Now Hear This (Shape)!

About 1% of the population has synaesthesia, the conflation of several modes of perception into one. Some synasthetes always associate a particular number or letter with a specific color, so 6 is always blue, or B is always lavender. But, a story on the BBC website today suggests that everyone makes similar associations, if to a much more limited extent.

Experimental psychologist Charles Spence and colleagues at Oxford University have found that people generally tend to associate larger shapes with lower pitched sounds and smaller shapes with higher sounds.

It seems our brains may use these synaesthetic associations, says Professor Spence, "to combine all of the different sensory cues that are hitting our receptors at any one time".

Which one of these shapes is 'bouba' and which one is 'kiki'?

Most people label the amoeboid-like shape a bouba, and the star shape a kiki. Further, Spence says that people tend to associate certain sounds with foods.

He said that two of the best examples are brie, which is "very maluma", whereas cranberries are "very takete".

Spence is working with a world-renowned chef to combine name dishes in way that influences their taste buds. But, is there anything to this but amusement?

Synaesthesia can be the stuff of what might be called pathologic brilliance. The well-known autistic mathematical genius Daniel Tammet (his blog is here) says that he sees numbers as shapes and colors. He wrote the books Born on a Blue Day and recently Embracing the Wide Sky. There are other examples. Whatever autism is (and it's probably a single term for a host of different places on the range of neural variation), a kind of remoteness from the everyday world of most people may be associated with aspects of mapping associations in the brain.

But if these are all very interesting facts, but what do they tell us about how our brains work? There is a lot written these days about fMRIs, or functional magnetic resonance imaging, that purports to show which part of the brain is 'for' what function. But, in fact most published fMRI images are composites from multiple people, because the brain isn't as divisible and predictable as it might seem. And, studies of the brains of people who lose a sense, such as vision, show that the part of the brain that was once 'for' vision can be remapped to touch or hearing.

From an evolutionary genetic point of view, this work seems to point to the idea that mammal brains evolved to localize types of function in ways that sequester them from each other--perhaps to enable easier recall, the way books in a library are catalogued by category numbers for easier shelving.

But memories and thoughts cannot be wholly sequestered, or animals could not integrate information to make holistic sense of their environment--which is vital to find food, detect predators, recognize mates and kin, and so on. The partial nature of sequestration is a fundamental aspect of life--all life--and is one of the generalizations about life that we explore in our book (and this blog).

Clearly, cultural experience associates different kinds of information. In our culture, we associate low sounds with large size, because many things that are large, like empty barrels, tubas, and so on make large sounds, while small birds & piccolos make high ones. But the fact that we make such associations, and ones like the shape-test above, does not imply that we're hard-wired to make them.

Too much genetic hardwiring would potentially cripple an organism to conditions its ancestors dealt with and that selected the lucky hard-wired ones for reproductive success. But it could be a disaster if environments change. Clearly, we think, it is functionally better to be soft-wired: genetically enabled to make associations by experience, file them, and recall them systematically as needed--this kind of adaptability is another generality about life that we explore in our book. Whether it's harder to understand how genes could evolve to be soft-wired rather than hard-wired is debatable, but most research in evolutionary biology is about what's hard-wired and takes a hard-wiring perspective.

Synaesthesia shows that the wires can become crossed in some people (at least sometimes for reasons having to do with genetic variation). But, in general, mammals are master electricians who install the wiring in each case where it best needs to be.

'The' mouse genome...at last!

A new paper in PLoS Biology reports the release of a better and more thoroughly documented genomic DNA sequence for a major strain of laboratory mice, the C57BL/6J strain. This strain is the one used in countless experimental settings and into which many transgenic modifications have been introduced. C57's are an old, venerable experimental model for mammalian development and also for biomedical research. So, the publication of the new results is important and worthy.

It will show us many things about the evolution of this type of mouse. However, conclusions about 'the' mouse have to be taken with some caution. First, like most laboratory strains, C57's are inbred. That means that from a starting cross between two 'parental' strains (derived from 19th century mouse-fanciers' breeds), brother-sister mating over many generations has led to mice that are not only identical to each other, but have identical sequences on both copies of their genome (the one they inherited from their father and mother, respectively). In the production of inbred mice, any genotypes that (due to inbreeding) are harmful don't reproduce. So what we have today are combinations of the alleles (sequence variants) at all genes that happened to have been present in the original parental animals and are also able to form a viable, compatible combination when there is no variation. They must be compatible both with embryonic development, as well as daily life after birth and successful mating.

These mice are in this sense not 'real' mice. Similarly, they're not real humans either! The new paper estimates around 1000 genes not shared with humans, and roughly 25% sequence difference between 'the' mouse (C57's) and 'the' human genome (that is, the reference sequence, itself a composite of DNA from various human donors).

In this sense, we have to be properly circumspect about the relevance of the new, higher quality C57 sequence relative to both mouse evolution and human disease-related research. In this sense, the now-typical hyping of the news release to the media needs to be judged as excessive and self-serving for the scientists involved (and the journals, news media, etc.). The new data need to be kept in perspective.

That said, the better we understand mice that we work with on a daily basis, and whose experimental results are in thousands of papers, the better our basic understanding of mammal biology and evolution will be.

What is different is more thorough and reliable DNA sequence data, a more complete coverage of all of the genome than we had before (some parts are difficult to sequence for chemical and other reasons), and documentation on recent ad hoc events such as the duplication or loss of chunks of DNA that happened on the way from our common ancestor with mice to the lab mice we have today. This kind of copy number variation (CNV) was not known until a few years ago, but could explain some trait differences (including disease). Also, some kinds of RNA that are copied from the genome have potentially important functions yet to be understood, and finding these in the mouse--and showing which are also conserved in humans or other species--is a step towards an understanding of the wealth of new DNA function that does not code for protein but does something else instead.

