Over at my other blog I have a post up about inbreeding fundamentalist Mormons. When brown Muslims are hittin' it with near relations that warrants eyes averted, but if I point to slack-jawed Anglos, well, that is BoingBoing worthy. But in any case, my post focused on an older article about the prevelance of fumerase deficiency among many children within the fundamentalist Mormon community of Colorado city. But one thing struck me about the article, the top-down pro-natalist and conformist nature of the community seemed to be a perfect example of the functionalist notions of evolutionary biologists like David Sloan Wilson. He promoted the reemergence of functionalism and evolutionary analogies in sociology and anthropology in Darwin's Cathedral, the hyper-fecund & genetically inbred fundamentalist Mormons are an ideal case of a group level super-organism, but just like a putative lineage of human clones who reproduce parthenogenetically they are clearly doomed. I suspect that functionalism isn't totally bunk, but like socialism it looks better on paper than it is in practice, really successful long term societies are more decentralized, flexible and fluid.

Human Lineage-Specific Amplification, Selection, and Neuronal Expression of DUF1220 Domains:

...A genome-wide survey of gene copy number variation among human and great ape lineages revealed that the most striking human lineage-specific amplification was due to an unknown gene, MGC8902, which is predicted to encode multiple copies of a protein domain of unknown function (DUF1220). Sequences encoding these domains...show signs of positive selection, and are increasingly amplified generally as a function of a species' evolutionary proximity to humans...DUF1220 domains are highly expressed in brain regions associated with higher cognitive function....

From the conclusion:

The genomic regions that harbor DUF1220 sequences appear to be particularly complex and, as a result, different genome assemblies differ with respect to the predicted number of DUF1220-encoded sequences. However, two recent genome-wide BAC aCGH cross-species studies...independently support the findings reported here that DUF1220-encoding genes show human lineage-specific increases in copy number and appeared with remarkable rapidity. If they indeed are the result of strong positive selection, they may play an important role in human lineage–specific traits....

John Hawks has more.

98% sequence identity with a chimp? Yeah, but we're all human where it counts baby (no mention of sperm or testes in the paper). Figure below the fold.

As someone who makes no bones about being against politically correct evolutionary biology, I will take up RPM's call to link to Panda's Thumb's chapter-by-chapter rebuttal of The Politically Incorrect Guide to Darwinism and Intelligent Design. They fight Creationism so I don't have too!

Some encouraging gene therapy news in Science:

Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes

Using a retrovirus encoding a T cell receptor, we report here the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood. Adoptive transfer of these transduced cells in fifteen patients resulted in durable engraftment at levels exceeding ten percent of peripheral blood lymphocytes for at least two months post infusion. We observed high sustained levels of circulating, engineered cells at one year post-infusion in two patients, that both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

According to reports in Swedish media (i.e. Dagens Nyheter) two late-stage terminal patients out of 17 trial subjects were cancer free after 18 months.

UPDATE: Here is the flood of Google News articles.

Human bodies maintain an optimal environment for cellular function. Cold-blooded animals function sluggishly when cold. I've wondered how bacteria manage to function at different temperatures. I'd assumed that bacteria are highly adapted to either high or low temperatures and that homeostatic feedback maintains biological systems in a viable range over modest daily temperature changes. But what happens when their environment rapidly changes? Does that bacterial line die out? Perhaps not.

Bacteria beat the heat

"A general rule for enzyme reactions states that as the heat rises, so does the reaction rate. Contrary to this rule, and the scientist's expectations, both reaction rates peaked at a certain point, and remained steady thereafter. For each enzyme, the peak occurred in the bacteria's 'comfort zone.' Further comparisons of the enzymes, which were nearly identical, turned up differences in just two of the hundreds of amino acids making up the enzyme sequence. When the scientists replaced these two amino acids in the enzyme adapted to the moderate temperatures with those of the heat-loving enzyme, they observed an increase of about 10 degrees in the average temperature at which the reaction rate peaked. Scherz: 'This study shows that enzyme efficiency is tuned to the average temperature of the bacterial habitat, rather than the immediate conditions. This may protect the cells from harmful swings in enzyme activity' "

In this experiment, changing two amino acids in an enzyme changed the temperature of peak reaction rate. The bacteria colony could adapt to new temperatures with just a few mutations. Life has evolved to adapt rapidly to changing environments. Lifeforms that couldn't adapt went extinct.

A few weeks ago I watched the Robert Wright Ann Althouse diavlog. One thing that struck me was that in the beginning they addressed Althouse's political ideology (i.e., was she a libertarian?). Althouse offered that she considered herself an independent, who voted for Feingold and Bush in 2004, splitting her ticket. Up until that time she has uniformly voted Democrat. She observed that her own experience is that when she did not toe the right-wing line she was ignored, but when she agreed with the Right they praised her. In contrast, the Left ignored her because of their disagreemants on several issues. The general opinion was that the Left shunned heretics and the Right sought converts. Interestingly, Wright spent the rest of the diavlog being surprised when Althouse expressed liberal views on particular topics, and even hopefully mooted the possibility that she could "come back" to "their side." This, throughout an interview where she had expressed a host of different views, some on Wright's "side," and also offered that historically she tended to vote Democrat. Watch the whole thing, and this is not meant as a criticism (I don't really create except as a data point in favor of what Althouse has referred to), but Wright seemed to exemplify exactly the tribalist purity which Althouse claimed was a problem on the Left, ignoring their commonality.

Anyway, I don't comment much on politics on this blog because I have nothing to say, but I was pretty shocked that Wright behaved in such a manner even after addressing this tendency with Althouse.

In the wake of the British National Health Service denying IVF treatments to very obese women Big Fat Blog says:

This recommendation is discrimination, pure and simple. What the hell, really? Fat people are told they can't adopt and told they can't get pregnant (from both societal and medical angles); let's just add in some more. For people who want to get pregnant, this is a slap in the face. And it speaks a little more to social engineering, methinks - don't even allow fat people to breed, because, well, their kids might be fat. And you know what that means.

No comment.

(via Dr. Joan Bushwell's Chimpanzee Refuge)

The New York Times has an article about a Malay woman who converted to Christianity and now wishes to marry her fiance, who is also a Christian. Her problem is the ideology promoted by the Malaysian government that by definition Malays are Muslim. Additionally, Islamic tradition reinforced by shariah imposes strong sanction, up to capital punishment, upon those who apostatize from the faith. The day to day reality of apostacy varies, there are many unbelievers within the Muslim world, but their rejection of religion is not public and they do not generally follow another religion. The woman profiled in the article not only rejected Islam, but, she converted to another religion and is making her conversion public knowledge and attempting to assert her rights to conversion through the legal system. "Moderate" Muslim nations like Malaysia are in a twilight zone, attempting to reconcile the medieval center of gravity of world normative Islam with their own acknowledgement that the "next stage" in national development requires a relaxation of the coupling between traditional norms and state sanction. The power and strength of Christianity, in particular evangelical Christianity, in concert with the the suffocating march of international liberalism is that it will confront a large number of Muslims and force them to turn away from the older norms of exclusion, domination and anti-individualism (radical Protestants also played this role in northern Europe). One of the advocates for the woman in question is himself a Muslim; in nearby Indonesia it is not unknown for nominal believers in places like East Java to transfer their religious identification to Christianity or Hinduism. A similar process of religious competition occurs in much of Africa as Muslims become Christians and Christians become Muslim. But, the unfortunate reality is that the "center" of the Muslim world, Saudi Arabia and the Arab world, represent the other antipode of fluid toleration of freedom in regards to choice of religion. For the world of Islam these are the Edgardo Mortara moments, but the outcome will not be measured via such sensational cases, but rather by the slow but inevitable wheels of liberalism grinding away at the edifice of medieval social control.

A. W. F. (Anthony) Edwards is one of Britain's most distinguished geneticists. He studied genetics at Cambridge as one of the last students of R. A. Fisher, and like Fisher he has contributed actively to both genetics and statistics. In genetics his work includes several influential papers on the reconstruction of phylogenies, and a widely-read recent article on 'Lewontin's Fallacy'. In statistics he is known especially for his development and advocacy of the concept of Likelihood as a criterion for scientific inference. He has also made a notable contribution to combinatorial mathematics by finding a method of constructing Venn diagrams for any number of sets. In addition to many scientific papers, he has written four books: Likelihood (1972; expanded edition 1992); Foundations of Mathematical Genetics (1977; 2nd edition 2000); Pascal's Arithmetical Triangle: the Story of a Mathematical Idea (1987; expanded edition 2002); and Cogwheels of the Mind: the Story of Venn Diagrams (2004). He has written extensively on the history of genetics, mathematics, and statistics, and has co-edited (with H. A. David) Annotated Readings in the History of Statistics (2001), and (with Milo Keynes and Robert Peel) A Century of Mendelism in Human Genetics (2004). He is also a champion glider pilot.

To see his replies to our 10 Questions, click on "Read full post".



1. You were among the last students of R. A. Fisher. Can you share with us some reminiscences of him?

I first met Fisher in the summer of 1956 and had much contact with him until his death six years later. I saw him last during the Second Human Genetics Conference in Rome in 1961 and subsequently corresponded with him. I have published quite a few of my reminiscences of those times in a number of different places. I have been fortunate in having had a lot of contact with the older generation who knew him better than I did - people like Barnard, Bartlett, Finney, Yates, Race, Ruth Sanger and Bennett - and with members of his family, especially Rose, Harry and Joan (his biographer) amongst his children. Being a fellow of the same Cambridge college (Caius) as Fisher, though not at the same time, has meant daily contact with people who knew him well. But the most important thing is his science, and there everyone can get to know him through his writings, which reveal a mind of extraordinary power and vigour. That is the Fisher whom succeeding generations should learn about and admire.

2. Like Fisher you have worked in both statistics and genetics. How do you see the relationship between them, both in your own work and more generally?

In a sense I have benefitted from being an amateur in both fields so that I see no boundary between them. Though I qualified in genetics the subject almost immediately changed so radically through advances in molecular biology that most geneticists would not now regard me as one of themselves anyway. My generation thought genetics was the study of inheritance; theirs thinks it is the study of genes. As to statistics, I attended eight lectures by Henry Daniels in Cambridge but am otherwise self-taught, being hugely influenced by Fisher's book Statistical Methods for Research Workers which he told me to buy (and then signed for me). Genetical statistics has changed fundamentally too: our problem was the paucity of data, especially for man, leading to an emphasis on elucidating correct principles of statistical inference. Modern practitioners have too much data and are engaged in a theory-free reduction of it under the neologism 'bioinformatics'. We had to navigate by the stars; they have GPSs.

3. Much of your early work (some of it in collaboration with L. L. Cavalli-Sforza) was on methods of inferring phylogenies. How do you assess the progress in this field since the 1960s, and how have your own methods stood up to empirical tests?

All my work was in collaboration with Luca Cavalli-Sforza. It was his idea. He hired me to join his group in Pavia in Italy, not specifically to work on phylogenies but to apply the new-fangled computers to human genetics generally. The late delivery of the Olivetti computer was a blessing in disguise because it left us time to talk about what we would do with it when it came. I was initially sceptical because I knew that linkage was statistically difficult and here was Luca proposing what looked like linkage on a tree whose very shape also required estimating!

I think progress on the theoretical side has been incredibly slow, despite the best efforts of Joe Felsenstein, the leading practitioner. In a few months in 1962 and 1963 Luca and I thought up three ways of tackling the problem: least-squares on an additive tree (his), minimum evolution or parsimony (mine) and maximum-likelihood on a stochastic model (very much a joint effort). Forty-odd years on people are still arguing about the relative merits of the descendants of our methods when all along they should have been concentrating on refining the statistical approach through maximum-likelihood, which was our real contribution. Of course, from a practical point of view the computer packages have taken over in a development parallel to that in human genetics, from shakey inferences based on too little data and doubtful logic to computer algorithms trying to digest too much.

4. Your recent article on 'Lewontin's Fallacy' criticises the claim that human geographical races have no biological meaning. As the article itself points out, it could have been written at any time in the last 30 years. So why did it take so long - and have you had any reactions from Lewontin or his supporters?

I can only speak for myself as to why it took me so long. Others closer to the field will have to explain why the penny did not drop earlier, but the principal cause must be the huge gap in communication that exists between anthropology, especially social anthropology, on the one hand, and the humdrum world of population and statistical genetics on the other. When someone like Lewontin bridges the gap, bearing from genetics a message which the other side wants to hear, it spreads fast - on that side. But there was no feedback. Others might have noticed Lewontin's 1972 paper but I had stopped working in human and population genetics in 1968 on moving to Cambridge because I could not get any support (so I settled down to writing books instead). In the 1990s I began to pick up the message about only 15% of human genetic variation being between, as opposed to within, populations with its non-sequitur that classification was nigh impossible, and started asking my population-genetics colleagues where it came from. Most had not heard of it, and those that had did not know its source. I regret now that in my paper I did not acknowledge the influence of my brother John, Professor of Genetics in Oxford, because he was independently worrying over the question, inventing the phrase 'the death of phylogeny' which spurred me on.

Eventually the argument turned up unchallenged in Nature and the New Scientist and I was able to locate its origin. I only started writing about it after lunch one day in Caius during which I had tried to explain the fallacy across the table to a chemist, a physicist, a physiologist and an experimental psychologist - all Fellows of the Royal Society - and found myself faltering. I like to write to clear my mind. Then I met Adam Wilkins, the editor of BioEssays, and he urged me to work my notes up into a paper.

I have had no adverse reaction to it at all, but plenty of plaudits from geneticists, many of whom told me that they too had been perplexed. Perhaps the communication gap is still too large, or just possibly the point has been taken. After all, Fisher made it in 1925 in Statistical Methods which was written for biologists so it is hardly new.

5. You have written several articles about Fisher's Fundamental Theorem of Natural Selection. Following a groundbreaking reinterpretation by George Price in the early 1970s, it is now generally accepted that the theorem as intended by Fisher is valid, but some biologists would still question its practical use or importance. Can you explain in non-technical terms the meaning of the theorem, how the correct interpretation differs from earlier misunderstandings of it, and your own view on its biological importance?

Oh, it's very simple. You must first recall the precise name of Fisher's book in which it is the centrepiece: The Genetical Theory of Natural Selection. He is studying the mechanisms of natural selection from the point of view of populations regarded as aggregates of genes. Of course he knows, and stresses, that this is not the whole story. But to him selection's defining effect is to change gene frequencies. He sees that this will only happen if there is variability in the survival rates of different genes.

Animal breeders promote artificial selection by imposing different 'fitnesses' on their stock according to desirability, breeding from some and not from others. They thus raise the mean value in the population of the character desired. Fisher saw that this process implicitly relies on a correlation between the character and fitness, so that progress will depend both on the magnitude of this correlation and the extent to which the character is genetically determined. What happens, he then asked, if we designate fitness itself as the character, making the correlation perfect? The answer is that the mean fitness of the genes will increase by an amount that depends on the extent to which fitness is determined by them. This is the fundamental theorem (in a modern paraphrase): 'The rate of increase in the mean fitness ascribable to natural selection acting through changes in gene frequencies is equal to the additive genetic variance in fitness'.

The theorem does not involve the mean genotypic fitness - that is, the weighted mean of the fitnesses of the genotypes - which is where most interpreters of it went wrong. Fisher's repeated denials that his theorem referred to the mean genotypic fitness, itself immortalised in Sewall Wright's 'adaptive landscapes', went unheeded. In 1941 Fisher even published an example in which gene frequencies were changed under natural selection but the mean genotypic fitness stayed constant. Nobody noticed.

The brilliance of the fundamental theorem is not merely that it expresses the central dogma of natural selection - the connection between genetic variability and selective change - but that it does so exactly. Fisher discovered what the rate of change was proportional to: not to the total variance in fitness of the genotypes but only to that part of it found by fitting a weighted linear regression to the genotypic fitnesses. This is the part accounted for by the regression itself, the so-called additive genetic variance. Animal breeders know it as the variance of the breeding values of the genotypes. The fundamental theorem disregards the way the genes are distributed through the population, which will depend on the amount of heterosis in fitness, the extent of assortative mating, and similar possibly transient effects. What matters to it are the changes to the mean fitness brought about by changing gene frequencies.

This, then, is the theorem whose 'practical use or importance' 'some biologists would still question'. Let them ask the animal breeders if it is any 'use', and let them ask themselves whether they think Darwin's theory of evolution by natural selection is of any 'importance'. If they do, then the fundamental theorem should help them to a deeper, Mendelian, understanding of it. If, however, they hanker after a theory that can make evolutionary predictions, like Wright's adaptive landscapes were thought to do at one time, they are crying for the moon. Possession of the fundamental theorem will no more enable you to predict the flow of evolution than possession of Newton's law of gravitation will enable you to predict the time of high tide at London Bridge.

It should not be forgotten, however, that shorn of its genetical complexities the theorem does have predictive power, just as the law of gravitation does when applied to the celestial movements that underlie the tides. 'In a subdivided population the rate of change of the overall growth-rate is proportional to the variance in growth rates'. The 'populations' could be economic sectors, for example, or even one's own savings accounts.

6. Your career since the 1950s spans the period in which computers, and off-the-shelf programs, have become widely available. Has this been an unmixed blessing, and do you think the development of statistics or genetics would have been very different if computers had been available in, say, 1900?

A mixed blessing of course, because the existence of programs hinders the development of the underlying theory. This is particularly true in statistics where, despite assertions to the contrary by Bayesians, the underlying theory is still a matter for discussion. The phenomenon can be seen in the field of phylogenetic trees, where programs based on different methods proliferate.

1900 is a peculiarly well-chosen date on which to hang the question. Not only was it the year in which Mendel's results became widely known but it was also the year of the publication of the second edition of Karl Pearson's The Grammar of Science, which included chapters on biological science for the first time. The Grammar of Science was hugely influential in its day, proclaiming that the function of science was 'not to explain, but to describe by conceptual shorthand our perceptual experience'. 'The man who classifies facts of any kind whatever, who sees their mutual relation and describes their sequences, is applying the scientific method'. The computer implementation of this sterile philosophy would have had a devastating effect, particularly on the development of statistical theory and the acceptance of Mendelism. All Pearson's formidable energy would have been devoted to amassing vast quantities of information to be sifted for correlations. William Bateson's 1894 six-hundred-page Materials for the Study of Variation treated with especial regard to Discontinuity in the Origin of Species would have been digitally scanned and computer programmers urged to uncover its secrets. It doesn't bear thinking about!

7. In statistics you are especially known for developing and advocating the concept of Likelihood and its use in scientific inference. Can you explain how Likelihood differs from probability, and why Likelihood methods are useful in evaluating hypotheses?

Likelihood compares statistical hypotheses; it has nothing to say about a hypothesis on its own, like a test of significance does. Imagine two statistical hypotheses, each of which predicts the probabilities of all the possible outcomes of an experiment - which need be no more complex than tossing a biassed coin a number of times and counting the heads. The experiment is performed, the heads counted. Given this count, was the probability of heads p1 (the first hypothesis) or p2 (the second hypothesis)?

Now imagine doing the experiment lots of times assuming the first, and then the second, hypothesis. Would you not prefer the hypothesis that had the shorter expected waiting time until the exact number of heads observed turned up? If so, you have just chosen the one with the greater likelihood. The likelihood of a hypothesis is proportional to the probability of the data given the hypothesis. Meaningless for a hypothesis by itself because of the undefined constant of proportionality, with two hypotheses to be compared on the same data this constant is irrelevant, and the ratio of their likelihoods (or the difference in their log-likelihoods) becomes a measure of the support for one hypothesis versus the other.

Likelihoods therefore derive from probabilities, but unlike the latter are not additive. Whereas you can sum the probabilities of two possible outcomes of an experiment to form the probability of 'either one or the other', you cannot do the same for the likelihood of two hypotheses; 'either one hypothesis or the other' is not in itself a hypothesis enabling the probabilities of outcomes to be computed, so no likelihood for it is defined. But you can graph the likelihood as a function of p and pay special attention to its maximum, the maximum-likelihood estimate of the probability of heads.

The concept of the likelihood function is fundamental to all approaches to statistical inference, whether Bayesian, Neyman-Pearson, or Fisherian. Not everyone agrees that it is meaningful standing alone by itself, but I (and others before me) believe it is. Doubters can always fall back on the above 'how long to wait' argument, which I think was due to David Sprott.

8. You have written extensively on the history of genetics, statistics, and mathematics. Apart from the intrinsic interest of historical studies, how important do you think a knowledge of the history of science is for practising scientists?

I find it essential, and cannot imagine doing science without it. Much of what counts as science nowadays is rather theory-free. We don't really have a word for it. Sequencing the human genome, for example, is a marvellous achievement relying on technical advances of great ingenuity but it did not require historical understanding. It differs intellectually from, say, the associated activity of trying to estimate linkage values between gene loci. The history of the latter, on which I have written recently, is an essential part of the study of the problem, and much modern work suffers from its neglect.

Celebrating the centenary of the publication of the Origin of Species in 1959, Fisher said:
More attention to the History of Science is needed, as much by scientists as by historians, and especially by biologists, and this should mean a deliberate attempt to understand the thoughts of the great masters of the past, to see in what circumstances or intellectual milieu their ideas were formed, where they took the wrong turning or stopped short on the right track.
I agree.

9. R. A. Fisher was a keen eugenist. What are your own views on the role (if any) of eugenics in the modern world?

Fisher's world was so different from ours, in three ways in particular. Then (say the period between the wars) nation-states were much more independent of each other so that it was possible to discuss population matters for Britain in relative isolation; secondly, it was a time of concern about the possibility of a declining home population; and thirdly many scientists were in the first flush of enthusiasm for the application of Mendelian principles - so recently elucidated - to man. None of this is true today.

For myself, though I was once a grateful holder of a Darwin Research Fellowship of the Eugenics Society (now the Galton Institute), since boyhood I have been more concerned about the quantity of people on earth rather than their quality. In the early 1960s I was a founder-member of a body called, I think, the Conservation Society, which does not seem to exist today. Its main platform was that too large a population would be unsustainable. At the time there was much discussion about over-population which was seen as one of the greatest dangers facing mankind. Interestingly, the worse the problem gets, the less it is discussed. Yet the mounting dangers we face, such as the possibility of global warming, are all exacerbated by too high a world population, given its enthusiasm for motor-cars, aeroplanes, and environmentally-damaging activity generally. It seems that people fear the charge of racism if they comment on population growth - they intuitively understand Fisher's fundamental theorem.

10. Like yourself, your brother, J. H. Edwards, is also a distinguished geneticist. Nature, nurture, or sibling rivalry?

Well, certainly not sibling rivalry. It is true that we have been sufficiently alike at some stages of our lives to have been mistaken for each other. At the Rome Conference of Human Genetics in 1961 we were in a lift with the Swedish geneticist Jan Lindsten when he engagingly introduced us to another participant as 'the two most confused brothers in genetics'.

