Thoughts on the latest schizophrenia genetics report

The news and social media were headlining a report last week that presented some genetic findings, and even aspects of a possible causal mechanism, related to schizophrenia.  As habitually skeptical readers of these daily stories, we wondered how substantial this claim is.

The report in question was a Nature paper by Sekar et al. that identifies variation in the very complex MHC genome region that, based on the authors' analysis, is statistically associated with schizophrenics relative to unaffected controls. These are variants in the number of copies of particular genes in the C4 'Complement' system.  The authors show that gene copy number is correlated with gene expression level and, in turn, with some changes in brain tissue that may be related to functional effects in schizophrenia patients.

Comparing genotypes and disease status, in ~30,000 cases and controls of European ancestry, in 40 cohorts from 22 countries, the authors find that genotypes with higher C4 gene copy numbers are more frequent in schizophrenics, and there is a quantitative relationship between copy number and expression level in postmortem-tested neural tissue.  The relevant potential mechanism involved may have to do with the pruning of synapses among neurons in the brain.

The authors estimate that the relative risk of the highest-copy number genotype is 1.27 times that of the lowest. The lowest risk genotype is rare in the population, comprising only about 7% of the sample population, meaning that almost everyone has a middling relative-risk genotype.  That is comparable, say, to most of us having middling height or blood pressure. But the net population absolute risk of schizophrenia is about 1%, so that the absolute risks associated with these various genotypes are small and not even very different from each other.  The careful work done by the authors has many different components that together consistently seem to show that these copy number differences do have real effects, even if the absolute risks are small.

How that effect or association arises is not clear, and the findings are certainly not the same as explaining schizophrenia as a C4 disease per se.  As the authors note, around 100 or so other chromosome locations have been associated with the disease in genome-wide mapping studies that have been done.  That means that if their results stand up to scrutiny, C4 variation is one component of what is basically a polygenic disorder.  The association for each C4 genotype category is the effect averaged over all other contributing causes in those people. The absolute risk in individuals with a given copy number is still very small, and may depend on other genetic or environmental factors.

Schizophrenia is not a single disorder and has a spectrum of onset age, sex, symptoms, and severity of occurrence.  Many authors have been warning against using a single term for this variety of traits. Whether that is relevant here or not remains to be seen, but at least as presented in the their paper, some of the current authors' results seem not to vary with age.  This study doesn't address whether there is a smallish subset of individuals in each C4 category who are at much higher risk than the average for the category.  However, the familial clustering of schizophrenia suggests this may be so, because family members share environments and also genomic backgrounds.  One might expect that C4 genotypes are interacting with, or if not, being supplemented by, many other risk factors.

Even if average risk is not very high in absolute terms, this paper received the attention it did because it may be the first providing a seemingly strong case for a potentially relevant cellular mechanism to study, even if the specific effect on risk turns out to be quite small.  It could provide a break in understanding the basic biology of schizophrenia, given the dearth of plausible mechanisms know so far.

Because the statistically riskier genotypes are found in a high percentage of Europeans, one would expect them to be found, if at varying frequencies, in other populations than Europeans. Whether their associated risks will be similar probably depends on how similarly the other risk factors are in other populations.  C4 copy number variation must be evolutionarily old because there is so much of it, clearly not purged by natural selection--another indicator of a weak effect, especially because onset is often in the reproductive years and would seem to be potentially 'visible' to natural selection. So why is the C4 variation so frequent?  Perhaps C4 provides some important neural function, and most variation causes little net harm, since schizophrenia is relatively rare at roughly 1% average risk.  Or, copy number changes must happen regularly in this general MHC genome region, and can't effectively be purged, but is generally harmless.  But there is another interesting aspect to this story.

The Complement system is within a large, cluster of genes generally involved in helping destroy invading pathogens that have been recognized.  It is part of what is called the 'innate' immune system. Innate here means it does not vary adaptively in response to foreign bodies, like bacterial or viruses, that get into the blood stream.  The adaptive immune system does that, and is highly variable for that reason; but once a foreigner is identified, the complement system takes part in destroying it.  So it is curious that it would be involved in neural degeneration, unless it is responding to some foreign substance in the brain, or is an autoimmune reaction. But if the latter, how did it become so common?  Or is the use of C4 genes in this neural context a pleiotropy--a 'borrowed' use of existing genes that arose for immunity-related functions but then came also to be used for a different function?  Or is neural synapse regulation a kind of 'immune' function that hasn't been thought of in that way?  Whatever it's doing, in modern society it contributes to problems about 1% of the time, for reasons for which this paper clearly will stimulate investigation.