But one mouse is not the same as mice! There will, for example, be at least some variation among C57's even in any given lab, and between labs, depending on when they obtained their mice from a supplier. This is because mutations accumulate over the generations. In real mammals, CNVs are often polymorphic: each of us may vary in the CNVs we have between our two copies of the genome, and there is variation among people within populations and among populations. The same is true, of course, at every functional DNA unit: there is lots of variation.

Using an animal model like C57's essentially sweeps these issues under the rug. We hope what we learn is robust enough that we are not being misled. But when the same transgenic experiment is done on different mouse strains, around 30% of the time the results are quite different. Similarly, different humans with the same known disease mutation can have very different traits (e.g., Craig Venter and Jim Watson, whose sequences have been published, have several 'disease' variants yet they don't have the disease).

We need to keep in mind that a collection of mice from the same inbred strain, like we have in cages in our lab, is like copies of a snapshot of one (artificial) mouse rather than a natural population. But if we do keep that in mind, at least it is best to have a well-focused snapshot at high pixel resolution! That's what the new data help us with.

So this is a good bit of new data, that will make life more interesting and reliable for all sorts of scientists, not just those working on disease. Whether the public, at whom the exaggerated publicity releases were aimed, will actually reap the suggested benefits or not, is a separate, though important, question.

How long would it take to walk to the ends of the Earth?

"Who started walking out of Africa? Not everybody walked. Very few people walked, and they walked to the ends of the Earth. The geneticists now have found that the people who migrated had a particular gene, and this gene makes you a risk-taker, a wanderer. Bipolarity is an extreme version of this gene, and the people who migrated, they had this gene."

This is a quote from Indian political economist, Deepak Lal, on the BBC radio show, The Forum, which aired 05/24/09. Lal went on to say that the people who inherited this gene for risk-taking are now ethnic minorities, which explains why they tend to "punch above their weight".

But the people who migrated out of Africa are ancestors of us all. If they had a gene 'for' risk-taking, all of us would have it, not just today's ethnic minorities. And, it can't be argued that for genetic reasons ethnic minorities tend to succeed more often than majority populations because the minorities are or were majorities somewhere at some time.

It's amazing how misguided smart people can be about genetics and population history. Granted Lal is an economist, not a population geneticist or anthropologist-- but he spoke so authoritatively! Darwinian scenarios, of the BS as well as plausible variety, are so easy to put forth with an air of confidence! But, is this all air, or does it actually matter when people get it so wrong? We suggest that it does for a number of reasons because it happens in many contexts, with ramifications, not just on BBC radio programmes.

First, the idea of a gene 'for' risk-taking has been reported, but the original study has been difficult to replicate, in part because it's difficult to define risk-taking, and in part because genes 'for' behavior have been quite elusive. Populations considered to be high risk-takers or violent by some, with a high frequency of the DRD4 mutations originally associated with risk-taking, might be considered to be pacific by others, for example. So, this trait is, like most complex traits, difficult to define and genes 'for' it difficult to confirm. If one thinks about genetic mechanisms, many genes would contribute to such traits, and they would be very culture-specific or their manifestation would be, at least.

Second, genes 'for' bipolarity, again as for all complex traits, have not been confirmed. Mapping genes making major contributions to psychiatric disorders has been very problematic, at best. Some candidates have been found, but even they generally account for only a small fraction of the instances.

Third, ethnic minorities are only such at certain times and places.

Fourth, can we really conclude that ethnic minorities are all feisty? It's funny how people with guns, money, or power can seem so much more adventurous than those who haven't the same assets.

These simple (or is it simplistic?) Darwinian arguments reflect incredibly naive population biology. Basically, nobody 'walked out of Africa' in the alleged sense. People did not have travel posters or travel agents. They might go upstream or 'over there' to find game or plants they liked to eat. If nobody was living there (or only brute Homo erectines), they might decide to kick them out and take over a nice campsite. Nobody ever heard of the ends of the earth! They did not know there were island paradises in the Pacific to go vacation at.

Young adults would pair up and move to better pastures, perhaps to get away from their annoying parents or pests in their little hunter-gatherer bands. They would, however, generally stay in touch--not go too far, because family was everything for social survival (and mates in the next generation). Gradual expansion would be on foot and in a sense by everyone, going over the next hill for open territory. Nobody would know they were going anywhere!

Each generation, village exogamy (kin-based mating rules) would mean that the 'explorers'' children would have to return to their former hearth and home to find mates. There would be large amounts of inter-village gene flow, back and forth, each generation.

It is possible that among those who chose to pop over the hill, those more inclined would have some slightly increased probability of doing that. But in the overall scheme of things, genetic drift and other kinds of chance would have watered down any such signal.

The genetic data clearly show that the farther from Africa people are, the smaller the subset of 'African' genetic variants they carry. This does not mean that they purified African adventure genes, and those in Tierra del Fuego aren't pure adventurers, nor less so than the Bantu marauders who captured each other in wars and sold the victims into slavery (unless there is an adventure gene in the slaves that made them turn themselves in?)

In historic times, and in invasions, hordes of armies or boatloads of pilgrims were forced to travel and settle elsewhere, in large numbers. They were not selected based on Indiana Jones genes.

We'll be a lot better off in evolutionary reconstructions, especially as regards behavior which clearly reflects social biases of the authors, if we temper our view based on a realistic understanding of the demographic chaos that is life!

For God's sake!

We have just reviewed a book by CE Cosans, called Owen's Ape & Darwin's Bulldog: Beyond Darwinism and Creationism (Indiana Univ Press, 2009). It's an interesting discussion of the famous debate between Darwin's public (pugilistic) advocate, TH Huxley, and Darwin's opponent Richard Owen (founder of the British Natural History Museum). The question was whether humans have distinct anatomical characters compared to apes (genes were not known at the time).

The brain, naturally, was the organ of interest. Huxley claimed that there were only quantitative differences between the anatomy of ape and human brains. Owen claimed distinct differences, including a structure called the hippocampus minor. The debate was long, public, and bitter. In the end, because Darwinism won the nature-of-life debate, Huxley is treated as the winner of this debate, too. But Cosans provides good evidence that, considering their worldviews and what they actually said, Owen's interpretation was perhaps closer to the anatomical truth. Cosans analyzes the history in terms of theories about science and its relationship to the empirical world and our interpretations of it.