In fact I am 7 1/2 years younger than John, and due to mother's illness, father's war service, and wartime privations generally, I hardly encountered him until the end of the war when I was ten. We developed boyhood enthusiasms for science quite independently, he for biology, me for astronomy. But there was a common factor in our education from thirteen to eighteen. We both attended Uppingham School, though of course not at the same time, and were exceptionally well-taught in science and mathematics, in some cases by the same teachers. I cannot stress this influence too strongly. Since I only went to Uppingham because my elder brother did, is that nature or nurture?

Subsequently John's main influence was when I was learning about likelihood (see the preface to my book Likelihood). He, being medically qualified, keeps me straight on medical matters and I try to keep him straight on things statistical. I deliberately stayed off linkage theory so as not to get too close to his interests. John was more influenced by Lancelot Hogben and J. B. S. Haldane than I was. There is a wonderful letter from Fisher to R. R. Race in 1960 in which he refers to me as 'my Edwards from Cambridge' and to John as 'only one of Hogben's [pupils]', so at least Fisher got us straight.

And John introduced me to gliding. Though not exactly a 'champion', to use your word, I have enjoyed fifty years gliding and hope for a few more yet.

Labels: 10 questions

Within my brain, foun-tains over rugged moun-tains of my terrain, diggit I came too far to front. So I'm meditatin on how to maintain. Stepped off at City Hall into the rain... - Black Thought

That ain't a igloo, that's my watch. And that ain't snow, baby that's my chain. That's not an ice tray, that's my teeth. And that's not a snowcone, that's my ring. - Paul Wall

Two very important papers came out yesterday in Science. One (from the Bear Lab at Picower) demonstrates that inhibitory avoidance learning can induce LTP (long-term potentiation) in the hippocampus, and the other (from the Sacktor and Fenton labs at SUNY-Downstate) demonstrates that a particular variant of Protein Kinase C (PKC) known as PKM-zeta (that is necessary and sufficient for LTP maintenance) is necessary in the hippocampus for long-term maintenance of a spatial avoidance memory. Together, these papers make one much more confident about making predictions about the cellular mechanisms of memory based on electrophyz studies in the hippocampal slice. The Scientist has a nice summary of these two, and I suggest reading it. I think the two papers could be even further integrated by taking into account a recent discovery by the Malinow group concerning PKC's role in AMPA receptor trafficking.

By the way, as I get deeper into this post I realize that it is going to make no sense if you don't understand at least the basics of neurotransmission, so if you aren't comfortable with that try a little of this before you read on.

Update:From Todd Sacktor in the comments:

ZIP is quite specific to reversing late-LTP. We showed in Serrano et al. and Frey's lab showed in Sajikumar et al. (both in J. Neuroscience) that it did not affect baseline synaptic transmission or reverse early LTP. We are currently looking at other types of behavioral memory (including the inhibitory avoidance used in the Bear study).

It's too early to say whether GluR1 phosphorylation is that important for the PKMzeta effect.

Note also that the Bear paper showed that even training had miniscule effects on field potential recordings in the hippocampus. This was consistent with our observation of no effect of ZIP on baseline field recordings. It may not be that surprising that caged animals have no or few novel events in their lives, the memories of which are worth preserving in the hippocampus. Thank you for reading our paper, Todd

If all that above seemed like an alien language, just give me a second and I'll unpack it. First off, the behavioral paradigms. Inhibitory avoidance is sometimes known as passive avoidance. All the rat has to do to avoid a shock is to sit still, but the rat is placed on an inch-high platform in the light and the shock grid is in a dark area of the chamber. Rats would much rather be in this dark area, so they have a tendency to step down. The first time they do this, they get a mild foot-shock. Learning is measured by how long it takes them to step down a second time, but this paradigm is so widely used and consistent that we can assume the rat learned the association without even bothering with a test trial. It is not entirely clear just what it is that rats learn during inhibitory avoidance training. It seems that they should be learning an association between the stepping behavior and the shock. On the other hand, inhibitory avoidance could just be a fancy version of contextual fear conditioning (CFC). In CFC rats are simply placed in a box, given a little time to explore, and then administered foot-shock. The indication of learning is a stereotyped behavior known as freezing when they are placed in the same context. This is an adaptive response to fear for rats at least in part because predators (like hawks and whatnot) have poor foveal vision, so they do a lot better if they have a moving target. Point is, rats stand still when they are scared. So it is not clear in inhibitory avoidance whether rats are scared of the step down or are more generally afraid of the apparatus leading to freezing. The reason I'm bothering to make all this distinction is that the association between a cue and a shock has been traced to the amygdala rather than the hippocampus. The hippocampus is thought to encode the context by binding its features up as a single index cue that can be associated with shock in the amygdala. It is possible that the hippocampus constantly takes snapshots of the various aspects of the context together and that stringing these together makes up the film of vivid episodic memory that some refer to as 'mental time travel'. This makes it curious that the LTP-like changes in the Bear Lab paper are found in the hippocampus when there are "walk-through" controls that get all the same contextual/episodic information except for the shock. My tentative take is that trained and control animals both encode the contextual information, but that shock provides a modulatory input that says, "hey, why don't you go ahead and lay the memory of this context down a little more permanently.. i have a feeling it's going to be important later.." This sort of input could come from the amygdala.

In the PKM-zeta study, the behavioral paradigm is Active Spatial Avoidance. The rats are placed on a slowly spinning circle. One portion of space is declared the "shock zone" and remains stationary while the rest of the world spins, so the rat has to keep moving to keep from being eventually moving into the shock zone due to the platform's rotation. It's like being a vampire who has to remain outdoors and near the equator. This task could again be separated into two separate types of learning. The rat needs to encode the overall spatial scheme, which is something we expect the hippocampus to be good at, and it has to associate a particular portion of the map with shock. It should be noted that use of this behavioral paradigm is not nearly so widespread as inhibitory avoidance, so less is known about the neural substrates, but the hippocampus appears to be involved. A good way to parse the various forms of learning necessary for the task would be to allow the animal access to the spatial environment without the shock reinforcer, so it can learn the spatial information first. You might expect a more rapid acquisition curve once the shock is turned on, and this improved acquisition might be affected by hippocampal manipulations. The drug manipulations in this study were in the hippocampus, and they knocked the memory out, so something that the rat needs to know to perform this task is encoded in the hippocampus. I'm just not sure if it is a cognitive map or some "episodic" memory like "Remember that time when i was in this spatial area and I got shocked? I better get outta here." One is remembering a space and one is remembering what happened in a space.

Now let's take it down a level or two. What is LTP? It is a model for memory at the cellular/synaptic level. A long time ago, Donald Hebb suggested that information in the nervous system was probably stored as changes in the synaptic connection between neurons. In particular, he suggested that they synaptic strength or weight would be increased when the pre-synaptic neuron and the post-synaptic neuron fired coincidentally. I dunno if it was Hebb who came up with the paraphrase, but everyone paraphrases this principle as "Cells that fire together wire together." In 1973, Bliss and Lomo were able to demonstrate a cellular phenomenon that did just what Hebb has imagined. They found that high-frequency stimulation of a set of synapses led to enhanced strength. The strength is ascertained by giving baseline pulses of fairly weak stimulation and measuring the post-synaptic change in electrical potential. After high-frequency (tetanic) stimulation, the electrical response to baseline stimulation is potentiated. The emerging consensus is that synaptic strength is determined by the amount of ion flow through AMPA-type glutamate receptors in response to pre-synaptic glutamate release. Thus, you could enhance synaptic strength either by making existing AMPA receptors more permeable or by putting more AMPA receptors in the synapse. This latter is known as AMPAR trafficking. Modifications to AMPA receptors accompany LTP induction and memory acquisition. In particular, one portion of the AMPA receptor (the c-terminal tail of the GluR1 subunit) has a bunch of little spots on it where it can be accessorized. It's like, does Paul Wall really wanna roll out with his neck, wrist, and grill iced up tonite or is he far from home and might get his chain snatched if he comes too flashy? Then he might only wanna display his Balla Status with his neckpiece.

Three of these spots (S818, S831, and S845) are partially understood. The general idea is that more accesories = stronger synapses. S831 can be modified by CaMKII and PKC, but this doesn't seem to be sufficient to drive trafficking. S845 is modified by PKA, but this isn't enough either. In fact, it seems more like the S831 modification controls ion flow (channel conductance) more than it does trafficking. The Malinow group at Cold Spring Harbor just reported a month ago now that they had characterized S818. S818 is modified by only by PKC isoforms. There are several versions of PKC (11, I think), and they have special expression patterns and activation requirements. S818 is in a part of the AMPA receptor that is close to the cellular membrane and is packed full of positive charges. The membrane is made of lipids and may have trouble playing with charged molecules. PKC adds a bunch of negative charge to S818 and helps neutralize the membrane-proximal region of the AMPA receptor allowing the AMPA receptor to fuse into the membrane and start contributing to synaptic strength. So PKC-mediated phosphorylation of the GluR1 subunit of AMPA receptors may be a central mechanism in enhancement of synaptic strength (LTP). This was not known until a month and a half ago which explains why the Bear lab only checked on the status of S831 and S845 after inhibitory avoidance training.

The Bear lab attempted to show that learning induces LTP with four results: 1) After training, S831 is modified the same way it is after LTP. 2) After training, there are more AMPA receptor subunits in or near synapses. 3) After training, baseline stimulation of the synapses produces greater post-synaptic potentials. 4) Synapses that show this enhancement are harder to potentiate with high-frequency stimulation (i.e. the normal way you induce LTP). The third and fourth are really the money. They were made possible by the use of multielectrode recording arrays. Learning doesn't just globally increase synaptic weights. That would be silly. The changes have to be fairly synapse-specific. So if you just stuck one recording electrode in the hippocampus you might miss the change. Bear and co were able to monitor the status of several recording sites at once. After training, some small portion of synapses were enhanced, while the others seemed to drop off slightly. This drop off is really interesting to me because it looks a lot like some sort of homeostatic signal that might keep overall excitability in the right range for a good signal-to-noise ratio. That's the problem with just using LTP in your model. Eventually you would get everything strengthened to the max, and you couldn't tell one piece of data from the other. The paper is more bland and probably more reasonable. "We interpret the coherent decreases in fEPSP slope as reflecting changes in the behavioral state of the animals over the duration of the recording experiments."

There is one little disconnect in these observations though. The AMPA receptor changes are fairly short-lived. They are up a half-hour after training, but back down after 1-2 hours. The synaptic strength changes, on the other hand, can last over 3 hours, and we know that the memories last much longer than even that. The authors suggest that only a few of the initially enhanced synapses actually stick it out and contribute to the long-lasting potentiation. This would drop the number of synapses displaying the AMPAR-related biochemical markers so far down that the assays just aren't sensitive enough to detect them anymore. Perhaps another issue is that in order to detect the changes in amount of synaptic AMPA receptors they normalize to actin levels. I haven't had anyone explain to me yet why you would expect actin levels to remain constant during synaptic modification. Go back and read here and here. Actin is a cytoskeletal protein that is associated with dendritic spine morphology and is dynamically regulated in response to LTP induction. One could easily imagine an initial burst of AMPA receptor insertion followed by changes in the actin cytoskeleton to produce larger synapses and accomodate the new strength setpoint. The drop off of the AMPA receptor signal back to baseline could really reflect a slower rise in synaptic actin. Also, there is another potentiality that can't explain the overall levels data but could explain the rapid fall off of the S831 modification. The S831 modification may be a simple, fast response to do the trick of enhancing synaptic responses quickly while the slower-reacting process of AMPAR insertion is taking place. S831 modification, remember, allows more ion flow, but doesn't seem to affect receptor insertion. I could see S831 doing its duty to begin with, but then handing off responsibility to a more permanent change effected by S818 modification and an increase in total number of receptors in the synapse. So the mechanism of synaptic strength enhancement would evolve over its lifespan. There would be mechanisms for acquisition that were separate from those involved in maintenance.

Maintenance. What a memory does day-to-day when you aren't recalling it or forgetting it. All those phone numbers you know are sitting there as configurations of synaptic weights that have to stay at the right weight as they receive noisy input and all the consituent synaptic molecules are degraded and replaced. The Sacktor lab has made a very nice case for a special role for PKM-zeta in memory maintenance. PKM-zeta is an atypical isoform of Protein Kinase C. Most PKC's are activated in response to increases in intracellular signaling molecules (such as calcium and diacylglycerol (DAG)), but PKM-zeta doesn't need any of that. It just goes. You make PKM-zeta and it starts doing its job. It is thus referred to as a constitutively active protein kinase. PKM-zeta isn't required for LTP induction. It is required for LTP maintenance. In fact, just washing PKM-zeta onto a hippocampal slice will cause increases in synaptic strength. This increase is probably due to increased AMPA receptor insertion. Sacktor and co have a molecule called Zeta Inhibitor Peptide (ZIP) that specifically inhibits PKM-zeta and no other PKCs or other kinases. They showed that ZIP can return potentiated synapses to baseline even after they have been potentiated for 22 hours. So we've got a drug that specifically affects LTP maintenance and we think LTP = memory, so let's put the drug in and see if it affects memory. Sho' nuff. If you drop ZIP into the hippocampus 22 hours after active spatial avoidance training the animal drops back down to pretraining peformance levels. It forgets everything. This isn't a temporary retrieval impairment. The memory is still gone a week later. That, my friends, is money. Some eternal sunshine type isht. The whole hippocampus isn't messed up cos the rats can acquire new memories even under the influence of the drug. It only screws up fairly new memories that have been stored.

There are a couple of things to note about this discovery. The manipulation is still effective on month-old memories. If you've read any accounts of memory research you will be familiar with the case of H.M. He is commonly used to illustrate the principle of systems consolidation. Some people believe that the hippocampus is only a temporary memory storage site and that (maybe during sleep) it trains up other permanent storage sites in the neocortex. For instance, H.M. basically had his hippocampus removed, and he still seemed good at remembering stuff from his childhood (which was presumably consolidated) but wasn't so hot at memories acquired shortly before his surgery. People have extended this observation to rats and showed that lesioning the hippocampus has less effect on month-old memories than on day-old memories. This whole area is very controversial though and there is growing support for the notion that the hippocampus never stops playing a role. This set of experiments speaks to the issue of systems consolidation by showing that month-old memories are abolished by a drug manipulation targeted only to the hippocampus. There are caveats and complexities, but it certainly looks on the surface like synaptic changes in the hippocampus are still housing the memory. But this brings me to my other point. What is really happening when they drop ZIP into the hippocampus? Is every synaptic weight getting dropped down to its lowest possible setting? Do the rats forget everything that the hippocampal memory system was responsible for? There are control experiments where ZIP is shown not to affect baseline synaptic responses, but why shouldn't it? It seems like the rats should have some information stored in their hippocampi already. Surely some of the weights are already set at high levels. Why wouldn't ZIP knock those off? I'll get back to you when I figure all that out. Perhaps memories really are consolidated, but it just takes longer than a month. That doesn't mean they have to leave the hippocampus, but perhaps the maintenance mechanism changes such that it isn't reliant on PKM-zeta activity anymore.

I don't know if the anyone but the Malinow lab is capable of assaying the state of S818, but I think it would be really interesting to take a look at the correspondence between PKM-zeta levels and S818 status. You could directly control the weight of a given synapse by modulating the local amount of PKM-zeta to determine what percentage of newly generated AMPA receptor subunits get modified at S818 and inserted into synapses. I should say that I am not implying that PKM-zeta is the only determinant of synaptic strength. One should be skeptical about 'magic bullet' hypotheses. No single molecule is going to do the trick. Also, while these studies make a strong case that LTP may be more than just a model of memory, the link still is not complete until we can perform an engineering feat using the theory. Can we actually implant a memory in an animal by inducing LTP at the proper synapses? From a 2003 paper by Richard Morris (that you can download for free if you want):

The fourth criterion, surely not yet met, is mimicry: were it feasible to alter the pattern of synaptic weights in a network in an appropriate manner, the animal should behave as if it remembered something that, in practice, had not happened. Tim Bliss calls this the 'Marilyn Monroe' criterion. This weakness of the available data apart, a rich array of physiological, pharmacological, molecular engineering and other techniques, allied to behavioural studies, have now tightened up the link between activity-dependent synaptic plasticity and memory to a point where it is reasonable to set aside a scientist's natural scepticism about the central principle.

I just finished Carl Zimmer's excellent book At the Water's Edge, a general audience recounting of two major events in macroevolution--the evolution of tetrapods and of whales. One of the major recurring themes is how past events in evolution constrain the probability space of the future. This passage (in a section describing Hox genes and limb development) stopped me cold:

Neil Shubin has found one of the most striking demonstrations of how the innovation of the limb imposes a new order. In 1991 a freak freeze turned a pond in Marin County, California, to ice. It killed hundreds of rough-skinned newts and perfectly preserved their corpses. Shubin, who was working at the time at Berekely, got hold of the newts while they were still frozen, and in the years that followed was able to study 452 of their limbs. In this one gathering of a single species, he discovered an orgy or variation: almost a third of the newts had some dramatic oddity in their limbs...Yet the variation was actually very limited and biased. Fusions and extra bones always occurred along the path of the branching limb axis that Shubin and Alberch had identified in 1986.

My two thoughts/questions:

1. One-third of the individuals in this small population had dramatic variation in their limbs (bone fusions, extra bones). That's a lot. Does anyone know of numbers like this for humans? Are we as polymorphic as this in terms of structure?

2. The fact that all these mutations occured along the branching limb axis set essentually by Hox genes is striking, and emphasizes the role of development in determining natural variation (ok, yeah, evo-devo people have been saying this for years. duly noted). Have these sorts of results been found in other organs (like say, the brain)? I think this is going on my list of books to read.

Today's science column by Anjana Ahuja in the London Times, available online here, has a couple of stories.

First, she describes a new book by linguist Charles Yang about the acquisition of language. Yang apparently argues that babies are born with an extensive set of innate grammatical capacities - sufficient to cover all the world's languages - most of which are then discarded or suppressed as the baby learns the specific grammar of its own 'mother tongue'. It's difficult to tell just from this description how Yang's theory differs from those of Chomsky or Pinker, but it sounds like he hypothesises a much richer innate repertoire of grammar than they do. I have no idea how this stands up to the evidence, but I can't help thinking it sounds very inefficient in evolutionary terms. Wouldn't one expect a relatively simple and general language capacity to evolve first, and then specific languages to evolve (culturally) to be consistent with the general innate capacity? Whereas Yang seems to envisage an elaborate evolved capacity, much of which is never used in any single culture. But the book sounds like one to add to the reading list - eventually!

The second report is about the Hobbit controversy. The point to note is that there is a further paper forthcoming in the Journal of Human Evolution, which defends the Hobbit as a distinct species. No doubt Dienekes, John Hawks and others will comment in due course.

Nothing much to do with genes, but while looking up the online edition of the Times to find Ahuja's article I came across the following 'breaking news' item, here, the text of a remarkable letter by the Austrian girl who was kidnapped and held captive in a basement for 8 years. If it is really all her own work, it shows an astonishing intelligence and maturity in the circumstances.

The LA Times just ran two article about genetic engineering (here and here). I can't guarantee that these articles are free of "idiotic mistakes" of the kind that drive Greg Cochran nuts, but I thought they were interesting. A money quote:

Gene therapy is making a comeback after a series of serious setbacks that threatened to permanently derail human tests. In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal, immune disorders.

Spurred by this success, plus the development of new techniques aimed at making the therapy safer and more effective, more than 300 gene therapy trials, including the one for Parkinson's at UC San Francisco, are underway in the U.S. and abroad.

Here is a portion of an email I received from an occasional correspondent:

I often find Indians scientists, doctors and engineers singularly uninformed/uninterested in anything much beyond their own expertise. The trend is increasingly pronounced with passing generations. My parents' generation had a lot of spill across the sciences and humanities. A reasonably educated person could carry on a conversation about several topics without necessarily knowing the technical minutiae of each one. Scientists and philosophers within my family conversed and debated each other with ease. My own generation lost some of those interdisciplinary skills. The current generation in India is even more compartmentalized.

The comment is not India-specific. Many of my friends with little or no science background are poorer for it. They make grand generalizations about human "nature" with pretty much zero understanding of the biological constraints, and psychological propensities, of our species. And yet, in my experience many scientists are utterly clueless outside of their own field of expertise. Many "old timers" on this blog will remember David Deutsch getting schooled by godless capitalist in regards to evolution and genetics. In a broader sense, if scientists stuck to talking about their particular set of questions that would be fine, but their attempts to discuss history or international politics in my opinion are often as nuanced or informed as Post Modernists who use the gloss of mathematical terminology in their hucksterism.

And yet the demands of the modern world mean that there are few Leibniz's, and it seems unlikely that anyone could be a Leibniz. Even within fields like "biology" and "chemistry" there are clans which never meet and speak in mutually unintelligible dialects.

Ironically, though today we often (at least among the elites) deny the importance of a "canon," it maybe that a canon is even more important in providing common points of reference as our professional interests become more specialized. Analogies and metaphors are laced throughout our speech, conversation and dialogue, and yet they rely on some level of common knowledge and deep understanding of the conceptual structures which characterize a particular idea or system. To some extent the canon does not matter in regards to content. I think the substance does have utility in other ways, e.g. a knowledge of American history, and the Constitution and the Bill of Rights, might be beneficial to Americans, especially the elites, in the way they approach their responsibilities as a citizen. But, the important point is to facilitate smooth communication. Of course, we all have pop culture. We all know Real World and Nelly. That's a common lexicon. But is this sufficient? Is the idea that we should know Great Books simple snobbishness? Does watching Real World allows us to generate templates of the "Angry Black Guy" (e.g., Kevin from New York I, etc.) or "Rural Virgin" (I forget) which aid in getting across our points?

The New Yorker has an interesting piece up about the characters involved in the Poincare Conjecture. I have to say, Grigori Perelman seems out of central casting for Simon Baron-Cohen. And the behavior of the Chinese mathematicians is remiscient of some of the problems pointed out by Richard Nisbett in The Geography of Thought in regards to the development of a science-for-science's-sake culture in East Asian cultures.

I just finished reading Decisions, Uncertainty, and the Brain: The Science of Neuroeconomics by Paul Glimcher though, and I would recommend it to a friend. The book is about 5 years old now, and neuroeconomics is kinda blowin' up. Glimcher believes that neuroscience has been dominated by a paradigm based on finding the minimal neural circuitry necessary to produce stereotyped reflexive behavior and that we need to shift toward understanding the goals of the nervous system to fully understand how behavior is generated. I read the book because I wanted to get a grip on the neuroeconomics and decision-making papers that are flying off the press, so the philosophical and paradigmatic issues weren't really necessary for me although they led me down some entertaining avenues of thought. If you just want an intro to neuroeconomics and the types of experiments involved, you could probably skip up to chapter 10 and read the last 100 pages or so. I think the most obvious application of this field is judicial. It seems like you could set up this problem in terms of economics and then look for neurological indicators and ?interventions?. Glimcher has addressed the law in at least one article but focused on the application of neurobiological evidence in courts. All that aside, below I just want to give you an idea of the scope of the book and the fields he draws from to make his case.

