel without existing peace agreements (which did not exist between the surrounding Arab countries and Israel at the time) Israel would simply have to neutralize Arab forces again with the same threat level over and over again. With no intention of ‘exterminating’ the surrounding Arab countries creating militarized boundary regions would actually reduce the probability of future wars.

Based on the information above it would be appropriate for Israel to return the ‘seized’ territory if a peace agreement was signed with the corresponding country with appropriate conditions for its violation. Such a circumstance did occur with the peace agreement between Israel and Egypt at Camp David in 1979 resulting in the return of the Sinai Peninsula affirming the ‘land for peace’ scheme.

Proponents for an Arab Palestinian state consistently discuss elements of fairness and justice when talking about the development of that state. The problem with this mindset is there is nothing concrete that can be attributed to those characteristics. Most argue that the justification for that state comes from U.N. Resolution 181. However, the neighboring Arab powers and Palestinian Arabs rejected U.N. Resolution 181 at the time. Instead of accepting a Jewish and Arab state, their decision was to destroy the Jewish state. By taking this action the ‘fair’ result should be invalidation of U.N. Resolution 181.

For example Person A and Person B are interested in merging their widget companies and put forth a proposals to do so. However, before agreeing to the deal Person B attempts industrial sabotage in order to destroy Person A’s company so Person B’s company can then have a stronger hold on the widget market by itself. Unfortunately for Person B this attempt backfires and actually weakens their own company instead of damaging Person A’s company. How is it fair that Person B should then be allowed to accepting the originally negotiated deal and demand a merger with Person A’s company? Those who suggest that Israel should be bound by U.N. Resolution 181 in an manner are also suggesting that Person A be forced to accept the original merger agreement with Person B despite Person B rejecting it in favor of destroying Person A’s company. If a merger is to occur between these two companies, the original agreement is now null and void and a new agreement must be negotiated. On a side note the current request for statehood made by Abbas to the U.N. is akin to Person B simply asking the general business community to approve the merger of Person A’s and Person B’s companies without an official merger agreement.

The above logic problem is the chief concern which should have invalidated the 1988 Declaration of Statehood by the Palestine Liberation Organization (PLO). Ironically the PLO used U.N. Resolution 181 as the basis for the declaration despite not adhering to the territorial divisions created by the partition. For example under U.N. Resolution 181 the entire city of Jerusalem would not be governed by either the Jewish state or the Arab state, yet the PLO regard East Jerusalem has the de facto capital for the Arab state in Palestine. So the PLO is using U.N. Resolution 181 has a basis for declaring their statehood, but it is not adhering to the ‘less pleasant’ elements of U.N. Resolution 181. Of course these are elements missed by the General Assembly when accepting the declaration.

Also one of the chief issues which strips credibility from those who support the Arab Palestinian state is ignoring the culpability of Egypt and Jordan in the ‘Palestinian’ plight. If Egypt and Jordan had accepted U.N. Resolution 181, the rest of the Arab League would have and those referred to as Palestinians would have had their independent state. Instead most of these supporters choose to look at the immediate simple present instead of looking at the past and how it has shaped the present to determine whom to blame for the current problems in the Palestine region.

One could argue that based on the results of the 1948 war and the 1967 war that Egypt could have a claim to the Gaza Strip and Jordan could have a claim to both the West Bank and East Jerusalem. However, the argument of Egypt and Jordan ownership can get complicated because both claims made on the ‘disputed’ land by Israel and the respective Arab counterpart are due to the spoils of war. Note that these claims would now apply to the PLO as both Egypt and Jordan have given authority of their claims to the PLO.

For example in the 1948 war it could be argued that Egypt and Jordan occupied Israeli land if one were arguing from the perspective that the land west of the Jordan River was to comprise the Jewish National Homeland and that land was the ‘price’ for the 1949 armistice. If that argument were made then what is the difference between Israel taking that land after the 1967 war under the same ‘price for peace’ principle? The logical problem seems to be if one accepts the claim to these pieces of land by Egypt and Jordan how can one not accept Israeli claim to those lands under similar circumstances? This potential contradiction could have relevance in the application of U.N. Security Council Resolution (UNSCR) 242, which is frequently cited by proponents of an Arab Palestinian state. The thing is that the U.N. appeared to operate under a form of amnesty in recognizing the boarders after 1948, but not recognizing the boarders after 1967. However, again what makes one recognition superior to the other if both circumstances were similar when UNSCR 242 clearly states for the “inadmissibility of the acquisition of territory by war”.

Another potential logic hole with referencing UNSCR 242 in the Israel-Palestinian question is that fact the newly formed PLO rejected UNSC 242 when it was proposed in 1967 on the grounds that they would have to recognize the right of Israel exist if they did support UNSC 242. So once again, similar to Resolution 181, after failing to destroy Israel and ‘liberate’ Palestine, the Arab Palestinians come back to the table with the intentions of accepting the original deal that they walked away from decades earlier and expect everyone else to let them accept that deal without consequence. Of course sadly enough the acknowledged controversy surrounding UNSC 242 is in the language which may not force Israel to withdraw completely from the disputed territories, all depending on one’s interpretation, which unfortunately is frequently determined by who one supports.

Outside of the apparent illegitimacy of the global community to redistribute certain pieces of Israeli land to a group that has no claim over it, the other chief element that is commonly cited for the importance of maintaining the post-1967 boarders is Israeli security. Proponents of the post-1967 boarder arrangement believe that returning to the pre-1967 boarder arrangement would severely compromise Israeli security by taking away buffer territory which now shelter important Israeli infrastructure including the capital Tel Aviv and West Jerusalem. Proponents of the pre-1967 boarder arrangement believe that this argument is not applicable any longer because modern weaponry can reach all parts of Israel; also Israel has a significant military advantage over its Arab neighbors which can be used to protect itself. In addition instead of creating a buffer zone which will foster anger and distrust, some believe that giving up the land creates an environment of cooperation and higher probability of peace.

The problems with the arguments made by the pre-1967 boarder proponents is that while modern long-ranger missiles can reach all of Israel, withdrawal to pre-1967 boarders would also put all of Israel (now significantly smaller) in range of short-range rockets and mortars which is the preferred weapon of Hamas. The advanced military argument is a meaningless one because why should Israel be forced to bear the burden of once again having to maintain such military preparedness over such a small terrain. The argument that a demilitarized Palestine should allay those fears or that giving up the land will significantly improve relationships is difficult to accept because of the sheer dissatisfaction that most Arabs still have with the every existence of Israel. In this vein note that Fatah, the PLO and Hamas have all stated in the past that a principle goal is the liberation of Palestine and the destruction of Israel. Those three groups play significant roles in a prospective government, so peaceful relationships appear questionable. In addition both Israel and the Palestinian Authority have demonstrated an inability to prevent Hamas and other terrorist groups from smuggling in these small arms weapons on a consistent basis, despite quality effort, thus there is little reason to suspect anything to change within a new independent state.

The potential political structure should also cause pause. For example the possibility that the West Bank under the new regime of an independent state could, if current democratic trends continue, be controlled by Hamas would be heavily concerning for Israel. How diligent would Hamas be at maintaining the demilitarized zone? What would be the consequences applied by the global community if they did not? Also assuaging concerns by ‘forcing’ Hamas to recognize the right of Israel to exist as a condition of a peace agreement is illogical because Hamas can simply lie. In fact no rational person would expect Hamas to change their beliefs regarding Israel, which are heavily tied to tradition and religion, in such an abrupt and absolute manner.

Finally some argue that the reason for the formation of the pre-1967 boarders would be to create a level of sovereign consistency for the new Arab Palestinian state because without this adjustment ‘Palestinians’ would have to travel through Israel to move from the West Bank to the Gaza Strip or visa-versa. However, a problem with this line of thought is the morality of taking land from Israel to achieve this process. Another problem is that a number of proposed ‘land swap’ deals foster heterogeneity in an environment that has not effectively managed such a reality on such a consistent and large-scale.

One issue that will not be addressed in this blog post is the question of whether or not ‘Palestinians’ are being mistreated within the boarders of Israel. This issue is very complicated as it involves citizenships and residencies within the Israeli state among other things; however, there is reason to believe that some level of abuse is occurring. Unfortunately a number of individuals tie sympathy to ‘Palestinians’ as a reason for taking Israeli held land and turning it into a Arab Palestinian state which is inappropriate. The appropriate response would be to address the causes of those alleged abuses in Israel and eliminate the rationality behind them.

The final issue regarding fairness is the question, should modern day ‘Palestinians’ be held accountable for the mistakes of their forbearers? Under most circumstances the obvious answer should be no. Unfortunately if such an answer is given and one favors the establishment of an Arab Palestine state how can one reconcile such a decision with respect to fairness to the Jews? Israel has to give up land that it has gained not through offensive action, but defensive action because it is surrounded by a homogenous group of individuals that want to destroy it. The sad state of affairs is that someone has to deal with an unfair situation and the reality is that Israel have had to deal with far more from the Arabs than the Arabs have had to deal with from Israel. To give ‘Palestinians’ an independent state against Israeli wishes sends a message that in the end Arabs can violate any agreement with Israel they want and still get the original deal.

If establishing an independent Arab Palestinian state is not appropriate what is an appropriate response to strife among the ‘Palestinians’ and Israelis? One option would be to offer ‘Palestinians’ a fast path to Israeli citizenship so they would have an opportunity to participate in Israeli government. One could argue that such a proposal would not be well received by ‘Palestinians’ because of the ongoing relationship between Arabs and Jews, especially related to Arab pride. However, if the idea of their own state was no longer in the cards, ‘Palestinians’ may be more inclined to accept Israeli citizenship. Another issue is that Israel must do a better job of maintaining property boundaries between different individuals. With property boundary adherence the key issue is non-discrimination and following the appropriate legal guidelines.

Overall the biggest question in establishing an Arab Palestinian state is how to create it. For most the creation of this state appears to be a means to an end, facilitate peace between another group of Arabs and Israel. However, there are no guarantees that such a peace can be maintained, especially with the long-standing animosity between the two parties. Applying the element of fairness is difficult due to the outright initial refusal of arrangements, which would have established an Arab Palestinian state associated with the history of Arab hostility to Israel. Weakening Israel as a cost to creating such a state for Arab Palestinians would demonstrate an environment where there are little consequences to negative and unjustified Arab actions. While a number of individuals may claim such a stance is unfair, which is true in a way, it is more inappropriate to resolve one aspect of unfairness by taking another unfair action. It cannot be argued that Arab Palestinians have made any significant contributions to the success of Israel, thus to weaken Israel for the benefit of Arab Palestinians would be unfair and wrong. Therefore, it appears that the establishment of the an Arab Palestinian state demands a certain leap of faith which goes against existing precedent.

Scratching the Surface of Criminal Behavior

2011-09-26T08:25:00.000-07:00

In the formation of a global society, such a society will need to answer the question of how to reduce to prevalence and significance of crime. In a broad sense criminal activity can be divided into two categories based on the motivations that drive the action. Gain crimes are actions that are taken in effort to either gain financial resources or political influence. The overall level of violence associated with a gain crime tends to be low. Damage crimes are actions that are taken in effort to inflict either physical injury on another individual or structural harm to some institution. In contrast to gain crimes, damage crimes typically have significant violent elements.

Effective neutralization is interesting between these two categories because gain crimes are more instinctual due to the nature of human self-worth and greed contrasting morality, basically the desire to acquire resources with greater ease than conventional and available means allow. Damage crimes have a more defiant driving motivation. An individual commits a damage crime because he/she wants to inflict some level of physical or psychological damage to an individual or group typically with single-minded motivation, the desire for vengeance or superiority.

It is appropriate to divide gain crimes into two separate categories: major and minor. While eliminating minor gain crimes would be nice for the most part their effect on society is limited. Behaviors like speeding, jaywalking and similar traffic violations can be considered examples of minor gain crimes. Ironically any minor gain crimes, which have probabilities of detriment, can be neutralized through simple logical analysis regarding the insignificance of the gain. For example suppose an individual elects to speed and run the occasional red light to save time. Normally it is reasonable to assume that these actions will save no more than 2-3 minutes of travel time in most experiences. Clearly running red lights greatly increases the probability that an individual is involved in an accident, especially a fatal one. So initially one could argue that the individual in question is significantly increasing his/her chance of being involved in a fatal accident to save 2-3 minutes in travel time during a given trip. In addition there are moral ramifications applied to running the red light in that any accident involves other individuals who took no illegal actions.

Regarding the question of increasing fatality probability one could argue that this increase is a misrepresentation of the actual significance of a fatal accident, that the increase in this case is more political speak than anything. Political speak in this case is defined as: ‘on their face meaningful statements which later appear less meaningful after more in-depth analysis.’ For example consider one country at three different times, Time A, Time B and Time C, in sequential order from past to present. At Time A the country has a GNP of 9 million with an annual growth of 1.5 million over the next year. At a later time, Time B, the country could have a GNP of 24 million and see a growth of 6 million over the next year. Finally at an even later time, Time C, the country could have a GNP of 8 million with an annual growth of 2 million over the next year. Upon completion of that year the appropriate authority may then make the statement that GNP growth is at its highest level since Time A. This statement is somewhat misleading because although the percentage of GNP growth is at its highest level since Time A, the absolute growth, is not. While the statement may imply ‘rate of growth’ unless explicitly stated most individuals will take the statement to mean absolute growth.

Returning to the speeding example, one could argue that the probability of getting involved in a fatal accident is so low that even though running red lights significantly increases the probability the probability is still low. For example assume that the probability of a fatal accident is 0.01% versus 0.1% when running a red light (note these are not actually figures, just trend relevant numbers for the sake of the example). The change in probability is 10 fold, definitely significant, but the overall probability is still quite small, so one could argue that the importance of the change is mitigated. So one could argue that such a relative increase is still not enough to prevent an individual from preferring to save 2-3 minutes a day at the cost of increasing their probability of death.

However, the above abatement of risk argument typically falls apart because most individuals who commit minor gain crimes do not only commit them once. Thus, simple time-risk association can be used to demonstrate the overall detriment of such behavior. For example suppose an individual runs an average of one red lights per 100 minutes of drive time. This individual drives 15,000 miles per year at an average of 40 miles per hour resulting in a total drive time of 22,500 minutes per year resulting in 225 run red lights in a year. Running this many red lights would increase the probability of getting into an accident due to this action to 22.5%. Running these red lights saved an average time of 450-675 minutes per year.

Suppose that due to this increase this individual dies at age 40 years and 0 days and had been receiving the time saving benefits since age 19 years and 0 days. Had this individual not run red lights due to typical life and occupation expectancies you would have lived to the age of 71 years and 0 days and worked until the age of 63 years and 0 days (this individual makes a lot of life decisions on his birthday). So how much time did this individual actually save? Looking at the overall numbers shown in table 1, this behavior actually cost the individual up to 16,284,150 minutes of existence.

Table 1

So in this example taking the action of running a red light is not logical or intelligent at all. Of course an individual may believe that the probability of a fatal accident is so small that the numbers themselves are meaningless and in the end it is up to the individual to decide whether it is worth the potential of wasting some number of years of his/her life to save a number of minutes that only amounts to miniscule amount of the time that could be lost. In addition one must remember that this ‘additional’ time is not actually extra time, but simply the ability to utilize available time in a different way other than in transit, so if the individual in question does not effectively use this time it is meaningless to increase the probability of death, regardless of the overall probability.

Significant gain crimes are obviously more difficult to neutralize than insignificant gain crimes because logic cannot simply act alone. Revisiting that rational, significant gain crimes are appealing because they allow an individual to save time and/or resources while acquiring an equal or greater amount of resources than would have been available under conventional means. There are two strategies that can be utilized to limit the occurrence of such crimes.

First, increase the certainty of punishment. In the typical cost-benefit analysis there are two important factors relating to the cost, its severity and its certainty. Most criminal activity is largely dependent on the certainty of negative consequences. Most criminals act out of one of two rationalities: 1. Necessity of action where the criminal action is taken to ensure future survival (stealing food, etc.) 2. Dissociation of consequence where the criminal action is taken because the criminal does not believe that he/she will be caught. For this mindset severity of consequence is minimized because if one does not believe he/she will be caught then the consequence for being caught is unimportant. Therefore, if law enforcement is able to increase the certainty of these negative consequences criminals will be less likely to engage in any actions that would trigger those negative consequences. In addition increasing the certainty of capture will also increase the amount of resources that the criminal will need to devote to evade capture, thus reducing the profitability of the criminal venture making it less attractive to the potential criminal.

The biggest concern with this first strategy is the resource expenditure required to increase the certainty of punishment. Both technology and training of law enforcement need to remain at an equal to or higher than level versus the technology and strategies generated by the potential criminal. In addition not only will society need to provide the resources to capture criminals it will also need to make a significant number of arrests in the initial stages of enforcement programs to demonstrate to possible criminals their future if they elect to commit crimes. After capturing the criminals incarceration of these individuals may result in the construction of new detention centers adding additional land and financial costs. Overall the strategy of increasing certainty of punishment largely emulates the prevention-cure analogy, an ounce of prevention equals a pound of cure. The cost of the necessary technologies, personnel and incarceration should be less than attempting to neutralize more rampant significant gain crime in the future.

The second strategy focuses on reducing the overall benefit derived from these criminal actions to the point where the criminal no longer views the action as worthwhile. The best way to achieve this goal is to create barriers by either limiting distribution channels or restricting access to middlemen and/or customers. For example dealing illegal drugs is much more difficult when the number of individuals available to purchase the drugs is small because most individuals elect not to take drugs. Logically it is easier to eliminate customers of illegal or unnecessary products through the use of education and financial cost-benefit analysis with viable alternatives; however, some would argue that such strategies have not found success when actually applied in society.

Education is the first and theoretically most promising strategy for eliminating potential suppliers and buyers for criminals. By improving the awareness of individuals to unnecessary and/or detrimental actions, these individuals would be less inclined to commit such actions. For example for the major gain crimes of embezzlement, identity theft and grand larceny the victims are frequently careless or lax in security standards so the education process revolves around making more practical decisions that better safeguard information and limit the opportunities. Education in this respect is the easiest way to reduce this type of crime because an individual only needs to be made aware of existing defense mechanisms and how to utilize them. This is not to say that this education, even if followed by all individuals, will completely end this type of crime, but it will increase both the entry and maintenance costs for criminals engaging in these activities which will reduce the number of criminals. Unfortunately as previously mentioned an ample number of individuals to not even take the basic steps to protect themselves, such as using the word ‘password’ for their security procedures. This lack of action is detrimental for all of society because it easy ‘scores’ further instills resources and confidence in criminals driving more criminal action.

For individuals who fund criminal activity by purchasing the fruits of the action education can also reduce criminal opportunity. There are two types of buyers for criminal activity those who are unaware that the product is stolen/counterfeit and those who are. For those who are unaware, information relevant to the product purchased, both in cost, authenticity and availability can help differentiate between legal transactions and illegal transactions. For instance when attempting to purchase goods knowing the typical retail cost of the items and defining physical characteristics can serve to differentiate between stolen goods and legally acquired goods. Overall in a situation where the authenticity of the product could be questioned, the old adage of “Caveat Emptor” remains a good rule of thumb. One topic for debate may be whether or not harsher penalties should be attributed to buyers of stolen property who do not take reasonable steps to authenticate the legality of the purchased merchandise.

For individuals who know the transaction is illegal education can only offer some level of support regarding certain products. For example illegal drugs like heroin and cocaine can lose some of their desirability in light of the deleterious effects those drugs have on the body. In addition one can also inform drug users how much money they would save by eliminating drugs from their lives. Unfortunately education has little effect on neutralizing an individual making a non-consumable purchase, like buying a stolen stereo, because the individual is aware that the stereo is stolen, so the only education possibility would be on a subjective moral level.

Although education is a necessary and important first step, it is clearly not a “silver” bullet. For example one may cite that the federal government has been fighting a war on drugs for decades including multiple public service announcements, the most memorable being the fried egg-brain association, along with the D.A.R.E program and drug use has not collapsed into an activity only conducted by the most loathsome bottom dweller. With most criminal activities, the first step is to educate the individual to the detriments of participating in such an activity, the second step is introduce viable alternatives to the criminal behavior that will either provide similar, if not improved, sensory experiences or opportunities for resource acquisition. Therefore, it is not only essential to reduce the desirability of criminal activity, but also provide other opportunities or tasks that can replace the criminal activity. In essence this two-pronged strategy creates a situation where the criminal activity is not appealing while implying the availability of another more beneficial, to the individual and maybe even society, activity.