The analysis of this history is fine, but Cosans also delves into what Darwin, Huxley, and Owen believed about God (and hence his subtitle). This is only peripherally relevant to the main event, the debate about anatomy. It makes a saleable subtitle, and we guess that these days nobody can simply leave the religion vs 'creationism' fight alone.

The point here, however, is not who believes what and why in that regard, but that the religion debate provides a distraction, that we constantly see these days, away from the merits of the various scientific cases. In particular, we should no longer be concerned as scientists about what Darwin's or Huxley's personal religious views were. Darwin's writing is of interest to history, certainly, but not as a sacred text (though one to be revered, to be sure!).

What we think today about biology and its nature needs to be evaluated in terms of what we know and what we can testably speculate about. The gravitational pull of gossipy food-fights is natural, since even scientists are human. We have enough trouble being objective about the science itself, such as the relative roles of natural selection, population structure, environmental change, and chance in the nature of life. But too often we relate these discussions to irrelevant, but often highly emotive, sideshows.

We don't need that in order to struggle with truly fascinating questions such as what makes humans seem so different from other animals, despite great similarities in our genomes!

Genetic leaf-litter

There are many ways in which everyone is a conceptual prisoner, encaged in culturally based limits. We are born to, and trained in and entrained by our circumstances, and these in turn are a legacy of history. We can try to escape from this but probably the most we can hope for is to keep subtle assumptions and constraints at bay. In genetics, there is a pervasive concept of the 'wild type', a concept that goes back into the history of genetic research, referring to the natural allele at a gene, that was favored by a history of selection, relative to which other alleles (mutational variants) were viewed as generally rare and harmful (waiting to be shortly removed by natural selection).

There is a tacit extension of this gene-specific concept to the whole genome (or even organism) as when 'normal' inbred laboratory mice are referred to as the 'wild type' relative to an experimental modification such as a transgenic gene knockout mouse of the same strain. Sometimes this is clear shorthand, but beware of conceptual shorthand! An implication of this kind of genetic thinking is that in regard to human traits, including especially disease, there is the normal human genome as represented by 'the' human genome sequence available in genome data bases, and the disease-causing mutants. But in fact genomes are very large sequences of DNA that serve as targets for mutation in every cell, every individual, every generation.

We know that biological traits are the result of developmental processes that include countless genes (of the classical protein-coding type as well as many other functional DNA sequence elements). Species contain large numbers of members--there are about 7 billion of us humans stalking the Earth. What this means is that there is a potentially huge amount of variation at most if not all viable spots in our genome. After a mutation occurs, it may proliferate if its bearer successfully reproduces. Over time, some of these alleles grow in frequency to become quite common.

When genomic DNA is sequenced in a number of individuals, this variation is easily detected. But whether affected by natural selection or just by the chance aspects of reproductive success or failure, most allelic variation that is present in genomes at any given time is rare. Relative to the more common variants, this genetic variation is a kind of leaf-litter of variation. Even with hundreds of thousands or, indeed, hundreds of millions of very rare variants present in our species, any small sample will pick up some of them by chance.

In a small sample, those will seem to be more common than they are; so if we sequenced 5 people (10 copies of the genome) the lucky variants whose true population frequency is only a few in a billion that by chance are in the 5 people we sample, will seem to have a frequency of at least 10% (one copy of the 10 we sampled being the variant). The tip-off that this genomic leaf-litter exists is that most of the variants are not seen in other samples, or if common enough to be sampled more than once, usually only seen in samples from the same geographic region (because that's where they arose as new mutations, and were transmitted to descendants who remained living in the same continent). In developed countries, variants that cause disease will show up in specialty clinics at major medical centers.

In trying to find variants by mapping, as in genomewide association studies (GWAS) that compare sequences between cases and controls, we may feel that we have so far detected the common, but not all the rare causal variants that exist. But we may also feel that if we can just enlarge our samples, we'll get a much better handle on the nature of the effects of these variants, or we'll detect the remaining variants that haven't yet been detected.

This is likely to be an illusion, as the growing number of those of us who argue that very large GWAS will not bring a big payoff of the kind envisioned and promised by those who argue for this kind of project. There are several reasons for this skepticism. First, it is hard to detect rare things with statistical significance, much less to get a good idea of their effects and action. One needs huge samples to get enough instances to show that the variant is meaningfully more common in cases than controls.

But second, the leaf-litter phenomenon means that as sample sizes increase, more and more rarer and rarer variants will be picked up. It will be difficult to show clearly that they are causally involved with our trait, but even if they are they will have less and less effect on public health. They will vary from population to population, and sample to sample from the same population. Environments may affect whether carriers of the variant manifest the disease, and most such variation will at most have minor effect on risk of disease (if the effect were stronger, the allele would have been removed by selection, or we would have been able to detect it in family studies).

And if it requires more than one such variant, or even many of them, to combine to produce disease, the detection and evaluation situation will be that much more challenging, if not pointless. There will always be exceptions, as is true about the nature of life. But the leaf-litter phenomenon is real and there is plenty of evidence for it. It is predicted by population genetics theory. And it is consistent with results of mapping studies that have been done to date. Ironically, perhaps, while the individual rare alleles have little detectable effects, their aggregate effects in the population may account for the observed heritability (familial aggregation of risk, or similarity of trait values) of most traits, including disease. That heritability, which is clearly there, is what has been considered mysterious given the failure of linkage or GWAS studies to find the genes that are responsible.

We are presented with a kind of epistemological paradox: the genetic variation exists, but we may have insurmountable challenges to find most of it. Indeed, it is somewhat mystical even to argue that it exists as individual effects, if they cannot be found or replicated by current statistical genetic methods. Evolution 'cares' about reproductive success, not about simplicity in genetic causation. From a population perspective, evolution occurs because mutations occur generating variation that selection and chance can effect from one generation to the next.