Part I: History

Chapter 1: Describes beginnings of scientific method (Francis Bacon) and application to human physiology (William Harvey). He introduces Vaucanson's duck, a mechanical duck created by a Jacque de Vaucanson which will serve as a recurring symbol for the reflex-based, deterministic view of behavior. The main purpose of the chapter is to introduce Descartes and Cartesian dualism. Descartes needed the soul to explain "unpredictable and nondeterministic behaviors...that the clockwork scientific explanations available...could not hope to mechanistically explain...".

Chapter 2: Lagrange and Laplace do so well in describing the physical universe with analytical mathematics that it seems certain that biological systems will also eventually succumb. In 1833, Marshall Hall presents a paper to the Royal Society in which he transected frog spinal cords and found reflexes in the bottom half and volition in the top (dualism creeping into physiology). There is more detail regarding the history of spinal reflex physiology the innerworkings of the Royal Society.

Chapter 3: Charles Sherrington was a smartypants, but he is this book's villain. Sherrington conceptualized behavior in terms of the reflex-arc. A receptor organ receives a sensory stimulus, this stimulation is transmitted by way of a conductor to an effector organ. This is the simplest explanation for the reflexes that we are all familiar with, but Sherrington had to bring in inhibitory components too to explain how one muscle can tighten while one loosens in a coordinated fashion. Pavlov takes reflexes up into more complex behavior, and we start to think behavior is deterministic and if we had good maths we could explain the whole damn thing. Godel looms into view to ruin everyone's party. The Godel issue seems more like zeitgeist party-pooping than a necessarily devastating issue for the reflexological paradigm.

Chapter 4: "The whole function of the nervous system can be summed up in one word, conduction." This quote will haunt Sherrington for the rest of the book. Reflex theory can't deal with spontaneous behavior (we are subjected to a thought experiment in which a cat is placed in a sensory deprivation chamber) and internally generated oscillations. We need feedback (reafference) and oscillators to explain the function of the nervous system. Also, the same goal-directed behavior can be achieved through a number of different motor programs, so the goal must be decided followed by the computation of the proper motor program, implying a hierarchy. A hierarchy is not simple conduction, so this is another challenge to the Sherrington's formulation.

Chapter 5: Computational models. Classical models have an input layer, a hidden layer, and an output layer. A speech model called NetTalk is discussed. The point is to show how much modern neurobiological models and experiments are informed by the reflex paradigm. A big chunk is devoted to explaining some interesting experiments performed by the Newsome lab demonstrating that neurons in area MT (a part of the neocortex containing neurons sensitive to moving visual stimuli) fired in direct correspondence to a monkey's reported perception of the direction of stimulus motion, and that perception could be influenced by stimulation of these neurons. Newsome employed a Michael Shadlen to model the data computationally, and they came up with a nice deterministic model to explain motion perception. Glimcher says this is all well and good, but we are limiting ourselves to unnatural experimental paradigms because of the Sherringtonian influence.

Chapter 6: David Marr is one of the heroes of the book. Marr was a theorist and computer scientist who wrote a book called Vision in the late 70s as he was dying of leukemia. Marr said you can't understand flight by studying feathers. You have to understand aerodynamics. By analogy, we can't understand the nervous system by studying neurons and mechanisms, we have to use theory and understand the goals of the brain. Marr did this for visual perception, but Glimcher notes that two immediate objections arise. One is that the definition of the scope of a nervous system goal seems arbitrary, and two is that it is not clear that evolution is concerned with computational goals or that the brain does things in an efficient goal-directed way.

Chapter 7: How to dissect up the nervous system to get some goals to understand. Fodor and colleagues argue that cognition is divided up into independent modules. Michael Gazzaniga, working with split-brain patients (much communication between left and right hemisphere is removed to isolate epileptic foci), shows that the different halves of the brain were specialized and can work independently. So cognition can be divided up into goals, and it doesn't have to be completely arbitrary. Gould and Lewontin show up to introduce phyletic and architectural constraints that could raise problems for Marr. Evolution may not be able to get you to the optimal computational solution. But Glimcher points out that there are cases where we are darn close to optimal. Rhodopsin is the molecule in your eye that converts light into a biochemical signal so it can influence neural firing. Rhodopsin can detect a single photon. That's as good as you could hope for. There is also a section on convergent evolution in African cichlids suggesting that an evolutionary goal may be important than how you get there.

Part II: Theory and experiments

Chapter 8: What's the overall goal? Maximizing inclusive fitness. "I want to suggest that we can characterize the function of the nervous system as decision making." Decision making should produce behavior that increases inclusive fitness. It is easy to make optimal decisions if you are omniscient, but organisms living in the world have to make decisions in the face of uncertainty. We need probability theory to deal with uncertainty, and we ought to define the goals of the nervous system in terms of probability theory. A history of probability theory featuring Blaise Pascal follows. Probability of an event X value of that event = Expected Value. Value doesn't predict how people will behave though. One man's trash is another's treasure and all that. Bernoulli came up with Expected Utility to describe the case in which, for instance, the same absolute amount of food (Value) is more motivating when you're hungry than when you're satiated. We get a fairly detailed description of Bayesian likelihood estimation. Bayesian theory is the optimal tool for decision-making in uncertain conditions. Economics uses these tools to predict behavior. We should use economics to define the goals of the nervous system and call it Neuroeconomics.

Chapter 9: John Krebs' behavioral ecology defines optimal goals using economics and explains natural animal behavior in terms of decision-making. The "prey model" is developed in this context and uses probability theory and economic models to define the most efficient predator behavior. When should a predator bother to collect food and when should it pass? The prey model is empirically tested, and a bird called the titmouse seems shows behavior very close to that predicted by a probabilistic economic model. This shows the utility of defining behavioral goals using economic models.

Chapter 10: This is the longest chapter and the meat of the book. We get an introduction to the neuroanatomy of both visual processing and motor control of the eye. Primates can be trained to move their eyes based on visual stimuli. We know how the info gets in and where it goes out, but where is the sensory input connected to motor output? Research has focused on an area that seems anatomically well-positioned for the job called the lateral intraparietal area (area LIP). A major leap occurs when Herbert Jasper and Edward Evarts develop a system for recording from single neurons in awake behaving primates. A controversy ensues in which one camp insists that parietal neurons encode high-level motor commands and another camp says they are rather involved in high-level visual processing (i.e. attention). There are a lot of experiments described with regard to this controversy. I think Glimcher is trying to illustrate how bogged down we can get when trying to interpret neuro-data using the receptor-conductor-effector model.

Glimcher and Michael Platt stepped into the fray in 1997, but their major move came in 1999 when they tested the idea that the LIP was encoding economic parameters necessary for making decisions about which way to move the eyes. Neurons in the LIP have a preferred position in the visual field that they would like to fire for. Glimcher and Platt varied the probability that this location would be the target location (the place to which the monkey must move its eyes to receive a reward) across trial blocks. The firing rate of neurons in the LIP corresponded directly with the prior probability of reward at their preferred location. When, conversely, the probability of reward was held constant and the amount of reward was varied, neurons in the LIP also showed a direct relationship between activity and reward value. Probability of reward X value of a reward = Expected Value (and perhaps Expected Utility, see here for more).

In the prior experiments, the monkey was eventually told by a visual cue which way to look for reward, but Glimcher wanted to ask whether monkeys make probabilistic decisions in the face of a probabilistic problem. He drew on an observation by Richard Herrnstein that pigeons could match their behavior to an experimentally controlled probability landscape, so-called Matching Behavior, to produce a paradigm in which monkeys could demonstrate their matching proficiency (even though this wasn't the optimal strategy). Monkeys did model the probability and value setup with their actions and neurons in the LIP tracked the estimated value of a given eye movement. Glimcher isn't satisfied though because the monkeys didn't perform the economically-defined optimal deterministic strategy but instead behaved probabilistically. The next chapter attempts to explain why sometimes probabilistic behavior actually is the optimal course predicted by game theory.

Chapter 11: Intro to Game Theory. This is also my first real encounter with game theory, so expect me to be getting it wrong for a while. Starts with Von Neumann and Morgenstern. The optimal solution when faced with an intelligent adversary is sometimes to become as unpredictable as possible. When your best move is to vary which type of move you make you have arrived at a mixed strategy solution. You act unpredictably. VN and M only did the math to predict mixed strategy solutions in competitions in which one entity's gains are mirrored by the adversary's losses (zero-sum). John Nash was able to expand the math to include non-zero-sum games. The treatment of Nash's contribution is fairly detailed. Glimcher says that Nash allowed us to consider that nondeterministic (uncertain, probabilistic) behavior is often optimal. I'm still not clear on why this is Nash's insight instead of VN and M's, but I will take Glimcher's word for now. John Maynard Smith brings game theory into biology and evolutionary theory, and finds probabilistic behavior is evolutionarily stable. Finishes with a description of experiments by D.G.C. Harper showing that ducks behave according to the laws of economic theory. Glimcher makes kind of a big deal out of the idea that animal behavior can be 'fundamentally unpredictable' and 'irreducibly probabilistic'. I'm thinking that his usage of the term irreducible is a little uncommon. In the next chapter he attempts to discover neural correlates of this unpredictable property. This seems like a step toward reduction of the problem to me, such that if we really knew the brain, the behavior would no longer be uncertain.

Chapter 12: The work or shirk game is introduced pitting a worker against a boss checking up on him. People act according to the principles discussed above and act really randomly. Glimcher and Mike Dorris took the game to a computer versus a monkey. Monkeys act right too. Neurons in the LIP fire at a consistent rate when probability and value of rewards are varied but relative expected utility is maintained. If you look at a finer grain, you can see that neurons are adjusting their firing rates with updates after each trial and that these updates work in the manner predicted by a Nash equilibrium solution.

Chapter 13: This is a wrap-up chapter. Glimcher proposes a bunch of other experiments he's done or would like to do. He has a couple concerning visual attention and motion. Some on the neurobiology of encoding prior probabilities. He mentions the basal ganglia as a potential spot for this type of learning, but doesn't really review what the basal ganglia is/are all about. There is also some on the encoding of value and how dopamine might be involved.

Chapter 14: This is the second wrap-up chapter focused on philosophy. Descartes was wrong. We don't need dualism. We don't need reflexes at all. We need a continuum of behavior from probabilistic to deterministic. He seems to have a pretty nice take on free will. "Free will may simply be the name we give to the probabilistic behaviors that are mixed strategy solutions. Our subjective experience when a mixed strategy solution requires the activation of a lawful neuronal randomizer." Return to Vaucanson's duck. Animals act indeterminately aaaand they don't have to have souls to do it.

Hope this gets some people interested in reading the book and maybe getting further into the area. I am going to be trying to discuss some of this stuff as it comes out. In general, I get more excited about brain mechanisms than ecology or theory, but these perspectives seem to have been really important in developing Glimcher's views. I could've stood for a little more neuroscience background. We got a fairly good treatment of the LIP, but I'm really not familiar with single-neuron recording, and I'm sure there are caveats and pitfalls to this research technique (one being that it is purely correlational). One obvious next move is to either attempt to manipulate expected utility behavior by stimulating this area or to affect the same by ablating the area.

The Golden Rule & Christian altruism, God & conservatism part n... and God & morality are follow ups on the Heather Mac Donald vs. the Right who are religious saga. Heather has received a lot of flack from her political fellow travellers, and though I don't necessarily agree with every element of Heather's argument, I do think the Right has moved too far in soaking its arguments with the imprimatur of divine sanction. Ramesh Ponnuru made big noises about how his argument in Party of Death was not religious, but most outside of the Right ignored him because they simply can not conceive of any conservative argument as not having a religious tinge (I think this preconception is false, but, I think it is supported by the close connection between evangelical religious groups and modern conservatism). The Right does not need to turn to Randian godlessness, rather, it should perhaps temper some of its populist evangelicaism so to as spread the tent a bit bigger. (Also, check out Right Reason for responses to some of my posts. Does anyone know how many blogs Steve Burton contributes to? Besides God that is)

Also, two posts on hybridization in the human context. Pictures too.

Yo, there's a new Transformers movie coming out! Check out the new Megatron, ill.

Interesting paper I found Sex, status, and reproductive success in the contemporary United States (PDF). Since you can read the whole paper, I won't summarize it for you, but below the fold is a graph that some might find of interest.

You've probably heard about the new technique to facilitate the use of embryonic stem cells without destroying them? Devil Boy Jake has a science oriented review, and Poreless Anthis has a more public policy focused post. I have no particular insights on this topic, as I noted in my own post, though in the comments godless offered a comment which reflected some of my own cautious perceptions, to which Darwin Catholic responded. Over at The Corner not a word out of Ponnuru, and Lopez is rather subdued, so perhaps much ado about nothing....

Dr. Luigi Luca Cavalli-Sforza is a professor of genetics at Stanford University. Dr. Cavalli-Sforza's magnum opus The History and Geography of Human Genes is a landmark of human historical population genetics, while his text coauthored with Walter F. Bodmer, The Genetics of Human Populations, is one of the most thorough introductions to the field of population genetics with an emphasis on our own species. Originally trained as a medical doctor, his work has spanned a range of fields from microbiology to theoretical anthropology. Recently Dr. Cavalli-Sforza's life has been the subject of a full length biography, A Genetic and Cultural Odyssey. One may view a list of representative publications here.

Below are his responses to "10 questions."


1) Can you tell us what R.A. Fisher was like as a teacher and a department head? It is sometimes said that true geniuses do not make for the best instructors or superiors.

As a teacher, his lectures were quite good. It may have helped that I knew at least some of the things of what he taught. As a superior, he was tolerant of his inferiors with whom he did not get along, but ignored them, and was absolutely loved by all the others, with whom he was very generous, and this was true of me also. When Kenneth Mather, one of his best students and with whom I had worked in advance learnt that Fisher had offered me a job, he said "in the first fortnight it will be decided whether you will be friend or not". I certainly became a very good friend of Fisher, and am a very good friend of all Fisher's last students whom I had a chance to meet and work with, like Anthony Edwards and Sir Walter Bodmer, both of whom have a profound attachment to him. Fisher was very impatient with bureaucracy (who isn't, unless he/she is very lucky?), especially that of the University of Cambridge. He supported two of his potential, excellent successors: Guido Pontecorvo and Francis Crick, but his advice was not paid any attention.

2) When I read "Consanguinity, Inbreeding, and Genetic Drift in Italy" I was struck by the relatively mild differences between the two geographic halves of the nation. Considering the historical legacy of Magna Graecia, Byzantine and Arab rule in the south, in contrast to the Gaulish, and later Germanic influence in the north, I was expecting more between-population differences. I suppose that gene flow across demes along lines of trade equilibrated allele frequences between regions (while high relief resulted in enforced endogamy). If you agree with my assessment, were you surprised by those particular results?

The only "genetic" data in the book regarding the country as a whole are from surnames, which have little time depth: at most one thousand years, and reflect the cultural more than the deep genetic background. Nervetheless they are highly correlated with it, but cannot be used for between countries comparisons. The cultural unity of Italy is older than a thousand years; more than three thousand years in the south and two thousand years for the north.

The truly genetic data can be found in The History and Geography of Human Genes, especially pages 292-293, showing that northern Italy is more similar to western and central Europe, the center to the northern Balkans, probably reflecting in part the middle Neolithic diffusion, and the south the southern Balkans, reflecting the earliest Neolithic diffusion and the Greek and Phonecian colonizations of the first millennium BC.

3) I suppose it can be said "The History and Geography of Human Genes" was your most influential book. The PC maps as well as the cladograms were mental candy for those of us who were interested in the narrative that it told about human demographic history. Nevertheless, I have noted a tendency amongst some to view the conclusions you offered as a sort of "proof text." As an example, the affinity between Southern Chinese and Southeast Asians, and between Northern Chinese and other Northern East Asians, have been the subject of much discussion on internet forums. Did you anticipate that many would view your inferences as indelible Truth?

Nothing is indelible, or will be indelible until data from a much wider selection of markers will be available. In this century I hope there will be a chance of examining very extensive samples of individuals for the whole genome and this knowledge will be much more indelible, as much as the representativeness of the samples tested. I doubt that I will see it, but this is the rule of life.

4) Moving to, in the interests of frankness, less influential books, in "A Genetic and Cultural Odyssey" Linda Stone & Paul F. Lurquin note the relative lack of response to "Cultural Transmission and Evolution" within the social sciences. You seem to chalk this up in part to the lack of comfort with mathematical methodologies within cultural anthropology. Over the past few years a small group of anthropologists, Peter Richerson, Robert Boyd and Joe Henrich seem to be continuing the attempt to model culture using the techniques that have been fortuitous in the biological sciences. Do you think that we are past the high tide of 'interpretative' anthropology and that a more explicitly hypothetical-deductive methodology may come to the fore?

I entirely agree that the average quality of anthropological research, especially of the cultural type, is kept extremely low by lack of statistical knowledge and of hypothetical deductive methodology. At the moment there is no indication that the majority of cultural anthropologists accept science - the most vocal of them still choose to deny that anthropology is science. They are certainly correct for what regards most of their work.

5) "The Genetics of Human Populations" was recently re-printed. In the foreword, you and Walter Bodmer acknowledge that 30 years is a long time in scientific history, but that your work does offer theoretical insights which have stood the test of time. I was interested to note, for example, on page 530 you offer an estimate of the number of loci which result in the normal human variation of skin color at about 4 using classical genetic methods. Recent comparative genomic work suggests that there are other loci besides the well known MC1R, with a recent gene, SLC24A5, accountable for 30% of the difference in complexion between Europeans and Africans. It seems that the estimate of 4 loci may not be very far off the truth. Do you believe that the "postgenomic era" will by and large vindicate the synthesis of population genetics and evolution which crystallized in the 1930s under R.A. Fisher, J.B.S. Haldane and Sewall Wright? Or, do you intuit from the most recent batch of findings that we are in for a data-driven "paradigm shift" which will result in a new theoretical framework?

I was relying on the opinion of Neil Risch that our book is still useful because it contains knowledge that is important and is ignored in more recent books. Everything changes, but I believe the old paradigm that mutation + nat.selection + drift + migration is sufficient to understand biological evolution, and the basic theorems are still the same, with few additions. Of course, the use of simulation - of which I gave probably the earliest example for the role of drift on blood group genetics in the Parma Valley in 1967 (cited in Consanguinity, Inbreeding etc.)- has given much greater power to theoretical analysis, but it can hardly give results of the same generality as the mathematical approach. When one goes over to cultural evolution or other examples of evolution of self reproducing systems one needs to consider mechanisms of hereditary transmission other than the (generalized) Mendelian one. Also in biology it will be necessary to consider the general importance of lateral transfer, which will bring a partial revolution, but in cultural evol. it is imperative to give to it much importance, especially in the internet era. Still, it is difficult to completely ignore the importance of parent-child transmission in cultural evolution, as well as the niche influence (Odell Smith, Laland and Feldman), when one considers (e.g.) some surprising permanence of pagan rites in Europe.

6) In "A Genetic and Cultural Odyssey" you seemed rather unrepentant about not explaining the details of Principal Component Analysis though you obviously recognize the importance of mathematics to your work. The historian of science Will Provine has asserted Sewall Wright's original work which coalesced into the Shifting Balance was simply not internalized on a mathematical level by most workers, including disseminators such as Ernst Mayr, and that this resulted in subsequent confusions about the importance of random genetic drift and gene-gene interactions. Obviously biology is a science that is focused on a particular subject, life, as opposed to being hewed to any one method. Nevertheless, do you perceive in the next generation of trained biologists the mathematical aptitude and inclination to tackle problems both analytically and computationally so as to extract more insight from the excess of data generated by modern sequencing techniques?

I adore principal components, as you may have noted, and I was the first who introduced them into genetics (1963, Proc.Intl.Genetics Congress of the Hague). I also showed with Piazza in 1976 (Theor. Pop. Biology, 8: 127-165) that when a simple evolutionary model of mutation and drift is correct, principal components and trees give the same result, in the sense that eigenvalues and vectors calculated in the spectral analysis of populations x gene frequencies matrices correspond to the meaning and order of the nodes found in trees. But I have always found it difficult to explain rigorously principal components to people who have little confidence with mathematics, and I decided to test the skills of Lurquin and Stone, hoping they would do it better than what I usually do. Of course, the usual indication that it is a method to reduce the number of dimensions gives some ideas, but without an appreciation of the amounts of variance explained it may give a false sense of security .

7) Question #3 hinted at the powerful social impact your work has had in reshaping how we view the natural history of our species. One of the most contentious issues of the 20th, and no doubt of the unfolding 21st century, is that of race. In 1972 Richard Lewontin offered his famous observation that 85% of the variation across human populations was within populations and 15% was between them. Regardless of whether this level of substructure is of note of not, your own work on migrations, admixtures and waves of advance depicts patterns of demographic and genetic interconnectedness, and so refutes typological conceptions of race. Nevertheless, recently A.W.F. Edwards, a fellow student of R.A. Fisher, has argued that Richard Lewontin's argument neglects the importance of differences of correlation structure across the genome between populations and focuses on variance only across a single locus. Edwards' argument about the informativeness of correlation structure, and therefore the statistical salience of between-population differences, was echoed by Richard Dawkins in his most recent book. Considering the social import of the question of interpopulational differences as well as the esoteric nature of the mathematical arguments, what do you believe the "take home" message of this should be for the general public?

Edwards and Lewontin are both right. Lewontin said that the between populations fraction of variance is very small in humans, and this is true, as it should be on the basis of present knowledge from archeology and genetics alike, that the human species is very young. It has in fact been shown later that it is one of the smallest among mammals. Lewontin probably hoped, for political reasons, that it is TRIVIALLY small, and he has never shown to my knowledge any interest for evolutionary trees, at least of humans, so he did not care about their reconstruction. In essence, Edwards has objected that it is NOT trivially small, because it is enough for reconstructing the tree of human evolution, as we did, and he is obviously right.

8) Your lab has recently been focusing on Y chromosomal lineages. It seems that this is a clear extension of your previous program of analyzing demographically informative loci to aid in reconstructing the natural history and behavioral ecology of our species. A graduate of your lab, Spencer Wells, has outlined the utility of the Y chromosome in his recent book "The Journey of Man." Nevertheless, others, such as Henry Harpending at the University of Utah have argued that functional loci which have been shaped by selection should be the object of greater interest, and that neutral loci can only tell us so much about the nature of our species. Of late, data emerging from the HapMap has hinted at powerful selective pressures upon our species within the past few thousand years. Some would argue that the high frequency of deleterious recessive diseases such as Cystic Fibrosis (frequencies too high to be maintained by mutation-selection balance) should have prepared us for this. What is your assessment of the alternative program which is focused on signatures of selection as opposed to lines of ancestry?

