john hawks weblog

I lectured about the origins of Polynesian populations in my genetics class today, and after class I noticed this new paper by Jean Trajaut and colleagues (Mackay Memorial Hospital, Taipei) in PLoS Biology. Here's the abstract:

Genetic affinities between aboriginal Taiwanese and populations from Oceania and Southeast Asia have previously been explored through analyses of mitochondrial DNA (mtDNA), Y chromosomal DNA, and human leukocyte antigen loci. Recent genetic studies have supported the ''slow boat'' and ''entangled bank'' models according to which the Polynesian migration can be seen as an expansion from Melanesia without any major direct genetic thread leading back to its initiation from Taiwan. We assessed mtDNA variation in 640 individuals from nine tribes of the central mountain ranges and east coast regions of Taiwan. In contrast to the Han populations, the tribes showed a low frequency of haplogroups D4 and G, and an absence of haplogroups A, C, Z, M9, and M10. Also, more than 85% of the maternal lineages were nested within haplogroups B4, B5a, F1a, F3b, E, and M7. Although indicating a common origin of the populations of insular Southeast Asia and Oceania, most mtDNA lineages in Taiwanese aboriginal populations are grouped separately from those found in China and the Taiwan general (Han) population, suggesting a prevalence in the Taiwanese aboriginal gene pool of its initial late Pleistocene settlers. Interestingly, from complete mtDNA sequencing information, most B4a lineages were associated with three coding region substitutions, defining a new subclade, B4a1a, that endorses the origin of Polynesian migration from Taiwan. Coalescence times of B4a1a were 13.2 ± 3.8 thousand years (or 9.3 ± 2.5 thousand years in Papuans and Polynesians). Considering the lack of a common specific Y chromosomal element shared by the Taiwanese aboriginals and Polynesians, the mtDNA evidence provided here is also consistent with the suggestion that the proto-Oceanic societies would have been mainly matrilocal.

In a few words, the backstory is that linguistic evidence suggested an expansion of Austronesian-speaking peoples out of South China or Taiwan, because the most ancient branches of the Australasia languages are now found only on Taiwan. But genetic evidence so far has been against this hypothesis, sometimes called the "express train" model because it predicts a rapid spread of agriculturalists through Indonesia and on to Polynesia. That evidence has consisted of surveys of mtDNA and Y chromosomes throughout Polynesia and island Southeast Asia, which have shown that the lineages most common in Polynesians do not occur in populations west or north of Java. Based on this kind of evidence and some archaeology (which revolves around the identity of the Lapita culture dating to around 3500 years ago in Melanesia), anthropologists have suggested that there were extensive contacts among Melanesian populations, interactions with other populations further west, and ultimately the development of the maritime culture that could spread into Polynesia within the past 3000 years. Depending on the magnitude of genetic contributions and cultural contributions of different populations, these models are sometimes called "tangled bank", "slow boat", "slow train", or who knows what else.

So far all of it has been a little bit arbitrary. As I noted in my class today, there is every reason to expect that these ancient populations interacted with each other extensively even there was a relatively rapid dispersal from Southeast Asia leading to the ultimate colonization of Polynesia. This means that genetic evidence may not definitively show the mode of movement -- indeed, it might be fair to say that there was no single mode, since there almost certainly would have been a reticulate pattern of migrations no matter what the linguistic or cultural origins of the movement. The key here is that cultural origins are not genetic origins, and vice versa. As anthropologists, we want to know what circumstances led people to begin the migration across the Pacific Ocean. The genetic relationships of those people address that question only very indirectly.

The new study stands apart from earlier work, in that it shows that there actually are lineages in present-day Taiwanese populations that are shared with Polynesian peoples. It is one trace that the extent of population contacts was great enough to encompass Taiwan as at least one of the origins of Polynesian populations. This evidence is not sufficient to show that the express train model happened, but it does lend reality to the idea that the cultures responsible for the beginnings of oceanic migrations may have owed much to developments on the Asian mainland.

To me, the most interesting aspect of the study is that it demonstrates a difference between the mtDNA and the Y chromosome genealogy in the region. It is somewhat difficult to imagine how mitochondrial evidence of a Taiwanese origin would survive, while Y chromosome evidence would be erased. Trejaut et al. (2005) suggest that the proto-Austronesian communities "were matriarchal and matrilocal (as the Amis tribe still is in Taiwan) whereby the Y chromosome pool of the initial migrants was lost after being repeatedly diluted on the way toward Polynesia." Maybe so. On the other hand, it would seem like a more likely scenario for the movement of a coastal, seagoing population would involve men more prominently, as young men with limited prospects and resources made risky ventures in search of greater opportunities. This would be sort of a Viking model of male behavior, although not necessarily implying conquest but merely the pursuit of new resources and mating opportunities.