One could argue the curiosity is a significant motivating factor for buyers, especially of illegal drugs. While true, logic demonstrates that this curiosity is artificial. The curiosity largely associated with initial drug use is the typical ‘I wonder what is it like?’ despite plentiful information describing the positive short-term and negative long-term effects. The same curiosity motivator could be applied to putting one’s hand on a hot stove. Sufficient information exists regarding the outcome of such an action outside of direct experience. Despite the lack of direct experience there is not a rash of people putting their hands on hot stoves. Thus the curiosity motivator for drug use has simply maintained its faux legitimacy over touching a hot stove largely attributed to lack of acquired education regarding direct and indirect physical damage to the body.

Preventing damage crime appears to be more difficult than preventing gain crime. The chief problem, as previously mentioned, is the motivation behind damage crime. Although there may be some level of residual motivation through resource gain, the primary driving force is injury or damage to a person or group driven either by vengeance for a past wrongdoing or to prove one’s superiority over another. With this motivation cost-benefit analysis is more difficult as the cost becomes somewhat distorted because of the emotion and belief(s) involved in the action. Removing the cost-benefit analysis from the picture implies that very little can be done to dissuade the motivation beyond doing more to prevent the action before it occurs. Punishing the individuals after the fact is necessary, but its ability to act as an effective deterrent to future offenders is suspect. Overall there are four major scenarios when considering damage crimes, a single individual versus a group, a single individual versus another individual, a group versus a single individual or a group versus another group. In any of these situations the motivational factor can either be superiority or vengeance.

Looking first at the motivation of vengeance, interestingly enough although vengeance should be a stronger motivational force than superiority, it seems easier to derail, when using simple logic especially when large groups engaged against other large groups. The statement ‘an eye for an eye’ is an effective description behind vengeance motivation, with a counter being ‘an eye for an eye leaves the whole world blind’. The overall idea of the counter statement is to discourage one from retaliating when wronged for it will create a cycle of retaliation in which everyone ends up worse off.

Unfortunately this logical deterrent strategy seems to go against human nature and rational action. First, human nature tends to demand a response when one is damaged physically, emotionally, financially, etc. rather than simply shrugging it off, whether that response is an apology and proper redress by the damaging party or similar wrongdoing inflicted upon the damaging party. Simply shrugging it off can frequently lead to two possible interpretations. The damaged party is too weak to respond or the damaged party is unaffected/unconcerned by the action. To individuals with malice intent neither interpretation is favorable.

If the damaged party is viewed as too weak to respond there is a concern that the instigator may shift intrinsic interaction motivation from vengeance to superiority instead of eliminating any motivational element. It stands to reason that a shift in motivation to superiority will increase the negative interaction between the damaged party and the instigator whereas action motivated by vengeance is only a single event. The superiority motivator is largely demonstrated by the relationship between a bully and his/her victim(s). The concern with the damaged party appearing unaffected by the action is lack of satisfaction. If the vengeful party does not believe that the damaged party was sufficiently damaged then the vengeance motivator may not be satisfied and the individual may attempt another negative action against the previously damaged party in the name of original element ‘yet-to-be’ avenged.

While the above analysis seems to favor violence as a response to violence, such a belief is not wise. One option may be to attempt to restrict the number of retaliatory actions between the two parties as long as each side receives an equal number. Unfortunately that strategy would probably not be successful because the possibility exists that with each side knowing there are only a limited number of opportunities they would attempt to inflict maximum damage creating more overall damage than if there was no pre-set limit. So when one party commits a damage crime against another party there are three vengeance-motivated options that can be expected from the damaged party, none of which appear to be very attractive. No retaliation can be conducted, possibly leading to a greater number of negative actions. A set number of retaliation and counter action can be conducted, possibly generating a larger damage per attack ratio than might otherwise exist. Finally retaliation can continue for each counter action creating a cyclic nature of action counter action.

The only advantage stemming from the indefinite retaliation strategy is the possibility of no attacks in general. For example if there is not a significant difference between the power/resource levels of the conflicting sides, logic dictates that launching attacks is meaningless in effort to fulfill vengeance or demonstrate superiority because no significant change in the status quo would occur, simply more death and destruction. Two wrongs may not make a right, but the potential for two wrongs may eliminate the occurrence of the first wrong. Unfortunately in practice this strategy does not typically result in this logical outcome, as seen most notably in the Israeli/Palestinian conflict and the Shite and Sunni conflicts, because of strong religious and emotional factors involved in the crimes themselves, thus logic tends to be pushed into the background.

What happens between parties of differing power levels? If a weaker individual or group is attacked their options are few because to retaliate would invite 'vengeance' motivated attacks and to do nothing would invite more 'superiority' motivated attacks. Even though once again logic can fail in practice and weaker individuals can launch attacks against stronger parties. If a pre-emptive or retaliatory attack occurs by a weaker party it is important to analyze why the attack occurs.

The most probable reason for such action can be attributed to frustration. The weaker party is frustrated about either being weak in general or the negative superiority motivated actions of other stronger parties. The problem is that despite what is depicted in the movies these frustration-motivated responses rarely succeed in changing circumstances. After absorbing the attack the stronger party is not going to crumble resulting in the weaker party becoming the victor nor will the stronger party suddenly have a ‘new-found’ level of respect for the weaker party and stop initiating actions of superiority. Instead the more likely result is the stronger party will become agitated and begin executing vengeance-motivated actions. In addition the emotional nature of the response augments the danger. The worse case in this situation is that the frustration pushes the weaker party to act in a severe fashion far beyond anything the stronger party does which frequently results in significant bodily harm to the stronger party, the weaker party or uninvolved bystanders.

The second reason for an aggressive action by a weaker party would be an attempt to ‘stick-up’ for themselves. The concern with this motivation is similar to frustration in that such action will result in reprisal over respect. A third reason could be delusion in that the weaker party does not realize that he is the weaker party. Typically this reason is quickly eliminated as a motivating factor act the weaker party committees his action. Incidentally the best way to address vengeance motivated actions is to admit wrong doing before the action is committed and arrange proper redress.

The best option for the individual or group is to play defensively creating an environment where continuous demonstrations of ‘superiority’ cost more than their produced benefits and the lack of direct retaliation does not produce vengeance motivation. It is difficult for an individual or group to continue to devote resources to an action when those resources are wasted based on the result. If defensive techniques are not sufficient then the weaker party should request assistance from another party to bolster defense.

Overall negative actions will need to be dutifully addressed by society as with an expanding population characterized by no resource ceiling and unequal distribution resource acquisition opportunities are becoming fewer and far between. Therefore, continuing to educate the population as well as provide alternatives along with adequate and appropriate punishments are imperative to an evolving society.

Student Loans - The Coming Crisis?

2011-09-14T07:24:00.000-07:00

Recently some have begun to raise concern about a perspective bubble in the student loan market. In the past student loans served a vital purpose in society allowing intelligent students who lacked the financial means the ability to attend college augmenting their education and helping them develop the necessary skills to succeed in an advanced job. Success in these advanced fields garnered larger salaries which allowed for timely repayment of the loans and effective participation in the consumer-based economy. This system worked as long as each component: high quality colleges, available advanced jobs, available and skilled workers and effective lending institutions were present.

Unfortunately the “Great Recession” has greatly handicapped the availability of not only high-quality jobs, but even medium quality jobs, which adds significant delay to the repayment schedule, if payment occurs at all. In addition to this failure in the original system the rise of ‘diploma mills’ / ‘for profit’ colleges which charge traditional college tuition amounts, some charge even more, but typically provide a questionable education have also added undue stress on the education-loan-job cycle. The development of these stressors demand deterrent options, in case an economic recovery (which would restore the cycle to balance) is slow to develop, to avoid unpaid loans becoming a long lasting problem.

In this cycle a cause of concern is the relationship between private lenders and student borrowers. Before the “Great Recession” private lending to students for college was on the rise largely driven by ‘dream college’ syndrome (where the student wants to attend college x no matter what the cost) and dramatically rising college cost with over 100 now exceeding $50,000 a year.1 These two factors consistently drove college costs outside of the total yearly caps offered by federal government loans demanding that students seek financial assistance elsewhere. The problem for students is that the private lending industry with respect to student loans is almost completely unregulated with a significant number of instances where even the limited regulatory rules are ignored without consequence. This lack of regulation provides little protection for the borrower and its prevalence throughout the entire private student loan industry is frequently an unnecessary burden on student borrowers.

On its face the most glaring initial difference between federal student loans and private student loans is the variable interest rates associated with private loans opposed to the fixed rates of federal loans. Not only do the private loans use variable rates, but also these variable rates are unnecessarily high. Variable rates typically include a quasi-floor in a margin which is added to the prime rate to ensure the rate does not go too low. It is almost unheard of for these loans to have a rate ceiling. The standard argument used by private lenders for these high rates is to absorb risk, but such an argument is not substantiated. The student loan market is similar to the sub-prime mortgage market, which demonstrated that opportunity pricing governed mortgage rates over perceived risk that the borrower would default. Also most of this ‘risk’ based pricing forgets to note that higher interest rates, especially in this economic environment, should increase the probability of default. At the moment private student loan lenders are not deterred by that reality because bankruptcy laws are designed heavily in their favor.

Others try to justify a high variable rate based on the university that the given individual is attending using university prestige as a means to measure of potential future income. The problem with this justification is that outside of a very select few, university prestige has little meaning anymore in the workforce. The fact is that most of the value in the high variable rates stems from the desire to profit, nothing else.

This desire to profit is further emphasized in the numerous fees which private lenders add to loans and their general dealings with borrowers. Lenders constantly charge for loan origination, late payments, arrangement of deferments or forbearances, copies of loan payment histories and loan verifications.2 Not surprisingly most of these services are widely utilized by borrowers especially deferments and forbearances (when available) in effort to avoid delinquency and default when payments cannot be made. It is an interesting strategy by these lending organizations to charge a fee for a service that is designed to limit short-term payment burden due to a lack of available funds.

In effort to ensure a high volume and probability of collection, most observers view the behavior of private student lenders as both ‘predatory’ and unethical. This behavior is demonstrated through a majority of loans have mandatory arbitration clauses, typically buried and hidden, which strip the borrower of most court-based litigation avenues instead directing disputes to arbitration where the arbitrator is frequently selected by the lender.2 Also private lenders rarely offer flexible arrangements which could tie repayment rates to income, initiate rehabilitation for formerly defaulted borrowers or offer long-term repayment relief.2,3 In addition forbearance, is rare and deferment is unsubsidized (interest accrues). A number of subjective or poorly defined default triggers are commonly found in private loans such as a borrower could be declared in default if in the lender’s judgment they experience a significant lessening of ability to repay even if a payment has yet to be late or missed.2 Finally loans are typically not discharged even in the death of the original signatory or cosigner.

In addition the poor regulatory environment does little good for potential borrowers due to a lack of transparency and/or an ample amount of ambiguity. Such specificity gaps allow the lender to quickly change or manipulate elements in the loan to the lender’s advantage without the concern of legal reprisal. The lack of certainty in consequences for failure to abide by the limited existing regulations renders those regulations moot.

For example private loans under $25,000 are covered by the Truth in Lending Act (TILA), which largely governs disclosure and repayment timing.4 The TILA contains a ‘loop-hole’ of sorts in the special rules for interim student credit extension, which are used when the repayment amount and rate/schedule are not known at the particular time when credit is extended.2 Due to the lack of disclosure on the day the credit is extended, mandatory and complete disclosure is supposed to occur when an agreement on the repayment schedule is created; however, the creditor may delay disclosure until the due date of the first payment.2 Unfortunately this delay commonly creates violations mostly stemming from improper or incorrect APRs. Normally lenders provide two APR disclosures, one for the interim period before repayment and then one for the repayment period (the repayment APR is almost always higher). However, a significant number of times lenders incorrectly report this second APR to the borrower which is in violation of the TILA.4

Another regulatory problem is a lack of note inclusion. The lending organization, sometimes legally referred to as the ‘holder of the note’, is subject to the claims and defenses that the borrower can assert based on conditions created by the Federal Trade Commission. The basis of this information is provided in a notice in the note itself and its inclusion is required by the holder. However, a number of lenders (40% in one study) simply do not include the notice in the note in an attempt to limit potential liabilities (liabilities which frequently only exist when lenders break the law).2 In other instances 90% of those who included the notice also included contradictory information or clauses which sought to undermine the ability or the desire of the borrower to utilize the information in the notice.2

With respect to the ‘holder of the note’ one of the issues that is creating concern among financiers is a repeat of the sub-prime mortgage fiasco as securitizing student loans has continued to gain in popularity as a means to increase revenues. However, at the moment it is difficult to see such a crisis coming to fruition because unlike the sub-prime crisis the federal government handles a vast majority of the student loans. Therefore, any crisis from student loans involves one of two issues. The first crisis, as mentioned previously, is a slowdown in the economy due to less available capital that loan holders can spend in the U.S. consumer-based economy because they cannot discharge or steadily payoff their loans. A secondary element of this first crisis is that economic conditions could worsen to the point where individuals elect not to attend college creating further shortages in highly-skilled workers creating employment skill gaps.

The second crisis is lost government funds due to student loans not being paid back at a high rate. This second crisis is a long way off though due to the generally small total amount of the student loan program relative to the size of the government and the interest payments made by those individual who are able to pay back their loans in full filling some gaps. One concern is that if private lending does increase the significant lack of regulation and no borrowing limits the rate of default among student borrowers could increase dramatically worsening both potential crises.

Some may argue that private student lenders fill a need in the marketplace and that if a potential borrower does not like the terms that are given he/she can go elsewhere, that is theoretical basis of competitive capitalism. The problem with the ‘don’t like it don’t do it’ reasoning that is typical for those who want to strip any complexity from an issue due to its potential detriment, is that these practices are endemic within the private student loan industry thus there is rarely a viable alternative which would be more beneficial to the potential borrower. Therefore, if these funds are needed, which they most likely are otherwise a private loan would not be sought out, the borrower typically has to decide on college or no college. Selecting the latter frequently results in a negative for society because an individual is denied an opportunity to increase his/her skill set, intelligence and overall usefulness to society. Overall the argument that government should not regulate the student loan market is a foolish one that is not supported by reality. For example look at usury law for banks; standard government regulation on a similar level should apply for private student lenders because the environment has become homogeneous in a negative manner due to a lack of regulation and pure greed.

One of the crux issues involving the first potential student loan crisis is the difficulty in which student loans can be dismissed through bankruptcy. In 1976 Congress enacted a nondischargeability provision to respond to complaints that recent college graduates were abusing the bankruptcy system to eradicate their student loan-based debts soon after graduation.5 Whether or not abuse was actually occurring was controversial due to a lack of empirical evidence demonstrating the alleged abuse. Logic also seemed to go against this mindset because relative to inflation most college tuition was not excessive in the 70s and bankruptcy came with significant penalties. In some respects the logic behind using bankruptcy to discharge student loans before even trying to pay them back is similar to using abortion as a primary form of birth control, any benefits are heavily outweighed by the costs/detriments. Overall this nondischargeability provision applied to only federal and non-profit loans and had two exceptions. First, a debtor could discharge student loans when filing for Chapter 7 bankruptcy five years after loan maturity. Second, the debtor could discharge if he/she could prove ‘undue hardship’.6,7

The first provision was eventually abolished by the Higher Education Amendments of 1998, after a brief increase in wait time from five years to seven years, leaving undue hardship as the only means in which to discharge federal student loans.8 Seven years later the Bankruptcy Reform Act of 2005 eliminated the differences between how bankruptcy affected private student loans and federal student loans with private lenders receiving similar protections, which were previously held only for the federal government.9,10 Basically prior to 2005 loans from private lenders could still be discharged through normal bankruptcy, after the Bankruptcy Reform Act of 2005 the only means to discharge any student loan, federal or private, was through undue hardship. The U.S. is the only jurisdiction under review to have extended the application of the exception to discharge to non-government funded or guaranteed student loans.6

Applying for undue hardship occurs through filing an adversary proceeding after filing for bankruptcy. Typically the chief, sometimes the only, criteria for determining undue hardship is the Brunner test which includes three elements: 1. the debtor cannot maintain a minimal standard of living when factoring in repayment of the student loan debt with respect to current income and expenses; 2. there is no reasonable expectation that these circumstances will change within the timeline of the repayment schedule; 3. the debtor has attempted to find other avenues in which to provide some means to repay the loans;11

While the Brunner test is supposed to impart some measure of consistency in whether or not a student loan(s) should be discharged, one of the prevailing problems is that this consistency is left up for interpretation. This dependency on interpretation creates an environment where the attitude of the ruling judge tends to be much more important than whether or not the conditions of the Brunner test are actually met. Overall some individuals seem to misrepresent the student loan crisis as individuals always being mired in debt when in fact a past study found that 45% of individuals who filed for a discharge of student loans through undue hardship were successful. The crisis is that the discharge only becomes available when the point of undue hardship is attained, which means the person is probably in significant financial peril even without the loans. Note that it is a misconception that when discharge is granted through undue hardship that the entire student loan amount is forgiven; instead typically a given percentage is forgiven to a point where the loan debt is not longer viewed as undue hardship. In the above study where 45% of applicants received discharge, approximately 72% of the debt, on average, was discharged.7

From at least this study the fear of being saddled with student loan debt over the course of your entire life seems somewhat overblown; especially in this down economy where the unemployed have less reason to take personal blame for not having a job or having a much lower paying job than previously planned and thus not having the necessary income stream to pay back the loan in a timely fashion. For even those who agree with the premise that student loans are not a forever crippling albatross the problem of consistency is still a significant issue. Thankfully because the Brunner Test does provide some guidance the issue of consistency should be solvable by simply expanding the pool of judgment. Instead of having a single judge presiding over an undue hardship hearing five judges could preside with the majority ruling acting as the official decision. The most important issue for this solution would involve ensuring appropriate scheduling due to the lack of an ‘official’ undue hardship panel for the judges involved would be drawn from the pool.

However, some argue that a 45% discharge rate is too little, what about those 55% that are still saddled with their debt and no feasible means to successfully discharge it? First, it must be assumed that the expansion of ruling judges to 5 will result in a similar discharge rate for undue hardship, the accuracy of such an assumption is unknown. Overall the best solution is to simply eliminate the restrictions on eliminating student loans via bankruptcy, especially since no one has produced valid evidence on the original reason for its restriction, rampant filing to eliminate debt right after completing college. One could argue that the bankruptcy filing and penalties would prove to be a deterrent to fraudulent bankruptcy filing. Also an alternative to simply eliminating the discharge restrictions would be to create some level of interest forgiveness for those that successfully acquire a college degree. In this instance individuals that make effective use of the funds and have a higher probability of contributing to the economy should have a better opportunity to fulfill that potential by not having to deal with superfluous interest.

The issue of bankruptcy is only one element driving the potential student loan crisis; while there are others of minor importance, the second major issue is the rise of for-profit educational institutions. For the purpose of this post a ‘for-profit’ can be defined as: institutions of post-secondary education that are privately-owned or owned by a publicly traded company and whose net earnings can benefit a shareholder or individual.12

The rise of the for-profit educational institution was driven by filling the presumed need to offer more flexible courses and hours to currently employed individuals, typically older than traditional college students, who wanted to pursue advanced degrees largely motivated by thoughts of promotion at their current job. Some also argued that these institutions would remove any stigma associated with older individuals interacting in a traditional college environment with younger individuals. In addition for-profit institutions utilized an open admissions policy so their busy professional applicants would not have to be burdened by taking standardized tests. Unfortunately this intention has seemingly been corrupted by the pursuit of profits.

A scathing report about numerous acts of irresponsibility at best to outright fraud in the for-profit industry were documented by the GAO in 2010.12 While going over the entire report here is not appropriate the most detrimental elements in the report describe multiple instances of fraud where potential recruits were told to lie about their total assets and/or income to make themselves poor enough to qualify for government loans, the tuition disparities between for-profits and other available public institutions and the loan default disparity between students enrolled in for-profits and students enrolled in traditional colleges.12

In 2010 some members of Congress determined that the questionable tactics and frequent complaints regarding for-profits stemmed from a lack of regulations. Regulation was also deemed important because for-profits only accounted for approximately 10% of secondary education students, but utilized 23% of total federal loan funds and their students were responsible for about 50% of total loan defaults.12,13 Therefore, new regulations referred to as ‘gainful employment’ were proposed in typical draft form for all for-profit institutions over a given academic year.13

- At least 35 percent of former students must be actively paying down their federal student loans, defined by lowering their loan balance by at least a dollar.

- Graduates must spend no more than 30 percent of their discretionary income on student loan payments.

- Graduates must spend no more than 12 percent of their total income on student loan payments.