Why does this system 'misfire' only about 1% of the time?  One possible answer is that the C4 activity prunes synapse connections away normally in a random kind of way, but occasionally, by chance, prunes too much, leading to schizophrenia.  The disease would in that sense be purely due to random bad luck, rather than interacting with other mechanisms or factors. The higher the copy number the more likely the bad luck but too weakly for selection to 'care'.  However, that reason for the disease seems unlikely, for several reasons.  First, mapping has identified about 100 or so genome regions statistically associate with schizophrenia risk, suggesting that the disease is not just bad luck. Secondly, schizophrenia is familial: close relatives seem to be at elevated risk, 10-fold in very close relatives and almost 50-fold in identical twins.  This should not happen if the pathogenetic process is purely random, even though since haplotypes are inherited in close family members there could be a slight correlation in risk.  Also, the authors cite several incidental facts that suggest that C4 plays some sort of systematic relevant functional role.  But thirdly, since the absolute risk is so small, about 1%, one has to assume that C4 is not acting alone, but is directly interacting with, or is complemented by (so to speak) many other factors to which the unlucky victims have been exposed.

Something to test?
This might be a good situation in which to test a variant of an approach that British epidemiologist George Davey Smith has suggested as 'Mendelian randomization'.  His idea is basically that, when there is a known candidate environmental risk factor and a known gene through which that environmental factor operates, one can compare people with a genetic variant exposed to an environmental risk factor to people with that genetic risk factor but not exposed to test whether the environmental factor really does affect risk.

Here, we could have a variant of that situation.  We have the candidate gene system first, and could sort individuals having, say, the highest 'risk' genotypes, compared to the lowest, and see if any environmental or other systematic genomic differences are found that differentiates the two groups.

Interesting lead but not 'the' cause
Investigating even weakly causal factors could lead the way to discovering major pathogenic mechanisms or genetic or environmental contributors not yet known that interact with the identified gene region. There will be a flood of follow-up studies, one can be sure, but hopefully they will largely be focused investigations rather than repeat performances of association studies.

Given the absolute risks, which are small for given individuals, there may or may not be any reason to think that intervening on the C4 system itself would be a viable strategy even if it could be done. This still seems to be a polygenic--many-factorial--set of diseases, for which some other preventive strategy would be needed.  Time will tell.

In any case, circumspection is in order.  Remember traits like Alzheimer's disease, for which apoE, presenilins, beta-amyloid, and tau-protein associations were found years--or is it decades?--ago and still mystify to a great extent.  Or the critical region of chromosome 21 in in Down syndrome that has, as far as we know, eluded intensive study for similarly long times. And there are many other similar stories related to what are essentially polygenic disorders with major environmental components.  This one is, at least, an interesting one.

Big deal over a big meal.....for some! The tiny bite of FTO and obesity

"Small genetic change has heavy consequences," says the headline on a PR release from the University of Queensland, one of genetic epidemiologist Peter Visscher's academic homes.  Further, the release goes on to say that "[o]ne small change to the DNA sequence can cause more weighty changes to the human body, according to a new study..."

Has the gene for obesity been identified perhaps?  Well, no.  Even the release doesn't actually claim that.  Rather, if you look at the actual paper, published online in Nature on September 16, the research group reports, from a meta-analysis of 38 genomewide association studies (GWAS) of variation in height and BMI, that they've found a SNP in the FTO gene that they say is responsible for variation in BMI, body mass index.  The FTO gene, or fat mass and obesity-associated protein, codes for an enzyme associated with regulation of food intake.  Variation in BMI in the group with the obesity-associated SNP variant is about 7% greater than those without, and people with the variant are, on average, about a whopping 0.5 kg heavier than people without.  Visscher, one of the co-authors on the study, says that this is important "because it demonstrates that genes can be found that affect trait variability."

That is, if there is phenotypic variability in a trait for which the genotype is presumed to be known, this could indicate a gene by environment interaction affecting the phenotype.  This is known as the "reaction norm" of the genotype: a tree will be tall and straight in low altitudes, but the same tree would be short and wide higher up, for example.

Visscher goes on to say that the study provides an indirect way to get a handle on genotype by environment interactions, although they did not directly measure environmental variables so can't say this definitively.  But, he says:

“For example, if the effect of a gene on weight is smaller in people who physically exercise than in people who do not, then this will lead to less variation among people with two copies of the weight decreasing variant.

