john hawks weblog

A new paper in PLoS Biology by Xiaoxia Wang and colleagues finds that a gene called CASPASE12 (OMIM) has been under recent selection in humans. The twist is that the allele with a selective advantage is actually a null allele -- it doesn't produce any functional protein.

The substitution of a nonfunctional allele for a functional one produces a "pseudogene" -- a sequence with the form of a protein-coding gene, but that doesn't actually produce a protein. So the authors discuss this as a case of "pseudogenization", and trace the reason to one of the functional consequences of the loss of protein: increased survivorship from sepsis.

Our population genetic study provided strong evidence that the nearly complete fixation of a null allele at human CASP12 has been driven by positive selection, possibly because it confers resistance to severe sepsis. CASP12 is a functional gene in all mammals surveyed except humans [34], suggesting that it is indispensable in a typical mammal. The functional human CASP12 acts as a dominant-negative regulator of essential cellular responses including the necrosis factor-kappaB and interleukin-1 pathways; it attenuates the inflammatory and innate immune response to endotoxins [34]. Because an appropriate level of immune response that is neither excessive nor insufficient is important to an organism, one can imagine that the immune suppression function of CASP12 becomes harmful when the immune system cannot fully respond to a challenge. It is likely that during human evolution alterations in our genetic and/or environmental background resulted in a malfunction of the immune response to endotoxins, which rendered the previously necessary function of CASP12 deleterious in humans and the null allele advantageous over the functional one. Identification of such genetic and/or environmental alterations will be valuable for understating human-specific immune functions.

Sepsis is infection of the blood. It is most often caused by one of two bacteria: Staphylococcus and Streptococcus. These bacteria are near-ubiquitous, but each has pathogenic forms that are really nasty if they get into your blood. Drug-resistant forms are among the leading causes of death in hospitals today -- most of what you've heard about the problem of antibiotic resistance is directed toward finding solutions to hospital-related sepsis.

Of course, sepsis is never good. But drug-resistant bacteria in hospitals haven't been around very long. So we have to consider what used to cause sepsis, before hospitals did. Sepsis is a complication of many pathogens and wounds -- infections run wrong progress first to sepsis, then to death.

One form of sepsis strikes me as especially bad, and possibly especially common in history and prehistory: puerperal fever.

Puerperal fever used to be a common complication of birth. I like this intro from iVillage:

It turned maternity wards into morgues, but today few pregnant women have even heard of puerperal fever, an aggressive infection of the reproductive system following childbirth. It probably changed the course of English history by killing Jane Seymour, third wife of Henry VIII. It destroyed Isabella Beeton and ruined her husband's life and business. It finished off proto-feminist Mary Wollstonecraft, leaving Mary Shelley motherless.

In the 1700s, when it was known as childbed fever, puerperal fever could claim the lives of as many as 20 per cent of new mothers and would sweep through communities in terrifying epidemics. The infection - most commonly the bacteria staphylococcus and streptococcus - was often carried on the dirty hands and medical instruments of doctors and midwives.

For a long time, women (especially urban women) who sought out doctors to attend births had a way of ending up dead. One doctor might visit dozens of women, killing them all. During this time, women who lived in the country, were delivered by midwives, or just couldn't afford a doctor paradoxically did much better.

This is one of those things that makes you wonder why it took so long to come up with the germ theory.

Although it had its greatest incidence in the crowded cities of Europe 200 years ago, childbed fever was an omnipresent risk of birth throughout human history. Strep and staph are everywhere, and from an immunological perspective, women are uniquely vulnerable to sepsis after birth. Put the two together, and you have one of the major causes of mortality happening at a time that kills both mother and child.

So sepsis -- particularly this kind of sepsis -- was common and severe in terms of mortality. An allele that protects against it ought to be strongly selected. And although Wang et al. estimate the selection coefficient from sepsis survivorship data, seelction at the time of birth in reproductive age women will have more of a fitness effect. According to the study, there may be at least two others besides CASPASE12:

Pseudogenizations of the two paralogous MBL1 genes in humans and the finding that deleting Mbl1 increases survival in a mouse model of sepsis suggests that the losses of the two human MBL1 genes may have also been driven by positive selection. The common connection to sepsis among CASP12 and the two MBL1 genes reinforces the conjecture that the way humans respond to sepsis and/or the threat of sepsis to humans might have been significantly different from those in other species.