These draft rules would have began in June 2012 with the following conditions applying in each given situation:

- No penalties for a program that is abiding by all three rules;
- Failure to abide by one or two of the rules results in placement on restricted status which could reduce the amount of loans which could be offered to students attending the program;
- Failure to abide by all three rules results in black listing (no loans would be offered to students attending the program);

However, those draft rules were significantly altered in the favor of the for-profit institutions due to changes in enforcement and measurement after what some characterized as heavily lobbying by the for-profit industry. While the rules remained the same the enforcement penalties changed so dramatically that the rules were rendered rather meaningless. For example instead of starting in 2012 the rules associated with ‘gainful employment’ start in 2015, so for-profit institutions have another 4 years to participate in their current questionable practices before changing. Also accountability for rule violation was extended from 1 year to 4 years and a single strike was only given if an institution failed all three rules in a given year. Failure to comply with two of the three rules results in absolutely no penalty or consequence. Finally the penalties associated with various violations over the four-year evaluation period are:

- One strike requires the program to disclose that failure to prospective students;
- Two strikes requires the program warn students of excessive debt, the potential of closure and give students options for transferring to other schools as well as require the single strike penalty;
- Three strikes or more the program is black listed;

At the moment proponents for for-profit institutions, not satisfied with completely neutering these rules, have also filed suit in the U.S. District Court for the District of Columbia towards eliminating the rules entirely. Most proponents cite that the application of these rules will make it more difficult to offer loans, thus reducing the probability that low-income students can attend their institutions and receive a ‘quality’ education. Unfortunately this argument has little to no merit when recalling from above that for-profit institutions routinely and heavily overcharge their students for tuition relative to existing public educational institutions in the same region.

A second argument made by for-profit proponents is that these rules unfairly target only for-profit institutions and all educational institutions should have to abide by them. Once again this argument has little merit because the fraudulent and even predatory environment created by for-profits drove the creation of these rules. So why should a group that has not demonstrated this behavior be penalized in the same way as a group that has? Also a large percentage of for-profit enrollees borrow (upper 80s)14 which is more than traditional students, so once again targeting these rules make sense. Therefore, logic dictates that all these new rules, unchanged from their draft form, would have done on any meaningful scale would have been to reduce the amount of profit that for-profit institutions would have generated from their students, clearly something not in the interest of the for-profit proponents.

Another problem with the above rules is that they do not address the transparency problem that most students face when gathering information about for-profit institutions, especially because recruiters have a tendency to omit information they should not omit in their discussions with potential students.12 Therefore, additions to these rules need to be made. For example all colleges need to have an easily identifiable section on their websites (or a pamphlet available through mail) which identify current tuition costs for a given year, total tuition costs associated with a four year degree over a 4 to 6 year period, what colleges will accept credits from the particular college through transfer, accrediting agency with current status and a working hyperlink to the Department of Labor and Statistics content page to reference starting salaries for a given job.

Also referencing the lenders themselves borrowers should have a clearer picture regarding the terms of any loan, especially after repayment begins. This goal can be accomplished by requiring lenders to provide estimates of all important loan items that will apply once repayment begins. Note that these would only be estimates so they would not be binding, but they would give the borrower a better understanding of whether or not he/she could afford the loan and what to expect when going into repayment. Currently lenders are ‘encouraged’ to provide similar type information, but rarely do, so it should be required. There is no detriment to providing this service unless the lending institution is planning on screwing over the borrower.

Also the above rules do not demonstrate any way to measure the methods used by for-profits to ‘hide’ defaulters by using forbearance and other deterrence tools. Therefore, individuals who are almost guaranteed to default or even exceed the income caps can be shuffled to another analysis period to avoid penalties for the current period. Associating this ability to hide defaulters with the excessive administration failures required to even receive one strike, it is difficult to conclude that these rules will have any negative impact on for-profit practices.

This ‘hiding’ issue is also important because most of the information that is gathered and reported on regarding loan health and default rates only take into consideration defaults, not long-term ongoing delinquency avoidance. Delinquency is commonly defined as ‘failure to make monthly payments within 60 days of the due date when expected to’. Default commonly occurs when a borrower exceeds 270 days of delinquency.14 However, for students that have departed college, tools like deferment and forbearance are usually a bad sign regarding their ability to reengage in loan payments, especially in the current economic climate. Therefore, while these individuals have technically yet to default, for a number of them it is only a matter of time until they do, but when they will is not clear because of continued delay through the use of these various tools.

The problem with this situation is that most of these individuals who are delinquent or quasi-delinquent (avoiding delinquency through continuous use of forbearance, etc.) are basically in default because they are not making significant enough payments to pay off their debt, yet officially these individuals are not counted as in default so statistically the problem is typically worse than people think it is. Such inaccurate information may provide some pause to those that are concerned about student loans becoming another sub-prime mortgage crisis.

Overall if the current economic climate continues a high probability exists for a problem to develop in the student loan environment. While this problem should not be similar to the crisis that struck the sub-prime mortgage industry because the federal government is responsible for a vast majority of lending (over 80%),15 the more pressing issue is that without an effective and reliable means to discharge student loan debt the inability to find jobs will force borrowers out of the economy. Less money in the economy means less economic growth which hurts society in general. This situation can quickly start a self-sustaining feedback cycle (similar to what has been seen in the housing market), which further damages the economy and becomes even harder to escape. Another aspect of this problem is the lackadaisical attitude individuals in government have toward the for-profit education industry which frequently exacerbates the loan problem by charging excessive tuitions and other fees and using potential predatory tactics to convince recruits to pay them. Regulatory enforcement is needed for this industry to stem this contributing problem. In the end steps must be taken to address this problem otherwise the reduced capital in the market will create a significant drag on the economy as well as negatively affect the future educational prospects of millions of potential college students.

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Citations:

1. Brainard, J. “A Public University Joins the Expanding 50K Club of College Prices.” The Chronicle of Higher Education. October 31, 2010. http://chronicle.com/article/A-Public-University-Joins-the/125207/
2. Loonin, D, and Cohen, A. “Paying the Price: The High Cost of Private Student Loans and the Dangers for Student Borrowers.” National Consumer Law Center. March 2008.
3. Institute for Higher Education Policy, “The Future of Private Loans: Who is Borrowing, and Why?” at 6
(December 2006).
4. Truth in Lending Act. http://www.fdic.gov/regulations/laws/rules/6500-200.html.
5. B. Hennessy, "The Partial Discharge of Student Loans: Breaking Apart the All or Nothing Interpretation of 11 U.S.C. 523 (A)(8)" (2004) 77 Temp. L. Rev. 71 at 73
6. “Government Student Loans, Government Debts and Bankruptcy: A Comparative Study — Part 2” Office of the Superintendent of Bankruptcy Canada. http://www.ic.gc.ca/eic/site/bsf-osb.nsf/eng/br01679.html
7. Pardo, R, and Lacey, M. “Undue Hardship in the Bankruptcy Courts: An Empirical Assessment of the Discharge of Educational Debt.” (Tulane University School of Law, Public Law and Legal Theory Research Paper Series, Research Paper No. 05-06 (August, 2005)).
8. C. Morea, “Student Loan Discharge in Bankruptcy – It is Time for a Unified Equitable Approach.” Am. Bankr. Inst. L. Rev. 1999. 7(193) at n 2.
9. Pardo, R, and Lacey, M. “The Real Student-Loan Scandal: Undue Hardship Discharge Litigation.” Am. Bankr. L. J. 2009. 179(83).
10. The Bankruptcy Abuse Prevention and Consumer Protection Act of 2005, Pub. L. No. 109-8 § 220, 119 Stat. 23, 59 (to be codified at 11 U.S.C. § 523(a)(8)(B)).
11. Brunner v. New York State Higher Education Serves Corporation 831 F. 2d 395 (2d Cir. 1987
12. Kutz, G. “For-Profit Colleges: Undercover Testing Finds Colleges Encouraged Fraud and Engaged in Deceptive and Questionable Marketing Practices.” Government Accountability Office. Aug. 2010.
13. Program Integrity: Gainful Employment-Debt Measures. Education Department. 6/13/2011.
http://www.federalregister.gov/articles/2011/06/13/2011-13905/program-integrity-gainful-employment-debt-measures
14. Cunningham, A, and Kienzl, G. “Delinquency: The Untold Story of Student Loan Borrowing.” Institute for Higher Education Policy. March 2011.
15. DeRitis, C. “Student Lending’s Failing Grade.” Moody’s Analytics. July 2011.

How the gang of three, leptin, ghrelin and amylin, influence obesity

2011-08-31T08:03:00.000-07:00

Obesity is commonly defined as an excessive amount of body fat relative to lean mass.1 Individuals who are classified as obese typically suffer from additional health problems which either do not afflict or have dramatically lower rates of affliction in those who are not obese. Unfortunately in the United States excess weight gain, which commonly leads to obesity, has reached what some are calling epidemic levels with more than 60% of American adults either overweight or obese.1 In addition to the dramatic rise in adult obesity even more concerning is the even more rapid rise in childhood obesity.1

One of the more practical rationalities explaining this dramatic increase in obesity is a change in energy homeostasis between energy intake versus energy expenditure. Energy intake is almost entirely derived from food consumption where energy expenditure is derived from biological thermogenesis which includes basal metabolism, adaptive thermogenesis and physical activity.2 Based on this information it makes sense to argue that an increase in food consumption joined with a corresponding decrease in physical activity due to modern conveniences creates an imbalance resulting in weight gain and obesity.

This explanation can address most of the new increases in adult obesity, but it seems to breakdown when applied to children and infants. Surprisingly, in addition to children and adults, some research demonstrates that even infants have not escaped this obesity epidemic.3 Despite changing food consumption and exercise patterns in adults and young children to teens, little has changed in the diet of infants, either breast milk from mother or bottle formula. One possible explanation is that obese mothers are influencing these changes in their infants, which does have some backing from empirical evidence,3 but at the moment it appears to be a stretch to presume such an explanation to be the principle reason behind this increase.

This change in obesity rate with no definitive explanation stemming from energy intake has lead others to question if the above theory regarding disruption in energy balance is the most influential element behind the obesity rate increase. Make no mistake that an increase in energy imbalance in favor of intake is a significant component in increased obesity rate, but due to the infant ‘question’ it may not be the only significant component. Two other popular explanations have emerged to explain this gap: toxic compounds in the environment and increased viral infections.

These two additional explanations have generated certain levels of empirical backing which add to their legitimacy. However, these elements will not be addressed in this particular blog post, but in a separate post in the future. This blog post will focus on the biochemistry behind how the increasing energy imbalance induces such a significant level of weight gain when under normal circumstances adult body weight is relatively constant despite large variations in daily food intake and energy expenditure.4 Clearly the reaction of the body to hormones and other agents, which govern appetite and energy expenditure change in obese individuals versus non-obese individuals.

Among the hormones that direct energy homeostasis, leptin is widely viewed as one of the most important, if not the most important. Leptin is secreted by adipocytes at a rate which generates serum concentrations in similar proportion to existing adipose tissue.5-7 The principle role of leptin is to provide a measurement of energy to the central nervous system to determine what types of adjustments are required to properly maintain energy homeostasis.8,9 Under normal conditions higher than normal leptin concentrations result in limited to no appetite whereas lower than normal leptin concentrations result in increased appetite as well as reduced energy expenditure and an initialization of the starvation response.10

Most work involving leptin utilize mice as the model organism all which have six distinct leptin receptors (LR) that have been designated a through f and are sub-divided into three classes: short, long and secreted.10 The secreted receptor (LRe) is created via products of alternatively spliced mRNA or proteolytic cleavage of membrane bound LRs.10,11 Secreted forms only contain extracellular domains which bind circulating leptin acting almost like a leptin inhibitor of sorts.10,11 Short receptor (LRa, LRc, LRd and LRf) function is not fully clear, but they are thought to aid leptin transport across the blood brain barrier.11,12 Finally long receptor (LRb) is crucial for leptin action as it is the principle binding receptor, which initiates leptin influence on a given neuron.10

While leptin does act in various portions of the brain, the principle region of action is in the hypothalamus, acting on thyroid and growth hormones along with sex steroids13,14 largely due to high LRb mRNA expression and associated receptor expression.13,15-16 On a side note in addition to appetite, leptin also regulates glucose homeostasis independently of adiposity and regulates glycemia.17-20

The chief area of action for leptin in the hypothalamus is the arcuate nucleus (ARC). In the ARC LRb acts on two different types of neurons: first neuropeptide Y (NPY) and agouti-related peptide (AgRP) synthesizers and second pro-opiomelanocortin (POMC) synthesizers.13,16 For signaling POMC is processed to a-melanocyte-stimulating hormone (aMSH) which binds to melanocortin-3 or 4 receptors (MC3R or MC4R) inducing appetite suppression.21-24 NPY is an orexigenic (promotes food consumption) hormone which incorporates a negative feedback mechanism suppressing growth and reproductive elements as a means to reduce energy expenditure25-27 whereas AgRP is an inverse agonist for MC4R, which also decreases cAMP production.28 Basically both NPY and AgRP act to increase appetite and reduce energy expenditure in times when the body believes a low energy state exists. Leptin binding to LRb inhibits NPY and AgRP secretion16,29 and promotes aMSH secretion in a dose-dependent fashion30 due to promotion of POMC. So overall leptin actively influences appetite by inhibiting appetite promoting NPY and driving POMC synthesis.

When individuals become obese leptin levels do not decrease. In obese individuals leptin levels are actually still represented in somewhat proper proportion to corresponding adipose tissue.7,31-32 The inability of higher leptin concentrations to reduce weight or appetite has lead to the conclusion that obese patients develop some form of leptin resistance.

A vast majority of the studies associated with leptin resistance have taken place in mice, but is also believed to properly translate to humans as well. For the purpose of experimentation mice are commonly divided into a control group and a secondary group that becomes obese due to increased food consumption. This secondary group is commonly referred to as diet-induced obesity (DIO) mice because the obesity is developed through food consumption not genetic knockout or mutation.

In DIO mice the development of leptin resistance has been hypothesized to develop over three stages: first, mice gain weight increasing the amount of adipose tissue and corresponding levels of leptin, but appear to maintain a normal response to leptin. Second, associated leptin interacting peripheral neuronal areas suffer from diminished capacity to respond to leptin. Third, associated leptin interacting central neuronal areas suffer from diminished capacity to respond to leptin.33-35

Evidence for leptin resistance has built considerably over the years. For example between non-obese and DIO mice there are no changes relative to NPY, AgRP and POMC mRNA expression with no leptin exposure.29,36 After leptin is injected decreases NPY and AgRP mRNA expression occur in control mice, but did not change significantly in DIO mice.29 Also DIO mice appear to have less activation of MC4R compared to control mice,29 which makes little sense when considering that DIO mice have higher concentrations of leptin. Some believe that the lack of MC4R activation coupled with no additional reduction in AgRP expression drives leptin resistance downstreatm in the melanocortin system.29

With this information it makes sense to conclude that the leptin resistance is being driven by the leptin concentration itself, not by another element. Studies have appeared to rule out reduced LRb expression as a reason for resistance because LRb mRNA expression typically does not demonstrate a significant difference between control and DIO mice.29,37 While there are many other hypotheses regarding the mechanism of action, the two that receive the most study are the failure of extracellular leptin to reach its appropriate receptors in the brain and the failure of the leptin activated LRb signaling mechanism.38-41

After leptin binds to LRb a number of secondary steps occur. LRb binding initiates the activation of intracellular Jak2 tyrosine kinase. Activation of Jak2 triggers autophosphorylation of the four tyrosine residues on Jak2 as well as phosphorylation of the three tyrosine residues on the intracellular tail of LRb: 985, 1077 and 1138.10 With respect to positive action LRb residue 1138 is the most important as its phosphorylation recruits signal transducer and activator of transcription (STAT) 3, for activation which is directly responsible for transcription of POMC.10 Residue 1077 recruits transcriptional activation of STAT5, which is thought to increase energy expenditure.10

However, to ensure that the effect of leptin does not permeate to a dangerous level, leptin has an inherent negative feedback element. While leptin activation of Jak2 leads to phosphorylation on residue 1138 activating STAT3 leading to the transcription of POMC, STAT3 also results in the transcription of inhibitory suppressor of cytokine signaling 3 (SOCS3).10 SOCS3 acts as the principle negative feedback inhibitor of LRb by binding to residue 985 inhibiting STAT3 recruitment and possibly activation.42,43 Tyrosine phosphatase SHP-2, which is recruited by the phosphorylation of residue 985, is also thought to be a secondary inhibitor, but SOCS3 is considered more important (if not simply based on more confirmed function).42-47 The negative inhibitory ability of SOCS-3 is supported by SOCS-3 deficiencies resulting in significant increased leptin action.29,45 A third LRb inhibitor is tyrosine phosphatase PTP1B, but because this element appears to operate independently of leptin interaction it will not be discussed further.

The rationality behind a feedback mechanism seems straightforward. For obese individuals it may be appropriate that the body limit food consumption and supplement itself through the breakdown adipose tissue, but this process does not supply all necessary nutrients for long-term survival. Therefore, the leptin inhibition feedback mechanism seems designed so that the obese do not overeat, but do eat once and a while in attempt to acquire these essential nutrients. Also the feedback mechanism could be related to necessary changes in behavior which demand greater levels of short-term energy largely derived from food consumption. However, the feedback mechanism may overcompensate in its role in obese individuals.

Relating back to the second theory behind leptin resistance focusing on the activation of the signaling mechanism after the initial binding event, leptin resistance may revolve around an inhibitory desensitization event (similar to nicotinic acetylcholine receptors). For this theory an initial leptin binding event starts the positive secondary mechanism and extended binding begins the inhibitory mechanism. Thus, due to anticipated increases in leptin binding rate and absolute binding times as adipose tissue increases due to an individual becoming obese, leptin response rates at higher leptin concentrations will decrease due to desensitization of LRbs.

Higher baseline SOCS-3 mRNA in the ARC in DIO mice29,48 support the idea of desensitization as if leptin was losing affinity for LRb then SOCS-3 levels would not change significantly. However, what is the cause of this increase? One possibility could be suppose phosphorylation of residue 1138 occurs at a faster rate than phosphorylation of residue 985 (this makes sense if under normal circumstances a sustainable positive effect is seen), but the effect or SOCS-3 has a longer residence time than POMC (recall that POMC is cleaved into aMSH); therefore, the longer leptin stays bound to LRb the more inhibition begins to overtake leptin action. Under this scenario, the longer leptin stays bound to LRb the greater the inhibitory effect on residue 1138 reducing STAT3 activity. Overall the higher concentrations of leptin in obese individuals do not allow for a sufficient period of time for the LRb receptor to “deactivate”, thus leptin action is significantly more inhibited.

Another possibility may be that leptin could bind to the short receptors (LRa, c, d and f), possibly present on the neuron, which could trigger an inhibitory mechanism separate from the initial mechanism associated with LRb. The theory here is that the long receptors have a higher expression rate in neurons which allow for more binding opportunities with leptin, but the short receptors have a higher binding affinity for leptin. As long as there is free leptin the high frequency short-term binding to LRb wins out over the low frequency long-term binding to short LRs, thus leptin represses appetite. However, suppose in situations of high leptin concentrations (obese individuals) more LRe is synthesized and secreted (as a secondary mechanism of inhibition) which binds a lot of the free leptin changing the pattern of influence so that long-term binding short LRs start to have more influence than LRb which leads to leptin resistance. Overall this theory seems more unlikely relative to desensitization as increasing leptin concentrations, no significant reduction in LRb expression and increased SOCS-3 expression all support a form of desensitization and this secondary theory relies on some unknown functionality of certain leptin receptors.

One interesting side note on this element is that STAT3 recruitment decreases profoundly in the ARC, but small recruitment decrease is seen in the ventromedial hypothalamus (VMH) or the dorsomedial hypothalamus (DMH).48 One reason for this suggestion is that cytokine signaling-3 (SOCS-3) expression is also localized to the ARC over other regions49,50 as SOCS-3 reduces the effectiveness of leptin action, probably through inhibition in the secondary pathway. Another reason is that leptin concentration in the VMH or the DMH is not high enough to induce the desensitization element associated with leptin resistance and resulting prolonged decreased STAT3 recruitment. Finally a third possibility may be a more prominent associated helper effect of amylin in the VMH over the ARC.

One of the principle reasons for regionalized increase in SOCS-3 (the first explanation above) could simply be a volume difference due to ARC being localized in a region more conducive to transport of leptin across the blood brain barrier.51 This argument is further supported by a delay in the time course for LRb signaling in non-ARC neurons relative to ARC neurons when exposed to leptin peripherally injected, but this delay does not exist when leptin is centrally injected (central injection skips passage through the blood brain barrier).51

Recall that the concentration of leptin is tied to adipose tissue, thus when exploring the nature of obesity and the role of leptin it is appropriate to investigate the role of saturated fat. Experience with cell culture studies have shown that increasing levels of saturated fat induces increased insulin resistance both in signaling and gene expression due to inhibition of the receptor, receptor substrate 1 and 2 tyrosine phosphorylation and activation of insulin antagonists phosphoinositide-3 (PPI3) kinase and Akt.52-54 There are some conflicting studies regarding how dangerous saturated fat is with regard to catalyzing obesity in different individuals.55,56 A reason behind these opposing results is probably drawn from the complexity of gene response with regards to saturated fat.