It is obvious that natural selection has played a major role in human evolution, although most statistical methods for detecting it are rather gross. Quantitatively, however, I am sure that drift has been very important - it will take more work on different types of genes to see how much, relative to selection. For an estimate (78%) based on microsatellites, see Sohini et al., nov. 2005 Proc. Nat.Acad.USA. 102 : 15942.

9) In "The Genetics of Human Populations" you allude in passing to intergroup selection (page 750), and seem to suggest it played a non-trivial role in the reshaping of the overall character of our species' genome. To be clear, if you do accept group level selection, would you expect its power (vis-a-vis individual level selection) to increase or decrease with the rise of complex mass societies and the diminishment of tribes & clans?

It is a good question. I suppose the answer is likely to be (tentatively) positive.

10) Over the past 6 years you have had a somewhat heated relationship with Bryan Sykes of Oxford in regards to the apportionment of European ancestry into "Neolithic" and "Paleolithic" quanta in the context of the model of Demic Diffusion. Moving past the details of this scientific relationship, which interested readers can explore in your aforementioned biography, there have been other recent extractions of ancient DNA of supposed Neolithic immigrants which have been used to "refute" the contribution of this population because of the lack of contemporary descended haplotypes in most of Europe. Others retort that neutral markers by their nature may be subject to substitution and that over generations most lineages become extinct. The technical details are clearly lost on the public, and yet there is also a great interest in this topic. Have you any advice for a potential science reporter who is attempting to cross and bridge this chasm?

Neutral markers are clearly subject to less rapid evolution than markers under directional selection. Markers under balancing selection are more stable than neutral markers. There is no estimate of the quantitative importance of balancing selection. A list of 91 genes showing selection at the genome level (Sabeti et al., 2002 if I remember the date correctly) show that about 25% show mostly balancing selection.

Archeology can be very useful for tracing history, clearly. But genetic analysis on fossil bones requires hard work, and with the investment of time and money that is possible today the numbers of individuals and markers on which archeological conclusions are based is too small to be considered respectable, especially when examining very small genetic differences.

Labels: 10 questions

The most recent issue of the Lancet has an interesting case study: a child overdosing on morphine acquired through the breast milk of her mother (who was taking codeine, a chemical precursor to morphine). Normally, codeine is considered safe for nursing mothers. What happened here?

If turns out that newborns have trouble metabolizing morphine, but in general the amount of morphine in breast milk is low enough to avoid problems. In this case, however, the mother was heterozygous for a variant in the gene CYP2D6, which encodes the enzyme that converts codeine to morphine. As a heterozygote, she was an "ultra-rapid metaboliser", meaning the codeine she took was converted quickly to morphine. Confirming this, the concentration of morphine in here milk was higher than normal: "A morphine concentration of 87 ng/mL was found—the typical range of milk concentrations after repeated maternal codeine is 1·9–20·5 ng/mL at doses of 60 mg every 6 h."

The frequency of the fast metabolism allele varies between population--the case report claims a frequency of 1% in Finland and Denmark, 10% in Greece and Portugal, and 29% in Ethiopia. So codeine may generally be safe for Finnish mothers, but less so for Ethiopian ones.

Further, the fast metabolism phenotype itself varies between populations as well. One study found that Caucasian fast metabolisers had a faster rate of metabolism than Chinese fast metabolisers. So one gene is not enough to model the phenotype of codeine metabolism--one may need to take into account entire pathways.

The cute little girl to the left has Acute Lymphoblastic Leukemia. She needs a bone marrow donor. She's brown (obviously). I know I have many brown readers, some of you live near donor drive locations. If you read this blog, you also know that for those of us from small racial minorities our genetic distinctiveness can be a death warrant. Change occurs one step at a time. (via Sepia Mutinty, Nirali's website)

I just saw a re-run of a Charlie Rose roundtable discussion with EO Wilson and James Watson from last year. The free video is here; check out the bit starting around 44.30 for their comments on recent human evolution, natural human variation, and where biology (especially genetics) is headed. According to them, this is the future:

Wilson: "We've somehow got to bring biology and the social sciences and psychology together. The psychologists--most of the practicing psychologists, theoretical psychologists--and the vast majority of social scientists, who really determine a lot of the intellect that goes into our policies, our philosophies--legal philosophies--attempt no connection at all to the nature of humanity, or what human nature is on a biological level. This is a huge gap."

Watson: "The past century was the coming together of chemistry and biology, and this century will be the coming together of psychology and biology"

A few months ago Agnostic alerted us to an issue of PLoS Medicine devoted to skeptical appraisal of "disease mongering." In this issue the psychiatrist David Healy claimed that the evidence supporting the efficacy of medications commonly prescribed for the prophylactic treatment of bipolar disorder is either weak or nil.

As bipolar disorder is the most painful and debilitating non-terminal disease that I have witnessed so far during my brief time on earth (although mild forms may be conducive to creativity), I was sufficiently provoked by this claim to take a look at the literature in this area. In this post I give a brief report of what I have found. Please note that I have no particular expertise in neurochemistry, pharmacology, or psychiatry, and in any case I make no warrant for the comprehensiveness of this post. The findings in this field are unfortunately quite confusing and contradictory; authorities going over the same evidence sometimes come to opposite conclusions in their reviews, and there is no particular reason to trust my arbitration of this matter. So read at your own risk. However, I think this post is worthwhile if it reminds us that an incidental benefit of the pursuit of knowledge is the alleviation of human suffering. (Note: I personally believe that this is true of all knowledge, including the "forbidden" knowledge deemed by the skeptics of GNXP's more controversial posts to be wicked and irresponsible.) As always, of course, I welcome criticism and pointers from informed readers.

Related: Psychotic mania in bipolar disorder resembles schizophrenia in many respects; common symptoms include hallucinations (primarily auditory), delusions, disordered thinking, and loss of contact with reality. Moreover, a curious risk factor that the two diseases share in common is a seasonality effect; sufferers from bipolar disorder show an excess of winter/spring births. Greg Cochran and his colleages have written two papers that I know of addressing the likely infectious causation of schizophrenia (Cochran et al., 2000; Ledgerwood et al., 2003). Much of their arguments, including evolutionary considerations, are just as applicable to bipolar disorder. I hope that work on pathogenic hypotheses will become a top priority for bipolar-disorder researchers.


My impression is that valproic acid (also known as divalproex and by its trade name Depakote) is rapidly becoming the preferred treatment for bipolar disorder. Its reputation among clinicians is growing as a result of their experience with patients, and its undesirable side effects are demonstrably less numerous and severe than those of lithium.

Although there exist at present fairly detailed mechanistic hypotheses regarding how valproic acid, lithium, and other drugs might dampen epilepsy and the mood oscillations characteristic of bipolar disorder, my fallible impression is that none of these commands anything approaching a consensus that it is the correct explanation. In fact, I suppose that physicists and other real scientists would complain that explanations on the table regarding the mechanistic action of all mood-affecting drugs are rather handwavy. This uncertainty in our knowledge severely limits the kinds of inferences that can be made. For example, if the efficacy of a drug in treating symptoms at the height of their acuity is securely established, can we generalize this to its effectiveness as a prophylactic? It is hard to say without a more detailed model of the disease etiology and the mechanistic action of the drug. And so we resort to statistical black-box evidence.

There are actually two things that are wanted from valproic acid or any treatment for bipolar disorder: (1) efficacy in treating patients displaying acute symptoms; and (2) efficacy as a prophylactic treatment preventing the occurrence of future episodes. The evidence that valproic acid does in fact accomplish (1) looks fairly good to me. Many studies have found valproic acid to be effective in diminishing the symptoms of acute mania, and it is on the basis of these studies that the FDA has approved valproic acid for this use. The most-cited of these studies that I have found is by Bowden et al. (1994). The abstract:

OBJECTIVE--To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. DESIGN--Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness.... RESULTS--Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P = .017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P = .004) and 49% for lithium (P = .025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. CONCLUSIONS--Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium.

For references to more studies in this vein, the interested reader may consult Torrey and Knable (2002), an accessible guidebook aimed at non-academics. In fact, Torrey and Knable is a good background source for everything covered in this post; its descriptions of relevant studies are telegraphic but fair. (Incidentally, Fuller Torrey was an early adopter of pathogenic causation of mental illness.)

Now, the evidence that valproic acid works as a prophylactic is considerably more iffy. The gold standard for multi-center, placebo-controlleded, double-blind, randomized studies in this regard is Bowden et al. (2000), and its results on balance favor the effectiveness of valproic acid but are still somewhat ambiguous.

If we look at just the raw percentages of patients terminated from the one-year trial phase of the study within each treatment group, we seem to have some clear evidence that divalproex is superior to placebo. The percentage of patients on divalproex removed from the trial phase for depressive symptoms severe enough to warrant hospitalization (or for severe bipolar symptoms of any kind) was significantly smaller than the percentage of patients on placebo removed for the same reasons. However, it turns out that the sheer number or percentage of patients removed from a treatment group because of bipolar symptoms was not the a priori primary outcome measure. Rather, the authors employed the time elapsed until the occurrence of a bipolar episode (i.e., any episode severe enough to warrant treatment discontinuation or the prescribing of antidepressants). It is not clear to me why the latter outcome should be preferred over the former rather than both being seen as complementary, but apparently such is the convention in this research community. Now, none of the differences in "survival times" among the treatment groups were significant at the Bonferroni-corrected 0.05 level given the large confidence interval of this statistic. On the other hand, the numbers strike me as noticeably tending toward the expected direction. For example, the longer time to development of any bipolar episode by the divalproex group relative to placebo was marginally significant (p < 0.06). Also,

[a]mong patients taking divalproex at the end of the open phase, those randomized to divalproex had a 46% longer duration of prophylaxis in the maintenance phase (p = 0.03) than those randomized to placebo; they were also 42% less likely to be prematurely dropped from the study for any major affective episode (p = 0.04) and 32% less likely to be prematurely terminated for any reason (p = 0.002).

I gather that the hypotheses tested in the above quote were not formulated a priori but were a result of post hoc trawling through the data. For this reason we should be suspicious of the results. But if taken at face value, they suggest that the patients deemed by their doctors to be suited best for divalproex as a treatment for acute mania during the open phase (and in fact treated successfully for acute mania during the open phase with divalproex) were biased toward responding favorably to divalproex as a prophylaxis during the trial phase. This strikes me as an eminently reasonable explanation and should be tested in future studies. In a later follow-up, the authors present results of more post hoc analyses of these data with a focus on depressive symptoms (Gyulai et al., 2003). The results are promising, although again they should be taken with a grain of salt.

The overall marginality of the primary outcome measures may well be an artifact of the stringent criteria that patients had to meet before they could be randomized into the trial phase (full recovery from the index manic episode, two consecutive GAS score of 60+, etc.). These requirements were initially thought to make for a cleaner experiment, but in hindsight they may have unduly compromised its power by biasing the intent-to-treat sample toward patients predisposed to good outcomes. On the basis of previous studies the authors expected over half of the placebo patients relapse into mania, but only 22% actually did so. It is of course fortunate that the majority of the patients on placebo experienced such favorable outcomes, but strictly for purposes of the study the wellness of the placebo group is undesirable in that it may have created too high a baseline; if everyone is going to do relatively well anyway, then there is little room for a treatment drug to give a boost.

Another surprising result of the study was the relatively weak performance of lithium on a number of indices. But these indices suffered from the power problem noted above, especially because lithium was not the primary study drug and thus had a smaller treatment group than divalproex. As far as I can tell, these findings are atypical and not accepted as disproving the efficacy of lithium as a prophylactic treatment. See Muzina and Calabrese (2005) for a review of older studies supporting the effectiveness of lithium prophylaxis and also two recent placebo-controlled, double-blind, randomized studies conducted over a longer time period that found patients on lithium faring significantly better than those on placebo with respect to both manic and depressive symptoms.

The atypical (or second-generation) antipsychotics are also rising in popularity because of the mildness of their side effects relative to typical (or first-generation) antipsychotics. My subjective impression is that olanzapine (also known by its trade name Zyprexa) is becoming the atypical antipsychotic of choice. It has also, as far as I know, the only antipsychotic subjected to a placebo-controlled, double-blind, randomized study of its efficacy as a prophylactic (Tohen et al., 2006). Fortunately, the results of this study are much more clear-cut than those of the similar study of valproic acid--perhaps because this time the authors included in the intent-to-treat sample only those patients who had responded well to the study drug (olanzapine) during the open phase. From the abstract:

Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%).

See also Perlis et al. (2006) for a quantitative meta-analysis demonstrating the efficacy of atypical antipsychotics in the treatment of acute mania.

For the most part I will not discuss the undesirable side effects of these drugs, although they must certainly be given some weight in any decision as to whether they should be prescribed. The one side effect that I will briefly comment on is the risk of suicide. In his commentary Healy present a compelling analysis in favor of the contrarian conclusion that prophylactic treatment for bipolar disorder actually increases the probability of suicide. I have found one quantitative meta-analysis of the antisuicidal effect of lithium that is contra Healy (Tondo, Hennen & Baldessarini, 2001):

METHOD: Broad searching yielded 22 studies providing suicide rates during lithium maintenance; 13 also provide rates without such treatment. Study quality was scored, between-study variance tested, and suicide rates on vs. off lithium examined by meta-analyses using random-effects regression methods to model risk ratios.
RESULTS: Among 5647 patients (33 473 patient-years of risk) in 22 studies, suicide was 82% less frequent during lithium-treatment (0.159 vs. 0.875 deaths/100 patient-years). The computed risk-ratio in studies with rates on/off lithium was 8.85 (95% CI, 4.1-19.1; P<0.0001).

But even if we are to split the difference and say that prophylactic treatment for bipolar disorder does increase the risk of suicide in some samples, it is not clear that this is evidence of an undesirable side effect. In a perverse way, it may be evidence the treatment is working as intended. It is part of the clinical folklore that suicide risk among bipolar patients is greatest when they are recovering from an acute episode, not while in the midst of one. Patients suffering from severe depression may not have the energy to carry out a suicide attempt; often they simply lie in bed around the clock, lacking the will to face their troubles, hoping that the next time they open their eyes the bad dream of life will have passed away. If a prophylactic treatment succeeds in keeping a patient out of this kind of crushing depressive state, then given the influence of moderating variables not identified by the above authors, the patient may actually be more likely to carry out a suicide atttempt because of his increased energy and willpower. Now, I admit that this speculation on my part is completely non-rigorous. My hope is that results of relevant studies continue to be tallied; if Healy's effect turns out to be robust now that we are looking for it, then continued evidence for the efficacy of prophylaxis in preventing bipolar symptoms per se may force us to the entertain the kind of mechanism that I have just sketched.

So, in conclusion. I think that the tenor of Healy's commentary should be tempered somewhat with respect to the narrow arena that I have briefly examind here. Although I would like the evidentiary foundation of valproic acid's prophylactic value to be firmer, given its demonstrated efficacy in the treatment of acute symptoms I'm willing to give it an informative prior. More research is needed (as always, I suppose). With respect to olanzapine, I am thoroughly impressed by the results of the recent gold-standard study (robust across several post hoc analyses not discussed here) addressing its prophylactic efficacy.

There is always the temptation to leave problems to the experts charged with taking care of them, to trust that they are doing their jobs and are on top of things. We must all succumb to this tempation at least occasionally, as our resources of time, energy, and conscientiousness are finite. I hope that I am justified in feeling that our trust in this particular instance is justified. I also hope that readers who feel differently or want to add further nuance to the overall picture will leave comments. This is probably too much to ask, but I'd also appreciate it if readers aware of new developments in this area would email me relevant links or PDFs. This request extends indefinitely into the future. Thanks in advance.

There is an interesting article concerning the Official Poverty Rate in the latest issue of Policy Review. The thrust is that in the past 3 decades the OPR shows stagnation while all sorts of other indicators of the well-being of the lowest income portion of Americans are rising. How come? The OPR is based on income instead of expenditures, and income is a funky measure because year-to-year variance in income has been rising. A larger percentage of people who spend and live like they are above the poverty line are having occasional off-years where they dip below the income marker, but everything else points to steady improvements in the conditions for low-income families.

To summarize the evidence from physical and biometric indicators: Low-income and poverty-level households today are better-fed and less threatened by undernourishment than they were a generation ago. Their homes are larger, better equipped with plumbing and kitchen facilities, and more capaciously furnished with modern conveniences. They are much more likely to own a car (or a light truck, or another type of motor vehicle) now than 30 years earlier. By most every indicator apart from obesity, their health care status is considerably more favorable today than at the start of the War on Poverty. Their utilization of health and medical services has steadily increased over recent decades.

All of this is in one sense reassuring. These data underscore the basic fact that low-income Americans have been participating in what Orshansky termed “America’s parade of progress.” Orshansky had worried that the poor in modern America might be watching that parade and “wait[ing] for their turn — a turn that does not come”; fortunately, her apprehension has proved to be unfounded.

To state this much is not to assert that material progress for America’s poverty population has been satisfactory, much less optimal. Nor is it to deny the importance of relative as opposed to absolute deprivation in the phenomenon of poverty as the poor themselves experience it. Those are serious questions that merit serious discussion, but they are questions distinct and separate from the focus of this study — i.e. the reliability of the official poverty rate per se as an indicator of material deprivation.

As we have seen, the U.S. federal poverty measure is premised on the assumption that official poverty thresholds provide an absolute poverty standard — a fixed inter-temporal resource constraint. Such a standard should mean that general material conditions for the poverty population should remain more or less invariant over time. Yet quite clearly, the material condition of the poverty population in modern America has not been invariant over time — it has been steadily improving. The opr thus fails — one is tempted to say that it fails spectacularly — to measure what it purports to be tracking over time. As an indicator of a condition originally defined in 1965, the official poverty rate seems to have become an ever less faithful and reliable measure with each passing year.

Steve Hsu pointed me to this article The Quintessential Quant. The article highlights the standard, IIT, MIT, etc && physics, math, etc. need only apply. On the fly C++ under pressure, etc. But here is the money shot:

A typical offer, say sources, starts with a base salary of around $250,000, plus a guaranteed annual bonus that could double that. The best can command a cut of a fund's upside -- beaucoup bucks when you consider the multibillion-dollar asset pots. All this, yet, says Seanor, "most of these guys have never even had a real job."

Is it me, or does $250,000 K as a baseline salary seem a little low for the best of the best. The thing is, I have friends who spent 4 years memorizing junk in medical school and ground their way through a residency, and they are within spitting distance of that sort of salary. Granted, there's a lot more on top of that...but normalizing for how smart these guys are, on the scale of remuneration it seems they're getting jacked. Why don't they just start a business and get asset rich real quick?

Hawks on Hobbits. 'nuf said.

Perhaps because the topic is so removed from the orthodoxies of the day, this article on Pakistani Americans isn't totally idiotic. Points to note....

Fewer than 0.1% of Americans are ethnically Pakistani. 1.3% of Britons are ethnically Pakistani. 50% of Muslims in the UK are Pakistani. Assuming a low bound of 1 million American Muslims, that means 20% of American Muslims are Pakistani, at most. No shit there aren't ghettos, there aren't enough of them in the US population. While Pakistani youth in the UK lag behind the median in academic performance, the immigration policies of the US have resulted in somewhat above-the-median educational qualifications for this community in the USA. Sometimes the numbers are so nakedly clear & obvious that words are pretty irrelevant.

On the other hand,"In the United States there have been a few cases of young Pakistani men being arrested or tried in terror plots, in Atlanta and in Lodi, Calif., for example." My understanding is that the community in Lodi is not as professional or educationally advanced as in the rest of the nation (basically, they are exactly the peasant farming stock which predominates in the UK). That being said, this maybe a function of the nature of the Ummah and its nutty centripetal pull. Modern communication can be a bitch.

Over at my other weblog I threw up a 10 assertions about evolution post modeled on my post about 10 words about evolution. Other responses:

RPM
Robert Skipper
Afarensis
John Wilkins
John Hawks

I invite readers to try their hand in the comment box.

Mendel's Garden #4 is up.

After a month of reading it on and off I finally finished Robert Pape's Dying to Win. This is an excellent companion to Marc Sagemen's Understanding Terror Networks. While Sagemen focuses on what may loosely be termed the "Salafist terror international," Pape examines the phenomenon of suicide terrorism in a cross-cultural context. I am going to think a bit about this book before I blog it in more detail. I don't know if I agree with all of the conclusions, but there was so much data that I'm also not sure I've processed most of it (I promise, no idiotic "Fiskings" like The Jawa Report). I would like to add three points

1) Pape reiterates that the demographic profile of suicide terrorists the world over does not tend to show that they are poor, psychologically abnormal, without prospects or even young. Unfortunately the meme that they are all these things is extremely powerful, but the data just does not bear this out in the totality. And it hasn't for a long time.

2) Pape is skeptical of the sufficiency of Salafism even within the Al Qaeda threat. This is what is really interesting to me as I am not particularly interested in Hamas, the Tamil Tigers or the Chechens in anything but an academic sense. Pape shows that the % of Salafists within a nation is a poor predictor of the representation of that nation amongst those who engaged in suicide attacks against the United States on behalf of Al Qaeda. Rather, he shows that "American military presence" within a nation results in a proportionate 10 X greater likelihood of an Al Qaeda suicide attacker being from that nation. There are issues with the nuance of how Pape presented the data in my opinion, but I found the numbers interesting and not easy to dismiss even when they contradicted my prior hypotheses.

3) Pape had his graduate students try to ascertain the details of the identities of 41 suicide attackers in Lebanon in the 1980s. In hindsight his analysis of Hezbollah is of current interest, but that is neither here nor there. This is what he found:

27 were affiliated with Communist or socialist groups
8 were affiliated with Islamic fundamentalist groups
3 were Christian! (one of these a female Christian high school teacher)

Sometimes it is frustrating to have to rework my assumptions all the time, but that's life.

Props to Svoboda for most redonkulous imaging.

I started writing a summary of this interesting article on pig evolution, but hell, it's in PLoS, so they've already done the work for me. Here's the synopsis:

Brown adipose tissue (BAT) is unique to mammals. It is rich in mitochondria and generates heat to maintain body temperature during cold stress, referred to as nonshivering thermogenesis. BAT is found in abundance in rodents as well as in newborns of larger mammals, including humans. Uncoupling protein 1 (UCP1) is exclusively expressed in BAT and is localized to the inner membrane of the mitochondria. Its physiological role is to uncouple oxidative phosphorylation so that most of the energy in fat stores is dissipated as heat rather than being converted to ATP.

Piglets are sensitive to cold stress and rely on shivering as the main mechanism for thermoregulation. Furthermore, pigs are the only hoofed mammals that build nests for birth; in modern pig production, heat-producing lamps are used to keep the piglets warm. It is also striking that pigs appear to lack BAT.