If maternal lines actually remained as a stronger indicator of population origins for Polynesians, then I think we have to conclude that the population history was relatively unique. It would have to have involved the steady population growth and progressive fissioning of matriarchal communities, with little female genetic input from other groups. The maintenance of this female-centric population expansion, even as these communities spread into regions far from their initial source, would be an exceptional instance of the mediation of mating contacts by culture. The interesting part is that males presumably had extensive contact with adjacent populations, and the expanding matriarchal population apparently extensively integrated local males as it moved. In other words, the Austronesian expansion in this scenario was driven predominantly by a maternal core, even as it was surrounded by extensive expansion of other, non-maternal lineages. The main stream of maternal inputs remained central, while any initial male contributions from China or Taiwan became increasingly ephemeral.

On the other hand, there is a simpler answer available. If both these loci were affected by selection, then any difference between them would be explained in adaptive terms. There may be no reason to expect changes to these two molecules within the last 10,000 years, but if anything has been under selection certainly the mitochondrial DNA and the Y chromosome are the leading candidates. Recall that Genghis Khan's Y chromosome is supposedly in a third of Asians today -- it didn't get there by chance but by differential reproduction. There may not have been the possibility of such widespread reproduction of a single variant in the population history of Southeast Asia.

But it isn't really necessary to account for these observations. What we're seeing is a progressive increase in the frequency of a few Y chromosome alleles as we sample nearer to Polynesia. Geneticists usually look at this distribution backwards, taking the high frequency variants in Polynesia and looking for the source population in Southeast Asia or Indonesia. But this assumes that genetic drift, through successive founder effects, has been responsible for the increase in frequency of these initially rare variants.

Consider instead the scenario from the beginning to the end. How does an initially rare variant become very common in the descendants of the migrating group? Founder effects are one answer, but not the only one. What if natural selection has had a thumb on the scale from the beginning? Or what if subsequent population movement from Southeast Asia into Indonesia and Melanesia has carried advantageous Y chromosomes that have partially erased the initial distributions. Or what if an advantageous mitochondrial variant became more and more common as a result of selection in migrating populations?

The genes are far from answering these questions. Not only do we have to assume that there was no selection, but we can't even tell the various really complicated scenarios of population history apart. What's the difference between a slow boat and a slow train? How is the origin of populations of the Indian Ocean fit into this? There's a lot of work to come.

And it's for no small reason. As I lectured to my class today, the origins of oceanic populations ought to be one of the simplest problems of anthropological genetics. We're dealing with populations that are modeled well by an island model, which is unheard of in most human groups. Even so, humans have done everything possible in the past to make it difficult for us to recover that history. They mix with each other, they trade with each other, they move back and forth, they adopt new languages, and every piece of their history erases some of what has come before. So for me, the origins of Polynesians are a touchstone: if we can ever satisfactorily recover an answer, we can start to have some confidence about our ability to answer other questions that are more difficult.

References:

Trejaut JA et al. 2005. Traces of archaic mitochondrial lineages persist in Austronesian-speaking Formosan populations. PLoS Biol 3:e247. Free full text

Current thinking on the nature of differences between humans and chimpanzees (or any other pair of closely related species, for that matter) holds that large phenotypic differences may be the result of relatively small differences in gene expression.

Thus, the often-cited saw that humans and chimpanzees are 98 percent the same at the genetic level says almost nothing about the potential differences between the phenotypes of the two species, because identical genes may be expressed entirely differently by making slight changes to genetic promoters or inhibitors. This is not the only reason for the mismatch between genetic similarity and phenotypic difference, since a single point mutation may radically alter the amino acid sequence of a protein as well. But differences in gene expression are often assumed to be "tunable" to a greater extent than amino acid changes to proteins. Thus, certain slight changes to promoters might result in either slight or large differences in the quantities of a protein, the speed of transcription or post-transcription processing, or other biochemical attributes that would affect the phenotype.

The possibility of many different possible responses to changes in promoters suggests a fertile drawing board for evolutionary change to work. Such changes might especially be important in the structural differences separating humans from other apes, since ontogenetic development depends sensitively on the concentration of certain proteins and peptides in the developing embryo. A slight increase in gene expression in part of the embryo might increase the length of the leg, or alter the form of the pelvis. Scientists are actively looking for the actual genes that may have influenced these processes in human evolution, and some they have found.

So the story appears capable of explaining the phenotypic differences between humans and chimpanzees. The only problem is, nobody really knows how promoters work.

The problem is illustrated in a current study in Genome Biology by Florian Heissig and colleagues (2005), working from Svante Paabo's lab at the Max Planck Institute for Evolutionary Anthropology. The study examined genes with different patterns of expression (assessed by messenger RNA abundance) in chimpanzee and human tissues. They cloned the promoter regions of the genes and spliced them to a reporter gene to test directly the effect of the promoter on the gene expression.

The results were surprising:

Out of the 12 promoters tested, two (ACADSB, C10orf10) show a significant difference (ANOVA p-value

Three promoters (ACADSB, C10orf10, IMPA1) show activity differences in the promoter assays that go in the same direction as the expression differences of the corresponding genes in the tissues. Interestingly, the two promoters (ACADSB, C10orf10) that show qualitatively similar differences in the two cell lines are both in concordance with the tissue expression differences. For four promoters (CGI-51, SH3BGR, UNG, TERF) that show differences in only one of the cell lines, the difference goes in the opposite direction to the expression differences in the tissues (Heissig et al. 2005:R57).