For instance one study found that high dietary saturated fat intake significantly increased the risk of obesity by 32% in those carrying 2 or more risk alleles vs. those carrying 0 or 1 risk alleles based on the relationship between STAT3 and saturated fat.52 This study determined that a vast majority of individuals are presumed to have 2 risk alleles making them more susceptible to obesity due to saturated fat consumption.52 The interaction between STAT3 and saturated fat is thought to involve saturated fat activation of toll-like receptor-4 (TLR4) and cross-talk between that activation and the JAK-STAT3 pathway.52,57 This interaction may explain why mice feed diets higher in saturated fat appear to have more aggravated cases of leptin resistance. For example some research demonstrates that for diets equally high in total fat the one comprised predominately of poly-unsaturated fat does not significantly change NPY or AgRP mRNA levels in the ARC unlike diets comprised predominately of poly-saturated fat.58 Based on this result leptin levels should be inhibited less for unsaturated fat as opposed to saturated fat.

However, an unexpected side result is that POMC mRNA expression does not change regardless of principle fat component of the diet.58 This result is unexpected because with more leptin resistance there should be some corresponding drop in POMC mRNA expression. One explanation for this result could be that there was a decrease, but the decrease was not observed because the time frame of the experiment was not long enough. Overall ARC-based NPY and AgRP also seem tied to saturated fat content largely stemming from the increases in leptin concentration derived from saturated fat instead of just total fat content.

Another issue regarding leptin resistance involves how it influences overall appetite. For the purpose of this discussion take two individuals one who is not obese and one who is obese. The overall influence of leptin resistance can be viewed in two ways. First, when an individual moves from not obese to obese leptin loses effectiveness, but not in a negative fashion; the overall leptin effect is higher than that seen in the non-obese individual, but the leptin influence ratio decreases. For example a non-obese individual with 100 ug of leptin would eat 900 calories instead of 1000 calories whereas an obese individual with 200 ug of leptin would eat 850 calories instead of 1000 calories. Second, when an individual moves from not obese to obese leptin effectiveness becomes negative both overall and as a ratio. In this scenario an individual with 200 ug of leptin would eat 930 calories. The second scenario seems supported by conclusions that food intake is increased in obese individuals ranging from 14 to 17%58 as well as decreased STAT3 phosphorylation and other LRb signaling.10 Thus if this result accurately depicts the second scenario leptin resistance must be fairly significant, creating a positive feedback loop expanding the probability that an individual remains obese.

One question from this second scenario is that even while food intake increases in obese individuals, in the short-term NPY and AgRP mRNA (and protein) levels drop.58 There does not appear to be any significant information pertaining to whether or not these mRNA levels rebound in the presence of long-term leptin resistance. If the NPY/AgRP values do rebound then it would be significant evidence that leptin was the defining element connecting NPY/AgRP and saturated fat. If not, then there most likely needs to be a secondary element which links NPY/AgRP decrease and saturated fat apart from leptin. If this is the case the most promising element for this secondary linkage is STAT3 and its TLR4 saturated fat link.

Recent information has determined that leptin may not only regulate appetite, but may also interact with dopamine neurons stimulating the reward pathway in the brain.59-62 Leptin is now thought to act in consort with the mesolimbic dopamine system which is made up of dopamine releasing neurons in the ventral tegmental area (VTA) which innervate into the striatum, amygdala and prefrontal cortex.59 In addition to some neurons expressing LRb in the VTA, other studies have identified LRb expressing neurons in the lateral hypothalamic area (LHA) which project to the VTA.10 Therefore, it appears that there are two separate leptin based systems which could influence the dopamine based reward pathway in some context. This effect would especially be prominent if leptin limited the pleasure received from consuming food because then the development of leptin resistance would neutralize this limiting characteristic increasing the probability of greater food consumption in obese individuals.

With regards to leptin resistance and its overall influence on obesity it may have an important partner in amylin. Amylin is a 37 amino acid peptide hormone commonly co-secreted with insulin from pancreatic b-cells,64 which principally binds to receptors in the hindbrain area postrema (AP).65,66 The importance of amylin relative to leptin and obesity is a number of experiments have demonstrated that increasing concentrations of amylin in both non-obese and obese individuals induces weight loss with an increased reduction when combined with leptin.66,67 One lingering question is whether or not this weight loss can be principally attributed to amylin directly or if amylin reduces leptin resistance allowing leptin to be more effective.

One piece of evidence which supports the latter explanation and ties to the issue of leptin resistance is that amylin-augmented weight loss in DIO rats was observed with an increase in POMC expression in the ARC.68,69 This increase in POMC expression implies that weight loss seen in obese individuals due to increased levels of amylin would eventually be realized as reduced food intake due to aMSH binding, an increase probably stemming from leptin derived POMC increases.

While leptin activity in the ARC is important it appears, not surprisingly, that it not the exclusive operating area for leptin influence with regards to appetite control. Selective lesioning of leptin receptors on ARC POMC neurons does not completely replicate the development of obesity which accompanies general leptin deficiency (from knockouts).48 Also leptin resistance demonstrates a decrease in STAT3 signaling throughout the VMH and AP which support the notion of leptin resistance beyond the ARC.70,71 Therefore, the mechanism behind amylin induced reduction of leptin resistance could stem from amylin increasing signal effectiveness in the VMH and AP.66

Action in the VMH is supported by an approximate 43% increase in leptin signaling (derived from STAT3 comparisons) in the VMH without any direct increase in the ARC.66,72 An increase in STAT3 concentration coincides with other studies.67 The important targets for leptin in the VMH appear to be glucose-sensitive neurons and transcription factor SF-1.73-76 Transcription factor SF-1 could be important because it induces DIO in mice that lack it.77 One reason explaining this result is that co-localization studies identify SF-1 VMH neurons linked to leptin-induced activation of STAT3.66

No changes in leptin response were seen in the caudal nucleus of the solitary tract (NTS) with direct amylin treatment.66 Nor did amylin influence leptin, LRb or SOCS-3 concentrations via gene expression changes.66 Once again the lack of amylin influence on leptin, LRb, SOCS-3 could be a timecourse issue due to measurements not being long enough or taken at the appropriate time, but overall this is unlikely. Moreover it is unlikely that the AP is a site of cooperative action between leptin and amylin due to the low level of overall expression of leptin receptors and low leptin-derived STAT3 expression.66,78 Also amylin receptors are limited in the ARC and amylin administration does not activate c-Fos in the hypothalamus.79,80 Finally amylin functions through calcitonin receptor binding using receptor activity-modulating protein (RAMP) via a second messenger cGMP81,82 not through Jak kinases lke leptin. Therefore, if the principle area of action for amylin is the AP its action must propogate from the AP to an area more conducive for leptin action like the VMH.

Based on all of the results amylin influence seems to be localized to its respective receptors in the AP and through neuronal connections (probably polysynaptic) act upstream on the VMH enhancing leptin response through the NTS and the lateral parabrachial nucleus (lPBN).66,79,84,85 This conclusion is supported by amylin binding in the AP activating the NTS, IPBN and central nucleus in the amygdala to inhibit fasting derived activation of the lateral hypothalamic (LH) area65 where LH afferents are thought to influence VMH signaling.86,87 Also lesions on the lPBN blocked amylin-induced c-Fos expression.83 There is also some evidence to suggest that leptin binding is also increased in the DMN.66 In addition leptin may have a feedback effect on amylin in that amylin effectiveness is reduced in LRb knockouts.88

So how does amylin binding aid leptin? Amylin knockout mice exhibited overall reduced leptin signaling in response to exogenous leptin, largely patterned with a reduced residence time of action.66 This reduction in operational time (initially the leptin was able to function and later become less effective) is thought to involve a reduction in LRb expression.66 A smaller amount of LRb would result in faster desensitization of available receptors and loss of leptin activity.

The reverse of this thought process makes sense to why amylin may ‘rescue’ leptin action in obese individuals. Recall that STAT3 expression does not appear significantly reduced in non-ARC areas of leptin action like the VMH (this is probably the reason that most obese individuals do not incessantly eat). Increased amylin concentrations could increase the amount of LRb expression creating more leptin binding targets. More leptin binding targets would reduce the overall binding time a given LRb had with leptin generating more ‘deactivation’ time which could reduce the rate of desensitization. This theory is further supported by other data demonstrating a 70% increase in ARC leptin binding with amylin/leptin sustained infusion.67 However, there is little information regarding how long-term the weight loss produced by amylin augmentation may be. Overall it is difficult to conclude that amylin by itself can result in enough weight loss to reduce leptin concentration enough to eliminate leptin resistance in combination with greater LRb expression.

Overall leptin and amylin appear to have cooperative effect in managing energy intake and expenditure in humans. While leptin appears to have a greater overall influence, especially in non-obese individuals due to a lack of resistance, both molecules are able to reduce weight in non-obese and obese individuals individually, but their effects are significantly augmented when both are present. Like leptin, amlyin is also thought to increase energy expenditure.69,89,90 The nature of leptin resistance and the general decrease in weight in response to increased amylin levels due to injection or other means of administration leads to two conclusions. First, it seems reasonable to suggest that amylin concentrations in obese individuals could also be negatively affected either in a manner of overall availability or its overall effectiveness (similar to leptin). Second, amylin as an outside therapeutic target (endogenous administration) does not appear to have the necessary influence for use as a stand-alone treatment for obesity because while weight is lost, the overall obesity does not appear reversed.

Ghrelin is another element which may play a meaningful role in energy regulation affecting the probability of becoming obese. The principle role of ghrelin is to stimulate growth hormone release91-93 it is also thought to play a role in regulation of body weight.94,95 Its role in regulation comes from the response of increasing ghrelin concentrations stimulating appetite with a corresponding decrease in levels after eating, more than likely induced by insulin and leptin.96-99 Ghrelin exerts its effect by binding to NPY/AgRP neurons. The reason behind this appetite stimulation aspect of ghrelin could stem from its relationship with growth hormones as more available energy is typically advantageous to augmenting the effectiveness of growth hormones.

A vast majority of synthesized ghrelin is produced in the stomach so to act in the brain it needs to cross the blood brain barrier, similar to leptin. Studies have shown that due to the non-saturated, saturated transport structure used by ghrelin normal individuals typically have an inverse relationship between weight and ghrelin transport.100 Unlike what is believed for leptin, not surprising given the general opposition of their roles, triglycerides promote ghrelin transport across the blood brain barrier rather than inhibit.100 The ghrelin promotion effect makes sense if one believes that triglycerides are a signal to the brain for starvation.101 However, the loss of transport in obese mice is not accounted for by triglycerides leading others to conclude that there must be a second secreted molecule which drives this transport inefficiency. One possibility may be obestatin.

From a synthesis standpoint leptin inhibition of ghrelin seems to make sense both in the opposing effects on appetite as well as obese individuals having lower baseline concentrations of ghrelin than non-obese individuals.102,103 However, the interesting element to this lower baseline is that it does not appear to be uniform (steady-state). Instead the relationship between ghrelin concentrations in obese and non-obese individuals differed based on time of day with daylight levels being somewhat similar with obese individuals having much lower concentrations at night.94

Currently the reason behind the significant change in ghrelin concentration at night is unknown, but a consequence of this change may relate to obesity from a standpoint of energy expenditure more than energy intake. Despite significant increases in ghrelin concentration during the night in healthy individuals, there is little food consumption or need for food consumption to correspond to this increase; therefore, these concentration increases probably have more to do with growth hormone regulation than energy intake. Growth hormone activation typically results in greater energy expenditure. However, in obese individuals if nocturnal ghrelin concentrations are not increasing then there is less growth hormone activity which can result in stunted growth, less efficient cell repair and less overall energy consumption. Thus this change in ghrelin concentration could be another positive feedback associated with obesity in that the more obese an individual is the less energy he/she expends during the night through the use of growth hormones, thus increasing the probability of maintaining that obesity.

One final issue is that there is some question whether or not leptin transport across the blood-brain barrier is obstructed in obese individuals compared to non-obese individuals. If leptin transport activity is negatively influenced it could offer an alternative explanation to why greater concentrations of leptin may induce less leptin activity. Unfortunately there are two immediate problems with this theory. First, the methodology explaining how obesity negatively influences leptin transport is unknown and little viable explanations exist to why obesity would negatively affect transport. The best explanation could be that triglycerides, which typically increase in concentration as an individual becomes more obese, reduce leptin transport, but the demanded volume of reduction seems too high from an intuitive standpoint. Second, decreases in leptin transport are counter to the demonstrated increases in SOCS-3 concentrations in DIO mice. Therefore, even if leptin transport across the blood-brain barrier is reduced in obese individuals, which is still questionable,71,104-106 it is difficult to suggest that this reduction is significant enough to act as a meaningful explanation for ‘leptin resistance’.

Overall the process of moving from a non-obese individual to an obese individual from an energy balance perspective appears to lean heavily on hormone leptin. Leptin functions not only to influence appetite, but also reward pathways inducing a secondary biochemical means to affect food consumption and a possible interaction with saturated fat which may change leptin secretion patterns. The biggest energy balance element driving maintenance of obesity is the development of leptin resistance which probably follows a desensitization pathway with leptin saturation relative to LRb in the ARC. In addition to leptin, amylin and ghrelin also play important roles in appetite regulation and energy expenditure.

At the moment there does not appear to be a ‘silver’ bullet treatment for obesity on a biochemical level. However, there are opportunities for co-therapies to be successful. For example as previously mentioned it does not appear that increasing amylin concentration will be sufficient to overcome leptin resistance in obese individuals; however, co-therapy using an amylin mimic and an aMSH agnoist could work together to overcome a significant potion of the leptin resistance. Further study of obestatin could lead to a better understanding of its role, if any, in ghrelin function and whether or not it would be useful in treatment. Another option may be cholecystokinin which has shown to indirectly increase STAT3 concentration in low-dose leptin environments.107 Finally there is the lingering option of addressing SOCS-3 concentration changes through inhibition. Therefore, while addressing obesity appears to be a difficult mountain to climb, by better understanding the biochemical realities and changes between obese individuals and non-obese individuals both new drug therapies and food consumption strategies can be developed to combat obesity in a safe, cost-effective and appropriate manner.

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Looking at the Nature of Cancer and How to Treat it

2011-08-08T07:06:00.000-07:00

In the 1971 State of the Union address President Richard Nixon ‘declared’ war on cancer.1 Sadly despite a painstaking effort by many intelligent researchers, the war continues to drag on with no clear end in sight. Throughout the last forty years new strategies and new technologies have broadened the ability to attack cancer, but despite these advances, from a standpoint of long-term survival rates positive change has fallen to the old adage ‘walk a mile just to move an inch’. However, the advent of genetic engineering and nanotechnology has once again stimulated excitement in the cancer community driving the belief that genetic engineering eliminates the anonymity of a particular cancer and nanotechnology allows for more efficient combat. This excitement must be tempered with rationality and caution though for while new cancer-fighting strategies have flooded the research environment the methodologies which make up these strategies have yet to be fully assessed.

Scientific involvement in cancer can be divided among three different avenues: prevention, detection/diagnosis and treatment. For most of modern medicine the focus has be on that third avenue, treatment of cancer. Unfortunately most of the time in the past cancer treatment began at a much later time than desired because of limited diagnostic methodologies. As technology has advanced, there is hope for the development of better diagnostic strategies which will not only detect cancer earlier in its development, but also identify the type of cancer, information that can be used to better predict cancer prognosis and its development. With this additional information better treatments can then be applied significantly increasing survival rates.

However, the first prong of cancer, prevention, still remains slow developing because of a lack of genuine understanding regarding the origin(s) of cancer. While some claim eating food x or taking drug y should potentially reduce the probability of cancer occurrence, there is little to no scientific statistical evidence that have validated any of these claims. Some believe that certain anti-cancer drugs can be taken in a preventative manner, but these drugs also carry significantly detrimental side effects which reduces their attractiveness largely due to the low absolute percentage drops in cancer development in their application (chance of developing cancer type x goes from 1.3% to 0.9%). Based on this uncertainty this blog post will largely explore the strategies that are currently being used to combat cancer both from a standpoint of treatment and diagnosis and those that some hope to utilize in the future.

There are a number of individuals who would argue that diagnosis is the most important element in cancer treatment because very few individuals die from single organ/primary cancer, a notable exception being pancreatic cancer. Instead mortality much more frequently comes after metastasis. Another way to look at the diagnosis philosophy is that even an inefficient cancer treatment can manage cancer localized to a small region of the body, but even the most effective existing cancer treatments have a difficult time eliminating metastasized cancer. As previously mentioned this reasoning underscores one of the principle reasons cancer survival rates have increased at such a low rate over the last decades, earlier diagnosis of cancer has been methodologically difficult.

One major reason for this difficulty is due to the exhausting, side effect riddled and potentially toxic nature of cancer treatment. Due to the expense and strain required when treating a cancer case, physicians favor definitive diagnosis to confirm cancer which involves histologic examination of a specimen derived from a potential developing tumor. This entire process is commonly referred to as a biopsy. Due to the invasive nature of biopsies, physicians need some form of probable cause before considering one, probable cause which is typically acquired through some form of symptomatic, radiographic or visual abnormality. Unfortunately recognition of any of these abnormalities is rare in the very early stages of cancer development and by the time they emerge the probability for metastasis has significantly increased. Early diagnosis would be limited in importance if a very specific (no side-effects) and inexpensive cancer treatment were developed because then probable cancer cases that turned out to be false would not be detrimentally served by treatment, but such a treatment is not realistically viable at this point in time.

Currently biopsy is the only genuinely accurate means to determine whether or not an individual has cancer. The usefulness of some diagnostic techniques like mammograms have lingering questions over their statistical accuracy and whether or not they are useful to administer in the first place whereas other like Pap smears have demonstrated more reliability.2,3,4 However, biopsies have also come into question, not for their accuracy, but for whether or not they can inadvertently aid in metastasis.

The process of a biopsy involves inserting a needle into a cluster of cells thought to be cancerous and drawing off some of those cells. Through this process some have raised concerns that the penetration of the needle into the cluster of cells may dislodge some of these cells allowing them to be caught up in the bloodstream and carried to other parts of the body creating secondary cancers, in short accelerating metastasis. Some empirical evidence5 does exist to support this hypothesis, but fortunately new sterilization instruments have been developed within the injecting needle to minimize concern; unfortunately these new instrument have yet to be put into widespread use.

While biopsies are accurate one of the big goals in the cancer community is to develop a technique that rivals in accuracy, but is also much less invasive. Among the new diagnostic strategies being developed to avoid the invasiveness of a biopsy, cancer identifying biomarker are clearly gaining the most attention. Note that in biology the term ‘biomarker’ is used to describe two different types of elements.

First, biomarkers can be chemical molecules that are attached to other components in the body to identify them. For example various forms of fluorescent molecules, like luciferase, are commonly used to track the travel and/or presence of molecules in the bloodstream or observe some other biological function. Second, biomarkers can be DNA, RNA or protein that belies an abnormality within the body typically indicating some form of disease or deleterious condition.6 Basically biomarkers are biological characteristics, typically associated with DNA, RNA or protein expression, which are used to develop probability profiles regarding disease acquisition or probability of successful treatment with a given therapy.

The second definition for biomarker can be broken down further into diagnostic biomarkers and prognostic biomarkers where prognostic describes a biomarker that when present either increases or decreases the probability of a given condition over a given baseline average probability. A diagnostic biomarker confirms the existence of a given condition. In cancer treatment while significant publicity and research has gone into developing prognostic biomarkers, having gene x over gene y means greater chance for lung cancer, etc. the ‘black box’ nature of cancer negatively impacts the overall importance of those prognostic biomarkers.

The general idea with prognostic biomarkers in cancer should be to create two tiers of individuals: those without higher probabilities for cancer who continue to undertake standard screenings and those with certain prognostic biomarkers who undertake more specific and focused cancer screening in order to detect any higher probability cancers at an earlier stage in their development.

Diagnostic biomarkers have made significant gains in importance and viability over the last decade under the guidance of an improved understanding of genetics and the dream of personalized medical treatments. In order to replace biopsies, diagnostic biomarkers must be less invasive, preferably non-invasive, and accurate. The ideal for a diagnostic biomarker is an easily identifiable element which changes dramatically in concentration during the development of cancer vs. non-cancer and can be extracted through the examination of a blood, urine or saliva sample. In addition uniformity in the analysis is also necessary; it should not matter if the analysis is performed at laboratory A or laboratory B. Although speed of analysis is also viewed as important by some it is significantly less important than accuracy and invasiveness because the probabilistic mortality rate for cancer does not typically change significantly on a day-by-day basis so it should make little difference if the analysis takes 1 minute, 1 hour or 1 day to complete once an accurate biomarker has been established.