Genetic leaf-litter is thus the fuel for evolution. We may care to know the cause of each instance of a trait or disease, but Nature has only cared about viability and success, and tolerates the leaf-litter. As massive amounts of human DNA sequence are produced, we will see this. It will be an incredible playground for population and evolutionary geneticists. But what we do with it, in terms of identifying disease causation, is not clear.

Chronic diseases due to infection?

A new paper in the journal PLOS Pathogens, described here, reports that hypertension, or high blood pressure, may be due to infection with cytomegalovirus (CMV) in humans. At least it is in mice, particularly when combined with a high-cholesterol diet. Other viral infections have been associated with hypertension, but the focus in recent years has been on finding genes for high blood pressure.

Most people are infected with CMV--60 to 99%, according to the PLOS paper--and not everyone with CMV has hypertension, but if this new study is correct, it seems to be a significant risk factor. But, as we've discussed repeatedly here, recent attention has been on identifying genetic causation for common diseases, of which hypertension is one. Indeed, schools of public health had all but eliminated infectious disease programs in the '70s and '80s, because we'd conquered infectious diseases (it was rather confidently thought!) and the challenge was now to conquer chronic disease, which first seemed to be an environmental/lifestyle challenge. After that didn't work very well, attention turned to genes (real science--molecules!) and it seemed hopeful that we were going to explain the common complex diseases in genetic terms.

Why the infatuation with genes? Genes follow rules of inheritance, and human genetics was successfully finding genes for rare usually pediatric diseases like PKU or Tay Sachs, and most traits including disease concentrate at least somewhat in families, so it seemed that the same approach should be applicable to chronic disease.

It was clear (though less of interest to geneticists) that even with aggregation in families, environmental factors such as modern inactive over-fed lifestyles etc. could explain a lot. But with some exceptions, the extension of epidemiology to genetics was from concern with environmental exposures, not infection--the 'old' kind of cause that had been beaten by hygiene and vaccinations. But, it may be that a lot of chronic disease is infectious after all--a real lesson in humility if it turns out to be true!

So it turns out that infectious disease biology is a mix of real and important genetics (host, virus, molecular therapy and prevention), as well as the complexities of environmental exposures, plus complexity generally, etc. If genetics resources are concentrated on these kinds of molecular interactions, rather than trying to explain disease risk by host variation (which GWAS and other studies of these diseases clearly show will not be the major cause), then we have some interesting scientific days ahead. This could be--should be--an area where genetic approaches are entirely appropriate rather than forced. The relationships between host and parasite represent battles and evolution at the molecular level--mano a mano among molecules, so it is appropriate to study it at that level.

Paul Ewald has been saying for some time that infectious causes are more important, even for chronic late-onset diseases, than had been thought. He was largely ignored. Maybe he's right!

Many paths to a single trait

Ironically, there's a story today on the BBC website about an Australian ostrich farmer who needed emergency care for lung paralysis after drinking 4-6 liters of cola a day for some time. And, a woman who had an irregular heartbeat and extreme fatigue after drinking up to 3 liters of cola per day. The investigators warn that heavy cola consumption, because of its high sugar and caffeine content, could cause hypokalemic muscle paralysis (paralysis induced by low potassium) in anyone.

This response to sugar sounds very much like what we described in our post on single gene disorders on May 15. Does this mean that someone like the ostrich farmer actually has a mild form of hkpp, with a corresponding gene mutation, or are all of us at risk, given enough sugar or salt or other trigger, no matter our genotype?

Well, anyone whose potassium drops enough to affect the workings of their ion channels would respond similarly, thus anyone who consumes enough sugar to cause a drop in their potassium levels could experience this kind of weakness or paralysis. People with hkpp just happen to reach hypokalemic levels more easily, because of the inability of their ion channels to allow cells to release potassium as they should.

There are often many ways to a given trait, both genetically and behaviorally, and this trait appears to be the same. Like most traits, it appears to be multifactorial, or even polygenic, with a few factors such as some key gene mutations or specific environmental overloads producing disease, while it may be that most of us manifest some symptoms under some conditions: a spectrum of cause and effects.

The strident atheist scientists

The BBC has a 5-minute interview program and on May 16 their website aired such an interview with Richard Dawkins. Although a public figure, he is purportedly a professor of Public Understanding of Science, at Oxford. That is unfortunate, because he like many others in science these days (especially, evolutionary biologists) are cashing in on a kind of strident atheism that is a bad misrepresentation of science, just the opposite of what they should be doing.

Dawkins said in this interview, as he has elsewhere, that he doesn't believe in something for which there is no evidence. Therefore he says he shouldn't have to deal with God any more than with the Flying Spaghetti Monster. Of course, he has every right to doubt the claims of religion (or tooth fairies, or Santa Claus), or the literal truth of religions based on sacred texts that purport to relate to the real world. Many scientists, who spend their lives trying very hard to understand the world share his skepticism about the claims of religion and other 'mystical' kinds of phenomena.

But it's very bad science! We should be educating the public--and ourselves--as to what science as we know it is really about, not propagandizing our personal views on the world (or, at least, we should be clear that those are our views, and not based on science per se). The reason is quite simple, but we think just as important.

Science uses an array of methods to study a range of phenomena and has some semi-formal rules of decision-making (called the 'scientific method'). We agree, as a culture, that the principles of things like mathematics and our idea about logical reasoning are true. We agree on acceptable forms of measurement, data collection, data analysis for drawing both specific observational conclusions as well as generalizations (theories) about Nature. But therein lies the most important issue.

Dawkins and the professional atheists say that as scientists they don't believe in that for which there is no evidence. But what they really mean, and to give them credit may not even be aware of, is that they don't accept things for which there is no acceptable evidence. And that is a kind of tautology. Something is defined as 'true' (or, at least, plausible) if and only if it is within the realm of their kind of evidence.

