HIV and the T Cell Life Cycle

In an excellent review of a paper in the Journal of Biology (“Generalized immune activation as a direct result of activated CD4+ T cell killing“), Nienke Vrisekoop , Judith N Mandl, and Ronald N Germain discuss the life and death of the T lymphocyte.

T lymphocytes have a difficult existence. As mature cells, they are essential for immunity to infection, but in the early stages of their development in the thymus, more than 90% of them fail selection for the appropriate antigen receptors and die before export to the peripheral immune system. Those that achieve maturity spend weeks, months or even years circulating through the body, in constant search of a foreign antigen that their antigen-specific receptor can recognize, and needing continuously to compete for trophic signals necessary for their survival. Most fail to find an antigenic match and remain as small resting cells until death. A few encounter the right partner and undergo a transient bout of exponential clonal expansion, only for more than 90% of these progeny to be lost by apoptosis shortly after the antigen is cleared. The remaining 10% are maintained as memory cells (Figure 1), conferring lasting protection.

Understanding the mechanism of T cell death is a major concern when confronting HIV and its progression into full blown AIDS.

Although it is known that HIV kills activated CD4⁺ T cells, it is still a major unresolved question why these cells progressively decline after infection. It is clear that in infected individuals, the rate of loss of CD4⁺ T cells is greater than the rate of production so that the CD4⁺ T cell pool is gradually eroded over time, but it remains to be determined how the balance between these processes is impaired. It is unlikely that direct killing of infected target cells by HIV is sufficient to cause CD4⁺ T cell depletion. Natural hosts for simian immunodeficiency virus (SIV), such as sooty mangabeys, do not progress to AIDS and maintain near-normal levels of peripheral CD4⁺ T cell numbers despite high rates of viral replication [4]. In fact, the level of immune activation is a better predictor of disease progression than viral load. Consistent with this, HIV infection in humans leads to chronic generalized immune activation characterized by an increased rate of exit of CD4⁺ and CD8⁺ T cells and of natural killer (NK) cells from the resting state, increased T and NK cell turnover and death, polyclonal B cell activation with increased levels of gamma globulins, and elevated production of pro-inflammatory cytokines. Conversely, chronic immune activation is not seen following SIV infection in natural hosts that do not show progression to AIDS [4].

That is, there is a question as to what causes the autoimmune response that is so devastating to people with AIDS.  There are two proposed methods of activation.  The first is that chronic activation of the hosts immune system disrupts CD4+T cell homeostasis.  The second is the opposite, that HIV drops the CD4+T count out of homeostasis and the bodies over-active response is chronic immune activation.  The authors make the point that these two possibilities are not incompatible.

Clearly, the two possible causal relationships between chronic immune activation and CD4⁺ T cell loss are not mutually exclusive. In fact, chronic immune activation and the loss of CD4⁺ T cells may amplify each other in a loop that makes it difficult to establish which process underlies and drives the other.

The study in review attempted to induce this same response in mice.

Marques et al. [1] suggest that the OX40-DTA mouse is one approach to this issue and that the findings in these mice provide important insight into the control of lymphocyte dynamics in infected humans. Indeed, in the absence of exogenous infection, OX40-DTA mice do show features consistent with generalized immune activation (Table 1), including an expansion of effector CD8⁺ T cell numbers that inverts the usual CD4⁺:CD8⁺ T cell ratio, and increased serum levels of inflammatory cytokines. This generalized activation cannot be attributed to the release of microbial components into the circulation from the gut, because deletion of activated CD4⁺ T cells does not in itself lead to a breach in the gut epithelium. Notably, Marques et al. [1] show that the expansion of effector CD8⁺ T cells and increases in serum levels of inflammatory cytokines can be reversed following reintroduction of Tregs from normal mice, suggesting that the increased immune activation in OX40-DTA mice can in part be ascribed to a Treg insufficiency, which they propose is a key event in HIV-infected individuals leading to CD4⁺ T cell depletion.

There’s a lot more, and the review goes into much more detail.  But, I can see how this approach could be fruitful in illuminating the underlying causes of a disease that plagues such a large number of humans on the planet.

Astrobiology: Part of RNA Built in the Lab

Astrobiologists have built Uracil, a component in RNA, in space-like conditions in the lab.

“We have demonstrated for the first time that we can make uracil, a component of RNA, non-biologically in a laboratory under conditions found in space,” said Michel Nuevo, research scientist at NASA’s Ames Research Center. “We are showing that these laboratory processes, which simulate occurrences in outer space, can make a fundamental building block used by living organisms on Earth.”