One of the aspects of CASP12 variation noted in the study is the near absence (total in their sample) of the functional allele among non-Africans, and its presence among 12 percent of Africans in their sample. I think it's too early to make much of this, considering the limited samples -- is it in Australia, for instance? They interpret it as meaning that an out-of-Africa bottleneck made it more likely to be fixed outside of Africa. I would read the opposite conclusion -- perhaps the allele originated outside of Africa and hasn't swept to fixation within Africa yet. In any event, it points out two things -- dating these events is tricky because you need to know about selection intensity if you don't know about recombination frequency, and some of these recent selection events are near fixation. The not-yet-fixed is one reason for differences in selected variants between populations, the too-new-to-spread is another.

References:

Wang X, Grus WE, Zhang J. 2006. Gene losses during human origins. PLoS Biol 4:e52. DOI link

Back from the physical anthropology meetings in Anchorage, Kate Wong of Scientific American is posting news about the hobbits.

I won't quote much, so you'll go read it, but here's a tidbit:

[Taylor and van Schaik] found that individuals in one of these subspecies--Pongo pygmaeus morio, which resides in northeast Borneo--have a significantly smaller average cranial capacity than members of the other groups.

There will be further updates!

No story yet, in the history of the weblog, has had so many people writing to ask me if I am alive. Even my parents are asking me if it's real.

I am alive, and I have to say it is somewhat heartening that so many people care whether I'm watching. It's been sort of like H.G. Wells' Time Traveller (no Morlock jokes, please), just watching a couple weeks of this story's progress makes a few things about paleoanthropology and the press much clearer.

It is not a hoax. It is a BBC publicity blitz. And to me, it seems like a stunningly cynical PR blitz. In other words, we're being played.

First, the facts, which can be drawn both from a working paper by psychologist Nicholas Humphrey, John Skoyles and Roger Keynes, as well as the published paper in International Journal of Neuroscience by Uner Tan, and the genetic paper by Turkmen et al. (2005) in Journal of Medical Genetics :

1. There is a family of people in Turkey with 19 children (many adult), 6 of whom have a congenital form of cerebellar ataxia -- a condition in which the cerebellum does not develop to a normal size, with effects on muscle coordination and cognition.
2. Five of these six affected individuals walk on all fours, with their palms to the ground. One walks bipedally.
3. The cognitive deficits in the affected individuals include some linguistic limitations, although they communicate in Kurdish with a limited vocabulary and some can speak Turkish as well.
4. This family was studied by Turkish neuroscientist Uner Tan. Uner Tan is a real, live person (some have speculated that the name might be an anagram for "nature", indicative of a hoax). He has had a long career in neuroscience, and has a substantial publication record extending through the last several years.
5. Tan claimed in his paper that the connection between cognitive deficits (particularly emphasizing the linguistic) and the quadrupedal gait might indicate a link between these characteristics in the evolution of humans. Tan explicitly raises the idea of one or more macromutations causing bipedal locomotion to emerge suddenly from a quadrupedal ancestor, in association with human cognitive abilities. In his paper, the syndrome is described as a live model for human evolution.
6. A British group of researchers, including Nicholas Humphrey, were invited to investigate the family. A documentary film production became involved at this point.
7. A German team of geneticists took samples from the family, and found a region on chromosome 17 that appears to be associated with the ataxia (they term hypoplasia). The condition appears consistent with a recessive Mendelian inheritance; the parents are first cousins (once removed), which raises the likelihood of a recessive disorder being expressed. The German team claims that the gene involved may shed light on the evolution of bipedality.
8. Humphrey, Skoyles and Keynes deny that the disorder gives any indication of a coevolution of bipedality and language. Indeed, they are skeptical that the genetic basis of the trait says anything about the evolution of bipedality at all. However, they believe that the affected individuals have a unique form of quadrupedal gait, which they call "wrist-walking" because weight is borne on the heel of the palm. They argue that this form of locomotion may be a better model for the ancestral quadrupedalism of hominids than knuckle-walking.
9. The documentary is scheduled to run on BBC2 Friday, March 17 at 9:00 pm.

What about the science?

Of course, the most important question is whether any of this actually contributes to understanding human origins. Generally, I think the answer is no -- not just an itsy-bitsy no, but a great big honking no.