Biomarker developmental intent can take one of two paths: general or genetically specific. General uses viruses which only invade cells overexpressing a certain antigen or receptor, usually attributable to some form of cancer. The major advantage for the general method is an easier means to identify cancer, while the major disadvantage is it is unable to determine the location or the type of cancer. Not surprisingly these strengths/weaknesses are basically reversed for more genetically specific methods where one can better identify the type and possibly even the specific mutation of cancer. However, due to a wide variety of cancers among the same general diagnostic category (for example there are 15-16 different types of breast cancer, which are typically simply referred to as breast cancer in lay speak)1 there is a chance to miss cancers with small mutational differences. Due to the importance of biomarkers in the future of cancer treatment a wide variety of techniques are being explored with some promising ones highlighted below.

One of the challenges of creating personalized cancer treatments is that genetically specific biomarkers first have to be individually synthesized from each patient because of a lack of personal genetic information from that patient. Fortunately almost all cancer cells experience both DNA repair mechanisms breakdown and a widespread rearrangement of chromosomes due to chromosomal instability.7,8 In addition this near certainty of genetic disruption appears to occur near the earliest stages of tumor formation (tumorigenesis) and is thought to persist throughout tumor development.7 Therefore, cancer cells develop a form of uniqueness apart from the original cells they mutated from, yet maintain a form of homogeneity in their development between different patients. Through this pathway different cancers would develop different rearrangements which could be used to not only differentiate between cancerous cells and normal cells, but between different types of cancer.

In effort to take advantage of this form of cancer development some researchers have turned to high-throughput screening to identify these genetic changes and create biomarkers which could identify those changes.7 One technique to create these biomarkers is to use recurrent somatic structural (usually single-base) alterations, especially for hematopoietic (blood) malignancies9-12, but these structural alterations do not persists in most solid tumors limiting the techniques usefulness for total detection. Also analysis of somatic single-base alterations have polymerase error rates derived from the specific bases of interest, which can produce false positives.7

The use of Personalized Analysis of Rearranged Ends (PARE) has demonstrated that specific identified breakpoints can detect tumor DNA at very small sensitivities (small amount of tumor DNA among large quantities of non-tumor DNA) within the blood or plasma.7 One of the reasons PARE works is that like all cells tumors secrete parts of their DNA into the bloodstream, a sample of blood can then be taken and these DNA pieces amplified through polymerase chain reaction (PCR) and later matched to previously developed biomarkers. Using PARE is thought to result in almost zero chance for false positives because the diversity of the combinations that are amplified through PCR should not appear in non-tumor cells.7 This process is more accurate than examining somatic single-base alterations because of the aforementioned false positives drawn from some instances when cancer cells have similar somatic single-base alterations which mimic normal non-cancerous cells.

Unfortunately PARE analysis is still in early stages of development and significant questions still remain. The biggest question for PARE as well as all somatic single-base alteration techniques is whether or not these somatic DNA alterations persist throughout tumor development. There are two possible design methods to address this problem: first, identify a large number of PARE biomarkers for a particular type of tumor and test for all of them using the reasoning that not all of those biomarkers would be lost over progressive tumor development. Second, identify the various PARE biomarkers that exist throughout the lifecycle of a tumor tracking when certain biomarkers appear and disappear in relation to the stage of development. One useful feature with regards to the second method is that if researchers are lucky unique PARE biomarkers will exist for specific time designations in tumor development so not only could PARE biomarkers be used to identify whether or not a patient has cancer, but also its stage of development, which could demand a specific treatment regimen.

Other problems revolve around the costs associated with developing these PARE biomarker libraries. The initial sample studies which were used to generate a proof-of-concept for PARE biomarker viability utilized 12 tumor variations (6 colorectal and 6 breast) where each required an average of 194.7 million reads per patient creating an assay cost of approximately $5,000, which is very high for clinical repetitive use.7 Fortunately because the initial proof-of-concept study utilized a new technique that has not been fully brought to scale proponents believe that significant opportunities exist for cost reduction both in general sequencing demands as well as PARE specifics like less stringent mapping criteria and lower physical coverage.

The final major problem that exists in the development and use of PARE biomarker analysis is although PARE should not produce false positives a non-zero probability exists for the generation of false negatives.7 At this point PARE requires at least one rearrangement template molecule to be in the analyzed plasma sample to develop a positive result. In the very early stages of cancer development these required templates may not be available for a given sample. While not a crippling concern in the methodology, if correct it does limit the overall diagnostic potential of PARE, especially because the gap is on the front end not the back end of the cancer lifecycle.

The majority of new cancer detection techniques focus on general detection through blood sampling, but others have been developing techniques for regional detection of specific cancers. A possible advantage to these more regional strategies, despite their cancer type detection limitations, is the potential to demonstrate broad biomarker association with certain cancers creating another base point for potential treatments. One of the more promising detection methodologies involves examining saliva for specific biomarkers.

Not surprisingly the focus when testing saliva for cancer is to detect oral squamous cell carcinoma (OSCC) and other similar type cancers. While biopsies generate worthwhile results, a more specific method appears to be on the horizon. Tapping into the same type broad strategy that is used in PARE biomarker development, saliva contains a multitude of mRNA where non-cancerous mRNA and cancerous mRNA have different sequence structures.13 The origins of these mRNA samples tend to be the three major saliva glands, gingival crevice fluid and desquamated oral epithelial cells.14

In addition to mRNA, saliva also contains microRNA (miRNA) which more accurately cluster in various forms of solid tumors than mRNA creating a better opportunity for detection, thus increasing testing accuracy over mRNA in detecting cancer.15 miRNA are created through transcription by RNA polymerase II or III because they initially represent a portion of an intron of mRNA and typically act as post-transcriptional regulators.14,16 However, for miRNA to be a useful biomarker for cancer detection a significant difference in the concentration of at least one miRNA between cancer and non-cancerous states must be identified where it is attributable to the cancer itself.

A possible marker to reflect the difference between miRNA in those with OSCC and those without OSCC has been isolated to two specific forms of miRNA. In both whole and supernatant saliva two salivary miRNAs, miR-200a and miR-125a, had different concentrations relative to whether the patient suffered from OSCC or not.13 Interestingly the concentrations of these two miRNAs were lower in the OSCC patients than the non-OSCC patients.13 In most situations biomarkers are selected based on their increased concentrations for deleterious conditions not decreased due to easier detection parameters (larger concentrations over smaller concentrations). There is also evidence to support miR-200a playing a role in other head and neck cancers, so this method could be expanded from OSCC patients to other cancers.17-19 While at the moment the use of miRNA diagnostics have focused on head, neck and oral cancers, it stands to reason that expansion of this technique may provide a means to general cancer diagnosis for other types of cancers as well if more miRNA associations can be identified. Signs do look promising in this avenue of detection.

The two previous techniques, PACE and miRNA concentration changes, focused on using inherent biological elements associated with the tumor and its lifecycle as biomarkers. The advantage to this system is specificity and a general level of certainty. However, there are no guarantees regarding the successful creation of a PARE library, which even if successful is still years away. Also there is no further information regarding the probability that other cancers demonstrate miRNA concentration shifts and if they do determining what type of shift will be difficult. Therefore, other researchers have sought a more general method of detecting cancer by foregoing identifying a specific type in lieu of simply identifying any type.

The application of exogenously distributed biomarkers requires a delivery mechanism that has acute specificity towards tumors over non-tumors. There are typically four practiced techniques used to achieve this goal: ligand-guided active targeting20-22, passive Enhanced Permeability and Retention (EPR)23,24, tumor microenvironment-dependent targeting25, 26 and viral injection.27 Regarding the fourth element, viruses are sometimes referred to as ‘nature’s nanoparticles’ and due to their behavior and target functionality, that are useful for delivering genetic information to target cells. Not only are viruses effective targeting devices, but their inherent replication abilities upon reaching their targets also add a form of positive autonomy with regards to molecular expression.

Taking advantage of these elements one of the chief and more versatile tools in battling cancer is the oncolytic virus. Oncolytic viruses are viruses which are typically engineered to have dramatically higher infection rates for cancer cells over non-cancer cells. In fact the fewer non-cancer cells a particular oncolytic virus infects the better. This infection disparity is developed one of two ways: first transductional targeting which involves changing the docking antigens on the viral coat to respond to a protein that is expressed at a much higher rate in cancer cells vs. non-cancer cells.28 Second, non-transductional targeting which involves genetically engineering the virus so that it only replicates in response to cues that are limited in non-cancerous cells, but are of a higher frequency in cancer cells.28 Specific tumor-only promoters are usually the cue utilized in these types of oncolytic virus. Attenuation is also used where specific genetic deletions are applied to the viral DNA, which then progressively neutralize cancer-required proteins.

There are natural oncolytic viruses28, but engineering viruses is viewed as a more effective way to address the wide demand for oncolytic viral use due to the diversity of cancer cells. Among the types of viruses that are converted into oncolytic viruses adenoviruses and herpes simplex virus (HSV) are the most effective due to their double-stranded DNA providing greater storage stability (reducing mutation probability), consistence tolerance of high production titres, transduce both dividing and quiescent cells efficiently, express transgene products and are scalable.27

One of the chief uses of oncolytic viruses is in the associated production of an artificial biomarker for general detection of cancer. The general method of oncolytic viruses involves an association with a detection element, normally some form of fluorescent marker. The general idea is that because the vast percentage of cells infected by the oncolytic virus will be cancerous, after cell lysis due to infection or induced secretion the concentration of fluorescent marker in the blood stream should increase significantly generating a high probability that the individual has some form of cancer. Also there is the potential that the overall differences in concentration could provide a basic means to track the progression of cancer development.

One of the more promising general detection techniques involves the use of HSV with a controlled mutation of the ICP6/UL39 and late viral protein ICP34.5 to limit viral replication and amplify dependence on late gene expression.27 Upon entering a cancer cell the modified HSV virus induces the cancer cell to secrete a specific biomarker, which would then be measured from the bloodstream to determine a basic pattern of cancer progression. One group of researchers who tested this concept selected gaussia luciferase (GLuc) as a high quality biomarker for use in this particular experiment because of ease of secretion, extent of lumination (1000 times brighter than other luciferases), detectable in both blood and urine in vivo and greater sensitivity than other popular biomarkers like alkaline phosphatase.29,30

The use of GLuc as a biomarker was explored using various tumor locations such as: intra-peritoneal, subcutaneous, intra-muscular and orthotropic intra-renal tumors.27 Regardless of tumor location, GLuc results were consistent with more than 90% of the tumor mice presenting higher concentrations of GLuc than non-tumor mice.27 One concern from these experiments was whether or not smaller tumors would produce the necessary vascular surface area required for HSV to infect the tumor. A lack of sufficient HSV infection would reduce the sensitivity of the overall test. While a relevant concern, it is not surprising as the most common concern with cancer diagnostic techniques is the question of what is the minimum detection limit for the given technique.

A more important concern involves the immune response limiting the overall effectiveness of the biomarker because since approximately 80% of the population has been exposed to HSV at one point in their lifetimes there will be a significant immune response.27 The problem from the immune response is that the baseline for no cancer is no significant concentrations of biomarker in the bloodstream because HSV is only infecting a small amount of cells due to the lack of cancer cells to drive infection. An immune response can reduce the number of HSV in the bloodstream after injection, which will in turn reduce the total ceiling for biomarker secretion making it more difficult to determine whether or not the patient has cancer with appropriate confidence. This problem underscores another important requirement for such a technique, the establishment of a ratio or scale to judge tumor progression relative to biomarker concentration. Clearly such a ratio would develop small differences between patients, but a general range scale could be developed as a universal measure for broad cancer progression designation.

Another concern regarding potential immune response is elevated levels of macrophages having a detrimental effect on tumor prognosis due to recruitment of these new macrophages into the tumor microenvironment, which benefits the tumor. One possible strategy to reduce problems with the immune system would be treating the patient with immunosuppressant drugs during the treatment protocol before infection with HSV and for a short time afterwards. Some may argue that the use of immunosuppressant drugs create a problem as studies have shown that extended use of immunosuppressant drugs increase the probability of developing cancer.

Such a concern does not appear applicable in such a scenario for two reasons. First, the application of any immunosuppressant drugs would only be over a very short time frame almost eliminating any legitimate increase in probability for new cancer development. Second, the methodology of cancer development may moot this point. Not surprisingly the immune system appears to be best at neutralizing tumors in their beginning stages and significantly lose effectiveness more than likely due to the formation of the tumor microenvironment as the tumor develops. Therefore, unless the oncolytic virus detection procedure is undertaken during the very initial stages of cancer development any risk associated with the application of immunosuppressant drugs should be minimal.

In a similar vein to the idea of using oncolytic viruses to release a fluorescent molecule into the bloodstream to identify cancer, some researchers want to use oncolytic viruses to deliver fluorescent molecules that instead of amplifying in cancer cells bind to exclusive cancer cell receptors to identify specific locations of tumors. The preferred protein comes from the crystal jelly and the viruses utilized operate similar to other oncolytic viruses except these viruses do not actually lyses the cancer cells.31 Instead their amplification leads to the further amplification of these crystal jelly attached proteins which then fluoresce the cancer cells creating a visual differentiational characteristic from non-cancer cells. Developing this technique is thought to not only better determine whether or not an individual has cancer, but in the future may even assist in a more accurate surgical removal of smaller tumors that could escape detection through sight alone.

Unfortunately there are two significant problems in developing this technique. The first problem is that very few colors can penetrate tissue due to frequency mismatch. Early testing identified that low frequency red is the most successful lumination color, but is still somewhat weak.31 The second problem is overall cost. Even with successful fluorescence, accurate assessment of the fluorescence currently requires a special camera which scans the body slice by slice and typically cost $750,000 dollars.31 The concern with this problem is that there is little potential due to physical tissue barriers of developing a stronger fluorescence which will not require this type of expensive camera. Thus, the chief hope for proponents is that direct costs associated with the camera will drop during the development of the technique. While this technique may not pan out to be successful it represents an important characteristic in cancer diagnostics and treatment: focusing on a wide variety of detection methodologies using logical theory in order to determine what works and what doesn’t to develop the best approaches.

In addition to new biomarkers, an older piece of technology has been augmented to aid in the diagnosis of cancer, especially with regards to metastasis. Normally when a patient is diagnosed with cancer he/she undergoes a sentinel lymph node biopsy to determine if the cancer has metastasized. In the body a clear fluid called lymph, which is part of the interstitial fluid, moves through lymph vessels eventually leading to a lymph node.32 From a technical standpoint the interstitial fluid becomes lymph after entering the lymph capillary and mixes back into the blood after exiting through the left or right subclavian vein.32 Lymph nodes are small round organs which filter out harmful substances from the lymph like bacteria. The most common lymph nodes are found in the neck, underarms, chest, abdomen and groin. The sentinel lymph node is viewed as: the first lymph node which become cancerous after taking in cancer cells which originated from the principle tumor (the reason for this definition is because in some cases by the time the biopsy is carried out multiple lymph nodes could be cancerous).33

The biopsy involves removing the lymph node closest to the identified principle tumor using the logical reasoning that most metastasized cancer will spread in an orderly and organized manner as the blood moves away from the tumor infecting nodes closer to the principle tumor rather than randomizing infections. Traditionally the lymph node is identified by injecting a specialized radioactive dye (usually filtered sulfur colloid tagged with Technetium-99m) near the principle tumor.33 After allowing for sufficient time for migration, the dye is tracked through a scanner to determine if any lymph nodes are stained with the dye. If significant amounts of dye are in a lymph node and respond to a certain gamma probe range then that node is excised and examined further under a microscope looking for cancer appropriate histological features. If the cancer has metastasized then a number of patients (some estimate up to 35%) have to undergo additional biopsies to confirm and to further evaluate how far the cancer has metastasized.34

Depending on the number of lymph nodes removed side effects for the procedure will vary.33 For instance if only a small number of nodes are removed then the most common side effects are associated simply with those of normal minor surgery (pain and/or bruising at the site of incision) and slight difficulty moving the affected body area. When more nodes are removed then the side effects increase to the potential for swelling due to excess fluid build-up (lymphedema), numbness, infection and a burning sensation. Most physicians believe that these side effects are justified for the advantage of having a better idea to how aggressive a treatment will be required for the patient based on the prevalence of the cancer spread. However, there is argument over whether the early removal of the SLN improves survival rates.33 SLN biopsies are most commonly used for breast cancer and malignant melanoma patients.

A new technique which appears to be more effective than SLN in both reducing side effects and accuracy in determining the SNL incorporates microbubbles into an ultrasound to aid detection.34,35 Initial experiments utilizing microbubbles as an additional enhancement agent in an ultrasound has accurately identified the sentinel lymph node in 89% of eighty breast cancer patients studied.34 For this process the microbubbles are small (1-4 micrometer diameter), constructed of a lipid or albumin shell, filled with a biologically inert gas (usually perfluoropropane) and typically behave like red blood cells from a hemodynamical perspective, thus they can be modeled and accounted for during the ultrasound in a predictable fashion.35

Microbubble augmented ultrasound has also been explored as a means to monitor changes in tumor vascular which could aid study of how anti-angiogenesis agents fail by tracking the changes in tumor vascular development.35,36 Some initial studies have in fact used this technique for such a purpose. One of the major advantages to this technique is that microbubbles can be selectively applied to specific regions through conjugation with certain ligands.35-37 The application of the angiogenesis mapping technique involves targeting microbubbles to specific vascular markers such as VEGFR1 or VEGFR2. Observing changes in the expression of these receptors is a viable means of tracking vascular changes due to expression patterns largely correlating with molecular demand and availability.

Unfortunately the promise of biomarkers have lead some to place more emphasis on their importance and accuracy vs. what they genuinely deserve. The perceived usefulness and power of the biomarker has spawned a form of bias where some researchers continue to believe that a given biomarker possesses a high association with a given condition even after large meta-analyses have demonstrated much less significance to that given biomarker.38,39 Basically researchers will still cite an initial analysis of a biomarker which has a stronger positive effect than a later more thorough analysis. For example researchers would cite a paper that calculated a 25 times greater association over a later paper calculating a 4 times greater association from a meta-analysis.38

This bias is not surprising, other studies have demonstrated a positive correlating bias towards other aspects of important/popular research, however, it can be quite detrimental to determining viable treatments. The continuing lack of definitive answers regarding the origins of cancer and its progression means that refusal to abandon once promising biomarkers could create more confusion and inaccuracy in the pursuit of both cancer diagnosis and treatments. The difficultly in giving up on what once appeared to be a significant step forward in understanding and/or treating cancer is understandable, but unless biomarkers are looked upon accurately, addressing cancer appropriately will be all the more difficult.

Diagnosis is only part of the battle against cancer. Streamlining treatment efficiency through exploration of different strategies is also an essential part to the future development of a cure. While lower costs and efficiency are useful features to treatment, the primary goal needs to focus on certainty of tumor death in a way that can be properly confirmed. Presently there are three mainstream treatments of cancer: chemotherapy, surgery and radiotherapy.

Among these three treatments surgery is still the preferred choice because of its overall success rate due to the direct elimination of cancer with associated visual conformation. Unfortunately surgery is not a universal treatment. The highest probability of success for surgery logically occurs in the median lifespan of a tumor when the tumor is large enough to identify and isolate from other healthy cells, but before the tumor metastasizes. After the tumor metastasizes surgery is no longer an attractive option because of its invasiveness and the general trauma it inflicts upon the body. If the tumor is too small surgery is more risky because it is difficult to confirm whether or not the entire tumor has been removed due to lack of tumor size. Fortunately chemotherapy is widely paired with surgery as a combination treatment strategy: eliminate a significant amount of the tumor via surgery and destroy the remaining weakened cancer cells via chemotherapy.

The term ‘chemotherapy’ now describes a methodology of cancer treatment that involves the use of anti-neoplastic drugs most commonly delivered intravenously. Development of the chemotherapy strategy evolved in the very early stages of the biochemical revolution before any specific biochemical markers and genetic information was uncovered about various cancers. Without the knowledge of nanotechnology or even very specific differentiating biochemical signals or proteins, cancer treatment demanded a much broader strategy. Anti-neoplastic drugs operate by interfering with mitosis; therefore they are most effective against cells which have a fast rate of mitosis, a common feature for most cancer cells. Using this anti-mitosis strategy chemotherapy techniques could attack cancer without having specific information on the location of the cancer (necessary for surgical strategies) or the specific type of cancer (necessary for individualized treatments).