The paper is very short and to the point, but the implications are striking. Humans and chimpanzees exhibit the same amount of sequence divergence for promoter regions with different activity levels versus promoters with the same activity level. Many genes that differ in activity exhibit no difference in promoter activity. Genes that have higher gene expression in one species sometimes have higher promoter activity, but just as often have lower promoter activity. In other words, the promoters are not an indication of the outcome.

And the study only examined genes with substantial differences in expression between chimpanzees and humans. For genes with similar patterns of expression, the authors have this to say:

If many genetic differences do indeed influence the expression of a single gene, the proximal promoters of these non-differentially expressed genes would be expected to differ in their activity almost as frequently as the promoters of differentially expressed genes (Heissig et al. 2005:R57).

Why should this be? Gene expression is the outcome of a cascade of events within the cell, including the production of enhancer molecules of various kinds, the binding of such enhancers to promoter sites, the metabolism of the gene product within the cell, including the speed with which it may be taken up by receptors, and the correlated effects of other genes with similar products. Again, this system is ideal for evolutionary fine-tuning. But it means that several different changes -- at different genomic sites -- may be necessary to optimize any given function.

The really bad part of this is that it means a comparison of human and chimpanzee genomes may actually tell us nothing about how the phenotypic differences between the species arose.

Now, these results may be considered as tentative, since the number of genes examined was only 12. But if the pattern holds true of other genes, even for a substantial minority of genes, it bodes ill for our ability to use genomic sequences to predict gene expression levels in tissues. And predicting phenotypic differences in body structure or behavior is many levels removed from gene expression. So for the high-level structural questions we are likely to ask about human evolution, no answers are likely to be forthcoming from genomic comparisons alone.

The paper concludes:

Our results imply that although many promoters may differ in activity between humans and chimpanzees, it will be difficult to predict physiologically relevant gene-expression differences from promoter activities observed in cell lines, even between two closely related species such as humans and chimpanzees. Further work is necessary to elucidate to what extent this applies also to allelic DNA sequence differences in promoters observed within a species. Further work is also needed to elucidate whether a general paradigm for how genome structure translates to gene expression activity can be derived (Heissig et al. 2005:R57).

If indeed the expression of genes is the product of a different complex cascade of events for each gene, then it may be that no "general paradigm" will ever be possible. Insights about human evolutionary changes may end up coming not from genomic comparisons, but from experimental work. Look for lots and lots of different human and chimpanzee genes to be turned on and off in cell cultures to determine not only their function but also their effects on the expression of other genes.

References:

Heissig F, Krause J, Bryk J, Khaitovich P, Enard W, Paabo S. 2005. Functional analysis of human and chimpanzee promoters. Genom Biol 6:R57. Free full text

Carl Zimmer has put together this week's news about language evolution. In one paper, mice with knockout versions of the FoxP2 gene were found to have trouble with their squeaks! In other words, the gene may be involved in vocal communication in most mammals. The second paper demonstrates the existence of a neural area homologous with Broca's area in macaques. This would show that one cortical region underlying language function in humans is broadly shared among anthropoid primates, although not elaborated to the extent found in living and fossil Homo.

Both of these are stories about homology. Humans aren't unique in the presence of either FoxP2 or Broca's area. Instead, these emerged long ago. Both of them may have been involved in vocal communication for a long time in our lineage, in other primates, and potentially in many other mammals.

So human evolution didn't have to originate new language-related functions for these elements out of whole cloth. There was already a simple structure there to work with. Human evolution elaborated on this ancient foundation.

The details, of course, remain to be worked out. FoxP2 is far from the only gene related to language, and Broca's area is far from the only cortical region. Different areas may have yet other origins, may have been put together in new ways during human evolution, and may have been expanded upon (or in some cases possibly even reduced) to result in our unique configuration.

Anyway, read Zimmer, and I may write more on the Broca's discovery later.

On the Scientific American website, there is a long article by Michael Shermer (editor of Skeptic magazine), describing his trip to the World Summit of Evolution, held in the Galapagos Islands this month. Some of the attendees:

It was a veritable Who's Who of evolutionary theory, including William Calvin, Daniel Dennett, Niles Eldredge, Douglas Futuyma, Peter and Rosemary Grant, Antonio Lazcano, Lynn Margulis, William Provine, William Schopf, Frank Sulloway, Timothy White and others.