But I will qualify that for a couple of aspects of the story, since there is the potential of finding some interesting facts. So I will cover the different hypotheses in turn:

Is Uner Tan right? Is the condition really evidence of a rapid coevolution of bipedality and language? No. Human bipedality and human cognition are both highly complex traits involving anatomical, developmental, and behavioral specializations. Each of them involved hundreds, and for cognition I would say thousands, of different genetic changes. There was no small set of macromutations that caused these traits to arise.

Furthermore, the pathology manifested in this family does not indicate any kind of earlier evolutionary stage. There was no time when people with modern human limb proportions walked on all fours. It is doubtful that australopithecines, who were largely apelike in their cognition, ever walked on all fours. A developmental disability that causes mental retardation and inhibits the development of normal bipedal walking does not indicate any kind of earlier form of hominid.

Tan's paper has but a single reference in its bibliography -- to himself. And he's an editor of the journal, International Journal of Neuroscience. It happens every year or so that some paleoanthropology story breaks about a paper in some non-anthropological journal. These don't benefit from peer review by paleoanthropologists.

Is the gene underlying the condition important to the evolution of bipedality? This hypothesis is almost impossible to test, because "important" could mean almost anything. If "important" means that the gene underwent at least one substitution as a result of its relationship to bipedality, then the answer may well be yes.

But that doesn't really show that the gene is "critical" or "crucial" or "significant" or any other random signifier. If what we mean by "important" is that bipedality would not be possible without a particular genetic change in that gene, well, I think that is pretty difficult to test. You would have to show a link between gene expression profiles and the development of bipedality in normal people, not pathological ones. You would have to demonstrate a history of substitutions in the gene that match the timing of bipedality. And you would have to show that other functions of the gene either did not interfere with its evolutionary role in bipedality or were deemphasized because of that role.

I think it's really unlikely that a gene that causes cerebellar ataxia was a critical bipedality gene. It may be necessary to walking normally, but it probably (indeed, evidently from the nature of the disorder) is very important to a lot of other things as well. A gene that breaks early brain development is no more likely than other genes to have a specific function role in the development or practice of bipedalism in humans. More on the genetics of broken development below.

Is the specific form of quadrupedalism -- the "wrist-walking" -- of these people a clue about the nature of pre-bipedal hominids? This is the most likely to be scientifically interesting. And it raises the possibility of a test, if you could find bony correlates of the wrist-walking that could be distinguished from knuckle-walking or other forms of locomotion. And the question is well within the tradition of paleoanthropology -- I mean, we even have people studying knuckle-walking anteaters for goodness' sake.

On the other hand, there are several reasons to be skeptical. The working paper by Humphrey, Skoyles and Keynes only includes a couple of paragraphs on the evolutionary question, so it isn't fair to suppose they have presented a summary of all the pluses and minuses of the hypothesis (that early hominids or their ancestors were wrist-walkers in this way). What it has going for it is that early hominids were not chimpanzees or gorillas. Their hands had finger and thumb proportions much like ours, unlike the very short thumbs and long fingers of great apes. In other words, they were not adapted to suspension below branches in the way that apes are. So it is credible to think that if they walked quadrupedally, or evolved from a non-suspensory ancestor, that they might have different quadrupedal gait from living apes.

But although they didn't have the hands of apes, early hominids still had powerful wrist flexor muscles, as indicated by their curved hand bones and large carpal tunnels. The length and strength of these flexors -- necessary for suspension in great apes -- limit the extension of the wrist. This is one of the reasons why chimpanzees and gorillas are knuckle-walkers and orangutans are fist-walkers: their hands do not extend as easily to a palm-down position for weight-bearing. So although monkeys and other primates are palmigrade, apes are not. Humans can extend our wrists more readily, and walk palm-down when we want to, which is usually limited to the first year or two of life. But for early hominids, and presumably their ancestors, this may have been more difficult.

Now the most interesting part about the wrist-walking idea is that it might itself have caused greater hominid wrist mobility, which became more important to hand control and flexibility for toolmaking. But I think that more likely places the effect before the cause: if wrist flexibility and hand morphology evolved for the purpose of toolmaking, then there is no need to invoke an earlier wrist-walking stage. So while the speculation is worthwhile, I think it is unlikely to prove important.

Pathology and evolution

The fundamental question is how much a pathology can tell us about an evolutionary change.