However, there are other cells in the body that have a fast rate of mitosis as well, most notably associated with bone marrow (red and white blood cells), digestive tract (stomach) and hair follicles. Note that other healthy cells could be damaged by chemotherapy as well, but with a lower probability due to their slower rates of mitosis. Due to potential collateral cell damage the most common side effects from chemotherapy include myelosuppression leading to anemia and immunosuppressant, mucositis increasing ulcer probability and alopecia almost guaranteeing the most telltale sign of chemotherapy treatment, hair loss.

Despite decades of experimenting with chemotherapeutic applications resulting in an effective treatment methodology, chemotherapy still has problems. First, due to the collateral damage nature of chemotherapy once the cancer metastasizes the effectiveness of chemotherapy significantly drops not in its ability to kill tumors, but in its ability to kill tumors without killing the patient in the process because so much more of the drug is needed.

Second, tumor identification still functions principally on a visual scale which makes it difficult to know when to stop a chemotherapy regiment. Basically the tumor shrinks to a size where it is difficult to know whether or not the patient still has cancerous tissue, thus whether or not further chemotherapy treatments should be administered under threat of causing unnecessary healthy cell loss.

Third, biology does not typically remain static, thus cancers can, and have, evolve mechanisms of resistance against various chemotherapy drugs; therefore, chemotherapy regiments that seek to significantly increase patient lifespan apply numerous drugs to reduce the probability of tumor survival and associated development of resistance. However, the application of numerous drugs per treatment can significantly increase cost of treatment. Overall chemotherapy has actually been a very effective cancer treatment when treatment could actually make a difference, but it real effectiveness has been marred by the lack of quality logistics and diagnosis.

While first and second-generation chemotherapy treatments have proven somewhat effective at managing cancer because biology does not remain static and new chemotherapy strategies are being developed. One may ask the question of why new chemotherapy treatments are needed when nanotechnology and better understanding of genetics are available to develop more target-specific treatments? Chemotherapy treatments have been the most successful non-invasive therapies and although the promise of more target-specific treatments is worthwhile, over the last few decades these treatments have not amounted to any new breakthrough treatment which can rival the effectiveness of chemotherapy at the human level. Therefore, it is important to continue to focus on developing new chemotherapy treatments until new target-specific treatments are ready.

New application techniques have been applied in chemotherapy treatment such as isolated infusion or perfusion which modify rate of delivery and total amount of chemo agent delivered. Identification of appropriate dosage through either an infusion or perfusion methodology can limit the amount of site-nonspecific collateral damage as well as potentially penetrate more solid mature tumors at the site of application.

The third commonly used method of treatment is radiation therapy which involves the application of ionizing radiation in effort to damage the DNA of cancerous cells to the point where either the cell dies straightaway or triggers apoptosis. The DNA damage is caused by either photons or charged particles applied directly or indirectly. Direct action targets the cancer cells themselves whereas indirect action occurs through ionization of water leading to the formation of free radicals which precede to damage cells within the localized radius. Photons typically produce an indirect effect where charged particles are used directly.40 One chief advantage to using charged particles is that it frequently results in double-strand breaks over single-strand breaks.40 DNA repair mechanisms are designed to address single-stranded DNA damage, thus cannot effectively manage double-stranded breaks. However, because DNA repair mechanisms are typically compromised in cancer cells, single strand breaks are also significantly dangerous to cancer cells.

Most radiation therapy requires transition from an external source to the internal tumor, thus there is a high probability that the radiation will pass through healthy tissue. A common strategy used to reduce the damage potential to this ‘obstructing’ tissue is applying beams originating from multiple angles all with an endpoint focused on the tumor. Basically multiple beams are used at an individual radiation intensity which heavily limits permanent damage potential to the contacted healthy tissue, but with all of these beams meeting at a single point (the tumor) the collective radiation intensity can hopefully destroy the tumor. The lack of lateral side scatter from the charged particles also helps limit the healthy tissue collateral damage.40

While photons comprised the first major radiation therapy, they could be falling out of favor (proton proponents have high hopes for their revival) due to two chief problems. First, oxygen is a potent radiosensitizer, thus the higher the oxygen concentrations in the localized region the higher the generated free radical concentrations and the associated cancer damage probability. Unfortunately for photon radiation therapy most solid tumors create an inflammatory microenvironment that is generally hypoxic in nature. The reduction in available oxygen reduces potential free radical concentration reducing treatment effectiveness. Second, hypoxic states may be detrimental to normal cells and tissues, but cancer cells and tumors appear to be more resilient in such an environment, possibly even more dangerous. Thus as photon radiation therapy consumes oxygen to make free radicals it not only becomes less effective, but also may make the remaining cancer cells more deadly.

Unlike photons which have a set energy value, charged particles can more precisely target a tumor incorporating the Bragg peak effect as well as be charged to different peak amounts for optimal decay upon reach the tumor.40 For example as photons move through the tumor environment they pass through healthy tissue when exiting the body. The multiple to single to multiple beam design attempt to reduce damage, but does not entirely eliminate the probability, thus any additional damage when exiting is entirely collateral because the tumor has already been targeted. In the case of charged particles the particle charge can be designed so that the bulk of the charge is expended at the tumor and the exiting particle has no damage potential.

A newer radiation therapy, brachytherapy, involves using sealed radioactive sources that are implanted into the body at precise locations. Brachytherapy can provide a larger level of radiation over a much more controlled and localized area near the tumor eliminating any collateral damage away from the tumor site.41 However, one of the chief drawbacks to brachytherapy is the surgical requirement. Adding an additional invasive step to a cancer treatment is always troublesome. Some argue that surgery as well as brachytherapy can be combined into a single surgical event, but whether or not surgeries are combined is determined on a case-by-case basis and is typically not as successful as most hope.

Overall the usefulness of radiation therapy is defined by the radiosensitivity for a given cancer. Leukemias, lymphomas and germ cell tumors are the more sensitive to radiation followed by epithelial cancers whereas melanoma and most forms of renal cell cancer are radio-resistant.40 However, while leukemia is sensitive to radiation, their widespread dissemination through the body makes treatment more complicated. Therefore, radiation therapy is mostly useful on smaller tumors that have yet to metastasis.

The above three therapies have been useful in the past and continue to be useful in the present, but a better understanding of genetics and the advent of nanotechnology have opened the door for the development of new cancer treatments which are less broad-based than chemotherapy and more site and target-specific offering the hope of greater treatment probability with reduced side effects. The two major new categories of treatment evolving from these new understandings and technologies are agents that specifically target a particular protein and delivery mechanisms which specifically target cancer cells themselves.

In the first half of the 2000s, one of the most promising new ideas for cancer treatment was derived from the chemotherapy distinctive question of ‘what is a cancer cell doing at a greater rate than normal cells other than dividing?’ One clear answer was forming new blood vessels (angiogenesis) to catalyze and maintain rapid cell division and tumor development. When cancer cells are underdeveloped and simply beginning to form solid tumors those cells are supplied with nutrients through diffusion from adjacent blood vessels. However, the rapid uncontrolled cellular replication of cancer cells demands new blood vessels to ensure proper oxygenation. Angiogenesis is commonly viewed as a fundamental step between the evolution of cancer cells from a benign state to a malignant one.

The process of tumor associated angiogenesis proceeds in a series of controlled steps, similar to sprouting angiogenesis; first endothelial cells from pre-existing blood vessels are transported and accumulate nearby in order to form the base matrix for the formation of the new blood vessel. This step requires angiogenesis factors, most notably fibroblast growth factor (FGF-1) and vascular endothelial growth factor (VEGF), to stimulate the existing endothelial cells to produce proteases to break them from their pre-existing matrices allowing for migration towards the cancer cells.42-44 The next step involves the proliferation of the endothelial cells and the extension of the solid sprouts to connect the new vessels to the existing neighboring vessels. After the sprouts extend towards the source of the angiogenic stimulus (the cancer cells) the endothelial cells migrate using integrins.42,43 Finally the sprouts begin to loop becoming fully operational vessels.

Based on the above understanding of angiogenesis and the fact that tumor size typically ceilings at 1-2 mm with little chance for metastasis when only having access to diffused oxygen and nutrients (no new blood vessels), most anti-angiogenesis drugs were designed to repress vascular endothelial growth factor (VEGF) thereby reducing the number of blood vessels that would be developed to support tumor growth.42

The hope surrounding anti-angiogenesis was because angiogenesis and tumor growth were not directly cooperatively regulated elements (one did not directly influence the other) tumor growth would remain unchanged relative to the number of blood vessels until the tumor grew to a size that could not be supported due to a lack of nutrients, a direct results of fewer blood vessels, eventually leading to the death of a vast majority, if not all, of the cancer cells. There was and still is significant aplomb regarding anti-angiogenesis drugs because of the perceived universal nature in their ability to treat cancer regardless of type (in the initial stages of development all tumors need a number of blood vessels) and with limited collateral damage.

Unfortunately some studies have demonstrated that while the theory behind eliminating blood vessels leading to tumor death makes sense, the empirical results do not strongly support the theory. While knocking out VEGF does result in fewer blood vessels those vessels that form are better organized, for when VEGF is not disrupted, blood vessels are numerous, but ‘leaky and chaotic’.42,45-46 It has been hypothesized that this better organization could provide even more nutrients to a tumor, despite the fewer number of vessels, because typically VEGF knockouts resulted in the formation of larger tumors than non-VEGF knockouts.45

In the short-term this result seems to eliminate the usefulness of VEGF blocking anti-angiogenesis drugs, but there may be a silver lining in that while fewer numbers of blood vessels may allow for better nutrient transport, they would also allow for better chemotherapy agent transport as well increasing the probability of drug delivery and tumor death.42 Unfortunately this result has not been supported by empirical evidence provided by patient use of Avastin.45,46 One explanation for this lack of coordination may simply be resistance to the chemotherapeutic agent. In fact Avastin, the most noteworthy anti-angiogenesis drug, which received FDA approval in 2004 just recently had its short-term approval as a preventative treatment for breast cancer expire with no further extension by the FDA.

One question is why do VEGF knockouts create stronger (less leaky) more organized blood vessels. Two explanations come to mind. The more obvious explanation is just like with almost everything else cancer cells heavily overexpresses VEGF creating a signal pull on the endothelial cells in a large number of different and contrasting directions instead of having one or two uniform signals directing strong migration and amalgamation of endothelial cells which would create a strong more extensive blood vessel. Also VEGF plays a role in vessel permeability, thus an excessive concentration of VEGF could create a ‘leaky’ type vessel behavior. The second explanation is that the cancer cells express VEGF and maybe another unidentified signaling molecule and while this unidentified molecule is better able to induce vessel formation, VEGF is produced at greater concentration which masks the effect of this unidentified molecule; a masking that no longer exists when VEGF is blocked by knockout or certain drugs.

Another study has demonstrated that the use of anti-angiogenesis drugs also appears to increase the invasiveness of cancer cells and the associated probability of metastasis.47 This increased probability seems to occur due to an increase in hypoxia due to the fewer blood vessels relative to tumor size which results in the cancer cells synthesizing a greater amount of Met and hepatocyte growth factor (HGF).47 HGF could act as a molecular trigger which induces cell migration. Therefore, for any form of anti-angiogenesis strategy to work it appears that Met and/or HGF need to be inhibited as well.

Another strategy has been to target the endothelial cells which create the new blood vessels themselves. One reason this method is supported is because the endothelial cells that are recruited to form these new blood vessels are thought to be much more genetically stable than the associated cancer cells. However, other studies48 support a loss of genetic stability in endothelial cells which are recruited by cancer cells. Some argue that this lack of stability could allow cancer-derived vessels to develop a higher probability for drug resistance similar to cancer cells; however, the lack of stability may be more controlled than that of the original cancer cells directed by the cancer cells themselves (1 or 2 mutations vs. a cascade), thus eliminating any serious detrimental resistance potential. In fact if this assertion is accurate, the endothelial mutation may actually provide a new means to attack cancer which will not affect non-cancerous systems.

Other elements aside from VEGF have also been identified as potential therapeutic targets for cancer treatment. Similar to the aforementioned biomarkers explored for diagnostic purposes, manipulating the changes in concentration of various elements can be used as a means to control or even eliminate cancer expansion. One of the principle advantages of targeting VEGF for cancer treatment was that the role of VEGF was known and increases significantly with the progressive advancement of cancer. Unfortunately these two principles are lacking in a lot of the other promising targets for either there is a lack of certainty in function or a lack of identifiable exclusive regional change.

The lack of certainty in function is a problem because although concentrations of a given element may change significantly between cancer and non-cancer patients, but whether or not the element acts in some measure of positive/negative feedback or is simply a byproduct of tumor growth is unclear until specific information pertaining to the function of the element is determined. For example from above one useful biomarker for head, neck and throat is miRNA 200a. However, further research is needed before miRNA 200a can be thought of as a therapeutic target or just a byproduct from a form of transcription mismatch caused by a somatic mutation transforming a normal cell into the type of cancerous cell which typifies these types of cancers.

Lack of exclusive regional change is also a problem because if the element is determined to play a feedback role of sorts in the progression of cancer it would initially look like an appealing therapeutic target. However, if that element also plays a critical role in the normal cell growth and/or function then targeting that element will more than likely make cancer treatment difficult at best with lots of side effects and collateral healthy cell damage and pointless at worse as it ends up killing the patient due to too much healthy cell damage. A good empirical example for these two principles is the relationship between tumor development and tumor necrosis factor alpha (TNFa).

New York physician William Coley first deduced the existence of TNFa in 1890 after discovering a former cancer sufferer, Fred Stein, had his cancer ‘cured’ after a post-operative bacterial infection. After talking with the patient and much research Coley developed his ‘Coley’s mixed toxins’ therapy which seemed to have some success treating tumors.49 However, recreation of Coley’s successes were few and far between. In 1962 O’Malley used endotoxin-derived serum to initiate tumor necroses in mice drawing the conclusion that the serum contained some form of ‘tumor necrotizing factor’.50 The term ‘tumor necrosis factor’ was officially coined by Carswell later in 1975 by determining that the necrosis was caused by a factor made by the host cells in response to the endotoxin, not directly through the endotoxin itself.51 Even later it was determined that TNFa and a molecule previously known as lymphotoxin bound themselves to the same receptor and were part of the same genetic family. Lymphotoxin is now commonly known as TNF-beta.52

In the immediate aftermath after confirming the existence of TNFa it appeared that TNFa would be a powerful candidate in the treatment of cancer. Early on this belief was supported by evidence demonstrating high doses of human recombinant TNF inducing necrosis in both syngeneic and xenografted tumors.53,54 At lower doses in combination with melphalan or doxorubicin chemotherapy treatments, TNFa appeared to increase tumor blood vessel permeability and aided in the delivery of the chemotherapy drug in addition to destroying tumor vasculature.55,56

Unfortunately the belief in TNFa as a cancer treatment agent was short-lived. In 1984 Wallach determined that TNF is only weakly cytotoxic to malignant cells when used alone.65 Apoptosis activated with high probability only when inactivating certain downstream TNF signaling using a combination of metabolic inhibitors.52 Later investigators discovered TNF mRNA and TNF itself in malignant and stromal cells during biopsies along with a somewhat proportional relationship between higher concentrations of TNF and lower survival rates.52 The TNF-cancer relationship finished flipping in 1996 when Kollias developed the first TNF-knockout mouse and using this model in 1998 demonstrated that TNF-knockout mice developed fewer skin tumors when treated with a skin carcinogen relative to non-TNF-knockout mice.66,67 Basically the less TNF the animal had the fewer number of tumors it developed, TNF acted as a tumor promoter.

Now instead of trying to treat cancer by increasing TNF concentration the strategy shifted to treating cancer by decreasing TNF concentration. Unfortunately TNF plays an important role in the inflammation response. Changing the inflammatory response at a general level in the body has demonstrated mixed results as TNF inhibitors have generated positive results in treatment of rheumatoid arthritis, but in other inflammatory disorders TNF inhibitors have been linked to tuberculosis along with other infections and even lymphoma in some cases.59

One interesting result with regards to expression of TNF is that its signaling pathway components appear to have widely variable concentrations between individuals.52 Such a result may demonstrate that the overall role played by TNF in cancer development is heavily variable and dependent on the type of somatic mutation that induces cancer initiation in the first place. This result may explain why in recent Phase I and Phase II cancer trials TNF antagonists have resulted in disease stabilization in only 20% of patients.60-62 Anti-TNF therapies may not be a universal treatment for all patients or even a majority of patients, but instead a controlled specific personalized treatment after identifying average TNF concentrations in the blood stream.

While TNF treatments may not be the ‘silver bullet’ some hope exists for cancer treatment, research into TNF did identify another promising target for cancer treatment, nuclear factor kappa B (NF-kB). NF-kB lies at the end of one of the multiple TNF pathways that is triggered when TNF binds to either of its receptors (TNFr-1 or TNFr-2) and is partly responsible for triggering the inflammation pathway.

Beyond the pathway connection between NF-kB and TNF there appears to be a large amount of evidence that suggests sustained activation of NF-kB is rampant in various solid tumors and cancer types. For example major components of the NF-kB pathway are activated in human lymphomas,63 pancreatic cancer,64 cervical cancer,65 carcinomas,66 prostate cancer,67 colon cancer,68 head and neck cancer,69 esophageal cancer70 and lung cancer71. While the pathway is active in all of these cancers, the methodology of this activation and its specific components differ.

Five different molecules make up the nuclear factor kappa beta (NF-kB) transcription factor family: NF-kB1 (p105/p50), NF-kB2 (p100/p52), Rel A (p65), c-Rel, and Rel B.72 These different molecules commonly associate with one another to form various heterodimeric and homodimeric elements. The formation of these hetero and homodimeric elements is normally required to induce receptor activation as the NF-kb molecules typically remaining inactive in the cytoplasm before compound formation sometimes through additional interaction of ankyrin-containing inhibitor-kBs (I-kB).72 The I-kB inhibition complex for NF-kB members is typically made up of three different inhibitor elements (IKKa, IKKb, and IKKg).72 Also note that only the Rel members of the family (Rel A, Rel B and c-Rel) have transactivation domains which can activate transcription.72,73

The most common compound element among the NF-kB family is NF-kB1/REL A or (p50/p65), which is commonly regarded as the ‘classic pathway’ and is activated by TNFa.73,74 This classic pathway has also been identified in having a role in the promotion and pathogenesis of cancer where activation is largely induced by cytotoxic agents and maintained by oncogenic activation of various tyrosine kinases. An alternative to the classic pathway is induced by binding of other TNF family members and processes p100/RelB to p52/RelB.73,74 The alternative pathway components, which includes IKKa/IKKa homodimers, largely regulate survival of premature B lymphocytes and development of peripheral lymphoid tissues.72 Both pathways are complex with various cofactors such as CK2 or Akt influencing whether NF-kB compounds will have a gene inducing or gene suppressing effect including multiple overlaps.72 This complexity makes a straight application of ‘agent that inhibits element x in the NF-kB pathway’ as a treatment difficult because in some cancers it will promote survival and in other cancers the same element will promote death.

Of the five members of the NF-kB family, fully processed NF-kB1 (p50) seems to be the most important. Not only can it form a heterodimer with p65 which can then activate the classic pathway it appears that its formation of a homodimer (p50/p50) can actually inhibit classic pathway activation.76 While the formation of homodimer (p50/p50) can still bind at the kB binding sites, recall that only those Rel family members have the necessary transactivation domains to begin gene transcription. Therefore, homodimer (p50/p50) binding instead of heterodimer (p65/p50) prevents gene transcription and the activation of the classic pathway.76,77

While cancer cells themselves initiate the initial stages of forming a microenvironment, full expansion and functionality of the microenvironment seems to require the recruitment of macrophages; a recruitment tied to NF-kB. Macrophages are multifunctional and highly versatile cells which can engulf microbes or cell debris from appropriate, usually injured, sites secrete a variety of cytokines, present T cell antigens or aid in the activation of lymphocytes.76 Not surprisingly this behavior is governed through a phenotype alteration brought on by environmental molecular cues.

These behaviors are typically categorized into two subdivisions of macrophage activation: M1 or M2. M1 activation is classified as classically activated where the macrophage exhibits a pro-inflammatory phenotype largely resulting in secretion of bactericidal factors and T-helper-1 (TH1) promotion and typically occurs through activation by lipopolysaccharides (LPS) and interferon gamma (IFNg).76,78 M2 activation is classified as alternatively activated where the macrophage exhibits an immunosuppressive phenotype largely resulting in secretion of cytokines and the promotion of the T-helper-2 response (TH2) and typically occurs through activation by IL-4, IL-10 or IL-13.76,79,80 In either case macrophages that possess a phenotype are also sometimes referred to as tissue macrophages.