This has no necessary connection to the environment, except if we understand that the rest of each person's genome is part of the FTO's environment.  The physically external environment, perhaps the internal bacterial environment, and the genomic environment are all involved.  This doesn't change the point of the story, however.

Unlike the press coverage of this study, the co-authors downplay the significance of their findings with respect to explaining variation in BMI or height, and report that they haven't actually tested or found any gene by environment interaction to explain the modest effect of the FTO SNP that they did find. Possibly it is the genomic variation that, in the context of one of the FTO variants, leads to more trait variation than the same genomic variation in persons with the 'normal' FTO variant.

The paper concludes:

Overall, our findings are consistent with a low heritability of phenotypic variability and no common genetic variants that account for a large proportion of variation in environmental or phenotypic variability. They also indicate an absence of widespread genotype-by-environment interaction effects, at least for height and obesity in humans and with interaction effects large enough to be detected in our study in which specific environmental factors were not identified. Nevertheless, the demonstration that individual genetic loci with effects on variability can be identified with sufficiently large sample sizes facilitates further study to understand the function and evolution of the genetic control of variation.

But this is (forgive us) culpably overstated!
Genes code for proteins and they interact with other things--often, they're catalysts which means they affect the rate of other reactions in the cell.  Or they interact with other proteins, in ways whose efficiency depends on how tightly or effectively they bind with each other, or with DNA, or other cell products.  Expression levels of a gene are similarly about quantity of effects.  This means, almost by definition, that genetic variation affects variation, depending on the other things most any gene has to interact with.  Further, most disease effects associated with genes (or their interaction with environments) affect the age pattern of onset of traits like body weight, or of disease.  Again, these are quantitative effects on variation.

Roughly before WWII, Native Americans and 'Hispanics' who are admixed with Native Americans and Europeans, had very little diabetes or gallbladder disease and had a more typical body shape.  Since 1950 or so, they have experienced a near pandemic of such disorders, with morbid and even lethal consequences.  And increased BMI is one of the well-known, classical effects of this (a topic on which Ken has written for many years).  There is no absence of GxE evidence!  One would say there was only if one is, as this study seems to be, only dealing with present-day populations.

The main author of this paper is a very capable scientist, working in Australia.  And surely he knows that the same kind of thing absolutely and in well-documented fashion, applies to the aboriginal population of Australia.

So, then, why is this paper significant?  According to the authors, it's because they've shown that individual alleles can be responsible for variation in phenotypic variation.  Important?  New?  You be the judge.

We should conclude on a more positive note.  We don't challenge the results, which seem perfectly reasonable: FTO, one of the clearest and most replicated obesity-related genes known, has only a tiny effect as the authors have noted, and the extra variation means that the variant SNP allele has little if any predictive value.  Yet genome-based prediction is what you're being sold by the science these days.

Our point is to challenge the  overstatement, which we think is part of a systematically misleading campaign to geneticize almost everything.

Reductionism, part II -- The Tunnel of Love

Choosing to wear blinkers
Yesterday, we suggested that even the early geneticists were well aware of the multifactorial causation of traits, and asked how the 'gene for' thinking that has driven so much recent research, largely without satisfying results, came to predominate as it does currently. Today we suggest that science restricts its view intentionally, as a pragmatic way of discovering the nature of aspects of Nature. Indeed, the early geneticists did the same. And we point out that the price we pay is the way scientific methods restrict the degree to which we understand things more broadly.

'Gene-for' thinking is pragmatic -- understanding the molecular basis of genes and how they work is easier than understanding, say, polygenic interaction or the effect of the environment on development.  And of course great progress was made in molecular genetics throughout the 20th century, which only reinforced the view that the molecule was the thing. This, coupled with formal population genetics, gave researchers rules (how genes segregate, how DNA codes for proteins, and so forth) for cataloging how genes work, giving the field a theoretical framework within which to plan, execute and interpret experiments.

Discoveries in other fields sometimes reinforced the determinist view as well. Following not long after the 'one gene one enzyme' dictum was hypothesized by Beadle and Tatum in 1941, e.g., the coming of the computer age underscored the view of genes as the program or blueprint for life, an appealing and seductive idea that is yet to die. Even if a blueprint needs an architect, and a foreman to supervise the building.