Here the authors show that the UCP1 gene is disrupted in domestic pigs and their wild ancestors. The inactivation of UCP1 was estimated to have happened about 20 million years ago. The finding provides an explanation for the poor thermoregulation in piglets that may have led to the evolution of the unique maternal behavior in this species.

My reaction on reading the synopsis was that the reverse explanation for the evolution of the maternal behavior could be possible-- that the selection pressure on UCP1 could be negligible (allowing the mutation to spread) due to the maternal behavior. But no:

The wild boar is the only porcine species that has adapted to temperate climates, whereas all other Suidae live in tropical or subtropical environments. The wild boar has then evolved compensatory mechanisms to adapt to a cold environment. Newborn pigs use shivering for thermogenesis, and the wild boar is the only ungulate that builds a thermoprotective nest for giving birth.

This could be a great example of how the "parameter space" of evolution is limited by the vagaries of history--the ancestor of the wild boar lost the ability to make this protein, reducing the probability of getting it back to nearly zero. So when the animal's range expanded to cooler climates, different pathways were those that faced selection. There's more than one way to skin a cat.

Too many to describe each of them:

"Genome-wide genetic association of complex traits in heterogeneous stock mice" Nature Genetics 38, 879 - 887 (2006) -- News and Views -- Interesting technique to handle correlation structure in the QTLs. They were able to account for ~75% of the additive variance while most QTLs found were in the 1-5% range.

the Nature Genetic miRNA supplement

"Dissecting the complex genetic basis of mate choice" in model organisms -- Nature Reviews Genetics

Evolution of primate gene expression -- Nature Reviews Genetics

• Genes expressed in the testes have experienced positive selection both with respect to their expression and to their sequences among primates.


• Gene expression in the brain has diverged less than that of other tissues analysed to date, but a tendency for acceleration of changes on the human lineage relative to the chimpanzee lineage could indicate positive selection.

Molecular analysis of flies selected for aggressive behavior. -- Nature Genetics - "Selective breeding was used to create a population of fighting fruitflies"*

You'll want to read this:

Daniel Garrigan and Michael F. Hammer "Reconstructing human origins in the genomic era" Nature Reviews Genetics 7, 669-680 (September 2006)

Abstract:

Analyses of recently acquired genomic sequence data are leading to important insights into the early evolution of anatomically modern humans, as well as into the more recent demographic processes that accompanied the global radiation of Homo sapiens. Some of the new results contradict early, but still influential, conclusions that were based on analyses of gene trees from mitochondrial DNA and Y-chromosome sequences. In this review, we discuss the different genetic and statistical methods that are available for studying human population history, and identify the most plausible models of human evolution that can accommodate the contrasting patterns observed at different loci throughout the genome.

Summary:

• Over the past two decades, phylogenetic analyses of mitochondrial DNA and Y-chromosome polymorphisms supported a simple model of human origins, called the single origin hypothesis.


• The single origin model proposes that anatomically modern humans trace their ancestry to a single small population that lived in Africa, and that, following a speciation bottleneck, the population expanded and completely replaced archaic forms of humans.


• More sophisticated methods of analysis, based on the coalescent approach, are being applied to a plethora of new genomic sequence data.


• These new analyses of multilocus sequence data show a large variance in the shape and depth of genealogies for X-chromosomal and autosomal loci, and present a more complex picture of human demographic history.


• Non-African populations have reduced diversity and fewer rare polymorphisms than African populations, suggesting a history of bottlenecks. By contrast, African populations do not exhibit the predicted patterns of polymorphism after a speciation bottleneck.


• These genome-scale patterns could be best accounted for by models that involve low levels of gene flow among archaic populations before the emergence of anatomically modern humans - that is, they imply the existence of ancestral population structure.


• There is also growing evidence that some highly divergent genetic lineages might have entered our genome through hybridization between an expanding anatomically modern human population and archaic forms of humans.


• Further tests of the predictions of these models await more systematic surveys of DNA sequence variation in multiple human populations, along with more sophisticated methods of population genetic inference.

Wendy Johnson and Thomas Bouchard are tearing up the "Articles in Press" section of Intelligence. Their latest work expands on their recent paper on sex differences in mental abilities described by Darth Quixote.

The follow-up, "Sex differences in mental ability: A proposed means to link them to brain structure and function", argues that the pattern of male-female differences in non-g factors could be explained by structural differences in the brain, which they propose to study. They conclude:

there appear to be two basic dimensions of residual ability that underlie g (Johnson & Bouchard, in press). They involve rotation-verbal and focus-diffusion cognitive approaches to problem-solving. Men and women tend to differ on these dimensions. Men are concentrated more toward the rotation pole of the rotation-verbal dimension and women are concentrated more toward the verbal pole. Men are concentrated more toward the focus pole of the focus-diffusion dimension and women are concentrated more toward the diffusion pole. Three different batteries of mental ability tests show very consistent patterns of lack of measurement invariance across sex and each of the two residual ability dimensions. This is consistent with the hypothesis that these dimensions identify differences in cognitive approaches to problem solving that may be reflected in individual and sex differences in brain structure and function. This hypothesis can be readily tested using two novel approaches to scoring the WAIS. In addition, knowledge of participants' positions along these dimensions may help to explain already observed individual differences in brain structure and function. We propose that investigation of these dimensions will contribute substantively to our understanding of how the biological brain produces abstract intellectual performance.

Related: The open letter to Nature; Debate at the PLoS blog

Over in The Corner today Heather Mac Donald stated:

The Bible is as open-ended a text as any other. Ever since Medieval theologians tried to contain Biblical interpretation through hermeneutics, it has evaded all efforts to rein it in.

Long time readers of this blog will know that I tend to accept this as a good first approximation. So check this out Pro-war Buddhist monks in brawl:

...while a "peace protest" in the capital turned into a brawl with hardline Buddhist monks

Some of you are likely weirded out at this point, but those of you who follow politics in places like Sri Lanka and Myanmar know that Therevada Buddhism can be a hammer as well as a lotus. The Western perception is that Buddhism is a calm and pacific religion, and yet so has Christianity been, right? Oh, wait.

The model is: white man = omnipotent oppressor, non-white man = helpless victim. The New York Times headline is: Minority Students Decline in Top New York Schools. The graphic? Here:


Is something off with this graphic in relation to the headline, or what? Ah, click the link in the story, and you see this:



What kind of dumb macaca does The New York Times think I am? I've observed this before with the tale of the invisible Asian. Imbler Volokh has observed how Asians become white.

The decline of institutional racism was a Good Thing. Hell, I wouldn't be blogging today if institutional racism, and the cultural consensus that it was supported by, did not die off. But unfortunately the consensus has flipped toward a different form of manicheanism from the older one where whites are the super-race destined to replace all the inferior breeds. Instead, now they are fundamentally morally obligated to redress their sins. But for those sins to be expiated another group must suffer to witness and offer a blessing. Success just isn't part of the script. It is modern America's contention that diversity is good, but diversity is also complicated. If one wishes to perpetuate a racial relationship crystallized when minority = black, then one should have prevented the mass immigration which began adding more parameters to the model. But the old biracial nation is gone, and the racially sensitive have no answers because they'd rather be conservative and stick with what's worked over the last generation.

I have post on my other weblog where I follow the discussion about God & conservatism over in The Corner and offer my own commentary.

There are many polls about the public's attitude toward evolution, well, check this in The Wall Street Journal, Most Americans Strongly Support Using Genetic Data for Some Uses. Take home message: genetics = good to identify criminals & fathers, genetics = bad if used by insurance companies and employers. Also, the public thinks that "science of genetics and DNA is" a very good thing. Of course, they don't really know what the science is, just some applied spin & reality promoted by various companies.

There has been some interest of late in the similarity between gene expression profiles in brain and testis. Why on earth would you make the same genes in these wildly different tissues? First off, there is this paper which confirms that there is, in fact, a significant overlap between human brain and testis expression profiles. A lot of the overlapping genes are named things like Ribosomal Protein L30. So a large portion of the overlap is genes involved in protein synthesis. I have no idea why. I'm not really down with their discussion though. They make a few suggestions that the expression overlap has something to do with human speciation, but they did no comparative genomics. I'm willing to bet that the similarity between brain and testis gene expression goes back at least to the origin of mammals if not further.

Some things to consider when analyzing overall expression profiles in brain and testes:

• The brain is mostly glia, and some classes of glia share a lot of properties with immune cells.
• The brain is diverse and contains many cell-types, so mashing up a whole brain to look for gene levels is bound to give you a teensy signal-to-noise ratio.
• Tissues that are immune-privileged include: Central Nervous System, Eye, Testes, Uterus

This last one may be really important for understanding the overlap. Immune privilege means that there is a barrier built up between the tissue and the blood, such that the immune system (T cells, etc..) doesn't usually invade. One could imagine that building this barrier requires some certain common cellular regulation. Also, the exclusion of T cells would make these areas seem unique.

While looking around for brain-testes lit, I found Jenny Graves. She studies the evolution of sex determination. She says that SRY, the testes-determining factor, is actually a degraded version of SOX3, a transcription factor that is expressed in the developing chicken, mouse, and human nervous systems. The two known human cases of SOX3 disruption are boys with mental retardation. SOX3 is supposed to be a negative regulator of SOX9 function, and SRY may get in the way of what SOX3 is trying to do by binding DNA that SOX3 might like to bind to. Recall that SOX9 is very important for differentiation of Sertoli cells, the cells that surround developing spermies and keep them safe and warm. Interestingly, Sertoli cells also form the Blood-Testes-Barrier, so they are the source of immune privilege. I recommend reading a Jenny Graves review. I just read this one.

Update: Brain-testes overlap paper in gnxp-forum.

Below the fold....

Thanks to Diana....

The fastest-evolving region in the human genome contains a non-coding RNA named HAR1F. In the study, the authors found that the HAR1F RNA doesn't seem to have the characteristics of a microRNA. They also checked the secondary structure of the RNA (the stems and loops that form when RNA base-pairs with itself and folds up) and found no similarity to other known non-coding RNA structures. HAR1F is found in Cajal-Retzius cells. Cajal-Retzius cells are the major source of a secreted factor called Reelin. One idea about the role of Cajal-Retzius cells is that they sit in the area that will be the outermost part of the cortex (the marginal zone) and release Reelin down towards what will be the innermost part (the subplate). So a gradient of Reelin is formed, strongest at neocortical layer II (outermost cell layer) and weakest at layer VI (innermost cell layer). This is thought to be important for establishing the cortical layers in the right order (but see here). Also, different parts of the neocortex have different amounts of each cell layer (i.e. visual cortex might have a thicker layer IV than motor cortex), and changes in Reelin expression might account for some of this.

To get an idea of what a non-coding RNA in the brain could be up to, you might check out this Perspective by Goodrich and Kugel. They review a number of recently characterized ncRNAs that affect transcription. Do we all know the central dogma? I'm never sure. Just in case, transcription is the process of producing an RNA strand by reading off the DNA template (the genome). Most RNA is made through the orchestrated efforts of a bunch of general transcription factors (TFIIB, TFIID, etc..) and RNA polymerase II (Pol II). All of these factors and Pol II itself are targets for regulation. You can slow down and speed up the machine by adding on or taking off phosphate groups on Pol II's amino acids, for instance. Besides, the general transcription factors there are specific regulatory transcription factors. Hox genes are a well-known example of these. They have specific DNA motifs that they like to bind to near their target genes, so they can get close and screw around with the DNA or the interaction between DNA and transcription machinery.

As an example, there is this ncRNA called Neuron-Restrictive Silencer Element double-stranded RNA (NRSE dsRNA). NRSE dsRNA relieves the genes that should be expressed in neurons from repression by a protein called Neuron-Restrictive Silencing Factor (NRSF). NRSF is this blanket repressor that keeps neuron-specific genes from being made in other tissues. The cells where NRSE is expressed then will be allowed to make a whole slew of RNAs that others aren't allowed to. So NRSE seems responsible for deciding where neurons get made, but then, of course, we don't know what determines where NRSE gets made. Anyway, this is just an example. ncRNAs can block transcriptional repressors and activate transcriptional activators, annnd if they get the notion, they can directly interact with RNA Pol II and speed it up or slow it down. Given HAR1F's developmental role, it might work in the higher branches of a control hierarchy and affect transcription of some neuronal genes that are themselves transcriptional regulators.

The transcript of Francis Collins's speech at the 2005 meeting of the American Society of Human Genetics was published in the most recent American Journal of Human Genetics. In it, he comments on the prospects of genome-wide association testing to find variants involved in complex disease. Not everyone thinks it will pay off as a stategy as much as Collins (as the leader of the primary funding agency for the HapMap) does. Here's his bet:

How successful will this strategy [whole-genome association] be? We don't really know. But I've recently made a wager with my former chairman, Tom Gelehrter. Tom is a professional cynic; I'm an incorrigible optimist. So, we're going to see who's right this time. I'm betting that, by the time of the ASHG meeting in 2008, whole-genome association studies will have led to the discovery of at least four validated-not just guessed at-susceptibility variants for at least five common polygenic diseases. I've asked Joel Hirschhorn to be the referee. And, of course, the wager is substantial: one beer of the winner's choosing.

The first time I (mis)read that, I was shocked that anyone would take him up on it. But on re-reading, it's clear he's saying there will be at least 20 validated susceptibility variants discovered in the next couple years-- four variants each for five diseases.

That's a hell of a wager--essentially he's betting that our knowledge of the genetic underpinnings of complex disease will take off exponentially in the next two years. But two years isn't such a long time--genome-wide association studies have only recently become feasible, so their results are still a little ways off. Still, though, I'm more of an optimist, I'd say I'm with Collins on this.

I might (if I remember and don't get bored with what is essentially stamp-collecting) try to keep score as the papers get published, and maybe someone will tell me if my final tab is in line with Hirschhorn's. The big key here is that the association studies have to be genome-wide, as opposed to in candidate genes. So far:
1. Obesity - INSIG1
2. Type I diabetes - IFIH1
3. Macular degeneration - CFH
4. Caridiovascular disease - NOS1AP (this study actually looked at an endophenotype, not the actual disease outcome, but I'm counting it anyways)

Fastest-evolving gene linked to brain boost. The paper will be in Nature tomorrow, but you can read the original paper online already, along with commentary.

Update: Hawks has way more.

[Originally posted by agnostic, reposted by Razib since blogger mystifies his assophilic self]

Sometimes you notice patterns that don't fully crystallize consciously until some precipitating event really "wakes you up" to the reality. I was riding the metro home tonight and across from me was a girl who was engrossed in Kafka on the Shore -- apparently a high-brow fiction book, not like The Da Vinci Code or something (I don't keep up to date on fiction) -- and who got off at the extremely affluent Friendship Heights neighborhood. So you get the rough idea of her IQ. Unusually for someone that smart & well-to-do, at least in my experience, she was smoking hot. She looked South Asian, maybe Persian. Then it clicked on a conscious level: for those of you who are say, aged 18-40 -- have you ever noticed how many hot, smart brown girls there are in your age group?

To put things in perspective, one estimate of South Asian Americans puts them at ~2 million, or about 2 orders of magnitude less frequent than Euro-Americans. So, assuming no difference across groups, the absolute number of their hot, smart girls should be about 1% the absolute number of hot, smart white girls. Now, "good looks" isn't as easy to research quantitatively, but even impressionistically, there's no way I've seen that low of a number of hot, smart brown girls. If I had to guess, I'd say they're overrepresented by about 1 order of magnitude.

Now, the stereotype I grew up with, and which I didn't see violated overall, was that looks and brains were pretty independent. In a recent post (and also here), Darth mentioned Jensen & Sinha's view that the correlation between height & IQ might reflect cross-assortative mating segregating alleles for both height & IQ into the same families. But, hypothetically, imagine a population that is already highly stratified by IQ / social status and has been for at least roughly 1000-2000 years. And imagine in this population, the males are at least or more likely than elsewhere to select red-hot trophy wives rather than intellectual equals (again, initially, say beginning 1000 or so years ago). This would tend to produce an even stronger correlation between good looks and smarts on the (sub-)population level.

The first assumption is met by the South Asian caste system (though history scholars can correct my time estimate), and the second is met by any geographical area that's wracked by pathogens, such as the Subcontinent. Buss & Gangestad (1993) found that there was a strong correlation between pathogen prevalence and emphasis that people from that area placed on "good looks" when evaluating a potential mating partner. In India, in particular, according to Buss' (1989) massive survey of cross-cultural mating preferences, males rated "good looks" as 2.03 (from 0 -- not important at all -- to 3 -- essential). Skimming the other countries, that appears at or above median. As an aside, Indian females rated this variable as 1.97 -- one of the few countries where there was no statistically significant sex difference in emphasis on good looks in a partner (along with Poland and Sweden). Assuming these two features have been present for even 1000-2000 years, that's 50-100 generations. Devlin et al (1997) found a narrow-sense heritability of cognitive ability amounting to 0.35; no one's quantified it for physical attractivenss, though a twin study by McGovern et al (1996) found a broad-sense heritabilty of 0.64, and this mostly reflects additive variance, as the MZ concordance rate was almost exactly twice the DZ rate.

Thus, the outcome of 50-100 generations of brainy, high-status males snatching up the prettiest girls in the area (where the looks of most are defiled by bugs) seems to be a (sub-)population where the common stereotype of the independence of looks & brains no longer holds. If you're looking for a girl who's both hot and smart, upper caste South Asians aren't a bad bet. Now, this leaves out personality traits, which may or may not complicate the search (informally, I've noticed that hot, smart girls tend to be more princess-y -- what a shock!). Yet, the violation of expectation here isn't due to wispy cultural factors -- whenever I've talked to people about the brains-looks relationship, the common response is that ugliness causes one to become smarter, since there aren't many ways to gain influence, and if looks ain't your niche, brains it is; whereas the hot person decides to coast on appearance rather than invest time in making themselves smarter. In reality, it seems the only way to un-do the common stereotype is cross-assortative mating between brainy guys and hot girls: kinda like how Dr. Strangelove imagines the re-population of the world will take place after nuclear holocaust. A world where girls are smart and hot -- the apocalypse wouldn't be so dystopic after all!

Open question for future research: does the same hold true for upper caste South Asian males? Intelligence in males & females is roughly the same thing, but "good looks" may be spring from distinct sources in males & females, or they may reflect a sex-blind source like strengthened immune system. As I discovered going through the hotcaptcha for judging guys, I don't have a reliable hunch for which guys are hunky or not, so I'll let any female readers offer their impressions.

Refs:

Buss (1989). Sex differences in human mate preferences: Evolutionary hypotheses tested in 37 cultures. Behavioral & Brain Sciences, 12, 1-49. Link (Ctrl+F "bbs" for free pdf)

Buss & Gangestad (1993). Pathogen prevalence and human mate preferences. Ethology and Sociobiology, 14, 89-96.

Devlin, Daniels, & Roeder (1997). The heritability of IQ. Nature, 388, 468-71.

McGovern, Neale, & Kendler (1996). The independence of physical attractiveness and symptoms of depression in a female twin population. Journal of Psychology, 130, 209-219.
[Originally posted by agnostic, reposted by Razib since blogger mystifies his assoliphic self]

The International Journal of Evidence-Based Healthcare has seen fit to advance the state of humanity's knowledge by publishing the article "Deconstructing The Evidence-Based Discourse In Health Sciences: Truth, Power And Fascism" in their latest issue:

Background Drawing on the work of the late French philosophers Deleuze and Guattari, the objective of this paper is to demonstrate that the evidence-based movement in the health sciences is outrageously exclusionary and dangerously normative with regards to scientific knowledge. As such, we assert that the evidence-based movement in health sciences constitutes a good example of microfascism at play in the contemporary scientific arena.

Objective The philosophical work of Deleuze and Guattari proves to be useful in showing how health sciences are colonised (territorialised) by an all-encompassing scientific research paradigm - that of post-positivism - but also and foremost in showing the process by which a dominant ideology comes to exclude alternative forms of knowledge, therefore acting as a fascist structure.

Conclusion The Cochrane Group, among others, has created a hierarchy that has been endorsed by many academic institutions, and that serves to (re)produce the exclusion of certain forms of research. Because 'regimes of truth' such as the evidence-based movement currently enjoy a privileged status, scholars have not only a scientific duty, but also an ethical obligation to deconstruct these regimes of power.

You can read the full paper here and you really should for only then can you savor such exquisite insights as:

Rather than risk being alienated from their colleagues, many scientists find themselves interpellated by hegemonic discourses and come to disregard all others. Unfortunately, privileging a single discourse (evidence-based medicine (EBM)) situated within a single scientific paradigm (postpositivism) confines the researcher to a yoke of exactly reproducing the established order. To a large degree, the dominant discourse represents the ladder of success in academic and research milieus where it establishes itself as a weapon used against those who praise the freedom of scientific inquiry and the free debate of ideas. . . .

Accordingly, we believe that a postmodernist critique of this prevailing mode of thinking is indispensable. Those who are wedded to the idea of 'evidence' in the health sciences maintain what is essentially a Newtonian, mechanistic world view: they tend to believe that reality is objective, which is to say that it exists, 'out there', absolutely independent of the human observer, and of the observer's intentions and observations. They fondly point to 'facts', while they are forced to dismiss 'values' as somehow unscientific. For them, this reality (an ensemble of facts) corresponds to an objectively real and mechanical world. But this form of empiricism, we would argue, fetishises the object at the expense of the human subject, for whom this world has a vital significance and meaning in the first place. An evidence-based, empirical world view is dangerously reductive insofar as it negates the personal and interpersonal significance and meaning of a world that is first and foremost a relational world, and not a fixed set of objects, partes extra partes. . . .

A starting point for health sciences would be to promote the multiplicity of what Foucault describes as subjugated forms of knowledge (savoirs assujettis): these forms of knowledge are ways of understanding the world that are 'disqualified as non-conceptual knowledges, as insufficiently elaborated knowledges: naive knowledges, hierarchically inferior knowledges, [and] knowledges that are below the required level of erudition or scientificity' (p. 7). These forms of knowledge arise from below, as it were, in contradistinction to the top-down approach that characterises the hegemonic thrust of EBHS. For Foucault, a subjugated knowledge is not the same thing as 'common sense'. Instead, it is 'a particular knowledge, a knowledge that is local, regional, or differential' (pp. 7-8).

And, you know, a paper on linking Evidence-Based Medicine to Fascism simply wouldn't be complete without a token quote from President George. W. Bush, but to find out how the authors make the linkage you'll actually have to read the conclusion of the paper.

Study finds gene related to brain development and function plays causal role in schizophrenia:

The study showed that genetic variation in OLIG2 was strongly associated with schizophrenia. In addition, OLIG2 also showed a genetic association with schizophrenia when examined together with two other genes previously associated with schizophrenia--CNP and ERBB4--which are also active in the development of myelin. The expression of these three genes was also coordinated. Taken together the data support an etiological role for oligodendrocyte abnormalities in the development of schizophrenia.