Pathological individuals are by definition to some extent unique: they do not exhibit the characteristic pattern of development or behavior that for most people is normal. Their phenotype did not have to survive and reproduce in the past -- and in the present it generally fails to do one or the other. They may be helpful in uncovering the course of development -- if a critical stage does not happen, what effects does it have?

An analogy mentioned more than once in this story is the alleged relationship between the FoxP2 gene and the evolution of language. But a clear consideration of this link yields some insight about the difficulties linking pathology and evolutionary changes.

FoxP2 was singled out because of a mutant allele that causes specific language impairment in a well-studied family. The disorder has some other effects, but it targets language fairly narrowly. That argues that the normal form of the gene is necessary for normal language development. Moreover, the gene underwent a recent substitution in humans, with a new allele arising and becoming universal within the last 200,000 years. This change suggests the hypothesis that the rise of language required this substitution.

But as yet, that is only a hypothesis. And is quite a bit of evidence that detracts from it. For one thing, only two amino acid substitutions separate the human FoxP2 gene from the chimpanzee form. If this gene was critical for the appearance of language, that criticality did not involve repeated changes. Considering that language is a complex trait, that means that many other genes are probably also involved. Which are the critical ones? And does FoxP2 count as critical with only two possible changes? And how can we establish that the most recent sweep in FoxP2 was related to language at all? After all, evolutionary changes in other genes could have left language dependent on FoxP2 function, without necessitating any changes in FoxP2 function. So the link between FoxP2 and language is very suggestive, but to say that the gene is necessarily critical in the evolution of language is just not yet demonstrated.

The main point is this: the fact that a gene breaks something doesn't mean that it was the key gene necessary to create something. Suppose that you want to figure out how a car works. So you look at cars that aren't working right, and you see what is broken. Now, you will notice that cars run sort of poorly with flat tires, they run with depleted batteries but won't start, they will run for a bit without motor oil, but then seize up, and so on.

Cerebellar ataxia breaks a whole lot of things. It's like breaking the crankshaft -- the engine might run, but it is going to make a whole lot of noise, and the car isn't going to move. We may conclude that the crankshaft is necessary for the wheels to move. But does that mean that the crankshaft is the key component of the wheel? Clearly not.

The analogy between cars and organismal development is useful because both systems depend on hierarchical functions. Early things must all work right for later things to develop. When an upstream gene (or part) breaks, it doesn't mean that downstream things affected by the broken gene were caused by the broken gene.

But in biological systems these hierarchical functions sometimes involve the same genes -- regulation can make early-acting things also have later effects. So we may not prove out a critical relationship between a gene and a function on the basis of pathology, but we may find it equally difficult to rule it out. Here it is clearly useful to keep in mind the null hypothesis -- the gene isn't the unique, specific, or important cause until proven otherwise.

In this context, it surprises me that nobody has commented on the other prominent connection between Nicholas Humphrey, pathology, and human evolution. One of his best-known essays compares the cave art of France and Spain to the figure drawings of autistic children. The point is that understanding certain pathologies in the present may give hints about the evolution of humans in the past. In the case of autism, the idea is that ancient human minds may not have had a very different ontogeny as language and the ability to use and understand symbols emerged.

The paintings and engravings must surely strike anyone as wondrous. Still, I draw attention here to evidence that suggests that the miracle they represent may not be at all of the kind most people think. Indeed this evidence suggests the very opposite: that the makers of these works of art may actually have had distinctly pre-modern minds, have been little given to symbolic thought, have had no great interest in communication and have been essentially self-taught and untrained. Cave art, so far from being the sign of a new order of mentality, may perhaps better be thought the swan-song of the old.

It is a more sophisticated idea than that autism is an atavistic trait -- a throwback to an earlier stage. It is an analogy -- the cognitive traits that autism affects may not have been present in some earlier human. I don't believe that story either -- although it may be worthwhile to explore what it would imply for certain human traits to be absent, the fact remains that ancient people had to live somehow. They were social primates, and traits underlying their (and our) sociality are deeply embedded in our development. Autism may affect some of those, for genetic or nongenetic reasons, but there is no reason to think that the trait associations found in that condition are relevant to the evolution of an earlier hominid.

With the quadrupedal story, they are on safer ground. But in that case, if the claims are not so bold, neither are the possible conclusions if they are right.