In fact, the idea that the early geneticists had a broader view is only partially true. That they did is well-documented, as we wrote yesterday, but it wasn't ever really put into practice. Then as now, experiments were conducted in a way that enabled these guys to find single genes that 'caused' the traits they were interested in; environment was controlled, and fruit fly lines homozygous for a trait known to be due to the effects of a single gene were crossed so that the effect of a given gene could be assessed, just as Mendel had done with his pea plants.

This is how Morgan mapped genes. And, why those genes were given names like 'hairy wing', 'small eye', 'small-wing', 'vermilion', as though they were the single cause of or were 'for' these traits, even though Morgan knew full well that wing characteristics or eye color were due to many genes. Indeed, he wrote in The Theory of the Gene, "... it may appear the one gene alone has produced this effect. In a strictly causal sense this is true, but the effect is produced only in conjunction with all the other genes."

The question thus becomes a philosophical one about causation. Philosopher of science Ken Waters has written a nice paper about this*, discussing the difference between 'potential' and 'actual difference makers' and how experimental method determines which is found, while prior assumptions determine which are sought. Although Morgan knew that it took many genes to change eye color in flies -- potential difference makers, in Waters' terminology -- the gene that actually changed eye color in his experiments, a direct consequence of the way he conducted them, was the 'vermilion' gene. The actual difference maker. The foundation for gene-for thinking was well-established right from the beginning, and reinforced all along the way.

And, of course, the idea that some of the early eugenicists may have understood that environmental influences could be important in development didn't prevent the Nazis from making life and death decisions based on heredity.

'Gene-for' fervor takes off -- and people actually believe it
After the discovery of the gene for cystic fibrosis in the late 1980s, genes for more than 6000 single-gene disorders were quickly identified. These are largely rare, pediatric diseases, but even so there seemed to be little reason to assume that geneticists wouldn't continue finding genes for disease, and then even for behavior and other kinds of 'normal' traits, even if an important aspect of pediatric disorders is that they occur near birth and hence are relatively less susceptible to environmental effects (not entirely, of course, because even the uterine environment can vary).

This kind of success at finding genes associated with traits was seductive, and the commitment to strong genetic determinism is now found not only among geneticists, but among epidemiologists, psychologists, economists, political scientists, and even further afield. Epidemiology, e.g., had its own history of success finding the cause of infectious diseases, as well as the effects of environment risk factors like asbestos or smoking. But, as with single-gene disorders, when the effect of a risk factor is large, it's a lot easier to find than when there are many cumulative risk factors, some genetic and some environmental. When epidemiology turned to common chronic conditions like heart disease, asthma or diabetes, which generally don't have a single strong cause, they ran into the same kinds of epistemological and methodological difficulties that geneticists were having with these same complex diseases.

Ironically, out of frustration with the difficulty of finding environmental causes for many chronic diseases, epidemiology turned to genetics, and the field of genetic epidemiology quickly grew. Only to be as stymied in terms of the fraction of cases explainable by known genes. The 'strictly numerical basis' upon which Morgan had identified so many putative genes was no longer good enough. Because the counts don't come out in Mendelian terms unless fudge factors (called 'incomplete penetrance', a determinist idea itself, as it imbues the gene with a mystical ability to be more or less expressed) are added to account for other causes relative to a gene under study, usually meaning the gene accounts for only a small fraction of cases and doesn't have nearly Mendelian ratios among siblings, etc.

And it becomes institutionalized
Then of course when the Human Genome Project was finished, the sequencing factories had to be kept running, so yet more promises were made about what we were going to be able to do with genes, more billions were spent on more classically reductionist 'count only' genetics -- and yet the same problems remain unsolved. We still can't enumerate the genes that are responsible for height, and for exactly the reasons Morgan spelled out in 1926, as we noted yesterday.

In fact, the scientific methods that we use identify genes that, when mutated in some ways, cause serious stature problems (Marfan's syndrome makes you very tall, many genes make you very short), but when we look at the normal range as seen in a sample of healthy people, these genes do not generate mapping 'hits' (as in GWAS association studies). And this is probably true of most traits -- it's easier to explain the extremes of their distribution than it is to explain the normal range.

It's not that genes are unimportant. It's that we are only taking into account part of the truth. This is driven essentially by methodological considerations -- we've got well-developed formal theory for genes and how they segregate in families, and what that means about how to find them. But it is more of a struggle to account in useful ways for complex causation -- useful, at least, in terms of dreams of miracle drugs or genetically focused personalized predictions.