Change Geeks Can Believe In: White House Goes Drupal

President Obama promised us change, and change we get.  The White House official website, whitehouse.gov, has changed its CMS (Content Management System) to the open source platform Drupal.

Drupal is, quite frankly, a pain in the butt if you don’t know any php, and aren’t comfortable learning the architecture of a site.  For most individuals who just want to blog, or have a small business website, I still think WordPress is king.  It’s easy as hell to understand and it’s quite flexible.  Nearly every site I’ve ever created I did with WordPress. I’m a mathematician, not a web developer.

But, for large websites needing lots of features or, in this case, for a large government, Drupal is well worth the learning curve.  It can do pretty well anything you want it to do.  It’s more secure than most CMS’s. And, it’s got a large community of developers backing it up.

WhiteHouse.gov’s switch is part of an effort on the part of the Obama Administration to make the white house a more interactive and “Web 2.0″ friendly place.  He is the first President to be addicted to his Blackberry after all.

House Passes Health Care Bill with Public Option

It looked dicey, but last night it happened.  The House passed the health care bill with a public option.  I’m not sure the Senate will keep the public option–regarless of 60% approval ratings for it in the public.  But, we’ll see.

According to the Huffington Post:

The Congressional Progressive Caucus had pushed hard for a “robust” public option that would have reimbursed providers using Medicare rates. Blue Dog Democrats beat back that effort, costing taxpayers $85 billion over ten years — money that will go to hospitals, doctors and drug makers, increasing the cost of health care.

The bill also prevents insurers from discriminating against people with preexisting conditions, caps the financial responsibility that insured individuals will face when medical emergencies strike, bans insurers for dropping folks because they get sick, and proposes a host of other insurance industry reforms.

It passed with only 220 to 215 votes.  All of them were Democrats except for one, Rep. Anh “Joseph” Cao, R-New Orleans.

“Twenty percent of the people in my district are uninsured and we have tremendous health care issues in the district, and I believe this is good for the people of my district,” Cao said minutes after the vote.

“I feel both courageous and lonely,” he said.

You can read the entire bill here.

Happy 40th Sesame Street: Let’s Count to 12!

This is how I learned how to count to 12.  Arguably the coolest counting song of all time (sung by the Pointer Sisters).  Thanks Sesame Street.

Ardipithecus, Poster Child for an Evolutionary Adaptive Plateau

“Ardi”, or Ardipithecus ramidus, has been much in the news lately.  Most of the reporting has been decent, but there are some clearly over hyped ones.  Thankfully, Paleoanthropologist John Hawks wrote an article for Seed magazine about Ardipithicus and its significance to the ongoing science of human origins.  He also wrote up a great FAQ page on his blog, where he goes into some real detail.

As paleoanthropologist C. Owen Lovejoy describes it, Ardi gives us a view of a previously unknown “adaptive plateau” among early hominins—a suite of anatomical and behavioral characteristics that lasted for a long, stable period in the early Pliocene environment. The Ardipithecus form might account for the bulk of the whole story of human evolution—a kind of hominin that was different from anything that came before or after.

New Paint Job

As you can see (unless you’re reading this via RSS or email), I’ve changed the look slightly of the blog.  It’s not a major shift, but I dropped one of the sidebars, and changed the decorations and fonts.  I’m still using Sandbox 0.6.1, but while the old theme was based on Biology by Ntuat, this new one is based on Blog.txt by Scott Allen Wallick.

The skeleton pic in the top right hand side of the blog is Ardipithicus, or “Ardi”, the new fossil that is getting so much press. It’s a bit large and creeps into the text, so I may need to alter it.  I’m planning on having the image change periodically, for fun.

I’ll be tweaking the CSS here a bit till I get it “dialed in”.  Hopefully that won’t seem to jarring to you.

Parochial Altruism and War: A Game Theoretic Analysis

North America during the Pleistocene

War, what is it good for?  Apparently, altruism.  In a paper published in Science, Samuel Bowels and Jung-Kyoo Choi took a game-theoretic approach to studying the evolutionary roots of both altruism and parochialism.  They concluded that neither would have likely evolved alone, but instead co-evolved, together being a powerful combination in the survival kit  of our Pleistocene and early Holocene ancestors.