Note that it appears the initial recruitment of macrophages is due to the presence of cancer, not due to molecules released by cancer. This initial recruitment of macrophages can actually lead to cancer destruction because they enter the local tumor environment with a M1 phenotype. In some situations it is rational to conclude that these macrophages actually do successfully eradicate the cancer, otherwise average cancer rates would probably be much higher than in actuality.43,81 However, in some situations the cancer cells are able to survive the initial onslaught. The means of survival probably involve one of two methodologies. First, the attrition methodology in that cancer replication outpaces the ability of the macrophages to kill cancer cells. Second, mutations in some of the cancer cell population allow these specific cells to resist the bactericidal factors released by the M1 macrophages and/or evade engulfment.

Macrophages that stay within or around the localized tumor environment for a certain, unknown, period of time interact with cancer-associated molecules which change their M1 phenotype to an M2-type phenotype.43,82,83 The converted phenotype seems to occur through a different pathway than genuine M2 phenotype activation, but behaves very similar to the M2 phenotype, thus it is called an M2-type phenotype.43 In fact this M2-type phenotype has been subdivided into 3 different classes (M2a, M2b and M2c).43 M2a is induced through IL-4 or IL-13 activation, M2b is induced through combined exposure to immune complexes and Toll-like receptor or IL-1R agonists and M3c is induced by IL-10 activation. Both M2a and M2b exert immunoregulatory functions, whereas M2c tend to suppress immune responses and induce tissue repair.43

These converted macrophages are commonly referred to as tumor-associated macrophages (TAM). Therefore, what could occur in the tumor microenvironment is that after this first ‘wave’ of macrophages fails to destroy the tumor, tumors alter that first wave into TAMs and then begin to recruit monocytes through various chemoattractants like CCL2 and VEGF.84-86 These monocytes typically extravasate across the tumor vasculature then later differentiate into TAMs.

The recruitment of TAMs starts the next stage of tumor microenvironment formation. TAMs are thought to be responsible for a large percentage of the VEGF released in the newly formed microenvironment.87 As previously discussed VEGF is one of the key components to initiating angiogenesis. In addition to VEGF, TAM also appear to up-regulate another pro-angiogenic protein, matrix metalloproteinase (MMP7) most notably in hypoxic regions of the tumor.43 MMP7 cleaves an active form of RANKL from the cell surface88 which increases RANKL concentration in the tumor microenvironment. TAMs also can provide a form of positive feedback by secreting additional amounts of IL-10 converting more macrophages into M2c types.76

RANKL is normally expressed by T-helper cells as a means to accelerate dendritic cell maturation as well as aids survival. The increase of RANKL concentration brought on by MMP7 in a tumor microenvironment could also serve the same role accelerating dendritic cell maturation which would accelerate the expansion of TAM concentration in the microenvironment. Interestingly enough there is some evidence to suggest that deletion of RANKL reduces the probability of developing breast cancer induced by medroxyprogesterone acetate (MPA).89 RANKL also appears to play some role in regulation of the T cell-dependent response. This element is interesting because a potential high concentration of RANKL in the tumor microenvironment may interfere with any coordinated immune response driven by T-helper cells by masking the tumor using certain antigen presenting dendritic cells.

Recall that one of the hypothesized reasons for the failure of Avastin was that the remaining blood vessels were able to better deliver nutrients to the tumors stimulating more effective growth than when VEGF is not blocked. There may be another explanation for the increased aggressiveness of tumors which survive Avastin treatment. Reducing the number of blood vessels could also create hypoxic conditions, which under most circumstances would be welcome because it would increase the probability of tumor death. However, recruited TAMs appear to significantly bolster the survival ability of tumor cells in hypoxic conditions.43

First, TAMs have a tendency to migrate towards hypoxic regions in the tumor microenvironment, at least in breast, endometrium, ovary, bladder, colon and oral cancers.90-93 In these hypoxic regions TAMs also up-regulate NF-kB and HIF1.94 The positive influence on tumors of HIF1 has been previously discussed and ATF4 and EGR1 have perceived positive unknown effects, thus higher expression rates should stimulate tumor growth and metastasis. Also basal NF-kB is necessary to drive significant HIF1a protein synthesis.78,90 Now it can be said that even without treatment of Avastin or another anti-angiogenesis drug that tumor microenvironments will develop hypoxic regions, but these regions appear to be more widespread after treatment with Avastin over no treatment because of the reduced number of blood vessels. Basically the tumors that are connected to blood vessels get stronger due to the greater level of nutrients provided by those vessels and those that lack vessels either die or survive in a hypoxic region due to the release of these various factors. Note that creating hypoxic regions is still thought to have more positives than negatives when treating cancer.

TAM behavior is largely controlled through the NF-kB pathway. Inhibition of IKKbeta results in a phenotype shift from M2-type to M1.78,95 In addition recall that the formation of homodimer (p50/p50) can actually inhibit classic pathway activation. It could be argued that these (p50/p50) homodimer interactions chiefly interfere with the activation of the NF-kB pathway in LPS.96 This ‘inhibition’ of LPS-derived NF-kB action reduces the probability of LPS influencing M1 phenotype shifts in macrophages thus increasing the probability for M2 phenotype shifts. While still not understood the relationship of (p50/p50) in the NF-kB pathway appears to be important. So one reason why neutralizing NF-kB behavior may demonstrate positive results in cancer treatment is the reduction of TAM in the tumor microenvironment reducing the ability of tumors to survive hypoxic conditions.

TAMs are not the only monocyte that is recruited by tumors to aid in their development. TIE2-expressing monocytes (TEMs) are monocytes which interact with angiopoietins 1-4.43 Interestingly TEMs do not express chemokine receptor 2 (CCR2) thus they are unable to bind CCL2 which means they require another recruitment factor than the CCL2 which recruits monocytes that will eventually become TAMs.43 One study suggests that ANGPT2 is the molecule chiefly responsible for recruitment of TEMs into tumors.97 In addition ANGPT2 also could regulate the rate at which TEMs release angiogenesis promoting cytokines through the suppression of IL12.97

The specific role of TEMs in tumor facilitation is unknown, but in experiments when TEM concentrations were eliminated in tumors a statistical reduction in angiogenesis and tumor growth was observed.98 However, while TEM was removed, the loss of TEMs did not influence TAM or neutrophil concentrations further supporting the notion that TEMs and TAMs are independent elements in tumor promotion. Also even though the TAM concentration was not influenced by the loss of TEM, angiogenesis loss was significant which seems to suggest that TEMs have more influence on angiogenesis than TAMs.

Tumors also recruit mast cells largely using members of the stem cell factor (SCF) family.99,100 Like TAMs and TEMs mast cells appear to have the principle purpose of aiding tumor angiogenesis for inhibition of SCF expression in rat tumors reduced tumor vascularity and angiogenic responses.101,102 However, the angiogenesis influence of mast cells may be weighted towards the initial stages of the angiogenesis over the later stages meaning blocking mast cells may be more important than blocking TAMs.103,104 The reason for this behavior could come from mast cell interaction with endothelial cells lining the vascular lumina of multiple myeloma.105 Mast cells also appear to de-granulate and release angiogenesis factors in hypoxic conditions largely directed through HIF interaction.106,107

Angiogenesis is an important element of tumor progression, but tumors recruit additional molecules which provide other tumor promoting effects. One of these molecules are Myeloid-derived suppressor cells (MDSCs). MDSCs is a broader term for a heterogeneous population of cells primarily consisting of immature myeloid progenitors for neutrophils, monocytes and dentritic cells.108 While mature neutrophils typically act as immuno-promoting, MDSCs seem to act as immuno-suppressive partially due to their competitive nature with neutrophils and corresponding low levels of major histocompatiblity complex (MHC) class II and CD80 expression.109-111 The other method MDSCs use to suppress T and Natural Killer cell activity against tumors is the release of arginase 1 and iNOS (a.k.a. NOS2A).112-114 Somewhat ironically the most accurate way to identify a group of MDSCs is to look for their immunosuppressive ability. Tumors appear to recruit MDSCs from the bone marrow into their microenvironment through cytokine BV8 (a.k.a. PROK2).115,116

While immunosuppression is the principle tumor promotion action taken by recruited MDSCs, in murine models they appear to aid in angiogenesis.108,115 However, there does not appear to be any definitive evidence that MDSCs release pro-angiogenesis factors. Their support methodology may be through their immunosuppressive behavior which allows the tumor greater opportunity to release pro-angiogenesis factors from other cells. The latter explanation may be the more accurate one because MDSCs can secrete IL-10 which increases the probability for higher concentrations of TAMs which aid in angiogenesis through the release of VEGF.117 Another explanation is that BV8 helps recruit other elements which aid angiogenesis apart from MDSCs. There is some evidence to suggest that one of these ‘other elements’ are neutrophils.118,119

Based on the duel role of BV8 as a pro-angiogenesis agent as well as an indirect immunosuppressive agent, looking for a way to neutralize the BV8 pathway could be a useful strategy in cancer treatment and even prevention. The focus on prevention could be even more appropriate because the more prominent effects of BV8 seem to occur in the earlier stages of cancer progression. One advantage in creating BV8 based treatments may be that most of the identified functions for BV8 seem to occur in development and childhood. One disadvantage, beyond the general lingering unknown, is a possible connection between BV8 and circadian rhythms.

Cell surface markers in human MDSCs are somewhat inconsistent, but support CD11b and CD33 expression, but no CD14 or Lin.120,121 One of the reasons cell surface markers are not valid identifiers for MDSCs is that there is some question to whether or not certain unknown characteristics can lead MDSCs to differentiate into mature macrophages, dentritic cells or granulocytes110,122 thus there is a wide variances of cell surface markers in MDSC clusters due to various cell types that man inhabit these clusters.

Earlier the mixed results of Avastin were discussed as a representation of addressing angiogenesis by neutralizing the signaling factors. However, others believe the best way to treat tumors is to prevent angiogenesis which would prevent tumor growth and dramatically reduce metastasis probability, but not through neutralization of angiogenesis factors, but neutralization of the cells which provide these factors. As discussed above there are four major targets to preventing angiogenesis from an origin perspective: TAMs, TEMs, mast cells and (not discussed neutrophils). Some researchers have already used specific DNA vaccines to enable cytotoxic T cells to attack TAMs resulting in significant reduction in population in pre-clinical murine models with associated reductions in tumor angiogenesis, growth and metastasis.123

Despite the success in targeting TAMs with this strategy, little information exists regarding whether or not such a strategy increases lifespan or will in the long term have results similar to Avastin administration. One of the bigger questions is that does the removal of TAMs even matter that much when TEMs appear to have a more pronounced influence on angiogenesis on an overall level and mast cells apparently driving a lot of the initial angiogenesis action. Either way more study regarding this anti-TAMs strategy needs to be done.

One mechanistic problem with limiting macrophages may be neutrophils picking up the slack. When macrophages were stripped of CCR2 (receptors for CCL2 a major recruitment molecule), neutrophils were recruited in much larger numbers than normal and augment angiogenesis maintenance.124 Such a contingency action by tumors seems likely for other long-term anti-macrophage treatment strategies as well (antibodies); therefore, somehow addressing neutrophil recruitment may also be necessary.

Another issue with attacking angiogenesis signaling molecules is that the two most prominent elements driving angiogenesis are VEGF and hypoxic conditions with both appearing to be non-starters at this moment. The disappointment in Avastin has raised questions regarding the usefulness of blocking VEGF alone. Also the hypoxic element could cause problems because a non-decisive reduction in angiogenesis through one pathway could result in the expansion of angiogenesis via hypoxic-induced agents. However, an important element to recruitment that could be fortunate is that pro-angiogenic factors do not appear to be released by recruited cells until they are actually in the tumor microenvironment. Thus tumor specific targeting elements that are properly designed could address a vast majority of the angiogenesis potential if applied early enough or in pre-emptive preparation for metastasis.

Unlike monocytes, B cells do not infiltrate into the tumor environment, thus inflammatory-based functions from innate immune cells were thought to operate through a more remote signal pathway.78,125 In the K14-HPV16 murine model B cells were able to activate Fcg receptors on myeloid cell.126 Also B1 cells could suppress LPS-induced genes (those which would drive M1 phenotype expression), possibly through the expression of IL-10, which then increase the probability that macrophages in undertake a M2-type phenotype.127 Inhibition of IL-10 switched infiltrated macrophages from M2 to M1 and stimulated a more aggressive innate immune response against the tumor.128 This result implies that IL-10 may be required for the maintenance of a tumor-induced M2 phenotype for recruited macrophages. Therefore, long-term inhibition of IL-10 may be a therapeutic strategy worth exploring.

Dendritic cells regulate adaptive immune responses and are the principle antigen-presenting cells (APC), which can induce primary and secondary T and B-cell responses.43,130 Dendritic cells are divided into two types of classes: myeloid (MDC) and plasmacytoid (PDC).130 Both are commonly identified through their unique cell surface markers (myeloid: CD11c, CD33 and Lin and plasmacytoid: CD45RA, CD4 and ILT3).131 Under normal circumstances MDCs originate in the bone marrow as immature cells which mature after acquiring any foreign antigen. After maturation the mature DC migrates to lymphoid tissue where they initiate activation of antigen-specific T cells.43 With respects to tumors, MDCs are less likely to initiate maturity reducing the number of mature DCs within cancerous tissue relative to healthy tissue.132 Instead immature MDCs are recruited into the tumor microenvironment by members of the CXCL family (notably 8 and 12), VEGF and HGF.133-135

In the tumor microenvironment immature MDCs function in two major roles. Immature MDCs aid in angiogenesis not only by releasing pro-angiogenesis cytokines, but also through their ability to be used as endothelial progenitors.134,136 There is also some question to whether or not immature MDCs can secrete members of the CXCL family to further recruit other cells into the microenvironment.137 Also some evidence exists to support dendritic cells initiating an anti-immune response via a TLR4-MyD88 pathway in the presence of dying tumor cells.138 Finally hypoxic conditions appear to reduce the probability of dendritic cell maturation perpetuating their immature, pro-tumor state.135,139 Despite all of the pro-tumor roles that dendritic cells activate, their overall role in tumor promotion is currently regarded as minimal; however that minimal effect may be amplified by the sheer number of dendritic cells in the microenvironment.

The prominent role that both TNFa and NF-kB have in tumor development was a major factor in the development of the theory that inflammation is a centerpiece in tumorigenesis. A number of individuals agree that inflammatory factors do play a role in the development of a clump of cancer cells into a full-blown tumor as the tumor microenvironment is aided in development by secretion of inflammatory promoters.140 However, there is some argument regarding whether or not inflammation actually can drive the necessary cellular changes to induce non-cancerous cells to become cancerous in the first place. Proponents of inflammation as cancer triggers have two points of argument: chronic inflammation eventually induces cancerous cells and viral induction. Viral induction, where tumorigenic pathogens such as Human Pamplona Virus (HPV) evade the immune system and establish persistent infections associated with low grade, but chronic inflammation, seems on surer footing than non-viral induced chronic inflammation.

One important side note is that when references are made to pathogen x, like HPV, causes cancer y the pathway of cancer inducement commonly comes from the NF-kB pathway.141 In large part the reason some of these pathogenic agents can enhance the development of cancer is that they typically have transactional domains which mimic NF-kB family members or NF-kB activation receptor sites.141 in the local environment where the virus persists. This interaction allows these specific pathogens the ability to enhance the developmental probability of cancer. For example individuals can still get cervical cancer even if vaccinated against HPV; however, the vaccination is thought to significantly reduce the probability of acquiring cervical cancer because it is thought that the most common pathway to developing cervical cancer seems to stem from NF-kB mimicry by HPV.

It is more difficult to link up non-viral chronic inflammation as the cause of the cancer. One method of action could be that over time the inflammation leads to the creation of a significant quantity of free radicals. These free radicals are then able to induce enough genetic damage to nearby cells localized within the region of inflammation that they eventually mutate and become cancerous. The major empirical problem with this theory is that individuals who suffer from conditions, which have origins from chronic inflammation such as rheumatoid arthritis or psoriasis, do not seem to develop cancer at any higher rates than those that do not suffer from these conditions.

Currently no quality explanation exists for these results relative to the above theory. Some proposes that other dietary or environmental carcinogens are not able to interact with the inflammation catalyzing the cancer development, but if such catalysts are required to produce cancer from chronic inflammation then it is difficult to argue that chronic inflammation gives rise to a significant number of cancer cases. In fact recent evidence demonstrates that mediators and most signaling pathways for inflammation are downstream of oncogenic mutations supporting a conclusion that cancer causes inflammation not inflammation causes cancer.140

Perhaps the best theory behind why chronic inflammatory conditions like psoriasis do not develop into cancer, as most inflammatory – cancer proponents would theorize, is that there is some evidence to suggest most of the macrophages in psoriasis express the M1 phenotype. This excessive expression of M1 phenotypes more than likely is derived from psoriasis being a T helper 1 mediated disease causing large accumulation of neutrophils and monocytes in the skin. The large-scale expression of M1 phenotype should increase the probability that those macrophages would attack cells expressing initial stages of tumor development. This increased probability of cancer termination could then mask the cancer inducing effects of chronic inflammation in chronic inflammatory conditions like psoriasis.

Recalling for a moment that one of the original ideas behind the importance of studying angiogenesis was to develop a means to design treatments which would force higher levels of oxidative stress on a tumor or pre-tumor due to a lack of nutrients and oxygen from the lack of blood vessels. Unfortunately not only has anti-angiogenesis treatments proven less effective than previously thought, the base idea of inducing high oxidative stress environments may have been in error as well. To understand whether or not this is the case it is important to investigate how tumors behave in these oxidative environments as opposed to normal cells.

Environments of high oxidative stress are created when the large increases in concentrations of reactive oxidative species (ROS) occur. Among those ROS elements the most dangerous are free radicals (O-) and super oxides which are commonly formed when electrons from the electron transport chain operate in error and interact with oxygen. In localized regions which cover tumor cells there is a higher probability for the formation of a high concentration ROS environment due to oncogenic transformation and alterations in metabolic activity (including angiogenesis processing vs. cellular growth rates).142,143 The result should not be surprising simply based on the premise that with less restraint on growth cells will undergo greater metabolic activity in order to expand their growth which will result in a greater concentration of ROS due to a lack of corresponding increase in antioxidants.

Normally an increase in ROS within the localized environment should be viewed as a positive in the context of addressing cancer because a higher ROS concentration leads to a higher mortality rate. However, in the case of cancer, there are questions about how ROS may change the nature of translation for various signaling molecules, some which stimulate cell proliferation and promoting cell motility.144,145 Initially an increase in concentration for molecules governing both proliferation and motility seem to make some sense on a logical level. A cell under high levels of oxidative stress three potential responses could be expected. First, cells would take an attrition response where they start multiplying at a much higher than normal rate with the ‘intent’ to out-propagate the threat (in this case the ROS agents), an attempt to sacrifice enough cells to either neutralize or mitigate the significance of the ROS agents in the oxidative environment. Second, cells would take a ‘bunker down’ response, similar to that of a bacterial spore, where all resources are devoted to survival of the given cell, no communication, no growth, just survival. Third, cells would simply try to move away from that high stress environment by increasing their motility. For cancer cells the first and third reaction appear predominant.

The most important consideration for addressing tumors is that their functionality commonly behaves like a double-edged sword in that they frequently develop alternative methods for accomplishing a given function. While these alternative methods can be frustrating through the complication or reduction of more common pathways, these new methods also provide possible new attack strategies if they can be successfully identified. One particular pathway which could involve a useful therapy is how tumor-based mitochondria behave in high ROS environments.

The chief safeguard to the mitochondria is that a double membrane with selective protein transport complexes protects it. However, if a detrimental agent, normally superoxides, compromises those membranes the raw mitochondrial DNA (mtDNA) is more susceptible to damage because of a lack of histones.145 Combine the lack of histones with the limited DNA repair capacity in the mitochondria and excessive ROS concentrations and mtDNA tends to be damaged more easily in cancer cells than other types of DNA. When this DNA is damaged it can compromise proper functioning of the mitochondria and result in the greater synthesis of ROS.