Shermer provides a rundown of many of the scientific presentations, and it is an interesting read. The paleoanthropology representative was Tim White, and Shermer gives him almost a whole page:

One of the best talks of the conference was delivered by the U.C. Berkeley paleoanthropologist Timothy White, in which he opened with a prediction made by Stephen Jay Gould in the late 1980s: "We know about three coexisting branches of the human bush. I will be surprised if twice as many more are not discovered before the end of the century." A glance at the extant fossil record looks like Gould was right. There are at least two dozen fossil species in six million years of hominid evolution. But the bush is not so bushy, says White. The problem lies in the difference between "lumpers" and "splitters" in species classification, and the social pressures to publish extraordinary new discoveries. If you want to get your fossil find published in Science or Nature, and you want the cover illustration, you cannot conclude that your fossil is yet another Australopithicus africanus [sic], for example. You better come up with an interpretation indicating that this new find you are revealing for the first time to the world is the most spectacular discovery of the last century and that it promises to overturn hominid phylogeny and send everyone back to the drawing board to reconfigure the human evolutionary tree. Training a more skeptical eye on many of these fossils, however, shows that many, if not most of these fossils belong in already well-established categories. White says that the specimen labeled Kenyanthropus platyops, for example, is very fragmented and is most likely just another Australopithicus africanus [sic]. "Name diversity does not equal biological diversity," White elucidated.

If I had a quote list, I'd add that one to it: "Name diversity does not equal biological diversity." On the other hand, White has himself had the cover of Nature once or twice....

And then there is this:

White then concluded his talk with a fascinating discussion of the recent discovery of fossil dwarf humans on Flores Island in the Malay Archipelago, located on the outside of Wallace's Line, meaning that even during the last ice age they could only have gotten there by boat. (White did note, however, that after last December's tsunami people were rescued from large floating rafts of natural debris, so it is possible that the founding population of Flores rafted there by accident and not design.) ... A second published specimen put to rest the pathology hypothesis that Homo floresensis was a microcephalic human. The best evidence, says White, points to insular dwarfing, a rapid punctuation event out of Homo sapiens that led to a shrinkage of these isolated people. Such dwarfing effects can be seen on this and other islands, where large mammals get smaller (like the dwarf elephant), and small reptiles get larger (like the Komodo Dragon). The chances of any living members of this species still existing in the hinterlands of Flores are extremely remote, but some observers have noted that the indigenous peoples of Flores recount a myth of small hairy humans who descend from the highlands to steal food and supplies.

You can read what I have to say about Homo floresiensis here. I'm telling you, the more this story gets repeated, the worse it's going to turn out.

Most of the meeting was relatively big-name evolutionary biologists of one kind or another. In the end, it sounds to me like the many of the invitees wanted to trash Darwinism to promote their own idiosyncratic theories. To some extent, Shermer displays his best skeptical take on these, although he describes one as "beyond [his] pay scale." A lot of famous scientists have problems with standard neo-Darwinism, and it seems that many were invited to this meeting, with very few representatives of the more standard point of view. So Shermer's article includes many "proclaiming the death of Darwin" stories. Interesting in this context that there appear to have been no evo-devo people at the conference, since this is probably the most important of the extensions to evolutionary theory, and one that resonates with pre-Darwinian biology to a much greater extent than ideas like Margulis' pansymbiosis or multilevel selection theory.

Read the article and see if you agree with Shermer that evolutionary biology is in a healthy state. My take is that a show of real health would have included a slightly different list of biologists.

This post from Geomblog caught my eye on the current Tangled Bank. It links to the defense and attack against Powerpoint, respectively, with some commentary.

Many of you who do scientific presentations may have seen the infamous pamphlet on the drawbacks of Powerpoint, and other bullet-point presentation programs, as presentation tools. As for myself, one of my students anonymously slipped me one a year or two ago -- after the first day of class, no less. I mean, if you are going to try to convince your professor not to use Powerpoint, then please wait until you've seen a few lectures to see if he misuses it!

To tell you the truth, I really dislike Powerpoint. It crashes at least once a day on my Mac when I'm using it, and I've never gotten it to display the same thing on two different computers in the same way. I almost always find myself saving presentations as PDF's for meetings, because they always display correctly. When I get the chance, I will probably defect to Keynote.

But two things stand out for me. First, once slides are in order with presentation software, there's no more organizing them. And you can give your show anywhere you can take your computer. For me, that's all the notes I need to give a lecture.

And second, students love Powerpoint lectures. The evaluations say so.

So I was interested to see this defense of the tool, and find it just about right. It's the speaker that matters, not the projection method.

This is an old paper that I ran across today, a review of tests of selection with application to humans. Martin Kreitman is well known as a specialist in the population genetics of selection. The abstract says this:

Attempts to understand the nonequilibrium configuration of silent polymorphism in human mitochondrial DNA illustrate the difficulty of distinguishing between selection and alternative demographic hypotheses. The range of plausible alternatives to selection will become better defined, however, as additional population genetic data sets become available, allowing better null models to be constructed.

And the conclusion says this:

An instructive example of this problem lies in the interpretation of human mitochondrial nucleotide polymorphism. In a very insightful paper, Di Rienzo and Wilson reported that the genealogy of mitochondrial sequences in non-Africans was more starlike in shape than might be expected under neutrality and that the distribution of pairwise differences was Poisson shaped (20; also see 74). Di Rienzo interpreted this apparent departure from neutrality as an indication of recent population expansion. Theoretical treatment of the problem provided additional support for the expansion hypothesis (90), but a bottleneck at ~50,000 -- 100,000 years ago, possibly caused by the selective sweep of a favorable allele, could not be rejected.