There's nothing at all wrong with doing this, but it does make science an axiomatic system for viewing some particular aspects of the world. What is wrong is not recognizing that this is what they are doing. In fact, there is a great deal of evidence for religious claims--even if that doesn't legitimately apply to claims such as the Biblical fundamentalists make about young earth and intelligent design.

Hundreds of millions of people claim that they have had what scientists would call mystical experiences. Many say they communicate directly with God. Whether that's literally true or not is, in fact, beyond the scope of current science. The reason is that current science doesn't deal with, and many if not most scientists won't accept, such types of subjective, personalized evidence as evidence.

Science says it deals with the material world, but that communicating with God is not material, and therefore not real in the sense of materialism. But what is 'material'? Before the discovery of, say, electromagnetic radiation, we could not deal with unobservable aspects of it (like parts of the spectrum we couldn't see). Dark matter in space is another kind of example. We can't see it in the usual way, and only claim it's there because it seems to affect the pattern of radiation as it passes to us through the cosmos.

Once a phenomenon is discovered and can be measured, it becomes part of the 'material' world and joins the panoply of scientific causes. We can never know what things we don't yet know, and it is a kind of arrogance to assert that things we don't know by our chosen way-of-knowing aren't true--or that there is 'no evidence' for them.

We cannot challenge the atheists' skepticism about the often patently false material claims of religion. But it is badly misleading the public 'understanding' of science to present science as if it is the only way of understanding the realities of existence.

What we are saying provides absolutely no support for religious or other mystical claims! We cannot, and do not, imply that claims of personal contacts with God are true or even what 'true' would mean in this case. The mistake Dawkins and other strident scientist-atheists make does not in any way lead to the conclusion that Genesis may be true after all!

But scientists and the public alike should realize that science is a part of our culture, not something handed down to us from the outside (by whom? God??)! It is a particular, and hence limited, way of characterizing the world. In terms of manipulating the world, it is immensely powerful. And it does seem to provide ever-better accounts of what we see around us. But it is a system that is based on a set of accepted rules. Religion and its kin are in a similar way cultural phenomena.

To a hard-nosed scientist, the comforting claims of religion don't seem to ring true, and that can be a depressing thought, given the pain and suffering that clearly are part of reality. Atheism is easy to understand. It is easy to make the personal judgment that claims of speaking with God are illusions. But personal conviction is not the same as science, and not what science is all about. If you don't want to accept as evidence such claims, fine. But it's part of your assumptions. And that's what the public, religious or otherwise, should understand about the nature of science in relation to the nature of Nature.

Dawkins was asked in the same interview what is the point if he doesn't believe in God. His answer was that the point is to enjoy life, to live life to the fullest. This seems to us to ignore Darwin's own lessons, to further perpetuate misunderstanding, not further the public understanding, of science. Dawkins has been called "Darwin's Rottweiller" because he has written so much in defense of evolutionary thought, but within a Darwinian framework, the point, if there is one, is only to survive and reproduce. And that is not even a 'point', as if there was some sort of ordained purpose; instead, it's just the nature of life.

Anything else we make of life, our values, our sense of beauty and purpose, our beliefs and so on, is our own invention. It may be the most important aspect of our lives as we experience them, for sure. But it is personal, and does not reflect scientific knowledge and there is no reason other than celebrity gawking why the opinion about the point of life of a scientist as scientist, is any more meaningful than anyone else's view. Again, this is relevant to science only so far as the evidentiary and topical basis of science goes, which would say that Nature has properties, but doesn't have a 'point'.

If Dawkins had said that science doesn't tell us anything about the 'point' beyond the Darwinian framework, and that this is not an area where expertise of any kind at all has any bearing, and that what he can offer is his own view of life for those who might be curious about it, then he would have been doing his job to enhance public understanding.

Even single-gene disorders are complex

We've written a lot about complex disease in this blog, but we thought it was now time to give the complexity of single-gene disorders its due. Genes for what are often called 'simple' Mendelian traits (traits that are inherited in families in predictable patterns) are much easier to find than genes for complex traits like heart disease or asthma, but that doesn't make them simple.

In part, it's easier to define a 'simple' trait--for example, some forms of oligodontia, or missing teeth, run in families and most forms are due to mutations in Msx1 or Pax9. But it turns out that even a trait that should be easy to define isn't so straightforward--when multiple family members are affected they aren't always missing the same teeth, or the same number of teeth. So, there's something about the timing of the initiation of teeth during development that varies, and probably not by much, but enough to make the phenotype unpredictable, and the variation may well be random.

And, of course more complex phenotypes are even more unpredictable, even if due to single genes. A rare genetic disorder called hypokalemic periodic paralysis (hkpp) is one such trait. This is a channelopathy, an ion channel disorder, usually of sodium ion channels, which regulate the flow of ions into and out of the cell, but in individuals with hkpp, they let potassium into muscle cells but don't let it out in a timely way, thus weakening or paralyzing the muscle.

Hkpp involves anything from fleeting weakness to full paralysis, and in rare cases can be fatal if breathing is involved. The attacks generally resolve within hours, or sooner if the individual consumes potassium, but sometimes can linger for weeks. There are known 'triggers', including heat, hunger, sugar, carbohydrates, alcohol, exercise, and rest after exercise, but attacks can happen even without a trigger, and not everyone shares all the same triggers. So, in a sense this would seem to be a classic case of gene by environment interaction--sometimes. Why is there no apparent trigger for some attacks? And, it's interesting that age of onset is typically during adolescence--so why were these channels seemingly doing their job properly during the active childhood years?

Causative mutations have been found in at least three genes, and have been traced in families, but 30% of the families with this disorder don't have mutations in these genes (and often don't share the classic food triggers), and individuals with the same mutation within an affected family can have very different forms of the disorder, from no symptoms at all to just one in their lives to daily episodes of full paralysis.