The paper is in PNAS. Interestingly the authors seriously consider the possibility of epistatic (gene to gene interaction) as being part of the risk for schizophrenia.

Labels: disease

Guess which group in Canada is the most religious? The least? Graph below the fold.

Scrawled on the wall of a toilet stall in my local math department:

(integral from 10 to 13)(2xdx) = what I did with your mom last night!

Begin at the beginning and go on till you come to the end; then stop. - Lewis Carroll

There is a rather comprehensive review of developmental events leading to sex differences in gonads, genitalia, and brain in the current Nature Reviews Genetics. I think one of the most interesting things that becomes apparent as you delve into this literature is that maleness in the brain can be attributed to three (if not more) dissociable factors: Testosterone, Sry (the O.G. sex determining gene), and other unspecified genes on the Y chromosome. To some extent these factors depend on each other, but it is possible to manipulate one experimentally and get behavioral/brain effects without affecting the others.

Sry is the gene on the Y chromosome that says to make testes instead of ovaries. There is only one highly-conserved domain in the SRY protein, and effing with it causes serious problems in sexual development. The structure of this domain suggests that SRY should be interacting with DNA (probably regulating the levels of other genes), but there is still no clear direct downstream target. Somewhere further downstream a gene called Sox9 plays an important role. A recent discussion in PLOS Biology (free!) lays out the story to-date. Sry leads to more Sox9, which in turn leads to more Fgf9. Fgf9 and Sox9 interact in a positive feedback loop to produce sustained high levels necessary for differentiation of Sertoli cells. Sertoli cells are one of the first male-specific cell-types to differentiate. They provide a comfortable niche for production of healthy happy sperm, and probably secrete factors to tell other cells to become other important male-specific cell-types.

This may be a good time to remind everyone what these genes do at the cellular level. Sox9 is a transcription factor. Transcription factors interact directly with the DNA and alter the production of other downstream genes. They often do this by either directly helping to recruit the transcription machinery or by recruiting chromatin modifying factors. Chromatin consists of the proteins (like histones) that DNA is all wrapped up in and around. Chromatin modification can loosen or tighten the DNA-protein interaction and make the DNA more or less available for transcription. Fgf9 is a growth factor (fibroblast growth factor 9, to be exact). Growth factors are generally secreted and bind to extracellular surface receptors. When growth factors bind to receptors they often induce an intracellular signaling cascade. The receptor itself is a signaling molecule that can modify proteins downstream and activate or deactivate them. Oftentimes a transcription factor will sit somewhere downstream in the growth factor receptor's signaling cascade, so growth factors can indirectly affect transcription.

You need all of that Sry, Sox9, Fgf9 business to get gonads and start making testosterone which has a major impact on the developing and adult brain. However, people are beginning to discover gonad-independent effects of Sry. A report in the February 2006 issue of Current Biology showed that SRY is expressed in the substantia nigra of the adult male mouse brain and seems to directly affect dopamine production. The substantia nigra is one of two major dopamine producing centers in the brain (the other being the ventral tegmental area). The report showed that specifically knocking down SRY on one side of the substantia nigra turned down the production of tyrosine hydroxylase (TH). TH is the rate-limiting step in dopamine production. Animals with SRY reductions showed motor deficits on the opposite side of the body from the depletion. Female TH levels and motor performance were unaffected by the SRY treatment (since they didn't ever have any SRY to knockdown), indicating that dopamine production is differentially regulated in males and females.

All this talk of dopamine and motor deficits got me thinking about Parkinson's. It seems that there is a 3:2 male-to-female ratio in PD diagnosis. People have been investigating the protective effects of certain female-specific hormones, but this genomic difference may also help explain some of the difference in susceptibility. As far as cognition goes, I'm afraid this doesn't help us out much. There are some hints that the substantia nigra plays a role in reward learning, but the VTA is the dopamine center that has been tied to higher cognitive function.

A day after the Current Biology paper came out, the Journal of Neuroscience had a paper out that separates the behavioral effects of Sry-mediated gonad generation from the rest of the Y chromosome. In a previous work, this group produced mice that had Sry deleted from the Y chromosome and inserted on an autosome. This allows you to have XY female mice and XX male mice (male and female here refer to gonadal sex). Presence of the Y chromsome minus Sry influenced aggression and parental behavior in the same direction that male gonads did. Also, the Y chromosome affected the amount of vasopressin in the lateral septum (associated with parenting and social behavior in rodents). So genes on the Y chromosome besides the major testes-determining factor help push the brain into maleness in a direction complementary to the effects of testosterone. There is a little speculation as to which genes these might be, but not much. This could still be a matter of higher gene dosage of some X-linked gene in XX over XY mice.

Sex differences in the brain begin before the testes are formed and thus happen outside the influence of testosterone. Testosterone plays a huge role, but the Y chromosome and particularly Sry do more than specify gonads. It may be that there is no essence of man, but that man is made up of components that can be varied independently. These gonad-chromosome mash-ups are extreme, but may be mirrored by more subtle variations in the naturally occurring population. Testosterone can enhance verbal, spatial, and working memory and increase aggression, but the aggression effect of chromosomal maleness persists in the absence of a male hormonal environment. I cannot readily pin a cognitive attribute on SRY effects in the brain, but the fact that it specifically affects dopamine in the substantia nigra suggests that it's affects will be circumscribed and independent of the gonads and the rest of the Y chromosome.

I don't know if this has been linked before, but I just came across this useful introduction to population genetics. It is an encyclopedia article by Anya Plutinski and Warren Ewens.

PLOS blogs has just linked to the open letter to Ben Barres we published (and agnostic's post). Ben Barres posts the first comment on the thread.

I recently read Randall Balmer's Thy Kingdom Come, a screed against the contemporary marriage between right-wing politics & evangelicalism from the perspective of a left-wing evangelical. I agree with many of Ross Douthat's criticisms of Balmer's book, what could have been an insightful and rich narrative of the organic evolution of evangelical Christianity in this country and the parallel emergence of the "New Right" within the last 40 years basically became a convential liberal polemic scaffolded by an occassional attempt to tie it back to Balmer's original thesis. Nevertheless, there is some good in the book, especially the beginning where Balmer illuminates the canvass which he will use to paint his picture. Balmer's focus on two issues and their relationship to the evangelical movement, abortion and homosexuality, is of particular interest to me.


Early on Balmer makes a bald claim which will likely come as a shock to many Americans: the rise of the Christian Right was not stimulated by Roe vs. Wade. This was actually not a big surprise to me. Last fall I had a period when I read a great deal about the history of Catholicism (and Judaism) in these United States, and the tardiness of the evangelical Protestants to the abortion issue was something that was noted multiple times. In Catholicism and American Freedom Catholic historian James T. McGreevy gives us a blow-by-blow of the growing anger by Thomistic intellectuals at the move toward legalized abortion. These intellectuals were archetypical "Americanists," whose hand was instrumental over the long view in transforming the Church in Vatican II, and they were idealogues who were aligned with the New Deal. But during the 1950s tensions began to emerge, especially between Jewish and Catholic intellectuals as the former began to take the side of the post-Protestant elements of the "eastern establishment" who fingered the Church as a block on the inevitable move toward secularity within the republic. The Thomistic intellectuals were simply the tip of the iceberg of a massive Catholic movement which took a strident and uncompromising stand on what we might term "reproductive issues." With the emergence of the birth control pill and the decriminalization of abortion in places like Colorado and California these intellectuals and the movements within the Church which they headed began to fight the long rearguard actions which have characterized the "Culture Wars" from the Right over the last generation. Abortion was clearly part of this.

So where were the evangelicals? In Thy Kingdom Come Balmer offers a cautious and somewhat suspicious editorial afte Roe vs. Wade from Christianity Today after the decision. But this was clearly not the signs of a movement and subculture energized. In contrast, the Catholic Church immediately moved and began to articulate theses which they had pushed forward against the likes of Maggie Sanger in the early 20th century. McGreevy even points to evidence of support for abortion rights among evangelicals in the late 1960s (e.g., a favorable editorial in Christianity Today in relation to the decriminalization occurring in places like California and Colorado). Additionally, it is important to remember that the governor who signed decriminalization in California was that supporter of Barry Goldwater, Ronald Reagan!

Balmer is a partisan, that much is clear. Though I am convinced that there was a strong latency in the reaction and the identification of the evangelical Christian Right with the abortion issue (the Catholic sources seem united on this issue), I am not convinced of Balmer's specific reasons given. Balmer offers that in the late 1980s he was in a meeting where Paul Weyrich castigated the evangelicals (Weyrich is an Eastern Rite Catholic, leaving the Western Church after Vatican II, but remaining in communion with Rome) and reminded them that abortion was not the reason they became politicized. The reason Weyrich gave was the case against Bob Jones university in regards to revoking its tax exempt status because of its discriminatory policies (e.g., not admitting non-married blacks because of fears of interracial dating, etc.). In the South during the late 1960s and early 1970s many "Christian academies" emerged specifically to avoid desegregation. Balmer contends that the real reason for politicization, or one of the primary ones, was the ghost of Jim Crow, and the later fixation on abortion was a way to make their motives seem more altruistic and noble. Balmer has an axe to grind here. I doubt abortion was the motivating reason, but was just Bob Jones University? I don't know, and I doubt it. Jimmy Carter's entrance into the presidential race in 1976 was probably another reason, as many evangelicals who later became part of the Republican establishment initially supporter their fellow evangelical in 1976, only later to turn on him because of his relative progressiveness on social issues.

To "understand" what happened with evangelicals in the 1970s, I think we need to take a step beyond Balmer's introspection, and his obvious bias in depicting evangelicals as badly as possible. Balmer makes it clear that anti-abortion evangelicals are very sincere, and one of his case studies is of a many who admits that he wasn't that focused on abortion in the 1970s (and even worked for a pro-choice Republican as chief of staff durign that period). But now he sports "choose life" buttons. I think it is important to remember the insights from some of Daniel Schachter's work with memory. Schacter reports on research which tracked individuals for 15 years and assayed their attitude toward racial issues. A clear pattern emerged: all individuals became more "liberal" as time passed, but, they back-projected their current views to the past, and by the 1980s seem to be under the impression that in the late 1960s while the rest of society around them was racist, they themselves were not. Of course, the researchers had tracked the individuals and so could note that the reality was that the individuals were tracking social changes, all the way claiming a particular individual evolution. What does this have to do with abortion and evangelicals? I believe that sometimes subcultures and societies "snap" or change rapidly. Though we don't have a good model for it, it seems like it is a sort of "meme fire" sweeps through so quickly so as to transform that culture and necessarily individuals who identify with that culture. On the reflective level individuals generate ad hoc "reasons" for their beliefs even though they were carried along with the rising or receding tide of cultural cognitive biases & beliefs. While Roman Catholic thinkers offer up explicit and unapologetic non-religious reasons for why abortion is murder (remember that the Church has shifted toward a more "pro-life" view as we understood more about embryology in the 19th century), evangelical thinkers who come out of a sola scritpura mindset where the Bible is the font of all they hold dear must search for "proof text." Balmer shows how generally weak this is in regards to abortion. This goes back to a point I like to make about culture and beliefs on this blog: be cautious about trusting someone when they justify their beliefs based on some text. There is a often a model which posits:

Individual(text) = Beliefs

I do not believe this is correct. Texts are large, often vague, and nearly anything can be extracted out of them given some effort and will.

And speaking of texts, the second issue I want to move to is homosexuality. I will put my cards on the table and admit that I am not generally burdened by hostility or animus toward homosexuals as individuals, though I have serious reservations about the identity politics nature of the current movement. I tend to support gay marriage as a state-by-state initiative, and suspect that a generation from now the current debate about homosexuality will seem antiquated. Honestly, it isn't an issue that is really high on my radar, though if I was homosexual I would certainly feel differently. Similarly, many conservative Christians get very worked up over this issue. There was a time when I conceded to evangelicals that it was right and proper for them to get angry about this, after all, did not their scripture condemn homosexuality? I did think that the rejoinder that most of the condemnation was in the Hebrew Bible was proper and correct, insofar as evangelicals generally reject close fidelity to the Law. Neverthless, I did know there were a few likely candidates within the New Testament to support Christian rejection of homosexuality as an abomination. I granted them their outrage though I did not share it.

No longer, and the reason is this: I read the New Testament, and though there are some somewhat muddled references to sexual abominations that can be easily (in my opinion) interpreted as referring to homosexual relations: Jesus' attitude toward divorce seems be so crystal clear that I was shocked that evangelicals would focus on homosexuality so much if textual fidelity was their concern. I went online and looked for evangelical apologia on divorce, and I went away disgusted, because it had the same contexualizing and mealy-mouthed tone as what some liberal Christians attempt with homosexuality. And unlike homosexuality the references to divorce are clear, unapologetic, extremely potent. The magnitude and direction of the vector is simply impossible to ignore. And yet the reality is that evangelicals do divorce, and their churches do justify divorce as a "necessary evil."

What does this matter to me, atheist that I am? It matters in two ways: first, it reaffirms my belief that the importance of text and explicated belief derived from text needs to be interpreted very cautiously. There might be something there, selective literalism is the nature of man, it is not the exception to the rule. Fundamentalists really aren't fundamentalist about anything, not only are they a recent reaction to Biblical modernism, their own take on scripture is totally riven with their own "interpretations" and wiggles and jukes around the plain reality. All this is fine and not of particular concern, what idols one dances around is not my business, but when people point to scripture as a justification for what they do, then it might behoove us to look at scripture. I have long had a non-trivial familiarity with the Hebrew Bible and I could engage in discourse the topic with any potential evangalists who came my way. Now that I have read the New Testament a few times I will do the same here. Do I believe in the importance of scripture? Not really, but sometimes it is easiest and most fruitful to gouge an enemy's eyes out with their own knife. Prejudice against homosexuality is probably somewhat an evoked property of culture, but then again, I suspect in mass societies so is patriarchy. But it is important to probe and decompose the assertion that I believe as I do because the "because the Bible tells me so." Fight the enemy on their own ground when possible and productive.

What does this tell us about religious culture in the big picture? Unfortunately, it tells us nothing but removes an explanatory angle from the commanding heights, and that is of axiomatic scritpure. There is more to human culture under the arch of heaven than can ever be comprehended and modelled between the covers of a piece of holy text. Text can justify post hoc, but it seems unlikely to me that it will prove a genuine causal component of variation (though again, I am still open to this because it is a simple and clear explanation). What we can conclude from the example of evangelicals and abortion, or, the shift toward premillenialism in the late 19th century is that sometimes ideas slot into some cognitive-cultural gap and sweep through the population so that after the fact it seems "natural" and "obvious" that x implies y in group z, and that group z was always as such. When your model fails to explain with the number of parameters you are using, you need to keep adding parameters.

Finally, I want to tack to one issue in Balmer's narrative which deals with religious history. Balmer states that "evangelicalism in America bears the marks of those initial influences-the obsessive introspection of the Puritans, the doctrinal precisionism of the Presbyterians, and the emphasis on a warm-hearted, affective spirituality from Pietism." It seems to me that in his later narrative Balmer speaks as if the last element, Pietism, is really the fundamental core of evangelicalism. I would not necessarily disagree, I do believe it is far more important in evangelicalism than the other two factors, especially the first. But, some of the trends in evangelicalism that Balmer deplores, such as the attempt to tear down the wall between church & state seem to me clearly derived from the first two factors, especially Presbyterianism. Patrick Henry, a Presbyterian, was behind an early move to declare Christianity the official religion of the early republic. The Pietistic strain which is dominant in American evangelicalism does look askance at church establishmentarianism, and it is somewhat peculiar that American evangelicalism seems to synthesize emotive and unreflective Pietism with a muscular Presbyterian this-worldly politicism, but Balmer sets up a strawman when he dismisses the authenticity of those who would emphasize the non-Pietistic foundations of American evangelicalism.

Some of you may have read the recent news report of a paper by William Flynn and James Flynn arguing that the white-black IQ gap has steadily narrowed over the last 30 years. I believe that this paper, as well as a rebuttal by Phillipe Rushton and Arthur Jensen, will be published in an upcoming issue of Psychological Science.

Our own resident educational psychologist Alex Beajuean is analyzing these and other relevant data using a model-based approach that is more sophisticated than the techniques used by Dickens and Flynn. We may deliver a report here at GNXP when this analysis is done. In the meantime, we have made a little graph showing the results of the studies conducted during the period covered by Dickens and Flynn, including those studies that Dickens and Flynn omitted from their analysis (and that Rushton and Jensen argue should have been included):


As you can see, the gap between white and black children does indeed seem to be decreasing over time. The gap between adults, however, does not show any noticeable trend. Perhaps the adults are lagging behind a true gain by blacks as a whole, but remember also that the correlation between genotypic and phenotypic IQ increases with age. Without further analysis, I suggest simply keeping this graph in mind as we go forward.

Labels: IQ

Check it, Fat Factors in The New York Times Magazine. Fatties, you're just sick!

I'm spending the day in Seattle, and boy is it beautiful. I met Dennis Dale today. Dennis tells me he wants some critique of his writing, so go check out his weblog. Tomorrow I'm going to drop in on a ghost of Gene Expression past (in fact, the man responsible for the name, the logo and the general style skin of the blog), Joel Grus. By the way, did you know that Saud bin Abdul Aziz, king of Saudi Arabia between 1953 and 1964, was a habitual drunk? Apparently of such Yeltsinesque proportions that "the family" had to force the abdication of this dissolute potentate.

A reminder to UK readers that Armand Leroi (see his 10 questions on the sidebar) is presenting the first of a 2-part TV series: What Makes Us Human? on Channel 4 at 8.10 p.m. tonight (Saturday 12 August).

Update from Razib: From the comment boards:

http://www.mininova.org/tor/395390

I am currently the only seed but I have uploaded the torrent at a number of profile sites to maximise visibility so speed should pick up as interest and swarm builds. Hope it's good. Bruce Lahn is featured btw.

I have a post on my other weblog that Turkey should not be let into the EU because it is more Creationist than the United States. I know that there are other reasons, but I think it is important to find wedges and avenues to convince those who aren't already part of the choir on these sort of issues, and the possibility that Turkey would unleash a bunch of literalist religionists in the secular funhouse that is post-Christian Europe is something that I think needs to be mentioned. If secular liberals think that "Jesusland" is bad, wait 'till they experience "Prophet Land" (Peace be upon him). One interesting finding of the new study: there isn't really a strong relationship between being conservative (supporting right-wing parties, being pro-life on abortion) and being against evolution in most of Europe, while in the United States there is a strong correlation. I emailed Derb about this, because I think it goes to supporting our contention that the connection that some conservatives in the United States make between the necessary relationship of their politics and anti-Darwinian stance is simply a function of particular American historical conditions (i.e., the coalescence between fundamentalist Christianity, literalism and Creationism, combined with the vibrancy of radical Protestantism in this nation). The flip side of this in the United States is that there are some on the Left who believe that to accept evolution is to necessarily accept the axioms of the Left. Ultimately all this politicization is simply a function of the American scene, it is not a universal law.

(my ideas in regards to politics, God and evolution have lately been strongly influenced by the reality that R.A. Fisher, the man whom I hold up as the most important figure in evolutionary thought aside from Darwin himself, was both a Tory and a Christian)

Satoshi Kanazawa has a paper in press at The Journal of Theoretical Biology which is of some interest. Here is the abstract:

The generalized Trivers-Willard hypothesis...proposes that parents who possess any heritable trait which increases the male reproductive success at a greater rate than female reproductive success in a given environment will have a higher-than-expected offspring sex ratio, and parents who possess any heritable trait which increases the female reproductive success at a greater rate than male reproductive success in a given environment will have a lower-than-expected offspring sex ratio. One heritable trait which increases the reproductive success of daughters much more than that of sons is physical attractiveness. I therefore predict that physically attractive parents have a lower-than-expected offspring sex ratio (more daughters). Further, if beautiful parents have more daughters and physical attractiveness is heritable, then, over evolutionary history, women should gradually become more attractive than men. The analysis of the National Longitudinal Study of Adolescent Health...confirm both of these hypotheses. Very attractive individuals are 26% less likely to have a son, and women are significantly more physically attractive than men in the representative American sample.

The Triver's-Willard Hypothesis is pretty straightforward, but, let's take the finding that females are, on average, better looking than males at face value (Kanazawa seems to have used bilateral symmetry as a proxy, and let's ignore the confounding effect of greater male developmental instability). What does this imply? Well, it implies that sexual selection upon women has operated for a long period of time, because dimorphism takes a relatively long time to evolve relative to non-sex differentiated traits.

Addendum: You can find the full manuscript in the gnxp forum files under 'Kanazawa."

The American Conservative is asking for opinions on what makes liberals and conservatives. I was surprised by Heather Mac Donald's entry, as it seemed that she took an opportunity here to stand up for atheist conservatives. I knew Mac Donald was an unbeliever from her Luke Ford interview, but I'd always assumed she would be the typical secular conservative, keeping a low profile and giving religion its due in her political movement. Since this weblog is frequented by many who are both unbelievers and Right-of-Center (as both founders of the weblog are), I thought you'd find it interesting (via Steve).

Addendum: Also, if you haven't seen it, I highly recommend her most recent piece about immigration in City Journal.

I just got up, but if you are reading this I'm sure you'll have heard about the plot to blow up planes by British "Asians" (seems like brown Muslims whose parents' emigrated from Pakistan). The only comment I'd like to make is that this is the major problem with childish fantasies like Patrick Boyle's of bombing the Middle East¹ with tactical nuclear weapons as a solution to our terror problems: the monster lurks in the belly of the beast. What is easier? A domestic kulturkampf or global cultural revolution? We know that British Muslims are particularly nuts, probably thanks to a supine indigenous culture and an official policy of multuculturalism. Shifting the utilitarian calculus to the perspective of British Muslims themselves as a whole, will multicultural Leftists like Chris Bertram stand up for their allies when a culture of rejection and violence finally induces the majority to turn on the snakes in their midst, not distinguishing the good from the bad? I suspect that white supporters who made a tactical alliance with Muslim "community leaders" will quietly drop that connection, after all, it was never one based on principle but expedience in the interests of securing support against the "true evil" of center-Right politics and "xenophobia."

Addendum: I recommend everyone read Marc Sageman's book to get a sense of the matrix of necessary and sufficient conditions which give rise to the nihilism of transnational Salafists. These are a particular flavor of terrorist which emerges from the "vibrant" intersection of modernity and Islam.

Additionally, to see what I mean by kulturkampf, see this response to a reference I made to genocide in the Hebrew Bible:

Razib, your proof text from Numbers doesn't prove (or disprove) as much as you think. God's instructions to Moses there pertained only to that place, and that time, and only with regard to the Midianites. It was certainly not a general instruction for the conduct of war. So there's nothing in the Torah that a believing Jew has to distance himself from in terms of how we live today. (Non-believing Jews more or less distance themselves, by speech or by deed, from 90% of it anyway.)