Abstract

Altruism–benefiting fellow group members at a cost to oneself–and parochialism–bostility toward individuals not of one’s own ethnic, racial, or ther group–are common human behaviors.  The intersection of the two–which we term “parochial altruism”–is puzzling from an evolutionary perspective because altruistic or parochial behavior reduces one’s payoffs by comparison to what one would gain by eschewing these behaviors.  But parochial altruism could have evolved if parochialism promoted intergroup hostilities and the combination of altruism and parochialism contributed to success in these conflicts.  Our game-theoretic analysis and agent -based simulations show that under conditions likely to have been experienced by late Pleistocene and early Holocene humans, neither parochialism nor altruism would have been viable singly, but by promoting group conflict, they could have evolved jointly.

Background

Even Darwin noted that war was a powerful tool “used” by evolution to increase  altruism and solidarity toward ones own group members.  But, there have been two major questions lingering.

1. What is the process by which war became common enough to support the evolution of altruism in this context?
2. What is the likelyhood that altruism itself (conditioned on group membership) contributed to the high levels of lethal intergroup conflict among humans?

Neither of these questions has been well enough analyzed and was one of reasons the authors did their study.    Empirically, both altruism and hostility are quite important to members of other groups.

The empirical importance of both altruism and hostility to members of other groups is well established.  Experimental and other evidence demonstrates that individuals often willingly give to strangers, reward good deeds, and punish individuals who violate social norms, even at a substantial personal cost (4), while favoring fellow group members over “outsiders” in the choice of friends, exchange partners, and other associates and in the allocation of valued resources (5).

They site an example of a case in Papua New Guinea, “There exists strong favoritism toward ones-own linguistic group in giving to others,”  and a higher tendency to punish those from different linguistic groups.

They use the term Parochial Altruism in reference to a person to mean that when a person engages in hostile and aggressive behavior with another group, this person incurs a mortal risk, therefore a fitness loss verses those who refrain from such aggression.

Knowing Parochial altruism exists and assuming that neither Parochialism nor Altruism would have evolved in an environment (that is survived a selection process) that favored some other trait that resulted in higher payoffs, then how DID Parochial Altruism evolve?

A Solution

One possibility is that since oiur ancestors lived in a hostile environment where resources were scarce, Parochial Altruism could have evolved and thrived because those groups with high numbers of Parochial Altruists would have been more able to engage in aggressive action and “win” on behalf of their groups.

The two most important correlates of tribal warfare are natural disasters and resource scarcity.  The Pleistocene and early Holocene (roughly 125,000 to 10,000 years ago) are known to have been times of substantial volatility.  They also coincide with the most significant periods of human evolution.

Could Parochial Altruism have evolved in such a climate?

The Game

Bowel’s and Choi’s model consists of 4 types of players.

1. PA:  Parochial Altruists
2. TA: Tolerant Altruists
3. PN: Parochial Non-Altruists
4. TN: Tolerant Non-Altruists

Note that Parochials of both types are hostile toward other groups.  But, ONLY Parochial Altruists will engage in combat.  This is because PN’s won’t risk death for the benefit of others.

Their model has two types of selection acting at once.  Intra-Group selection favors TN’s and tends to eliminate PA’s.  And, Inter-Group selection which favors PA’s via selective extinction.

In a purely risk vs. reward scenario, it makes little sense to be a PA.  While there exists two benefits to winning a war (namely 1. Greater chance of future survival, 2. Opportunity to reproduce, thereby replacing those PA’s lost in war), the risk of mortal death incured by war “offsets this direct benefit by a wide margin.”  Therefore, each PA would be better off adopting a different strategy, in terms of their own reproductive fitness.  This confirms that PA’s are, indeed, altruistic according to the traditional meaning of the term.

3 Stage Game

The game runs in 3 stages.   In stage one, when two groups A and B meet, there is a probability that they will engage hostilely.  If they do not, then the game ends.  If  their interaction is hostile, they move on to stage two.

Stage two, given that their interaction is hostile, there is a new probability that A and B will goto war.  If they don’t, they move on, game is done.  If they do, stage 3.

Stage 3, they are now at war, the group with the higher number of PA’s has a higher probability of winning.  If this group is A, then A is more likely to win a war against the PA deficient group B.   Given that A is stronger (ie, has more PA’s) there are two options:  A and B draw, and the result is simply that both groups lose a certain number of fighters (PA’s); or A wins, and still loses a certain number of fighters, but also now gains a number of replicas that make up for that loss.