A similar description could be written for most 'simple' single-gene disorders. The more common the trait, or the more intensely it has been studied, the more this has been shown. Usually, the story is different in different populations, and this is what would be expected on grounds of evolution (population history): in each region of the world, different mutations have arisen or risen in frequency, there are different environmental exposures, and the genomic background (variation at genes other than the 'causal' gene) differs, even with similar phenotypes.

The classic examples are diseases like PKU, cystic fibrosis, and even genes related to resistance to malaria (like sickle-cell hemoglobin). Even the once-simple ABO blood group system is like this. So, if simple diseases are so complex, it's no wonder that complex diseases are so hard to understand.

Calgary

I (Ken) was just in Calgary, Canada for the first time. This was to give a talk to the medical genetic people there. Calgary, and its university, were exceedingly impressive. The people are sharp and active in many different, relevant areas of science.

They have an institute for the study of complex systems that I had not known about, but I met some of the people associated with it. As I have an affiliation with the Santa Fe Institute, I was very curious to learn what they are doing. It turned out that they are working on some very interesting aspects of biological diversity. Even when you just look at a single kind of cell (I was shown some results of studies of blood cells) there is a high amount of complexity, even when attention is confined to just two factors that are quantitatively involved in hematopoietic cell differentiation.

Another thread of work there involves the genetic basis of learning of 'handedness' in mice. This work appears to show that in this kind of trait, at least, patterns of behavior can be learned and then appear hard-wired. It struck me as showing genetic support for the ability to learn, but not for pre-wiring of a trait like handedness. Again, this is a kind of complexity of interaction between genetics and environment (and supported BF Skinner's model of 'operant conditioning' that was dogma a few decades ago, before the Nature-Nurture cycle turned to Nature, where it is--temporarily--at present).

Wherever there is a good university, there are many students and faculty doing impressive genetics. Much is being learned about specific genetic factors and functions. But much or most of it is also revealing the kind of underlying complexity that this blog is largely about.

When is science the 'solution'?

Perhaps an explanation is in order as to why we suggested in last week's post on C.P. Snow's Two Cultures that science can't be the solution to many of the problems people believe it can solve. This may already be obvious, but we were interested to see no other commentaries last week that addressed this, so we thought perhaps we should clarify what we meant, at least with respect to disease.

As we've discussed already in this blog, determining disease causation can be difficult. For more than 100 years, epidemiology has struggled with this, and now genetics faces the same problem. Infectious disease should be easy to explain--find the infectious agent and you've found the cause. (Though, even confirming the agent isn't always straightforward.)  But, what really 'causes' HIV/AIDS? The virus? If so, why is it that poor and minority populations are at highest risk? In the same vein, what 'causes' cholera, or malaria, or lymphatic filariasis, or river blindness, or any number of diseases that could be killing people in the rich world, but aren't? Is it the parasite, or poverty and the lack of political will to clean up the water and eliminate mosquitoes?

Similarly, what 'causes' the complex chronic diseases that are the significant killers in rich countries? In some ways, science knows a lot less about this--it's easier to find the proximate cause of infectious disease, but often harder to eliminate the more distal causes. With complex diseases, it's the distal causes (poor diet and lack of exercise, say) that are malleable rather than the proximate (genes and/or environmental triggers). People often talk about 'gene by environment interaction', but that is hard to measure, or even to understand. What is it about fat in the diet that increases risk of breast cancer, for example? And, while public health measures, such as clean water, can control many infectious diseases, public health is less likely to effectively prevent or control chronic diseases; that often turns out to be the responsibility of the individual, but health education is notoriously ineffective, and legislating health behavior is notoriously unpopular.

Since the end of World War II, the prevalence of type II diabetes, obesity and gallbladder disease have grown to epidemic proportions among Native American and Mexican American populations. The epidemiology, or patterns of disease in these populations make it seem possible that a simple genetic 'cause' might be responsible--perhaps not a single gene, but a small number. But, no such gene or causal pattern has emerged, even after 40 years of searching, and even if a simple genetic explanation is found, the ancestors of the people now suffering from these diseases had the same gene or genes but they didn't have diabetes or obesity or gallbladder disease. So, can we still say that these putative genes 'cause' disease? This seems to be a textbook case of gene by environment interaction, but if so, what are the environmental triggers, and how do they change gene action?

The same can be said of genes 'for' asthma or heart disease or breast cancer or other kinds of cancers, diseases that have increased in prevalence in the last two, three, four decades. Hundreds of millions of dollars have been spent on the search for these genes, and only a few, with small effect, have been found. And, even when they are found, they might explain some increased risk, but knowing them can't prevent or cure the disease.

Science is useful in many ways, but science alone can't prevent disease.

You'd be good for me

In keeping with last week's farm theme.

On the Road

No, this isn't a book title blog that refers to Jack Kerouac's famous hippie cult book (seemed great at the time!). It's because it has been a slow news day, with no miraculous claims being made in the science pages, not even very much murder and mayhem in the world. So I [Ken] have been trying to put together a talk, as I'm about to go on the road to various places in the next couple of months, to speak to some audiences who will be forced to listen to me expostulating about the state of affairs in genetics today, and how things biological got to be the way they are.

The first talk, next week, will be in Calgary, in Alberta, Canada, where I've been invited to give the 2009 Bea Fowlow Lecture to the Dept of Medical Genetics. My talk will basically be to a medical audience, but I also have a friend and colleague there, who's a biological anthropologist, multifaceted life-science author and editor, and workaholic administrator (named Benedikt Halgrimsson). He struggles, as we do here, with the problem of understanding the dimensionality, and underlying genetic basis, of craniofacial morphology. So there are a lot of unanswered questions to talk about.

Giving this lecture is a real honor....but it's intimidating! Not because Canadians are likely to be hostile (though they are hockey players). It's because they might expect me to have the answers--about what to do next in genetics! Unfortunately for all concerned, there's gonna be a lot of disappointment! Because the landscape in genetics, as we try to discuss in this blog, is at once fascinating, and frustrating: sometimes it seems we have such incredible powers to find things from DNA sequence to developmental process and how they can go awry in disease. And just when we think we have the answers in hand....they slip complexly through our fingers.