The release of excess ROS for the maintenance and stabilization of high ROS concentration environments is also important with respects to metastasis. Recall that above it was briefly discussed that one possible response to a high ROS environment was increased probability for motility and cellular migration. This response pathway seems to persist in cancer cells as well as normal cells. Some evidence already exists which suggests the mitochondria dysfunction and the corresponding increase in ROS production can enhance metastatic probability.145,146

The reason for this increase in metastatic probability appears to come from various ROS activating activator protein 1 (AP-1).145 AP-1 plays a major role in a number of critical biological processes including cell proliferation, apoptosis and differentiation. Among these processes AP-1 appears to also be able to bind CXCL14 (a.k.a. BRAK or MIP-2g), a chemokine of unconfirmed functionality.145 Unfortunately despite its ability to interact with AP-1 the function(s) of CXCL14 remains controversial due to conflicting empirical data.146,147 One possible function appears to be increasing the release of calcium ions in to the cytosol. It is hypothesized that this excess calcium is released from isolated ER microsomes when CXCL14 binds to IP3R.145

If this hypothesis is correct then there may be an interesting connection between CXCL14 and cytochrome C. Cytochrome C is one of the more common methods for the initiation of apoptosis. When cytochrome C is released into the cytoplasm, usually due to mitochondrial response to apoptotic precursors, it binds apoptotic protease activating factor149 and later binds to IP3R on the ER facilitating calcium release, similar to a theory regarding how CXCL14 is thought to behave. This calcium release acts as a positive feedback mechanism, creating cytotoxic levels of calcium, which results in the further release of more cytochrome C both into the cytoplasm and into the mitochondria. The release into the mitochondria leads to the activation of caspase 9 which begins the caspase cascade initiating apoptosis. So does CXCL14 create some form of cytochrome C mimic response or does it actually trigger the release of cytochrome C which is the agent which creates the cytoplasmic calcium concentration increase?

In addition this release of calcium into the cytosol may also support the notion of higher glycolysis activation in cancer cells. Most enzymes which function in glycolysis bind to the cytoskeleton and cytosolic calcium promotes assembly of actin filaments along with cytoskeleton re-organization which could in turn promote greater than normal activation of glycolysis dependent enzymes, thus increasing glycolytic activity. Intuitively such a thought process makes sense because under conditions of stressed and dysfunctional mitochondria there exists a real probability that these dysfunctional mitochondria will be unable to produce sufficient amounts of ATP through the Krebs Cycle and electron transport chain. Therefore, under periods of dysfunction the mitochondria could release molecules which indicate a dysfunction stimulating non-mitochondrial based ATP generating pathways, the most prominent one being glycolysis.

However, such a system would probably only be able to stem the ATP loss from the mitochondria for a short period of time largely because of a lack of required ATP concentration as well as eventual mitochondrial driven apoptosis. It is important note that clearly some cancer cells probably overexpress some type of anti-capsasin molecules which block mitochondrial driven apoptosis. Also there may only be a small window for metastasis through this mechanism as there have been observations that cancer cells with high ROS generations eventually reduce this excess generation falling back into a rebalanced dynamic equilibrium of ROS generation and ROS elimination, which aids overall sustained proliferation.145

One aspect of treating cancer that has not been addressed to this point is the scenario of relapse. There are two principle rationalities to explain the reemergence of cancer once a patient is thought to be in remission beyond an incredibly unlucky second separate and independent occurrence. First, that the patient was never fully in remission, some of the cancer become resistant to the applied treatment, incomplete surgical removal or an inability to target all cancer cells with chemo or radiotherapy. This explanation is understandable because there is no existing definite cancer detection technique, thus smaller cancer cells (typical post-treatment cells) are more difficult to detect. Second, during the development of the tumor cancer stem cells (CSC or cancer-initiating cells (CICs)) are produced, so even after the main tumor is eliminated these CSCs reinitiate cancer development.

Two different theories emerged to explain the functional heterogeneity (different proliferation ability and differentiated states) in cancer: small population of self-renewable cells (cancerous stem cells) that created all other cancer cells in the development of the tumor or clonal evolution where all cells have similar tumorigenic capacity.150-153 Early on there were serious questions regarding whether or not CSCs actually existed.154,155 However, while an expansion of empirical evidence has limited the concern regarding the existence of CSCs, it has not created a single predominant theory regarding their role in the development and progression of tumors. Also an increase in the supporting evidence for CSCs does not eliminate clonal evolution as a valid theory for cancer evolution as serial transplantations typically result in more aggressive tumors,156 CSC theory is just the primary cancer causing agent not the only one.

CSCs are loosely defined as stem cells that induce a cancerous state. There is no general acceptance to the origins of CSCs, do they arise from cancer cells or are do they mutate from normal stem cells. Devising these origins is difficult because CSCs have similar properties to normal stem cells like self-sustained replication, pluripotency and drug resistance genes like ABCG2.157 However, most cancer cells share most of these properties and with the genetic variances in cancer cells it cannot be dismissed that certain mutations could restore pluripotency to some cancer cells making them CSCs. It is difficult to conclude that normal tissue could become both cancerous and pluripotent in a small replicative time period, thus it makes sense to conclude that CSCs must be derived from a group of cells that already has one of those two traits, either tumors or normal stem cells. Basically the chief question of CSC origin come down to: do CSCs develop first which lead to tumor development or do tumors develop first with some of the cancerous cells mutating into CSCs?

Some evidence that supports CSCs originating from tumors is the enhanced chemotherapy resistance attributed to most CSCs seems to come more from previously exposed cancer cells over normal stem cells. Also haematopoietic malignancies moZ-TIF2, mil-AF9 and mll-enl16 all appear to grant stem-like properties on committed progenitor cells putting them on the pathway towards becoming CSCs.158-160

However, other evidence points to more CSCs coming from normal stem cell corruption. For example carcinomas seem to target epithelial stem cells and CSCs derived from carcinomas express similar molecules like Oct4 and Bmi1, have similar size, greater adhesiveness and similar patterns of gene expression.158,160,161 While one could argue that these features are common among stem cells in general, so CSCs derived from differentiated tumors would have them as well not just those derived from normal stem cells, the lack of a ‘missing link’ cell makes it difficult to decisively support that conclusion. Overall it may be just a situation where CSCs can develop from both potential pathways.

Despite the need for more information to determine a better treatment strategy, another reason behind determining the origins of CSCs is that some theorize that CSCs arising from transformation of a normal stem cell are more aggressive than those derived from a more differentiated progenitor cell.158 One association with this theory has been melanoma and its connection to epithelial stem cells. The theory tends to make more sense because it stands to reason intuitively that conversion of normal stem cells would result in faster tumor progression through greater cell division than conversion of a previously committal progenitor cell.

Some of the first pieces of evidence which supported the existence of CSCs was through fragmentation of human breast cancers into single cell suspension and isolation of subpopulations.162,163 This experiment found that tumor-initiating ability was almost exclusive to a small fraction of the cancer cells all which expressed CD44.163 Quick reminder that the term CD describes a particular cell-surface glycoprotein which involves cell-cell interaction. Other studies confirmed this CD44 expression as well as adding CD133 expression.164-166 After these studies it was concluded that CSCs either expressed CD44 and/or CD133.158 Unfortunately at the moment the expression patterns of type specific cancer seem to be either capricious or unknown as CD44 expression is found in head and neck cancers, pancreatic and breast cancer where as CD133 expression is found in brain cancer, liver and colon cancer.165-170 Also there does not appear to be a universal marker which identifies CSCs, but various groups of markers that hint at CSC characteristics. In fact some believe that CD133 is not a CSC maker, but a stem cell maker instead because it is also expressed in normal stem cells, but comparison of expression levels varies.163

The conservation of CD44 and CD133 expression through a wide variety of cancers has logically lead researchers to question whether these two elements confirm stem-cell characteristics. Work has been done to investigate the role of CD44 on CSCs. Application of a universal (works against all isoforms) CD44 antibody was thought to eliminate transplanted leukemic stem cells while a humanized monoclonal antibody for CD44 demonstrated tumor reduction in advanced oral cancer.171 Therefore it appears that CD44 does play some important role in tumor growth and/or maintenance. However, there are some concerns as administration of the CD44 ligand, hyaluronan,172 seemed to reduce breast cancer propagation, which is contradictory to what is expected. Also the biggest concern at the moment with using a CD44 antibody strategy is its major skin toxicity due to the presence of CD44 on normal skin stem cells.171 There is still hope that CD44 can be used as a therapeutic target in the right dosage because CSCs seem to express more CD44 than normal haematopoietic stem cells.171,173

Another question with regards to CSCs is their highly sporadic variable frequency relative to non-CSCs. Instead of most tumors consisting of relatively conserved flat ratios of CSCs the percentage of CSCs vary wildly relative to tumor type. For example CSCs in colorectal carcinomas have ranged between 1.8 to 24.5% and CSCs in melanoma have ranged between 1.6 and 20%.162,169 One reason behind this variance may be a non-uniform sampling or distribution of CSCs leading to inaccurate results (impurity in sample collection). However, the number of studies that report this wild fluctuation in CSC ratio seem to rule that conclusion out.

Some argue that the hypoxic, pH and nutrient variant microenvironment with necrotic elements create a form of stochastic aspect to the number of CSC within a given tumor formation.174 Therefore, it is difficult to assign a rationality to why one tumor formation may have x% of CSCs versus another tumor of same type that only has y% of CSCs. Another explanation could be that CSCs increase depending on a given event such as metastasis in order to replenish any losses from the principle tumor. Therefore, elements like CXCL14, which could promote metastasis, could also initiate the production of more CSCs.

Is there any evidence to support a suggestion that CSC ratio changes in tumors in preparation for metastasis? To address that question one must ask what role, if any, CSCs may play in metastasis. Most believe that the process of metastasis is preceded by an epithelial mesenchymal transition (EMT) at the invading edge of the tumor which leads to cellular detachment increasing the probability that the cell in question is caught up in the blood stream and can then move to a different place in the body.159,175 There is evidence to suggest that canonical pathways initiate EMT. Some have concluded that because canonical pathways can be activated during neoplasia that the reversal of differentiation that may convert progenitor cells into CSCs may also detach those cells from the tumor matrix.176 Basically this ‘accidental’ activation of the canonical pathway kills two birds with one stone with regards to cancer aggressiveness, more CSCs and increased probability of metastasis.

A more specific example of metastasis behavior was demonstrated when researchers found a distinct group of CD133+ CXCR4+ cells which exhibited stronger migratory activity in vitro over CD133+ CXCR4- cells.177 Both cell types exhibited similar tumor progression rates. In addition the CD133+ CXCR4- cells did not demonstrate metastatic activity in the liver where as CD133+ CXCR4+ cells did.177 Furthermore inhibition of the CXCR4 receptor significantly reduced metastatic potential in pancreatic tumors with no significant change to localized tumor progression.159 One outcome connecting metastasis and CSCs is that there could be two distinct types of CSCs. One that is developed for the purpose of metastasis (the more resistant nature of the CSC would be better suited for successful metastasis) and one that is developed for localized tumor progression which ‘hides’ inside a solid tumor.

On a side note the nature of metastasis also draws a question of whether or not macrophage fusion is required. Some believe that when cancer cells reach high grades of malignancy (solid tumor formation) the high plasticity of the cells along with the high inflammatory environment some of the cancer cells themselves progressively develop endothelial and immunity phenotypes. These new phenotypes allow these cancer cells to more freely transport within the blood stream increasing probability for metastasis. In contrast John Pawelek and his supporters believe that fusion between macrophages (most likely these TAMs that congregate near the tumor formation) and cancer cells fuse forming a macrophage/cancer cell hybrid cell that is capable of traveling through the blood stream.178

Both explanations have their problems. While the cancer plasticity theory makes sense, especially when considering the role of cancer stem cells in cancer progression, very little supportive evidence has been demonstrated for the ability of the inflammatory environment to induce immunity characteristics. The same story exists for the hybrid macrophage-cancer cell as while numerous studies have been done that supposedly produced hybrids, there have been no solid confirmations that those new hybrids actually were hybrids.179 The two reasons for the difficulty in detecting hybrids are that both the cancer cells and macrophages are almost virtually identical genetically and very narrow differences between genuine hybrids and two cells simply adhering to each other.

There is evidence to suggest that EMT induction is reversible which could revert converted epithelial-based CSCs back into epithelial cells.174,180 Such a strategy could be an anti-metastasis treatment option. The ability to reverse CSCs into non-CSC epithelial cells may also provide an explanation for the great variance in CSC ratio in various tumors. The undifferentiated and differentiated states of cancer cells may not be as permanent as previously thought and depending on given conditions cells may move between CSC and non-CSC states. Most of the existing CSC models do not incorporate a dynamic differentiated to undifferentiated state because of limited empirical evidence.

While little direct empirical evidence exists for this reversible differentiation ability, strong anecdotal evidence does exist. Take this scenario for example… a group of 100 cells exist where 7 are stem cells and 93 are non-stem cells. If one of the non-stem cells undergoes a genetic mutation which would induce malignancy under a non-reversible differentiation model such a mutation would be irrelevant because that mutated cell does not self-renewable capabilities, thus cannot develop into a full-growth tumor unless it also developed a type of telomerase (self-renewal) mutation; as previously noted such dual mutations seems unlikely. Therefore, such a cancerous mutation would need to occur in one of the stem cells. However, such a restriction does not appear viable to correlate known mutation probability rates vs. general cancer incidence in the general population (mutation rates would need to be much higher).

With regards to CSC chemo-resistance the more illuminating studies seems to involve brain cancer and CD133+ CSCs24. One theory behind why CD133+ cells survive over CD133- cells when exposed to a chemotherapeutic agent is that CD133+ overactivate the DNA damage checkpoint response system.159 The checkpoint system is designed to limit the ability of cells to enter mitosis with damaged DNA. Based on the overactivity of the checkpoint, CSCs may overexpress wee1 to ensure entrance into the checkpoint to repair single stand break damage. Also while CSCs are through able to survive chemotherapeutic agents than non-CSCs through drug pumps like ABCG2 another advantage CSCs have is the ability to enter the quiescent state. There is reason to believe that CSCs in the G0 phase gain a greater resistance to chemotherapy agents.181 So perhaps CSCs can linger longer in both G0 and G2 phases increasing survivability.

CSC location is also problematic when addressing treatment possibilities. CSCs are typically localized in the center of a solid tumor mass. The CSCs act as a keystone to the tumor continuing to expand the tumor from the inside in an outward fashion. Therefore, to neutralize these CSCs the treatment regiment must ‘bore a hole’ of sorts through the solid tumor to reach the center and the CSCs. However, boring that hole is difficult because as the treatment is destroying the more differentiated cancer cells that make up the outer portion of the tumor, the CSCs are continuing to synthesize new cancer cells which substitute for the dead cells in the tumor itself.

The lack of understanding surrounding CSC origin makes developing a treatment strategy complicated. Some argue that due to the general resistances against chemotherapy oncolytic viruses are the best option because of their cytotoxic and non-targeting nature. The problem with this strategy is that, more than likely due to their lack of definite differentiation, CSCs are could be resistant to infection with certain oncolytic viruses, like HSV-2 mutant, that can normally infect differentiated cancer cells.182 This problem can be overcome by adding certain specific elements like histone deacetylase inhibitor, trichostatin A, as it did for one type of breast CSC.182 However, because of incomplete information and possible heterogeneity surrounding CSCs it is difficult to confirm whether or not such a strategy can be universally applied or if it was simply valid for that specific experiment. For example Jordan identified parthenolide as a molecule that can selectively target human leukemia stem cells over normal stem or progenitor cells, but other cancerous non-leukaemia targets are unconfirmed.183 One element which demands further study is the question of whether or not intact IFN response is a defining characteristic of CSCs.

Another treatment strategy in its early stages is inducing CSC differentiation through exposure to bone morphogenetic proteins (BMPs).184 This result makes more sense when correlating the evidence that a reduction in BMP concentrations increases the probability for colon cancer.185 Forcing CSCs to differentiate could be the better treatment strategy than trying to kill them because there appear to be fewer, if any, CSC safeguards to preventing induced differentiation vs. toxic agents. Once differentiated the CSCs lose their ability to replenish cancer cells reducing the rate of tumor growth. This strategy seems to be supported by experiments which down regulated BMP resulting in more tumor aggression via alleged greater CSC proliferation.186 However, because BMPs could also cause normal stem cells to differentiate, the application of this type of therapy would need specific cancer targeting to ensure limited BMP exposure to non-CSCs. Despite these difficulties there is hope that a novel treatment can be developed to attack CSCs and undermine the continued progression and maintenance of the tumor collapsing it from the inside out.

While oncolytic viruses have been explored as a means for specific targeting it is not the only strategy. A new technological strategy attaches nanoparticles made from diamonds to chemotherapeutic agents to increase their effectiveness.187,188 The advantages of this new nanodiamond-chemo compound is that the nanodiamond is made from carbon, is non-toxic and does not drive an immune response.187 Also the addition of the nanodiamond increases the size of the chemo agent is thought to dramatically reduce the ability of tumors cells to use anti-drug pumps to eliminate the chemo agent out of the cytoplasm before it does any mortal damage to the cancer cells.187 Formation of the compound also seems to reduce chemotoxicity which should reduce detrimental side effects associated with such treatment.

Finally the nanodiamond can also act as a linker molecule bridging the chemo agent and another molecule, perhaps an antibiotic, which can increase tumor targeting efficiency. Nanodiamonds and similar elements like gold may also be an effective delivery mechanism for other agents like BMPs as well. At the moment there could be two drawbacks to adding nanodiamonds to the treatment. First, the additional cost associated with their manufacture and formation and second while initial tests have demonstrated reasonable biocompatibility there have been no real long-term studies to determine long-term side effects.

One of the trickiest issues in treating cancer is identifying sustainable treatments. As seen with Avastin above with respects to failed attempts to control tumor angiogenesis, researchers frequently discover drugs which perform well against cancer in the short-term, but when the treatment scope is expanded the effectiveness of these drugs falter making them almost no more valuable than existing treatments. One example of the ability of cancer to thwart these new drugs is in the new chemotherapy drug, vemurafenib, used to treat metastatic melanoma. In Phase III trials vemurafenib shrank tumors by almost 10 times more than dacarbazine (the standard treatment for metastatic melanoma at the time) [48% vs. 5%] and also improve six-month survival rate from 64% to 84%.189 Unfortunately the successes of vemurafenib were only short-lived as tumors switched from the BRAF triggered pathway to an alternative pathway, essentially becoming immune to the effects of vemurafenib.189 After factoring out the six-month survival rate improvement, the long-term survival rate did not change significantly. Ipilimumab, another melanoma drug, performs similar to vemurafenib in that it marginally increases short-term survival rate, but does not significantly change long-term survival rate.190

Cancer prevention has always been a questionable issue because, as demonstrated in this blog post, it is difficult to narrow down an effective measure of prevention due to the intricate nature in which cancer develops. However, for some specific cancers certain prevention therapies exist, most of them involving breast cancer because of the association between breast cancer development and oestrogen/estrogen. Early preventative treatments were Tamoxifen and Raloxifene which acted as competitive inhibitors with oestrogen. However, these two drugs did carry small risks of increasing the probability of womb lining cancer and blood clots which could increase the risk of heart attacks. The severity of these side effects were so great that most worried about using either as a preventative agent.

Some researchers believe that a new drug, Exemestane, provides a much better option due to its lack of side effects in initial clinical studies. Exemestane is an irreversible, steroidal aromatase inactivator which when bound to aromatase is converted to an intermediate that irreversibly binds to the active site on aromatase eliminating both elements.191 This type of inhibition is commonly known as ‘suicide inhibition’. Eliminating the available concentration of aromatase reduces the concentration of estrogen as aromatase is chiefly responsible for converting testosterone to estradiol. The reason for this lower estrogen concentration is that in post-menopausal women the ovaries stop producing estrogen, so estrogen production is largely reliant on the conversion of androgens. Of course exemestane is only effective against estrogen receptor positive breast cancer.191

Unfortunately there may be a drawback in using exemestane that has not yet been seen. Previous studies have demonstrated that animals exposed to aromatase inhibitors exhibit substantial gains in overall adiposity due to increased adipocyte hypertrophy and hyperplasia.192 Therefore, if individuals are placed on exemestane as a preventative treatment, especially post-menopausal women, there may be a significant increase in weight gain. At the moment there is no definitive information regarding whether or not this inhibition is developmental or time sensitive. Therefore, whether or not this weight gain side effect will affect those older women taking it for prevention is unknown.

Overall cancer research and therapy has come a long way in the last few decades, especially with regards to its functionality. Unfortunately while this additional knowledge has opened the door to new treatment options those options have yet to materialize into a cure. Fortunately promising attack avenues are still available and newer strategies are being explored each day. For example while VEGF neutralization strategies for angiogenesis may not be successful, focusing on the more overlooked TEMs than the TAMs could provide a better basis for attacking angiogenesis. Attacking BV8 may also prove to be useful not only as an anti-angiogenesis treatment, but also for anti-metastasis strategies.

Furthermore application of antibodies and/or nanomaterials to better target cancer cells could be aided by exploring RANKL inhibitory compounds which could reduce the potential of tumors to ‘hide’ from immune cells. CSCs could be attacked not directly through cytotoxic elements, but indirectly by BMP and its associated compounds to induce differentiation reducing tumor malignancy. Finally advances in diagnostic elements from PARE, miRNA screenings and microbubble ultrasounds to expansion of genetic information should improve diagnosis speed and associated survival rates. Overall the most important element to addressing cancer in the future is to continue to take positive steps forward and ensure that evidence and logic guide the way.
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