The PR

That some kind of PR machinery started this story is obvious. After all, a single-reference paper in an obscure neurological journal by a respected but obscure Turkish scientist would not ordinarily make international headlines. Nor would a story about a single family carrying a very rare mutation, regardless of what it did (indeed, the genetic paper by the German team in December did not create any press). And the fact that the documentary has clearly been timed to coincide with the release of Tan's paper is pretty blatant.

But this is the interesting part: Even the hoax-like appearance of it is part of the PR. The first news stories could not have broken through internationally without the sensationalist claims -- the "evolution running backward". To be sure, this story has had unusually long legs because newspaper editors are drawn to its freakshow quality (generally showing little apparent regard for its unfortunate subjects). And there is the video showing the people lurching around, which has become a popular e-mail chain mail. It is the same force that makes people tune into the Discovery Health Channel to watch "Trash Can Full of Skin", and "200 Pound Tumor".

Let's face it: World Science (slogan: "Long before it's in the papers") is not the New York Times. It seems like a great place to float a strange story. And after the first story, they followed up several times, first with news about the genetics.

By this time, blogs were on the story, and it might have been expected that I might write about it. I certainly got several e-mails from colleagues passing the story around. Thanks to all those who sent references and pictures!

It was not clear at this point that there was a documentary. That story emerged during the first week of March, with the BBC2 release, the producers at Passionate Productions themselves, and another World Science story about the feud between Tan and the British researchers. This story raised the question of payments to the family associated with the research and documentary, quoting bioethicist Arthur Caplan.

At this point, mainstream science writers picked up the story, notably including The Times online and a skeptical Carl Zimmer. And in what I think may be the first case of active blog-publicity-managing by a key player in an emerging paleoanthropology story, Zimmer retracted his post after a correspondence with Nicholas Humphrey [see update below]. And National Geographic News covered the story with perhaps the most unintentionally hilarious quote I've seen in a long time:

This bizarre case is not a hoax, according to experts who have studied the family.

The cynical part is that the entire progression of the story was predictable without any necessity of orchestrating it. You see, it has all happened before, with almost exactly the same sequence of events. It is the Flores story reborn.

Consider: a rare, unique, and strange discovery comes to light. Immediately many experts are skeptical, but it takes time for them to organize a response. In the interim, a few strong backers explain that unique evolutionary principles can explain the find, and some experts cautiously agree. Then, two things happen: first, there is a conflict between the Western backers of the find and a senior local scientist; second, a high-profile documentary appears in which the discoverers can take their case directly to the public.

It's an autocircus.

Only the documentary itself can save us from this madness. At least that seems to be the import of this quote from one of the producers, on Gene Expression:

Our film will, I hope, redress the balance and be seen as a sensitive, thorough and thought-provoking record of the family/phenomenon. We made it not for voyeuristic reasons (although of course the quadrupedal siblings are visually arresting) but because we thought it raised all kinds of fascinating scientific, and many other, questions. I think the reason it's created such a fuss because bipedality is something that defines us as human beings - separate and distinct from beasts - and their existence is challenging philosophically. You only have to look at the Bible, for instance, to see how the word "upright" is loaded with meaning about purity, morality etc. That's ingrained very deeply in us.

Yeah. Um-hmm. "Upright" is loaded with meaning about purity, morality, etc. Ingrained deeply. Yep.

UPDATE (3/14/2006): Carl Zimmer wrote me about his earlier comments, and wanted to make sure his post and retraction weren't taken out of context by either me or by readers who might not follow the link to his explanation. He writes:

As I explained, I retracted my post specifically because I realized I shouldn't be making speculations about the relationship between the research and the show if I hadn't done the reporting to back them up. In retrospect, I'd now says that if the post had been limited to my skepticism about their scientific claims, it would be still up now. But I screwed up, and I took responsibility for it. I don't appreciate your implication that I was being managed, which is not supported by the fact.

Definitely nothing sinister implied on my part, just that it is novel that somebody is watching blogs!

References:

Tan U. 2006. A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution. Int J Neurosci 116:361-369. DOI link

Turkmen S, Demirhan O, Hoffmann K, Diers A, Zimmer C, Sperling K, Mundlos S. 2005. Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. J Med Genet DOI link

This is too cool:

Scientists partially restored the vision in blinded hamsters by plugging gaps in their injured brains with a synthetic substance that allowed brain cells to reconnect with one another, a new study reports.