Academics like to bring in speakers to talk. Going to a talk has the appearance of real work, but gets a person out of the office. And there are often free refreshments, too. Talks largely are a kind of vapor-ware, though, since the next day, almost no matter what the speaker says, it's back to work as usual. Even in genetics, where a lot of us are hungering for better ideas, it's hard to shift research momentum. So, unlike Kerouac's travels, which were a lark, a ride into freedom, this one feels more like a trap!

Two cultures and the farm

[Anne, whose sister and brother-in-law are dairy goat farmers in New England, wrote this post.]

I visit my sister three or four times a year. When I leave academia behind and am stacking hay or feeding goats up on the farm, the idea of CP Snow’s two cultures shrinks into insignificance, or even irrelevance. Viewed from so far away, those two cultures on isolated, protected university campuses – there are good reasons that academia has been known as “The Ivory Tower” for centuries – merge into one, dwarfed by a much greater chasm, that between the academy and the outside world. On one side, at the farm on the hill, it’s hard physical work with survival on the line, and on the other, in the Pennsylvania valley I call home, it’s the life of the mind, where the main thing at risk is whether our research papers will be published and where we make a ritual out of running, forcing ourselves to remember that we’ve got a body and that it needs some care.

"What's Jack up to today?" I asked my sister.

"He's out tedding the fields," she replied.

When we had this conversation I had never heard of tedding. Every word I don't know is a window into the cultural divide, attached as it is to a set of practices I know little if anything about. Some words describe equipment I have seen when I drive by farm fields but never thought about – tedders, diskers, seeders – and some evoke a history as old as agriculture itself, since soil has been prepared for tillage as long as people have been planting crops, whether with hand held sticks, crude implements pulled by animals or mega-machines specialized to a single task.

The vocabulary of farming is a constant indicator of the divide, but there are many other landmarks. Separate calendars, for instance; academics measure their year by semester and holiday breaks, farmers measure theirs by season – planting, haying, breeding, birthing, harvesting. Or even by weather report – if it’s going to rain tomorrow, there will be no mowing of standing hay today because it won’t dry (but class will still be held). And, the seasons are likely to be delimited by events academics have no way to notice; my sister text messaged me one late April evening to say that the barn swallows had returned that afternoon.

The kinds of risks that farmers and academics are exposed to scarcely even overlap; farming has one of the highest accident rates in America and life expectancy of a farmer is on the order of four years less than that of a professor. Society has decided we’ve got very different economic worth, too; small farmers on average earn far less than half of what professors do. Farmers are at the mercy of unpredictable events beyond their control – drought, rain, animals contracting disease, the price of grain, the ever declining price the farmer earns for produce sold at market, the cost of health insurance – while unpredictability has been fairly well eliminated from a professor’s working life. A professor with tenure, at least.

I recognize that I could make similar comparisons between academics and miners, or soldiers, or athletes or musicians or visual artists and the lists would differ only in detail. The singular difference is that farmers provide the rest of us, including miners and artists, with sustenance. They are tied to the land and the seasons in ways that most of the rest of us can, and do, ignore.

I was at the farm when Ken heard that he and colleagues had gotten a large grant to study the genetics of the evolution of skull shape in primates. This project has nothing to do with disease, so doesn’t claim to be contributing to future health – a claim that sells a lot of science, particularly modern genetics, but this study is basic science.

When I told my sister about the project, she looked at me skeptically and asked, “Why do we care?”

And, surrounded as I was by goats and hard work, I couldn’t help but see her point, even though I work on this project myself. Why should her tax money be spent to fund a project to further knowledge that will have no practical application in any of our lifetimes, if ever, when she can’t even afford health insurance, and just barely the grain to keep her animals alive? Academics do provide knowledge, edification, and social advance for students. We also provide much highly technical knowledge that starts out very abstract and theoretical and some of it does, eventually, work its way to farm and field. Still, I felt a whiff of sympathy with Chairman Mao: send all the professors to the countryside, let them learn the value of real work. Though, in my version, they wouldn’t have to stay ten years; a week or two would do.

Strange Brew Clone Institute

How complex is 'complex'?

The word 'complex' is frequently used, though not always as clearly as it might be. In today's genetics arena it means a trait that is the result of multiple genetic elements as well as environmental factors that are usually unknown or not specified, but can include the genetic element's genomic background. Can we get a clearer understanding of this interaction in some way that has not yet been well-explored?

Most complex traits, whose genetic contributors GWAS and related mapping methods are designed to find (see earlier posts) show substantial evidence of being 'genetic' in some sense: there is correlation of the trait among relatives or an association of risk of the trait--like a disease--among family members.

The problem is that despite evidence for genetic involvement, GWAS and other methods have only been able to identify a small fraction of the contributing elements. One response is that we need larger studies. Another is that the objective is not to account for the disease in terms of genes, but to find genetic pathways that are involved.

Most common diseases have increased substantially, if not dramatically, within living memory and more importantly within the time since trustworthy epidemiological data on incidence (rate of new cases per year) or prevalence (fraction of persons affected) have been available.

This would suggest to reasonable people, even including some geneticists, that at least for preventive purposes the major responsible (and avoidable) factors for the disease are environmental, such as exposures to risk factors like toxins, lifestyle changes such as in diet, etc.

A few years ago, the molecular technology infrastructure for mapping studies was laid down, and paid for on the rationale that common genetic variants were likely responsible for these common diseases--and hence that genetics was a right way to approach them. Common variants for common disease (CVCD) became a mantra.

In response to the environmental and other arguments raised even at the time, proponents of CVCD and the investment in the gene-mapping infrastructure (e.g., the HapMap project) said that, yes, environmental factors clearly were involved, but the increase in prevalence was due to their interaction with common genetic susceptibility variants.