This sort of immediate and sincere apologia is what we need from Muslims! I cited a passage where Moses suggests to his warriors that all non-virgin females and males of the Midianites should be killed after their defeat. And I get an immediate response as to why it shouldn't be an exemplar for modern behavior! Bravo! Over a thousand years of being under the boot of Christians and Muslims who would brook no belligerency in their Jewish minority will do that to you. Of course, some radical Jews start to play word games and label their contemporary enemies Amalekites, but that's a different story.

Postscript: Emotional outburst: fucking animals! Now, if another 9-11 does happen, let's restrain the impulse to invade a country in lieu of actually stringing up all the major Al Qaeda principals on the loose across the world....

Addendum II: I think the term "Islamo-fascist" or "Islamic fascist" leads us on the wrong track in conceiving of the "problem" that the West, as opposed to Egypt or Indonesia, face. A better term might be "Islamic anarchists." The imposition of shariah law or the creation of an Islamic state in Britain or the USA is as realistic as an anarchist utopia emerging out of violence which triggers a revolt against the capital class. In contrast, an Islamic state in Egypt is plausible because of widespread support at the grassroots for groups like the Muslim Brotherhood.

1 - Though to be fair such retarded D & D boy-warrior fantasies dominate much of the blogosphere, and often crop up among the local imbeciles here too. We are animals after all :)

Lei points me to this report of unpublished work on the Maori of New Zealand and their relationship to a variant of MAOA and behavior genetics. The piece is a bit garbled and uses hyperbolic terminology, but, it seems that the Maori exhibit a high frequency of an MAOA variant linked to aggression in relation to the basal frequency within the white population. Why would this be? Well, the fact that the Polynesian settlements were often characterized by courageous voyages in search of new lands, and endemic warfare due to constrained resources once settled in those lands, it makes sense that the Maori would exhibit a genetic signature of natural social selection. Anyone who has seen the Maori Haka dance can intuit that these are no pussies. Here is what I said three years ago:

What if we find out that there are different frequencies of the variations of MAOA in diverse human populations? The implications for those who want to see it are clear-what will those of us who believe in equality before the law and the presumption of free will do if we stick our heads in the sand and ignore these possibilities? I don't have the answers, I'm not an ethicist, legal theorist or political philosopher, but those who are might have to begin addressing more controversial topics coming out of neuroscience and genetics sooner than they expect.

We should be cautious about focusing on just one study and one locus, but as the shape of variation across many loci from many studies correlated with many traits begins to emerge we will be able to construct some plausible predictive models.

Addendum: More stuff about the "thrifty gene." I'm on the record about this: fatness is not an adaptation, it is a response eating too much, not exercising, or metabolizing foods in a particular manner, or a combination of these three. Polynesians are grossly fat when introduced to a sugar and refined carb diet, but they weren't always grossly fat. Additionally, there is the hypothesis that they needed to be large and in charge so as to survive those long voyages, but what happens when you arrive in the land of plenty? All of a sudden food is not longer a constraint, shouldn't selective pressure be released all of a sudden?

As usual, lots of activity on my other weblog. I post on introgression multiple times. Also, baby formalisms that all GNXP commenters should be familiar with. Also, I am posting at Nation Building more often now (my main current political sentiment is that the Left is deluded at home and the Right is deluded abroad).

On non-GNXP related blogs, I point you to Nature's Numbers, a new blog by a maths student shifting toward bioinformatics. And over at ScienceBlogs I've been reading Good Math, Bad Math a lot. Finally, Darwin Catholic posts on the new eugenics, from a different angle then you would find at GNXP. Though I disagree on many issues with DC, I do think it is important to engage his perspective because a) a large number of fellow citizens hold such views explicitly or implicitly b) engaging an alternative position is often healthy in terms of smoking out one's own fundamental priors & priorities.

Joseph LeDoux is a University Professor and Henry and Lucy Moses Professor of Science, and a member of the Center for Neural Scienceand Department of Psychology at NYU. In addition to articles in scholarly journals, he is author of The Emotional Brain: The Mysterious Underpinnings of Emotional Life and Synaptic Self: How Our Brains Become Who We Are. His work has focused on the role of the amygdala in emotion and memory.

Be sure to check out the other interviews in the '10 questions' series in the sidebar. Below are 10 questions for Joe LeDoux.

1. Over the past two decades you have produced a detailed diagram of the neural circuitry involved in auditory fear conditioning, eventually tracing the storage site for such memories to a single nucleus of the amygdala. The fear system was appealing, in part, because it is relatively straightforward. Fear responses are stereotyped and have remained relatively constant throughout evolution. What, if any, emotional system(s) do you think will yield to this sort of fine-grained analysis next?

The key to doing all this for fear is that there was a good behavioral paradigm, fear conditioning, for studying fear. It's much easier to relate behavior to the brain if you have a simple and repeatable behavior that is reliably controlled by a stimulus. As soon as good stimulus-response paradigms are developed for other emotions, the brain will yield its secrets. There are good stimulus-response paradigms for reward but unfortunately these paradigms don't naturally relate to a specific emotion the way fear conditioning does.

2. In an Edge interview in 1997, you wondered about the interaction between a reactive emotional system and decision-making. Recent work in the fields of moral psychology and neuroeconomics are beginning to provide some insight into these mechanisms by integrating efforts across several disciplines. In what ways do your interests overlap with these fields? Have they affected your view of the mechanisms by which the emotional brain controls decision-making and vice versa?

I've been interested for a long time in a behavioral transition that occurs once you find yourself in danger. First, you react-evolution thinks for you. Then you act-you're dependent on past experience and your ability to make decisions in this phase. We've shown that the transition involves the flipping of a switch in the amygdala. I don't mean this literally. What happens is that reaction involves a circuit in which information flows from the lateral amygdala to the central amygdala, which then connects with areas that control reactive bodily responses (freezing behavior; changes in autonomic nervous system responses such as blood pressure, heart rate, breathing, sweating, pupil dilation, etc; and release of stress hormones). In order to take action, you have to inhibit this "freezing" pathway and activate a pathway in which active behaviors are controlled. This pathway involves the flow of information from the lateral to the basal amygdala. The switch flip metaphor refers to the output of the lateral amygdala, which is sent to different regions for reaction vs. action. Clinically, the reaction pathway is associated with passive coping, and the other pathway with active coping. Psychologists have shown that people do better in overcoming fear when they engage in active coping. So understanding how this transition occurs is important. All this is by way of answering your question about decision making. The brain makes a decision when it throws the switch. So I would say my interests do overlap a lot with the decision making disciplines but that really is a different world. I think part of the difference is that much of that field focuses on gains and losses of monetary rewards, which I think is very different from decision making in situations where bodily harm is at stake. However, the sophisticated analyses that have been developed in neuroeconomics might be very useful in the study of fear.

3. Several of the central mechanisms involved in synaptic plasticity (NMDA receptor, calcium signalling, AMPA receptor trafficking, spine dynamics, etc.) appear to be general, occurring at neocortex, hippocampus, and amygdala synapses. Are there major differences between mechanisms of memory in different brain regions? How could a drug, say for combatting phobia, target fear memory without affecting the other memory systems?

There is indeed a remarkable consistency of molecular mechanisms for different kinds of memory in different brain systems. This even holds across species as diverse as slugs, fruitflies, mice, and people. One implication is that the uniqueness of different kinds of memory is not dependent on the molecules so much as the circuit in which the molecules do their tricks. However, it is possible that so far we've mainly found the similarities and that subtle but important molecular differences are yet to be discovered. But let's assume that the first idea is correct-that the molecules involved are essentially the same. Even it the molecules that make memory in the amygdala and hippocampus are the same, it is likely that there are unique genes in these areas. If so the proteins made by these genes might be used as keys that unlock a molecular package that a drug is wrapped in. The drug goes everywhere in the brain but is only active in the area containing the protein that can unwrap it. Science fiction, but not science fantasy.

4. You have reported that some 30% of neurons in the lateral amygdala, and blocking AMPA receptor trafficking in just 10-20% of neurons produces impairments in fear memory. At this rate, it seems that a rat that is afraid of three things will have to overlap representations to fear a fourth. Does the fear system have limited storage capacity? What happens as you begin stacking multiple aversive memories into the same neurons, do they distort or overwrite previous memories?

Synapses, not whole neurons, are the units of information storage. Each neuron has many thousands of synapses. I'm sure the fear system has a capacity limit, and that would be very interesting to study. So far no one has studied that, at least as far as I know.

5. Have advances in genomics and bioinformatics (i.e. sequencing of several mammalian genomes and development of tools for exploring them) influenced your own molecular/cellular work at all? More broadly, what do you expect will be the relationship between genome research and neuroscience in the future?

I'm not very sophisticated when it comes to genomics. So I'm not sure I'm the best person to answer this question. But I do have an opinion. Genomics hit neuroscience in a big way. Probably neuroscientists were overly enthusiastic about the ability of techniques like gene chips to change the field overnight. It's easy to find genes that correlate with learning-too easy. The trick is analyzing all the data that come out and making sense of it. But genomics is here to stay and will make tremendous contributions in the years to come. The next generation of neuroscientists will be trained in both fields and will know better how to navigate the territory.

6. Several individual proteins and signaling pathways have been implicated in amygdala plasticity in the past few years. How do you conceptualize the interaction of these individual players in the bigger picture of the synapse? For instance, when a pathway like MAPK with multiple intracellular targets is implicated, do you mentally place more weight on the immediate downstream post-translational modification of synapse associated proteins or regulation of protein or mRNA synthesis?

I think we have to remain open minded about these kinds of things. To follow your example, we'd need to explore the various targets of MAPK to see which ones are critical and whether the critical ones lead to gene expression and protein synthesis. Then we could decide.

7. Some have proposed that a self-perpetuating 'mnemogenic molecule' (like a constitutively active kinase or a prion-like RNA-binding protein) might account for long-term synaptic plasticity and memory while others seem to suggest morphological changes are necessary. How do you think fear memories are maintained in the very long term? Are the same synapses even responsible for the memory trace throughout the life of the memory or do you imagine a systems consolidation type of mechanism where eventually the fear memory is moved to a remote storage site?

A few years ago we published a study showing that different cell groups in the dorsal subnucleus of the lateral amygdala participate in the initial learning of fear conditioning and in the long-term storage of the conditioned association. One, located in the superior part of the dorsal subnucleus learns rapidly and resets. The other, located in the inferior part of the dorsal subnulceus learns more slowly but retains the memory, even beyond behavioral extinction. So there is a nomadic quality to fear memory within the dorsal lateral amygdala. This means different synapses are involved in initial learning and persistent memory. The key issue is whether the synapses involved in forming the memory in the second circuit persist or change over time. I don't think anyone knows this. However, the fact that we could pinpoint a memory region in such a small zone in the amygdala gives us the hope that the question may be answerable.

8. You wrote a mild critique of Judith Rich Harris's book *The Nurture Assumption* when it was published eight years ago. In your own book *The Synaptic Self,* you expressed further reservations about the decidedly hereditarian perspective promoted by the emerging fields of behavioral genetics and evolutionary psychology. What do you think is the most crucial shortcoming of these new human sciences in their consideration of the causal influences on behavioral phenotypes? What role do you see for your own branch of neuroscience in the ongoing debate over the sources of human nature and individual differences?

I am a strong proponent of the importance of genes and heredity to behavior and mental life. But I think it's important to keep this stuff in perspective. Genes are important, just not all important. Indeed, I believe, as I argued in Synaptic Self, that important parts of personality are learned. This doesn't water down the importance of inheritance. Evidence for a genetic contribution to something doesn't mean that non-genetic factors are unimportant. Non-genetic factors influence gene expression from the moment the egg is fertilized. In terms of the brain, nature and nurture are not two different things but two ways of doing the same thing: wiring synapses. Through synapses, genes and experience influence who we are. The key issue is how synaptic change over the course of life determines what the brain knows and forgets, and what can be acquired or not.

9. The most obvious changes that occurred in primate brain evolution involve the building of more neocortex on top of the 'reptilian' brain. You tend to emphasize the continuity between the emotional brain systems from rodents to humans, but could you speculate some on how the emotional brain is different across species?

When studying animals it's important to ask questions of the animal that research on the animal can answer. When I study emotion in rats, I study how the brain processes the stimulus to elicit physiological and behavioral responses. The reason I study this in rats is because the brain mechanism that process danger and produce defense responses have been shown to be very similar in rats and people. Considerable evidence suggests that when we are conscious of a stimulus, whether its an emotional stimulus or not, prefrontal cortex is involved in the processing. I don't attempt to study conscious aspects of emotion in rats for two reasons. One is that there is no way to know what they consciously experience, and two because they lack the regions of the prefrontal cortex that appear important in conscious states in people.

10. If you had a chance to do it all over again what would you change about your education?

I grew up in a small town in south Louisiana. I don't think I really learned what the field of psychology was until I went to college. I had very little training in science in high school, and that didn't change in college since I majored in business. I went on to do masters level work in business as well. At one point I took a course with a professor who was studying the brain, and my world changed. I decided I wanted to be a neuroscientist. I was at a certain disadvantage not having studied science. On the other hand, everything I learned about science, once I started learning it, was relevant to what I was doing. So I wouldn't necessarily change my science education. I do wish I had more exposure to art, history, languages, and the humanities in general when I was growing up and in college. I think most scientists, most people in fact, could use better grounding in the humanities.

Labels: 10 questions

Grind ya teeth and just roll with it. Don't risk it. Fuck around and be a statistic. - Ghostface

genius re-post:
This article by McCoy and Platt in the September 2005 issue of Nature Neuroscience is an extension of past work and a clarification of what was previously observed. In the past study, they found reward-sensitive neurons in the posterior cingulate cortex. In this more recent study, the neurons are utility-sensitive. The difference is between measuring the more objectively available idea of reward size and the more subjective idea of utility. To quote the commentary by Daeyeol Lee, "In economics, the numerical measure of an individual's preference of subjective value for an object is referred to as utility."

Let's back up a couple steps, one step for anatomy and one for the previous results. First, let's get an image of where this posterior cingulate (CGp) is. Many are familiar with the corpus callosum, the giant bundle of white matter that connects the hemispheres. The cingulate basically wraps around this structure over the top. So if you were to take a brain and cut it in half lengthwise and pretend it was a rainbow, the third ventricle/thalamus/septum pellucidum and whatnot would be red-orange, the corpus callosum would be yellow, the cingulate would be green, the rest of the cortex would be blue, and your psychic aura would be indigo and violet. The portion of the cingulate that's further back toward the brain stem is the CGp. I'm not sure, but I'm betting there is a lot of vagueness regarding the boundary between the anterior and posterior. The illustration below is not color-coded in the way I described. I got it here and it from there it points to here:


Now waaaay back in 2003 is when McCoy et al. recorded reward signals in the CGp. They used single-neuron recording in a saccade (eye-movement) task to measure this. In order to get some delicious juice the monkeys had to stare at an asterisk in the middle of a screen (the fixation point), wait for a target spot elsewhere on the screen to light up, wait for the fixation point to disappear, then move their eyes to the target spot at which point they received said delicious juice. Every 50 trials they would alter the amount of juice received for a movement to the target spot. The saccade behavior indicated that the monkeys were noticing the difference. On trials when the juice reward was small, they would shift their eyes very quickly so as to have the most time to lap up as much juice as possible.

In addition to behavior reflecting changes in reward size, neurons in the CGp also seemed to be getting the picture. Two brands of neurons changed their firing rate in accordance with changes in reward size. One set signaled a short time after the actual eye-movement, and the other set signaled a short time after the reward was administered. A given neuron could increase or decrease firing at one of these times. Increasing the reward size seemed to be increasing the gain on the signal such that cells that usually increased firing would increase further with larger rewards, but ones that suppressed firing would decrease further with larger rewards. The authors interpreted the first firing period (after the movement) as predictive and the second as representing the actual value of the reward.

The monkey's saccade is thus analogous to going to bed on the night before Xmas and the firing that follows is the equivalent of dreams of sugarplums dancing in their heads. The firing after reward is reflects the actual receipt of sugarplums. If the neuron was of the increasing variety, then firing might be really high for one of those gigantic Pixie Sticks and quite lower for a protein bar. There is also an entirely statistically separate signal corresponding to no reward at all when one is expected. This is the "stop believing in Santa Claus" signal, and a neuron that usually decreased firing with lower rewards could still start firing like crazy when the reward is non-existent which goes to show that the signal is a special one. I don't know how this thing got so Xmas-themed so quickly. I must not have invoked the spirit of Ghostface hard enough.

So here's the deal with the newer paper. Maybe there are some kids that really love protein bars more than pure sugar. The reward scale would be all screwed up if we simply tried to measure it objectively. From the last set of experiments we can't tell whether the neurons are signaling something like "juice received" or something more subjective like "how awesome the next trial is gonna be cos I love juice." This is where the gambling comes in. McCoy and Platt cleverly found a way to rule out the "juice received" signal theory.

The first thing they did was to show that macaques in this task are exceptionally risk-prone. They looove to gamble. These monkeys are not wearing their safety belt while driving to Staten Island to try to peddle weight in Theodore Unit's territory. This was discovered using the same saccade task with the addition of another choice for the target point. After fixation, two choices were available: 1) a certain target that always delivered the same amount of juice or 2) a risky target that sometimes delivered less and sometimes delivered more but averaged out to the same amount as the certain target. The monkeys overwhelmingly prefer the risky target. In fact, they prefer the risky target even if it delivers a little less juice overall than the certain target.

So you can see where this is going. What are neurons in the CGp doing? Staying exactly the same all the time since the same average reward is received or changing with the increased preference for the risky target? The latter is the case and the authors take this as evidence that these neurons are actually signaling expected utility. The "expected" is in there because this study is a lot more about those neurons that fire right after the saccade but before the reward. The effect of increased risk is to once again increase gain in this population, and also to increase spatial selectivity. These neurons have a particular direction of movement they are more happy firing about. Increased risk causes them to be even pickier about all of that.

The weird thing is that neurons actually increase their firing rate for the next trial following both of the non-average types of trials. After either an exceptionally low or high reward, that monkey really wants to go for the risky target again. I don't understand it. Seems sort of like buying a scratch-off ticket and losing, getting all determined to win your dollar back, and spending five more bucks on scratch-off tickets.



So we get a peek at something that seems subjective by measuring firing rates. That's pretty cool because the realm of the subjective is often a tough one to quantify. For those who wonder why their tax-payer dollars are being spent on figuring out that monkeys are big gamblers, here's the last word from the authors: "Neurophysiological studies of risk preferences, as reported here, may serve as an important model for probing neural processes that underlie pathological risk taking in individuals with addictions to drugs, sex, food or gambling."

References:

McCoy AN, Crowley JC, Haghighian G, Dean HL, Platt ML. (2003) Saccade reward signals in posterior cingulate cortex. Neuron 40:1031-1040.

Lee D. (2005) Neuroeconomics: making risky choices in the brain. Nat. Neurosci. 8:1129-1130.

McCoy AN, Platt ML. (2005) Risk-sensitive neurons in macaque posterior cingulate cortex. Nat. Neurosci. 8:1220-1227.

Via Manish I found this peculiar article about a Muslim man who is the priest of a Hindu temple in Kashmir. The article implies that the man is a believing and pious Muslim, while simultaneously paying homage to Hindu religiosity through his services and work within a Hindu temple. I suspect anyone from a Muslim background will be perplexed, can such an individual truly be a believing and sincere Muslim and be a priest in a Hindu temple? A few years ago I would have offered a standard materialist explanation: the man has found a niche where he can generate a reasonable income where he would otherwise have been destitute (read the article). But today I am not so sure. Yes, I grant that material inducements are a likely a necessary condition, but, I would not deny that a man could be both a Hindu priest and a Muslim believer, and a sincere one in both capacities at that. Also, yesterday The New York Times Magazine came out with an article about HIV in South Africa. At one point the reporter notes that many women refuse free drugs during childbirth which would reduce the chance that their child would become HIV positive. The only individual who would know of the ingestion of the drug would be the nurse, who also holds the chart which indicates that the woman is HIV positive despite her denial. This sort of behavior beggars the imagination, but not really, we need to open our minds, and look at what's "going on in there."

Genetics and evolution are important disciplines necessary to comprehend human nature. But so is psychology. Unfortunately psychology is plagued by all sorts of quasi-sciences and fads, and its intuitive simplicity means that we are more likely to simply seek "science" which confirms our intuitions and feelings, as opposed to research which is more technically opaque and flies in the face of our preconceptions. Nevertheless, you have to start somewhere. Just as sociology needs genetics, so history and international relations needs psychology.

Most of you have likely heard of the paper out in The Proceeding of the Royal Society, Can the common brain parasite, Toxoplasma gondii, influence human culture?. Here is the relevant section from the abstract:

Toxoplasma gondii, explains a statistically significant portion of the variance in aggregate neuroticism among populations, as well as in the 'neurotic' cultural dimensions of sex roles and uncertainty avoidance. Spurious or non-causal correlations between aggregate personality and aspects of climate and culture that influence T. gondii transmission could also drive these patterns. A link between culture and T. gondii hypothetically results from a behavioural manipulation that the parasite uses to increase its transmission to the next host in the life cycle: a cat. While latent toxoplasmosis is usually benign, the parasite's subtle effect on individual personality appears to alter the aggregate personality at the population level...if T. gondii does influence human culture, it is only one among many factors.

The headline worthy aspect of T. gondii is that cats are a reservoir of this pathogen. But please note that warmer climate, high population density, working with soil and spoiled meats are also positively correlated with T. gondii infection. One interesting point that the author notes that T. gondii's affect on the sexes is inverted except for the trait of guilt, so it might be a wash if sexes are not separated in the analysis. From the paper, "...infected women, intelligence, superego strength (rule-conscious, dutiful, conscientious, conforming, moralistic, staid and rule-bound) and affectothymia (warm, outgoing, attentive to others, kindly, easy-going, participating and likes people) are higher, while infected men have lower intelligence, superego strength and novelty-seeking (low novelty-seeking indicates rigid, loyal, stoic, slow-tempered and frugal personalities); both infected men and women have higher levels of guilt-proneness (they tend to be more apprehensive, self-doubting, worried, guilt prone, insecure, worrying and self-blaming."

The author found a statistically significant correlation between neuroticism and T. gondii infection rates across nations. Variation in T. gondii infection explained about 1/3 of variation of neuroticism across countries. Other traits were so weak in their correlations (e.g., R² of 0.07, or 7% of the variation) that they did not attain statistical significance. But, when the samples excluded non-Western nations other traits did attain statistical significance. Hungary and China had higher neuroticism than expected from T. gondii infection rates, while Turkey had lower neuroticism. Similarly, Japan and South Korea were dramatically more differentiated in sex roles than their low T. gondii rates would have predicted, while Jamaicans seemed to exhibit lower uncertainty avoidance. When only Western nations were considered uncertainty avoidance and masculine sex roles were signficantly predicated by T. gondii infection rates, with the later yielding an R² of 0.27.