If it can be applied to humans, the microscopic material could one day help restore sensory and motor function to patients suffering from strokes and injuries of the brain or spinal cord. It could also help mend cuts made in the brain during surgery.

In principle, it seems like reconnecting severed nerves ought to be easy -- all you have to do is splice a long wire.

In practice, it's been nearly impossible. The nerve bundles are mostly composed of axons, the long branches of individual nerve cells that conduct impulses. So to fix a severed nerve, you can't just connect the opposite sides of the break, you have to coax new axons to grow across it.

So these folks have found a matrix that allows the neurons to grow through it, much as they do in the developing brain.

Within 24 hours, all of the animals treated with SAPNS showed signs of healing; with time, the gaps in their brain tissues closed up completely.

In the adult group, vision was functionally restored within six weeks. In one animal, the severed nerve tract was restored to more than 80 percent that of a normal animal. In other studies, the researchers found that nerves needed to be only about 40 percent healed for animals to have functional vision.

This is the simplest task of neural repair, fixing a wire. Fixing brains -- or building them -- will take a bit more, since we don't understand the complex connections that allow things to happen. But this is good, very good.

I found this quote from Vaupel et al. (2003) very interesting:

Death of the frail alters the composition of a cohort, lowering subsequent mortality and possibly offsetting increases in mortality resulting from cumulative damage.

Their paper is a commentary on a study of dietary restriction and longevity in Drosophila (Mair et al. 2003). Dietary restriction is known to promote longer lifespan in many model animals, including Drosophila. Mair et al. (2003) found that the effect of dietary restriction was not necessarily a long-term phenomenon -- instead, they found that the death rates of the flies were strongly determined by what they had been eating in the 2 previous days (!):

These investigators show that when flies fed a restricted diet are switched to a full diet, mortality soars to the level suffered by fully fed flies. Conversely, when the diet of fully fed Drosophila is restricted, mortality plunges within 2 days to the level enjoyed by flies that have experienced a lifelong restricted diet.

Vaupel et al. (2003) press the issue to consider the effects of lifestyle change on human mortality rates:

Following unification of East and West Germany (1989-1990), mortality in the East declined toward prevailing levels in the West, especially among the elderly (8, 9) (see the figure). Although conditions early in life do significantly influence human health and survival late in life (10), the German example--and other demographic data--provide strong evidence that such effects are of less importance (at least in more recent decades) than changes in current conditions (2, 11, 12). The second half of the 20th century saw a radical (and continuing) decline in old-age mortality in most developed countries: in Western Europe, for instance, from 1950 to 2000 the probability of surviving from age 80 to 100 increased 20-fold (13). Most of this increase is due to improvements in economic and social conditions and to ongoing medical advances (14).

Epidemiological and clinical research provide further evidence of the malleability of old age. For example, the risk of death for elderly smokers who quit falls, within 1 or 2 years, to a lower level than that suffered by recalcitrant smokers (15). There is a growing appreciation that even octogenarians and nonagenarians can substantially benefit from medical interventions such as cataract surgery (16) and hip replacement (17). Low-tech interventions at advanced ages can have an important impact. For instance, Fiatrone et al. found that physical training leads to significant gains in muscle strength, size, and functional mobility among frail residents of nursing homes: The oldest person studied (and helped) was 96 years old (18).

The bottom line is that mortality rates are malleable. They are changed not only by improvements in health, nutrition, and environment across the lifespan; they are also improved by short-term changes in older adults. That shouldn't really be a surprise (yes, I mean beyond the fact that this is a 2003 paper!), since most of us know somebody who, thanks to modern medicine, is living with some condition that would have killed them 40 years ago. But somehow medical changes seem to be exceptions, not "natural" in some way. The point of the experimental work and Vaupel et al.'s (2003) commentary is that medicine is not the only late-acting life-extender; broader changes in behavior, stress, diet, or social relationships.

Aristotle contrasted premature death with natural death due to old age--he asserted that nothing could be done about old age (19). More than 23 centuries later, many still believe that death rates at older ages are intractable (20). This view is reinforced by evolutionary theories of aging, which emphasize that senescence is inevitable because the force of selection against deleterious, late-acting mutations declines with age (21). Research over the past decade strongly supports an encouraging alternative--that aging is plastic and survival can be substantially extended by various genetic changes and nongenetic interventions (1-2, 5, 7-18, 20). For most species, damage to cells and tissues accumulates with age, and mortality rises. Nonetheless, aging is so remarkably pliable that interventions do not have to be lifelong. As illustrated by the Mair et al. report and other studies, interventions even late in life can switch death rates to a lower, healthier trajectory.