Mitochondrial DNA has been assumed to be nonrecombining (but for evidence of recombination, see 4, 24); the sweep of a favorable mutation anywhere in the mitochondrial genome will cause the fixation of a single haplotype. Support for the selection hypothesis has come from the analysis of nuclear encoded genes. The nuclear genome shows little evidence for a skew towards rare alleles (18, 37, 38, 42, 83, 106), and thus towards a negative Tajima's D, as predicted under the population expansion hypothesis.

Theoretical investigation of bottlenecks and subsequent expansions (25) shows, however, that Tajima's D can be negative or positive depending on the size of the bottleneck and the timing and magnitude of an expansion. Given that the mitochondrial genome has a smaller effective population size (being maternally inherited and effectively haploid) than the nuclear genome, the conflicting portraits of polymorphism in the two genomes may be consistent with a population bottleneck (25). The exciting possibility of a selective sweep in the modern mitochondrial genome remains, unfortunately, an unresolved issue (Kreitman 2000:553).

I was happy to run across this reference that I previously missed, and so I'm posting it for others. It's good to read a review that appreciates the difficulties of detecting selection and distinguishing it from demography. The final paragraphs are sobering:

The only current safeguard against gross misinterpretation of test results vis-a-vis selection vs historical demography is to have an a priori hypothesis about the type and direction of selection that are expected for the locus under investigation. The previously described work on Duffy provides a good example of this approach (37). There are two reasons to hope, however, that the situation for analyzing human polymorphism data sets will improve. First, as additional data sets accumulate, a reduction in the number of plausible historical demographic scenarios will be possible. The specific range of parameter values, for example, allowing mitochondrial genes but not nuclear genes to differ in the observed frequency spectrum of mutations may be shown to be unrealistic. Second, population history, whether it involves ancient bottlenecks, recent expansions, or specific population movements, affects the polymorphism of all nuclear genes equally. From a practical perspective, this means that the common signatures of human history on genetic variation should yield to the avalanche of data expected in future polymorphism studies. Better data mining techniques and sharper theoretical predictions are needed, however, to make this a reality (Kreitman 2000:553-554).

It should be possible, in principle, to construct a realistic neutral model of human variation that takes into account major features of human history. Such a model would then serve as a null hypothesis, a selectively neutral backdrop, against which to look for evidence of natural selection in individual genes. In no other organism is this possibility likely to be achieved at the high level of resolution possible for humans. Our species, despite its low levels of nucleotide polymorphism, issues in ethical sampling of native populations, and the inability to control matings, may thus replace Drosophila species as the poster child for molecular population genetics.

On a positive note, I think he's right that humans have become the best model for considering the molecular correlates of microevolution. We clearly know much more about ourselves than we do about other species, and it is hard to ignore evidence for long-term regional or local selective pressures.

I wonder whether we are at a tipping point now, in 2005, compared to 2000. Have we reached the point where no single demographic hypothesis can explain both mtDNA and other genetic variation? Certainly we are, but there is more than that. Many autosomal genetic loci are inconsistent with each other in their pattern of variation. Selection has affected most areas of the genome in different ways. And some of those changes have been very recent.

On the one hand, there is nothing surprising about this, since we know that humans have been evolving and still are. On the other hand, the universality of selection is not necessarily something anybody expected to find. We may need to ask ourselves, is there anything that doesn't bear the mark of selection on some linked site?

References:

Kreitman M. 2000. Methods to detect selection in populations with applications to the human. Annu Rev Genom Hum Genet 1:539-559. Full text online

In the wake of recent zombie-related films, there is this article from NEWS.com.au, by Nick Buchan:

US scientists have succeeded in reviving the dogs after three hours of clinical death, paving the way for trials on humans within years.

Pittsburgh's Safar Centre for Resuscitation Research has developed a technique in which subject's veins are drained of blood and filled with an ice-cold salt solution.

The animals are considered scientifically dead, as they stop breathing and have no heartbeat or brain activity.

But three hours later, their blood is replaced and the zombie dogs are brought back to life with an electric shock.

The next step is to test the method on humans, which the report says should occur within a year. The motive is to keep people alive after severe trauma or blood loss -- especially after battlefield injuries. When surgical repairs can be accomplished, the body would be restarted.

Is it creepy? I suppose if it leads to bloodlust (or brainlust), then yes.

The New York Times reports on the FDA approval of the drug BiDil (via Gene Expression). The story is also covered by Time magazine and Science.

From the article:

No one is sure why BiDil works better in blacks than in other races, but scientists theorize that it is because BiDil increases the body's levels of nitric oxide, a naturally occurring compound. Many heart failure patients suffer from a deficiency of nitric oxide, but the deficiency is more common in African-Americans.

Although the BiDil label will say the drug is for self-identified black patients, many cardiologists believe BiDil will work for many people of other races as well. Wall Street is factoring use of the drug by people of other races into its forecasts for BiDil. Analysts' sales predictions range from $500 million to $1 billion by 2010.