The author offers in the discussion "if T. gondii does affect cultural dimension, then it does not drive differences seen among the major cultural groups (e.g. Western, African, Asian). Tests among Western nations were possible owing to adequate sample sizes." Germans and Scandinavians are genetically and culturally close populations, so, it stands to reason that the impact of T. gondii might be outsized in explaining the between group variance in this case (note that Germany is far denser than Norway, for example). In contrast, the genetic & cultural difference between China and Germany is great enough that T. gondii might not explain much of the difference or similarity between these two populations. Jerome Kagan's work suggests that East Asian infants are already a bit inhibited and shy in comparison to European infants, so the genetically coded differences between the populations might swamp out T. gondii's modulating effect (though variation in T. gondii within China might be significant and explain differences in personality and culture between Guanghzhou and Harbin, for example). And of course, the cultural matrix in which one develops might also buffer and alter the development of the combined genetic and parasitically shaped biases. That is, just as T. gondii's effect might be seen as being contextualized by a meta-populational norm of reaction (e.g., Europeans vs. East Asians), so the genetic and parastical parameters likely unfold differently in different cultural matrices.

If you want to comment, read the full paper here (PDF) for free (since it is in our forum you will need a YAHOO ID). Here is an informative table from the paper: "Age-adjusted prevalence, aggregate neuroticism (N), the cultural dimensions of uncertainty avoidance (U) and masculinity (M)among nations. Original references for most of the T. gondii data...."


Related: Genius germs?

Today on msn.com I found metion of this article reporting a study of the effect of breastfeeding on the stress response of children at 10 years of age. The study involved almost 9000 children born in Great Britain in 1970. The occurrence of divorce or separation of the parents was also included in the statistical analysis, along with a few other variables such as maternal age and the sex of the child. As predicted, children whose parents had divorced or separated between when the child was 5 and 10 years old had higher levels of anxiety. In addition, children who had been breast-fed had lower anxiety than those who had been bottle-fed. Interestingly, the effect of parental divorce or separation on anxiety was only significant for the bottle-fed children. Parental separation and divorce were not correlated with breastfeeding themselves, and none of the other variables appeared to mediate the effect of breastfeeding.

I likely wouldn't have thought anything of this study before, but after reading about methylation of the glucocorticoid receptor gene in rats being affected by maternal behavior (see the "alter their response to stress" link in this old GNXP post), this makes me wonder if a similar effect operates in humans. Although there are many ways to explain the human child study that don't invoke this type of biochemical process, the pattern of altered responsiveness to an environmental event (parental separation/divorce) would be consistent with some kind of alteration in the stress response pathway itself.

Matthew Stewart is the author of The Truth About Everything, Monturiol's Dream and The Courtier and the Heretic. His recent piece in The Atlantic, The Management Myth, drew upon his experiences as a management consultant. Dr. Stewart received a Ph.D. in philosophy from Oxford University and a bachelor's degree from Princeton. Below are his responses to 10 questions.

(Other 10 questions)


1) Your recent essay in The Atlantic was rather amusing, we all have our MBA jokes I suppose (well, except for a small subset of MBAs themselves). How exactly did you get involved in management consulting in the first place? As you noted, your primary "professional" background was in academia and food service.

It was just one of those things. Toward the end of my last year in graduate school, long after everybody else had made their plans for the following year, I was playing pool with a couple of undergraduates who had accepted jobs as management consultants. At the time, I would have said that I was about as likely to become a ballerina as a consultant. Actually, more likely, since I at least had some idea what a ballerina does for a living. Still, since I had decided that I didn’t want to pursue an academic career and was in desperate need of gainful employment, I was inspired to fire off a dozen letters to prominent consulting firms. Only one deigned to reply. A senior partner of that firm just happened to be passing through town and had an hour to spare. Two weeks later, I had a job offer - as an "experimental hire," I later learned. I often wonder what would have become of me had I skipped that pool game or delayed a couple of weeks in sending off the letters. Did I miss my calling at La Scala?

My approach to management consulting was experimental, too - I initially planned to work for a year or two, then figure out what I wanted to do with the rest of my life. The job turned out to be quite different and much more interesting than I had imagined. I left it after three years in order to write my first book. When that failed to pay the rent, I returned to consulting and got into a situation from which I had some difficulty extricating myself. Eventually I was able to resume my career as a writer.

2) You seem to divide the "science" of management between the humanists & rationalists. In philosophy of course there is the continental and analytic tradition today, in which direction would you say your leanings would be, if you have any?

In both cases there is a kind of dialectic at work: the one really makes best sense as a response to the deficiencies of the other. That is, humanist management science arose out of the failure of rationalism to recognize that organizations are, well, made up out of people. But rationalism originated with the claim that human beings often aren’t very good at organizing things. In philosophy, the history is very different, but there is nonetheless a similar kind of mutual dependence at work between analytic and continental philosophy. Analytic philosophy began as a rejection of the Hegelian mushiness of late nineteenth-century English philosophy. If there is a general theme of continental philosophy, surely it must be the rejection of the excesses it attributes to reason or the Enlightenment.

At this level of generality, however, we are no longer talking about concrete history. (It's easy to show that, for example, many rationalist management scientists began from humanist premises, and the reverse.) We're really just playing with certain abstract ideas (e.g., about reasons and passions). So I prefer not to take sides.

3) In The Truth About Everything you seem to praise the sophists. Did you receive any flak about this from acquaintances?

Quite the reverse. I discovered a deep and hidden undercurrent of hostility toward Plato. People are just fed up with many of his dialogs. He turns Socrates into the pedantic advocate of some preposterous theories, and is manifestly unfair to the poor Sophists.

To be sure, the Sophists were not all sweetness and light, and I certainly don't see myself as championing them as the last word in wisdom. In bringing them closer to center stage, though, I want to draw attention to the fact that in many ways they embodied some of our own ideals about philosophy and society better than their more famous antagonist. While Plato was a dogmatic elitist, they were basically democratic skeptics. More importantly, the sophists were in some ways more authentically "Greek" than Plato and his heirs. I want to emphasize the extent to which the conventional idea of Greek philosophy is a construct of the middle ages.

4) A friend of mine is now a social scientist, but his background was originally in philosophy. He once mused to me that scientists are philosophically naive. Would you concur? If so, is this naivete a problem?

I can see why a social scientist might say such a thing. The social sciences, as far as I can tell, contain an awful lot of undigested philosophy. On the whole, however, I can't say that I have shared your friend's experience. I have met many scientists who seem philosophically well-informed, and I have observed that in the public sphere today it is often the scientists who carry the torch on the defense of Enlightenment values and other fundamental issues we usually think are the property of philosophers.

Social sciences aside, in any case, I don't see philosophical naivete among scientists as a problem for science per se. On the contrary, the history of science is replete with examples of scientists whose philosophical sophistication led them to make major mistakes. A number of famous scientists dismissed the evidence in favor of the existence of atoms, for example, on the basis of philosophical principles. On the other hand, a broader kind of historical (or maybe historico-philosophical) naivete can be something of a problem, inasmuch as it may lead scientists to fail to understand their responsibilities to and consequences of their activities on the rest of society.

Scientific naivete among philosophers, by the way, is more common and disturbing, at least to me, though the victims are usually only the philosophers themselves. I have read one too many philosophical essays purveying bizarre notions about quantum physics and obtuse thought experiments about planets abounding in a substance called H₃0. A fair number of philosophers often work with a high-school level caricature of science, without ever bothering to check out what scientists do.

5) What is your sympathy toward, Wittgenstein I or Wittgenstein II (assuming you believe that the two are genuinely separable)?

Long ago I found Wittgenstein helpful and inspiring, especially in helping me think through the issues of "meta-philosophy", or the philosophy of philosophy. At this level, I found that the similarities between Wittgenstein I and II far outweighed the differences. The change from I to II may have seemed radical to those committed to the philosophy of language; but now that that project seems safely confined to the history of futile endeavors, it is the continuity that dominates. In the The Truth About Everything, I put the main arguments of the Philosophical Investigations into the quirky numerical format of the Tractatus Logico-Philosophicus in order to make these points.

With the benefit of more study of the history of philosophy, I eventually concluded that the value of Wittgenstein's ideas (in both incarnations) was overblown. The near-total absence of historical perspective in him and his followers resulted in their failure to see that his critical work in many ways replicated earlier critiques, not always with improvement. I also found that just about everything he said that ranged beyond the confines of academic philosophy to themes of culture and value was either banal or barbaric. And one thing I still cannot abide is the cult of Wittgenstein.

6) Back to business, between writing The Truth About Everything and The Courtier and the Heretic did your attitude toward management consulting evolve at all? I ask because I got the impression from The Truth About Everything that you believed that philosophy is best lived and done by regular folk with jobs out in the 'real world,' but now you are retired from that world and a 'philosopher at large.'

"Philosopher at large" - now that is something I do get flak for from friends and acquaintances. My point in the The Truth About Everything wasn't that philosophy is best done by regular folks; it was that academic philosophy suffers from its lack of exposure to and interest in the so-called "real world." Life outside the academy isn't any more "real," nor is it necessarily better; but it is more representative of the human experience, and that makes it worth getting to know. I learned a lot as a management consultant, but my attitude toward that particular form of employment didn't change at a fundamental level: it is not, dare I say it, the best place to look for the eternal truths.

7) Are there genuine philosophical problems? If so, are exact solutions ever possible for these problems?

No. And no. The notion that there is a fixed list of philosophical problems waiting to be solved - "free will," the "mind-body problem," etc. - is a product of the institutionalization of philosophy. It happened in the middle ages, and it has happened over the past two centuries with the rise of the modern university system. Once philosophy becomes institutionalized in that way, it ceases to be genuine philosophy, in my humble view, and just becomes a sophisticated form of rhetoric for advancing a particular mix of ideological, sectarian, and institutional agendas. Genuine philosophy isn't so difficult to spot, even in the labyrinth of institutional philosophy. It is a set of tools, an attitude, a commitment to the search for truth, and a project aimed at emancipation from fear and superstition. Just like Epicurus said.

8) Do you believe that the Classical Greeks "invented" philosophy as such? Or do you hold that a spark of philosophy resides in the basal cognitive wiring of most human beings, and has since the emergence of modern humanity 40,000 years ago?

The philosophical instinct belongs to human nature. It is as much a dysfunction as a function of our cognitive apparatus. It arises from our remarkable ability to see patterns in experience. It is a product of the natural inclination to look for the pattern of patterns, or the pattern of everything. The Greeks certainly did not invent it. Even in the existing historical record, they weren’t the first; and many who came later simply re-invented it on their own.

9) What intellectual discipline appeals to you other than philosophy? In other words, if you had to select another domain for your contemplative energies, what would that be?

I went to college thinking I would major in physics, though what really interested me at the time was astrophysics and cosmology. Somehow I got sidetracked into metaphysics. I must have gotten impatient with astrophysics, thinking it was all about hot balls of gas instead of stardust. More recently, I have found myself drawn toward evolutionary biology. Alas, it is too late for me to be a scientist, so I content myself with reading lots of popularizations. What I do now is probably closer to what most people would call history than philosophy. Though I've never really been able to separate the two.

10) If you had to change anything about your education, what would that be?

As a good Nietzschean, of course, I wish for nothing but the eternal recurrence of Philosophy 305 and the rest of my courses. Nonetheless, I would say with the wisdom of retrospect that in my education I probably failed to learn as much as I could from the many talented individuals who had the misfortune of being my teachers. So perhaps I would have changed something about my ears.

Labels: 10 questions

The new issue of Trends in Neurosciences is basically the proceedings fom a symposium on the interaction between the genomic and the "post-genomic" in the aetiology of brain disorders including autism, language and memory disorders, and epilepsy.

I'll be reading this hippocampus paper about how early damage could permanently pause the development of episodic memory capability, and some might be interested in this one about viral infections in the developing and mature brain:

A number of different RNA and DNA viruses can invade the brain and cause neurological dysfunction. These range from the tiny polio picornavirus, which has only 7 kb of RNA genetic code that preferentially infects motor neurons, to the relatively large cytomegalovirus, which has >100 genes in its 235 kb DNA genome and causes various neurological problems in the developing brain but is comparatively harmless to adults. This brief overview of some aspects of neurovirology addresses the complex problems that underlie an appreciation of the contribution of viral infections to brain disease.

Two articles of interest. First, new results are going to be presented which shows no correlation between various forms of genes like microcephalin and ASPM and intelligence:

They also looked at the genes ASPM, MCPH1 and CDK5RAP2, which regulate brain size and activity
...

"Their findings [about a relation to brain size] were negative and they didn't find a relationship with two of the genes we were looking at," Dr Luciano said.

"We decided to take it a step further and look at intelligence and lo and behold we find a similar negative result."

I have heard of unpublished negative results looking for ASPM variation and its correlation with IQ, so no surprise. Also, Armand Leroi has a piece about microcephalics in Pakistan. Last year, when I interviewed him he mentioned to me that he was about to go off to Pakistan to record a documentary on this topic, so if you are British, watch for it (if it hasn't aired).

Related: Bruce Lahn's ASPM and Microcephalin papers.

The journal Evolutionary Psychology is completely open access. It is probably worthwhile to check in there periodically. A just-published original research article, "Do some taxa have better domain-general cognition than others? A meta-analysis of nonhuman primate studies," is getting some press coverage.

It seems to me this journal contains a fair deal of book reviews and editorials. Geoffrey Miller has a piece called "The Asian future of evolutionary psychology" that I find extremely dubious, even for a forum where speculations only loosely moored to any empirical findings are clearly invited. My take on Miller as a sensationalist who cares more about leaving vivid impressions than seeking the truth is confirmed to my satisfaction.

I don't really know what snips to cut out of the new Pew Survey, Muslims in Europe: Economic Worries Top Concerns About Religious and Cultural Identity. Focus in on the attitude of both Germans and Muslims living in Germany, they're kind of strange....

I read this review article by Marder and Goaillard today. It starts off pretending to be a relatively bland discussion of ion channel densities and ends up in some important theoretical territory. The gist of the article is that there is a parameter space underlying neural activity that can vary greatly while preserving cellular and network properites. At the cellular level, multiple configurations of different ion channels (some excitatory, some inhibitory, with varying conductances and activation requirements) are capable of producing almost identical cellular action potential firing (bursting) patterns. This variability in the means for achieving the cellular target activity level can be observed in the Purkinje cells of the cerebellum and other model systems, and long-lasting perturbations of one of the ion channel levels result in compensatory changes in other parameters to return to the activity level. At the network level, multiple configurations of synaptic weights can lead to the same network properties. Synaptic strengths in an oscillatory network of heart interneurons in the leech and in a rhythmic network in the lobster can vary widely (~3-fold) and yet display the same network rhythms.

The point is that many means can be used to achieve the same end, and if you block one path the system will just take a detour. This reminded me of Gerald Edelman's discussion of degeneracy in biological systems. He takes the idea that there are several solutions to a given biological problem and runs it up and down the scale. His table is reproduced below the fold:

Table 1. Degeneracy at different levels of biological organization

1. Genetic code (many different nucleotide sequences encode a polypeptide)

2. Protein fold (different polypeptides can fold to be structurally and functionally equivalent)

3. Units of transcription (degenerate initiation, termination, and splicing sites give rise to functionally equivalent mRNA molecules)

4. Genes (functionally equivalent alleles, duplications, paralogs, etc., all exist)

5. Gene regulatory sequences (there are degenerate gene elements in promoters, enhancers, silencers, etc.)

6. Gene control elements (degenerate sets of transcription factors can generate similar patterns of gene expression)

7. Posttranscriptional processing (degenerate mechanisms occur in mRNA processing, translocation, translation, and degradation)

8. Protein functions (overlapping binding functions and similar catalytic specificities are seen, and "moonlighting" occurs)

9. Metabolism (multiple, parallel biosynthetic and catabolic pathways exist)

10. Food sources and end products (an enormous variety of diets are nutritionally equivalent)

11. Subcellular localization (degenerate mechanisms transport cell constituents and anchor them to appropriate compartments)

12. Subcellular organelles (there is a heterogeneous population of mitochondria, ribosomes, and other organelles in every cell)

13. Cells within tissues (no individual differentiated cell is uniquely indispensable)

14. Intra- and intercellular signaling (parallel and converging pathways of various hormones, growth factors, second messengers, etc., transmit degenerate signals)

15. Pathways of organismal development (development often can occur normally in the absence of usual cells, substrates, or signaling molecules)

16. Immune responses (populations of antibodies and other antigen-recognition molecules are degenerate)

17. Connectivity in neural networks (there is enormous degeneracy in local circuitry, long-range connections, and neural dynamics)

18. Mechanisms of synaptic plasticity (changes in anatomy, presynaptic, or postsynaptic properties, etc., are all degenerate)

19. Sensory modalities (information obtained by any one modality often overlaps that obtained by others)

20. Body movements (many different patterns of muscle contraction yield equivalent outcomes)

21. Behavioral repertoires (many steps in stereotypic feeding, mating, or other social behaviors are either dispensable or substitutable)

22. Interanimal communication (there are large and sometimes nearly infinite numbers of ways to transmit the same message, a situation most obvious in language)

Neuroanatomy is also degenerate, and Edelman is not the only one to have noticed this. The interesting thing about having a degenerate rather than a redundant system is that when the system compenates for a perturbation, it does so imperfectly. You can drive on a spare tire and the network properties of your car seem all the same until you push it too far on speed or grip. This brings us to an important issue for behavioral neuroscience today. The literature is chock-full of lesion studies. The most famous cases in neuroscience, H.M. and Phineas Gage, are both lesion studies. More recently, transgenic mice with this or that gene knocked-out have flooded into the literature. In almost every instance the time following perturbation is more than long enough for compensation to occur. Lesion studies that produce no effect do not mean that the lesioned component isn't involved in a behavior in a normal brain. Perhaps more commonly overlooked is the fact that lesion studies that do produce effects do not necessarily mean that the missing component is involved either. Faulty compensation or overcompensation could lead to deficits that have nothing to do with the perturbation. Potentially poor analogy coming off the top of my head: If all the busboys went on strike, the waitstaff would have to do their job, and I wouldn't get my Dr. Pepper as fast, but this doesn't mean that busboys are usually responsible for bringing me my drinks.

Noppeney, Friston, and Price have suggested a framework for dealing with degeneracy in neuroanatomy, and I won't go all the way into it, but one of the approaches is to stop throwing away intra- and inter- subject variability in fMRI studies. Degeneracy reveals itself in this noise. This same point comes up in the Marder and Goaillard review:

For years, the limitations of their experimental tools have so concerned most reductionist biologists that they have assumed that much variation in measurements from cell to cell, day to day, and animal to animal are an outcome of measurement error, although, of course, we know that individuals differ in almost any property we can describe. Improvements in computational power and imaging methods now offer new ways to look at the complex correlations that will allow us to understand the mechanisms by which compensations in complex networks occur.

Several of these authors agree that degeneracy is generally a good thing because it makes the system robust. For instance, you can't have natural selection without a diverse population to choose from. In another interesting case pointed out by Marder and Goaillard, degeneracy in the network might prevent high network synchrony that could be maladaptive if it leads to epilepsy. One last irresponsible conjecture. When I started thinking about this in terms of evolution I was reminded about gene duplication. I don't know the literature that well, but I know that some believe that after gene duplication the gene is under less pressure to toe the line, so it can start experimenting with new sequences. This is supposed to be a driving force for invention of new protein activities as an enzyme with a particular activity develops a taste for some new substrate. I wonder if the nervous system on a larger scale ever works like that. Is there network duplication followed by release from selection constraint? The energy cost of a network duplication would be much higher than that for a gene duplication, but degeneracy is a big plus. This is easy to imagine for neocortical columns attaining new functions, but I wonder about older brain regions.

So stop throwing away all your variable data, reintepret all your lesion studies, and learn multivariate statistics, you degenerates!

I found this forward from Craig's List hilarious (below the fold)....

So I answer this girls post because she seemed like the type that I
was looking for; laid back, fun, sexy, with a good sense of humor an
attractive description. I sent her my pic and I suppose she was
impressed because she got back to me lighning quick. At 6'2 198lbs and
GQ good looks, I'm not going to say I'm the hottest guy on craigslist
but let's just say I do ok for myself and rarely field a complaint. So
this girl sends me a pic back and to be honest she seemed attractive
and very busty too (bonus!) She told me she was curvy, but of course
all the weight was in the right places. I was slightly worried that
she might be a tad bit bigger than I had hoped but she couldn't be
that bad, right? Wrong!

I got up to the UWS a little late and was 3 blocks from were we
decided to meet so I called her. She picks up the phone and says:
"OH!! I SEE YOU I SEE YOU!!!" And begings frantically waving at me
from over 2 blocks away like she needs rescue on a sinking ship. I'm
like thinking , jesus, calm down already. I hang up the phone. As I
approached (still over a block away) I had to clear my eyes hoping I
wasn't seeing straight. This girl was big. Real big! I almost turned
right around and ran but honestly I felt like a deer in the
headlights, more or less mentally paraylised but still moving slowly
toward her. As I got closer the visual carnage was too much to
contemplate: A girl that was 5'0 190lbs easy but the weight was 'in
the right places?' Now I'm no fashion plate but this girl was more
than a train wreck. Here's what she was wearing: shorts past her fat
knees, sneakers with white socks, and a Sponge Bob t-shirt tucked into
her shorts with a black belt. Are you kidding me? A s we were walking
to the corner bar I noticed her limping. I looked down. Her foot was
in a cast! Holy crap, I kid you not!

So I'm in the bar with her and trying to figure out how not to be
mean. Hell, I even bought her drink (which put me 6 dollars over my
fat chick spending budget of zero for the year). I was thinking maybe
just maybe she was really a cool person with a great personality.
Maybe she' could make me laugh? Wrong again. She went on to tell me
during over the course of the drink the following things: about her
grandmother who died but she missed the funeral because she hadn't
enough money to get home, her mom who was just diagnosed with breast
cancer, her cat in her apartment that won't stop pissing on the
furniture, (that sounded so homey), the fact that she's moving to the
bronx next month, her metro card that was stolen on the C train, her
mounting student loan debt, and the fact that she thinks most guys are
slime and only want sex.

I told her, 'you know what?'. "I'm slime, A big Slime". "So, I better
go". I drank the remainder of my beer like a frat boy in a chugging
contest. Put my glass down pat her on the back, wished her luck and
left.
Does it get any more depressing that that?

Via Yann, The golden age of human pigmentation genetics, in Trends in Genetics. Below the fold you'll find the table which encapsulates most of the relevant information.

Labels: Genetics, Pigmentation

After nearly a year of radio silence Aaron Haspel's God of the Machine is back.