I'm thinking about this in the context of the new study by Rachel Caspari and Sang-Hee Lee (2006) in AJPA. Here's the abstract:

Increased longevity, expressed as the number of individuals surviving to older adulthood, represents a key way that Upper Paleolithic Europeans differ from earlier European (Neandertal) populations. Here, we address whether longevity increased as a result of cultural/adaptive change in Upper Paleolithic Europe, or whether it was introduced to Europe as a part of modern human biology. We compare the ratio of older to younger adults (OY ratio) in an early modern human sample associated with the Middle Paleolithic from Western Asia with OY ratios of European Upper Paleolithic moderns and penecontemporary Neandertals from the same region. We also compare these Neandertals to European Neandertals. The difference between the OY ratios of modern humans of the Middle and Upper Paleolithic is large and significant, but there is no significant difference between the Neandertals and early modern humans of Western Asia. Longevity for the West Asian Neandertals is significantly more common than for the European Neandertals. We conclude that the increase in adult survivorship associated with the Upper Paleolithic is not a biological attribute of modern humans, but reflects important cultural adaptations promoting the demographic and material representations of modernity.

This would seem to indicate that recent human cultural innovations, as encompassed within the Upper Paleolithic of Europe but presumably shared by all living and recent people, were responsible for a vast increase in the survivorship of younger adults. More people were reaching older ages. This doesn't necessarily mean that these early modern people matched the longevity of historic populations, but it does mean that they must have escaped or delayed many of the major sources of mortality affecting earlier modern and archaic humans. And rather than being an aspect of human phylogeny, specifically the cultural changes indicated by 25,000 years ago appear to have been key.

The work on experimental animals and recent human demography comes together to indicate that nongenetic, environmental changes in mortality can be substantial. Not only can they be great, but they may be highly sensitive -- small changes in parameters may have a large impact on the chance of death. It doesn't take much figuring to realize that a small decline in age-specific mortality may have a large effect on average lifespan.

The death of the strong alters the composition of a cohort also. When a key person dies, it has ripple effects on small human groups. For people living on the edge, when a key person takes a risk, it impacts the entire group's chances of survival. When risks are less necessary, the entire group may benefit.

The secret to understanding the evolution of longevity is to show the channels through which changes in human culture allowed reductions in mortality. These changes are technological, organizational, and -- very possibly -- spiritual. All ways that humans deal with risk.

References:

Vaupel JW, Carey JR, Christensen K. 2003. Aging: It's never too late. Science 301:1679--1681. DOI link

Caspari R, Lee S-H. 2006. Is human longevity a consequence of cultural change or modern biology? Am J Phys Anthropol (in press) DOI link

There is a great article by Mary McKinney in Inside Higher Ed with advice about getting out of a procrastination funk (via Daniel Drezner).

General Norman Schwartzkopf once said, "The truth of the matter is that you always know the right thing to do. The hard part is doing it."

How true. And while wallowing in guilt at my own delay, my mind wandered to the many academics who go AWOL. I thought about graduate students who avoid campus to hide out from advisors, the professors who leave advisee e-mail unanswered, the peer reviewers who neglect reading manuscripts they've agreed to referee, the research collaborators who delay returning phone calls, and the purported authors of book chapters who ignore frantic pleas from colleagues compiling edited volumes. AWOL academics are rampant. Late manuscripts are endemic.

These disappearing acts lead to pernicious cycles. The longer you are out of touch with someone, the more difficult it feels to resume contact. The more you worry about resuming contact, the higher your standards become for the promised project.

There are several steps of advice, and the first three are very good:

1. Realize that your absence weighs heavier on your mind than the other person's. Advisors are not losing sleep over late dissertation proposals and journal editors aren't agonizing over missing manuscripts. The project is more important to you than anyone else.

2. Remember, when you do get in touch, the person is unlikely to be angry and punitive. We tend to be much harsher about our own tardiness than we are about other people's delays. Advisors know it is difficult to write dissertation drafts. Journal editors are accustomed to academics who take a long time to turn around R&R manuscripts.