Subsequent mapping, including numerous, often huge genomewide association studies, has generally failed to find such variants. The meaning of 'common' can of course be adjusted to fit results, but the bulk of the heritability of these many studied traits remains unexplained. It's a fair question whether these traits are truly complex and largely unmappable, or whether we just haven't studied them enough.

A kind of widespread relevant evidence may be the following. The substantial heritability of common disease as well as normal traits suggests that many genes contribute; the traits are often called 'polygenic' for that reason. But these many genes might individually vary in their effects. For many theoretical and empirical reasons, one would expect some alleles (genetic variants) at one or a few genes, to interact or respond more strongly to changing environmental factors.

If that is the case, then the more important genes that were not identifiable in case-control or family samples before the environmental change, should be mappable afterward. That's because those variants that would be the main responders to the environmental change, whatever it was. Their individual effects, modest before the change, should be major after it.

Yet, today, after a long list of diseases have had large, rapid increases in prevalence, the GWAS findings are as we have seen: they are not identifying much that is of population-scale importance. On the surface, this suggests that the argument about complexity really is correct: there are, indeed, many genes involved, but they each make very small net effect on risk. A few are detected whose effects are greater, but they are few and even their effects are only modest.

From this perspective, which is based on data, not theory, secular trends in risk and the failure of GWAS to find CVCD's is relevant data, suggest that complex traits really are basically homogeneous in terms of genetic causation.

Now, if this is true it constitutes material evidence that should change our understanding of the nature of these traits: why would it be that there are generally no major alleles waiting for environmental changes to give them a chance to be expressed? Indeed, isn't that just how natural selection is supposed to work, with environmental change favoring 'good' genetic variants in the population and raising them to high frequency? Those variants should have substantial effect on the trait so the organism carrying the variants would reproduce more successfully.

If our thinking is correct, then this tells us something. Perhaps the networks of which biological traits are built are internally adjusting--strong changes in one part of a pathway network lead to slowing down of others. Yet, secular trends show that the net result can involve major change. It is indeed somewhat difficult to believe that the genetic responses to environmental changes are so internally homogeneous that even after major stimulus none really stands out even when studied in large samples. There must be a message there--if we can but figure it out!

These are just superficial ideas at this point, but they could help direct changes in what we look for, or how we look. We are starting to use an evolutionary simulation program that Brian Lambert in our group has written (see the description of ForSim on Ken's web page for details) to see if this point is correct as we think, or if there is some aspect of genetic control that we are overlooking. Stay tuned for results.

Geneticist as cowboy?

This is a great cartoon, but .... what does it mean?? The geneticist is a cowboy? The cowboy was cloned?? Lab results show the guy's a cowboy? Any ideas??

GWAS on my mind

There's a classic blues song Georgia on My Mind that is ironically appropriate. The current Nature has two reports of mapping studies of autism traits (and there is reference to a third study published elsewhere). The study gained a lot of attention (or was given a lot of hype, depending on your view of these things). It isn't the first such story to get attention. These studies are treated as if they are major findings, and tend to reinforce the idea that GWAS are a powerful approach to understanding the genetics of complex disease. Despite the evidence, we can't seem to get GWAS off our mind.

Of course 'major' is a subjective judgment but after filtering the rhetoric in the media, and looking at what the actual papers and authors say, it turns out that, as before, these new findings account for less than 1% of autism cases (and such estimates are often upwardly biased for various statistical reasons). And the genes were known before as potentially relevant. And the different studies did not find the same genes.

This is par for the course, unfortunately, because autism is a sadly damaging disease both to the persons affected and those who care about them. One doesn't want to dismiss any findings that might materially help. But as even the authors of one of the studies pointed out in comments to the media (e.g., here), this is further evidence that GWAS are a fading tool, though that is not how the news media portrayed the result.




The sad fact is that in autism, as in many other diseases, there is plenty of generic evidence for genetic risk factors playing some role (because the disorder seems to cluster somewhat in families), yet the prevalence has grown rapidly only in a recent few decades. Yes, there is the lingering question of whether prevalence has actually risen, or just the probability that a child will be diagnosed with one of a broadened spectrum of disorders, but prevalence has continued to rise rapidly even in the last few years, while the definition of the spectrum has been the same, which makes it seem less likely that rates are simply reflecting increased or altered diagnosis. This shows that even if there are gene-environment interactions, the trait is preponderantly due to environmental factors--unfortunately, despite all sorts of guesses and wild guess, the factors are not yet known.

GWAS and other mapping approaches held out hope to many, and even to some extent to skeptics, that diseases like autism for which there was no good physiological understanding could reveal genes, and hence mechanisms that would lead both to understanding and eventually to treatment. But this hope really hasn't been borne out.

The current typical response (and that of the authors of these studies) is that we need larger studies of various genetic sorts. As we've said a few times in this blog, and as even some GWAS proponents believe, that is most likely to mean much more work to find much less, and unlikely to really crack the problem. Larger studies will in principle find rarer things, but that only works if the increase in study size isn't accompanied by even greater risk heterogeneity (an improved signal to noise ratio). Even complete DNA sequence can't automatically pull the rabbit out of the hat, because the more DNA examined the more variable sites one will find.

Since it is likely that much of what we're looking for is regulatory, and we don't yet know very well how to identify such sequences, we'll be awash in DNA data with no clearer biological picture. There are some subtle points afoot here. They have to do with the statistical nature of these studies. It's possible in principle that even with densely-marked GWAS no marker will have detectably strong association with the true causal site (or, worse, sites) in a chromosome region. Full DNA sequence would in principle include the site(s) directly, but the plethora of data may well obscure it. Generally, if individual signal is strong enough to be breakthrough-generating, we should have seen it by now.

So, each new study like these recent ones presses home the dual points: large association studies simply do not seem to be the way to understand these complex traits, and instead we need some clever person to show us a better way.

We need to get GWAS off our mind (though it doesn't seem likely to happen any time soon). Being negative about GWAS may seem unseemly. But it is an attempt to be constructive. These problems are so worth studying that they are worth studying right rather than just studying again and again in the same unsatisfactory way.