From B’s perspective, given that B is weaker (has less PA’s), there is only Draw or Lose. B could get lucky and draw, and only lose some PA’s.  But, there is a higher likelyhood of a loss.  In this case, B loses both fighters (PA’s) and civilians (made up of the other types).

In the paper they are quite explicit about what these probabilities are and why they chose them.  But, the point is that not every encounter with another group is hostile, not every hostile interaction results in war, and every war is won with a higher probability if you have a large number of PA’s.

Conclusion

They ran this game through a number of iterations accounting for hundreds of generations.  They found that transitions from quite tolerant non-altruistic (read: peaceful) groups to bellicose parochial altruistic groups can happen very rapidly–in about 200 generations, or about 5,000 years.

The markedly higher reproductive success of predominantly parochial altruist groups when interacting with groups with fewer parochial altruists could therefore explain the rapid range expansions that are thought to be common among some late Pleistocene human groups, and thus may partly explain sthe still puzzling second great hominid diaspora that swept from Africa as far as Australia in the course of no more than 10 millennia.

This study aids in the study of why group boundaries have such a profound effect on human behavior, from an evolutionary perspective.

In conclusion they add:

We have explained how Homo Sapiens could have become a warlike yet altruistic species.  But there is no evidence that the hypothetical alleles in our model exist, or that were they to exist they could be expressed in the complex behaviors involved in helping others and engaging in lethal conflict.  Theus, we have not shown that a warlike genetic predisposition exists, only that should one exist, it might have coevolved with altruism and warfare in the way that we have described.

They make a good closing point.  Theoretical (ie, mathematical) biology doesn’t “prove” that certain things are true.  It tests the validity of certain hypothesis and ideas, thereby opening up further possibilities for empirical research.

References:

Choi, Jung-Kyoo, and Samuel Bowles. 2007. The Coevolution of Parochial Altruism and War. Science 318, no. 5850 (October 26): 636-640. doi:10.1126/science.1144237.

Be a Heathen, Save a Pet

Eternal Earthbound Pets

If you are a devout Christian who is afraid what will become of your pet when the rapture comes and you are whisked off to heaven, then have I found the organization for you.

Eternal Earth Bound Pets is a charitable organization designed with your needs in mind.  Here’s the basics:

You’ve committed your life to Jesus. You know you’re saved. But when the Rapture comes what’s to become of your loving pets who are left behind? Eternal Earth-Bound Pets takes that burden off your mind.

We are a group of dedicated animal lovers, and atheists. Each Eternal Earth-Bound Pet representative is a confirmed atheist, and as such will still be here on Earth after you’ve received your reward. Our network of animal activists are committed to step in when you step up to Jesus.

Are you a confirmed Atheist?  Make sure you meet these requirements as stated in the Websites FAQ section:

Q: How do you ensure your representatives won’t be Raptured.

A: Actually, we don’t ensure it, they do. Each of our representatives has stated to us in writing that they are atheists, do not believe in God / Jesus, and that they have blasphemed in accordance with Mark 3:29, negating any chance of salvation.

In case you are in fact a lifelong Atheist and don’t know anything about Mark 3:29, here it is (from the New International Version of the Bible … ideally, that should mean nothing to you):

But whoever blasphemes against the Holy Spirit will never be forgiven; he is guilty of an eternal sin.

So, if you’re holy, find a heathen and feel secure.  If you’re a heathen, now is your time to do some good.  But don’t do TOO much good.  We wouldn’t want you getting yanked up to heaven against your will, leaving the poor pet all alone.

Gettin’ Boney With It: 78th Four Stone Hearth at Paddy K

Paddy K is hosting the 78th Four Stone Hearth Anthropology Blog Carnival, and the theme is Bones.

I was particularly interested by Adhominin’s look at mid Pleistocene Heidelbergensis.

At the conference, much attention was focused on the Middle Pleistocene “muddle in the middle” [3], particularly the role of Homo heidelbergensis in hominin evolution. While H. heidelbergensis possesses both archaic and derived traits intermediate between H. erectus and later members of the Homo genus, it lacks uniquely derived traits or autapomorphies, which are a prerequisite for defining a species.

H. heidelbergensis has traits that have been interpreted as nascent Neandertal autapomorphies, leading some researchers to propose that there was a continuous evolution of Neandertals [4-6]. This accretion model would make H. heidelbergensis a chronospecies on the continuum of the Neandertal lineage, a view championed by Jean-Jacques Hublin. The accretion model proposes that Neandertals evolved by anagenesis, i.e. non-branching evolutionary change.