BiDil is actually nothing new; it is a combined dosage of two generic drugs. Studies in the 1980's showed that the combination had no clinical benefit for congestive heart failure, but further work by its maker, NitroMed, showed that some patients did benefit -- especially patients of African descent. Even so, the FDA required that its benefits be shown in a clinical trial of African-Americans before approving its use. The trial showed a clear benefit: in black Americans, the drug leads to a 43 percent reduction in the rate of death from heart failure. The benefit was so pronounced that the study was halted last year in order to provide the medication to all participants.

Race is a "placeholder"

Why should the drug work in blacks but not in other groups? The short answer to this question is that we don't know that it does. The drug apparently doesn't result in health improvement when applied to large random samples of white Americans, but that doesn't mean that many would not benefit from the treatment. Nor does it mean that people of other backgrounds might not benefit. And conversely, it is not clear that every African-American will be best served by the medication: after all, the population of African-Americans includes people with a wide range of ancestries, some with a relatively high proportion of genes with other origins.

I like the way this researcher puts the problem in the Time article:

"Race is a placeholder for something else," says Dr. Clyde Yancy, a cardiologist at the University of Texas Southwestern Medical Center and a BiDil investigator. "And that's probably a mix of biomarkers, demographics and genes."

The point is, it would be more accurate if the genes underlying the difference were identified, and if potential patients were genotyped for those genes. That would find the best candidates for the treatment, and would leave out those who either would not benefit or who might be harmed by it.

The differences between people in the activity of the drug appear to be related to the metabolism of nitric oxide. Congestive heart failure leads to a deficiency of nitric oxide, which may have a protective effect on heart tissue. The full chain of nitric oxide production enzymes and effects is not yet understood; as excess nitric oxide can also damage the heart by causing an overgrowth of cardiac muscle tissue. But it appears that there are differences on average between African-Americans and white Americans in the effect of heart failure on nitric oxide levels. BiDil stimulates the production of nitric oxide, which evidently benefits blacks to a greater extent than whites.

Pharmacogenomics; or, bringing more drugs to market

In a news report by Robert F. Service, Science magazine is calling the drug a step on the road to pharmacogenomics, the application of treatments based on the unique combinations of alleles carried by each individual. The basic idea is that different people metabolize medicines differently and have different levels of activation of different genes, so that no one treatment affects everyone equally. If the effects of a drug could be predicted against different genetic backgrounds, both doses and combinations of drugs could be customized to fit the alleles that an individual has. From the article:

Although pharmacogenomics only recently entered the lexicon, the notion of treating populations based on the genes involved in health and disease dates from the 1950s. That's when researchers caught an initial glimpse that the speed at which different people metabolized drugs in their system was linked to genetics. But it took another 40 years to progress from those hints to medicines. In 1997, Genentech's Herceptin was approved to fight a form of breast cancer in which cancer cells overexpressed a protein called the HER2 receptor. In 2001, Novartis won approval for Gleevec to treat a form of cancer called chronic myeloid leukemia, in which an aberrant gene triggers a proliferation of white blood cells. And last year, ImClone's Erbitux went on sale to fight colon cancer by targeting a growth factor receptor on tumor cells. Since 1996, doctors have also genotyped the HIV viruses present in AIDS patients to help them select the best combination of drugs to treat the disease. The completion of the human genome project in 2001 allowed drugmakers to scan humanity's entire genetic sequence for links to a wide swath of diseases.

While this increased understanding of variability will likely result in great improvements in care, it will also result in greater potential for manufacturers seeking approval for new drugs and dosages. The Science article reviews the case of warfarin, a potent blood thinning medication whose effects are now known to vary in people with different genetic backgrounds, some of which are correlated with traditional racial groups:

The bottom line for physicians is both obvious and subtle, Martin says: Genotyping patients can save lives, and finding the right dosage may help get a drug through clinical trials. A traditionally run clinical trial will select a dosage that ensures safety for all participants, Peltz points out. If 10% of patients can tolerate only a low dose of a particular drug, that dosage will become the standard of care. That means 90% of patients won't receive an optimal dose, decreasing the chance that the drug will be shown to be effective. "The real value is in increasing the probability of bringing a compound to market," says Nicholas Dracopoli, a pharmacogenomics expert at Bristol-Myers Squibb in Princeton, New Jersey.

All in all, this promises a better outcome for everyone, and in that context it is good to see that the underlying science tends to drive manufacturers to make better decisions about development at the same time it may lead to better treatments.

What about race?

The article in Time, by Ta-Nehisi Paul Coates, focuses in more detail on the race issue, including the objections that many have raised to the research and the suspicions that exist within the African-American community:

The scars left by Tuskegee are slow to heal in the African-American community, and many blacks remain deeply suspicious of anything that approaches the emotionally charged intersection of race and medicine.

The AIDS epidemic is a prime example. According to the Centers for Disease Control, blacks account for 50% of new HIV and AIDS cases in the U.S., although they represent only 13% of the population. African-American women are especially at risk; their annual AIDS case rate is 25 times that of white women. Citing those statistics, significant numbers of black Americans subscribe to various AIDS conspiracy theories. According to a poll conducted for the Rand Corp. last January, 53% of black Americans surveyed believe there is a cure for AIDS that is being withheld from the poor, and 15% believe the disease was created by the government in order to control the black population. Phil Wilson, director of the Black AIDS Institute, says such attitudes are hampering his work with antiretroviral drugs. "The most common thing we hear with AIDS drugs is, 'Oh, they're going to experiment on you,'" he says. "The most cited example is the Tuskegee trials, even though most of us don't even know what Tuskegee was."