3. Lower rather than raise your standards when you're running late. Don't try to make your work more polished to make up for taking so long. Just try to get something sent out for feedback. End the cycle by chanting to yourself "A done dissertation is a good dissertation" or "A published paper is the only paper that counts."

Believe me, I have nobody in mind while posting this! Not even myself. Oh, wait...

I'm linking to this 1994 review article by Ernest Beutler (straight to PDF) because (a) it has over 400 references that pretty much cover every bit of G6PD knowledge up to 1994, and (b) the PDF is protected so I can't save a local copy.

This is really getting annoying. This article is from the archives of Blood and it is available for free download, for goodness sake! Meanwhile, I can hardly save a Nature paper anymore -- I've had some sitting open on my computer for weeks and I can't close them without having to go download them again.

I guess I'll probably start linking such things here more, just so I don't have to Google things I've already read.

UPDATE (3/8/2006): Thanks to all the readers who sent me the article! The DRM doesn't work on everyone but the current OS X seems to be especially clever about defeating my attempts to get around it (including your suggestions). The best I have seen so far is a compiler switch for Xpdf, so if you're technically inclined, there you go.

The ironic part is that I ended up cutting the G6PD reference from the paper! Oh, well; it will return in the longer version.

I've heard from several readers that the RSS feed isn't working for them. This is another of those problems where I can't replicate the problem myself (it works fine wherever I check), but I know it must actually be real because so many people have let me know!

I updated my server some time ago to an RSS 1.0 feed; for the time being I'll go back to RSS 0.71 to see if that helps.

If that breaks RSS for you, let me know!

UPDATE (3/8/2006): OK, that serves me right. Switch RSS and break the server! Meanwhile, I've noticed that RSS problems seem to correlate with posts that include non-standard HTML characters (for example, when I excerpt from another site that uses long em-dashes and forget to find-and-replace them). I guess some RSS readers can't deal with them? One of the hazards of site maintenance...

Seed magazine has a very good summary of neurogenesis and profile of Elizabeth Gould online, by Jonah Lehrer.

The structure of our brain, from the details of our dendrites to the density of our hippocampus, is incredibly influenced by our surroundings. Put a primate under stressful conditions, and its brain begins to starve. It stops creating new cells. The cells it already has retreat inwards. The mind is disfigured.

The social implications of this research are staggering. If boring environments, stressful noises, and the primate's particular slot in the dominance hierarchy all shape the architecture of the brain -- and Gould's team has shown that they do -- then the playing field isn't level. Poverty and stress aren't just an idea: they are an anatomy. Some brains never even have a chance.

It's a series of studies in "molecular scars", in which environmental factors have long-lasting effects on gene regulation, in this case inhibiting neuron growth and proliferation.

It's also a good description of the network of scientists studying the effects of long-term stress on the mammalian brain. Very good article.

I'm catching up on some blogging, and this story in New Scientist has been sitting on my computer for a couple of days:

Stealth sharks to patrol the high seas

IMAGINE getting inside the mind of a shark: swimming silently through the ocean, sensing faint electrical fields, homing in on the trace of a scent, and navigating through the featureless depths for hour after hour.

We may soon be able to do just that via electrical probes in the shark's brain. Engineers funded by the US military have created a neural implant designed to enable a shark's brain signals to be manipulated remotely, controlling the animal's movements, and perhaps even decoding what it is feeling.

Their plan is that making the shark smell phantom odors on the left will cause it to turn left, and vice versa -- sort of a horse-and-carrot approach. It's a trick they have already pulled off with rat whiskers:

The team is not the first to attempt to control animals in this way. John Chapin of the State University of New York Health Science Center in Brooklyn has used a similar tactic to guide rats through rubble piles (New Scientist, 25 September 2004, p 21). Chapin's implant stimulates a part of the brain that is wired to their whiskers, so the rats instinctively turn toward the tickled side to see what has brushed by. Chapin rewards that response by stimulating a pleasure centre in the rats' brains. Using this reward process, he has trained the rodents to pause for 10 seconds when they smell a target chemical such as RDX, a component of plastic explosives.

Now, my question is: will the sharks be our allies when the fearless superintelligent carnivorous, and (now) cyber-equipped mice finally escape our control and drive humanity to undersea refugia? Of course, if all these cyber-equipped animals get hooked to the internet, the mice will just turn the sharks against us to foreclose our escape!

As I see it, our only hope is that the trained dolphin squads are kept implant-free so that they will continue to hew to human command.