Blacks have good reason to be suspicious of studies like this, and not only for a historical reason. Race is a miserable substitute for the knowledge of alleles and genotypes in a study like this one. Compared to other populations in the world, Africans are more genetically variable, which means predicting effects for a drug for the entire population based on the average of study subjects is probably a mistake. The problem is worse when applied to African-Americans, which share much of the genetic diversity of Africans, but also include a relatively high proportion of alleles that are common in Europeans -- a proportion that varies greatly from individual to individual. And the socioeconomic and cultural differences between many black and white Americans also may affect the response to drugs and other medical treatments. In short, if doctors had better information than race alone, they had better be using it.

The problem is that they don't. Medical studies now recognize race as a valid category to consider, but many equally informative differences among subjects are still ignored. Drugs interact with genes, with foods, with environments, and with habits in ways that are largely unknown. Until these kinds of variables are tested more fully, the promise of pharmacogenomics will remain only a hope.

On the other hand, testing drugs based on information about racial groups is a step forward from not knowing anything about individual ancestries. I'm reminded of an episode of M*A*S*H where Klinger was acting sick and nobody believed him. Not until another soldier started having the same symptoms did Hawkeye and B.J. make the connection that complications of a drug administered to the whole camp, expected among people of Jewish descent, might also apply to Lebanese. Ancestry is an important part of understanding what has gone wrong when someone is sick, and the more doctors use it, the better. The challenge is to make the information really relevant at a genetic level, and not merely folk tales about race.

In the current issue of Anthropology Today, there is a great article by Greg Forth (University of Alberta), covering the ebu gogo legend, and the impact of the Liang Bua discoveries on the local peoples of Flores. Many thanks to reader Rob Kruszynski for the reference.

Forth is an ethnographer who has worked on Flores, and so is uniquely positioned to examine the non-scientific impacts of the archaeological work there. The best parts of the article are the descriptions of the author's own research into the legend, possessed widely by the people of Flores. He provides an autobiographical sketch of the way he first encountered the ebu gogo myth and how it featured in his earlier work, before the Liang Bua excavations. He also details how he became aware of the fossil discoveries and the role he has played in the public exposition of the ebu gogo story.

Is the ebu gogo actually a preserved memory of relict populations of Homo floresiensis? Forth balances the aspects of the legend that are shared with other legendary creatures, such as "bigfoot", with the fact that such stories are often too quickly dismissed as mere fantasy:

However much ebu gogo might recall Homo floresiensis (or vice versa), it is therefore clear that the first figure equally resembles characters that are generally considered to belong to myth and fantasy. (Another fantastic attribute of ebu gogo is their reputed proclivity to swallow things whole, including rice mortars, puppy dogs and piglets.) ... Certainly there are problems in interpreting ebu gogo as directly reflecting local memories of Homo floresiensis. Yet whatever the derivation of the Nage representation, ebu gogo really do seem different from the various categories of spirits that Nage describe with equal credulity -- and to that extent, I believe the possibility [that they represent a real animal] should be taken seriously. As noted, Nage themselves distinguish ebu gogo from "spirits" (a general category contextually designated as nitu) and they do so explicitly with reference to the hairy creature's lack of extraordinary powers -- for example, the ability to disappear, change shape, transform into animals, and so on (Forth 2005:15).

For Forth, the assumption that ebu gogo is "just another myth" is tantamount to assuming that "small-scale, non-Western societies are incapable of distinguishing empirical categories, the objects of ordinary intuition, from fantastic images dictated by religious tradition" (ibid.).

As for myself, I'm not sure I would go so far. Speaking as a native Midwesterner, there are a lot of stories that people tell about the old days that clearly are not literally true, but also lack supernatural elements. It is one thing to tell stories about Pecos Bill, who clearly had superhuman powers (harnessing a tornado, for example), and another to tell stories about how distant relatives interacted with the Indians during pioneer days. Clearly the latter happened, but the details can't be assumed to be true representations of the facts, even if they are accepted as valid family (or community) history. This is for stories that are scarcely 120 years old, and have passed through 3 or 4 sets of ears. The recovery of events from a longer time period in Flores may well retain a quality of truth. But the picking and choosing by anthropologists of those parts that correspond to a skeleton, and the discarding of parts that do not correspond (e.g., breasts so long that they are slung over the shoulders, lack of tool use) or the disregard to elements in conflict in differen accounts (e.g., some versions have "long arms and fingers", others do not) is not a valid way to approach the study of folklore. Forth does an excellent job of pointing out these consistencies and contradictions, and makes the ebu gogo story a very interesting one as a result.

On the topic of the effects of the discovery on local peoples, Forth relates the story of a Daily Mail reporter who arrived on Flores a week after the October 2004 announcement. He reports stories from local people of recent encounters with small hairy people, including the story of a man who claimed to have had the physical remains of such a creature at one time, now lost.

Among other things, the Daily Mail's man showed villagers an illustration of the reconstructed hominid that has appeared in numerous publications. And of course, what they claimed to have witnessed (or, in one case, obtained) looked exactly like this! One therefore wonders what chance there may now be of distinguishing indigenous representations from palaeoanthropological interpretations, especially in the Manggarai region where popular interest in Homo floresiensis is naturally most intense... (Forth 2005:17).

Not long after the discovery was announced, tour operators began offering packages on the internet, advertising five-day expeditions to the site from Bali.... If it hasn't happened already, one can also foresee the imminent opening of a "Hotel Hobbit." Just as ebu gogo was ultimately a victim of Nage expansion, Homo floresiensis is rapidly becoming a commodity of modern capitalism (ibid.).

Despite the rapid commercialization, Forth is doubtful that local peoples will benefit much from economic development, drawing upon the recent experience of development related to Komodo National Park, with the featured Komodo dragons.

The final section of the paper, titled "What if Homo floresiensis really did still exist?" raises the question of what domain of science would get to study them if they were found:

But one is immediately led to ask: how equipped would social or cultural anthropologists (as distinct from, say, primatologists or biological anthropologists) be to repond to this challenge? Some might not be particularly interested -- tending perhaps to an extreme constructionist view not just of cultures but of species, and then denying that there is very much new here at all. Largely because I don't really know the answer (nor, if it proved to be negative, why exactly it should be so), I would leave the question open. There is, however, a less hypothetical and more immediate question, namely, whether other anthropological disciplines (such as palaeoanthropology) -- and for that matter the media -- recognize a relevance for social or cultural anthropology in all this? Indications so far are that they probably do not (Forth 2005:17).

My guess is that social and cultural anthropologists have taken themselves out of the game. The emergence of humanity has not been a primary concern of cultural anthropologists. Few of them have written about the evolution of culture. Indeed, many of them have questioned the relevance of the culture concept itself, or have discarded it entirely.

I think this is a mistake. I think that economic and political anthropologists would have much to offer to the study of social interactions in Neandertals or other archaic humans. For people, ecology is not merely a matter of environmental contact but also of social negotiation, and the initiation of this process in early humans would be a ripe subject for the ecological anthropologist. And needless to say, the construction of incipient symbolic systems would provide a very interesting subject for the cognitive anthropologist. I study these things, and I use the insights of cultural anthropology regularly. But then I was trained as a four-fielder, which is a vanishing tribe in American anthropology.

It's a great article, but it isn't available online to non-members of the Royal Anthropological Institute, so look for it from your library if you want more.

I'm reading through the volume Integrative Paths to the Past (Corruccini and Ciochon, eds.) because of a piece of work I've been doing, and I came across this interesting passage in the contribution by Elizabeth Vrba, titled "An hypothesis of heterochrony in response to climatic cooling and its relevance to early hominid evolution."

Conversely, I suggest that acceleration and hypomorphism often evolve in warmer environments. In fact, the celebrated correlation of dwarfing of mammals on islands may well have less to do with the absence of predators and resource depletion (e.g., Lomolino 1985) than with the fact that island refugia for large mammals come into being in times of global warming and sea level rise--namely, maximal warming periods--and islands at all times enjoy a more mesic climate than the mainland uplands of the ancestors. Prothero and Sereno's (1982) results for North American fossil rhinoceroses is relevant: Dwarf species were associated with mesic forest-swamp "climatic islands" on the Miocene land mass, surrounded by savanna uplands on which larger rhinoceros taxa lived (Vrba 1994:355-356).

In other words, Vrba says that the reason we find dwarf elephants, hippopotamus, and other large mammals on the Mediterranean islands during the past few million years may be climatic. I'm not sure this accounts for the presence of dwarf mammoths on Wrangell Island, or the Catalina Islands for that matter, since full-size mammoths were on the adjacent mainland. On the other hand, migration is a factor affecting the evolution of continental taxa that simply isn't an issue for species trapped on islands. So there may be a combination of climate and the necessity for long-distance movement that makes sense.

In any event, this kind of explanation appears to be closer to the truth for phyletic dwarfs in continental regions than other explanations. Consider the Pygmies of West Africa: their small body size has been variously interpreted as a result of nutritional restrictions, inability to thermoregulate efficiently in the humid atmosphere, the need to maintain small mass for effective climbing, or sexual selection. It is not obvious that any of these explanations are applicable to other human populations with small body sizes, such the Negritos from Southeast Asia. There is obviously much thinking to do here, but I'm not sure that we have a very good explanation for dwarfism in human populations. Vrba's remarks lead to believe that we don't have a very good explanation for dwarfism in mammal populations in general.

References:

Vrba ES. 1994. An hypothesis of heterochrony in response to climatic cooling and its relevance to early hominid evolution. In Corruccini RS and Ciochon RL, eds., Integrative paths to the past: paleoanthropological advances in honor of F. Clark Howell. Prentice Hall, Englewood Cliffs, NJ. pp. 345-376.