Tunneling through the truth

An important reason for the combination of great success in discovery in genetics, and the relatively great failure to account for complex traits has to do with methodology rather than the state of Nature. As we said yesterday, the focus on fixed, chromosomally localized causal elements -- 'genes' in the classical sense -- was driven by Mendel's careful choice of experimental material, followed by similar constraints employed by Morgan and the other classical geneticists of the early 20th century.

The very same logic and approaches have been followed to this day. Genes are identified as localized causal elements in DNA and we study and manipulate them through variation that is studied, as much as possible, by removing all other sources of variation. Traits are narrowly defined, transgenic experiments use inbred animals manipulated one gene (or one nucleotide) at a time, and so on. This is done because it generates a cause-effect situation that is tractable.

That approach, or research program, led to the steady discovery of the nature of DNA, of genes as protein codes, and so on, up to the mapping of entire genomes of a rapidly growing number of species.

Yet at the same time, when it comes to complex traits, we know that we are not discovering the whole truth -- and we know why. It is the same control of variation that led to discovery, that leads to obscuring the whole nature of Nature.

In a sense, what science does is to 'tunnel' through reality. Like any other tunnel, the walls are reinforced to keep things outside the tunnel out, and to make a clear path within. The path is a particular gene we are interested in, and we manipulate that gene, and its variation, treating it as a cause, to see what effects it has. We know it really interacts with the world outside, but we standardize that world as much as we can, to reveal only the effect of variation in the single cause.

This is perhaps a tunnel of love of experimental design, but not so much of the nature of Nature, because by particularizing findings, even on a large scale, we systematically isolate components from each other whose true essence, and origins, are intimately dependent on their interactions.

Maybe tunneling through truth is the only way science can understand the world. From the point of view of garnering facts, and manipulating the world by manipulating the same facts, science is a huge success. But in terms of understanding Nature, maybe we need a different way. If so, as long as the reductionist legacy of the 300 year old Enlightenment period in human history lasts, we will remain the Tunneling species.

Tomorrow we'll discuss how the same kind of thinking has worked in developmental genetics and the EvoDevo world of research.

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*The Journal of Philosophy is only available online to members, but the reference is Waters, "Causes That Make a Difference", The Journal of Philosophy, 104:551-579, (2007).

Genetic reductionism, part I -- the path from broad to narrow?

What geneticists used to know
We've been reading the writings of some of the early geneticists, and have been struck by how many of the original concepts and how much of the jargon are still in use even after a century of major discoveries. Even many of the names TH Morgan gave to fruit fly genes in the 1910s and 20s, without knowing anything about the structure of genes and how they work, are still in use today. Their names, in fact, are a major reflection of the way that science actually works.

The figure to the left, a map of the four fruit fly chromosomes, with gene names, is from Morgan's book, The Theory of the Gene, published in 1926. In that book, he outlined his theory as follows:

The theory states that the characters of the individual are referable to paired elements (genes) in the germinal material that are held together in a definite number of linkage groups; it states that the members of each pair of genes separate when the germ-cells mature in accordance with Mendel's first law, and in consequence each germ-cell comes to contain one set only; it states that the members belonging to different linkage groups assort independently in accordance with Mendel's second law; it states that an orderly interchange--crossing-over--also takes place, at times, between the elements in corresponding linkage groups; and it states that the frequency of crossing-over furnishes evidence of the linear order of the elements in each linkage group and of the relative position of the elements with respect to each other.

Note that his theory of the gene rests almost entirely on the work of Mendel, fifty years before. By good luck (given what was known at the time), Mendel studied traits that were not closely located ('linked') on the same chromosome, so that Morgan's group was working with and expanding on rather then testing or challenging Mendel's theory.

Mendel knew that systematic hybridization experiments would elucidate patterns of transmission of the 'elements' that were responsible for traits. But only some traits; others were too complicated, and didn't follow the same patterns. Mendel tried the same approach in other plants and found that some did not follow his rules, in fact; but the doubts that led to were overlooked given his overall success. We now know that traits he avoided did not 'segregate' in the way the traits he chose did, because they are due to the joint contribution of many different genes, known today as polygenes.

Morgan presents his theory of the gene, and then adds the following, and this is important with respect to how they could know as much as they did without understanding much at all about genes:

These principles, which, taken together, I have ventured to call the theory of the gene, enable us to handle problems of genetics on a strictly numerical basis, and allow us to predict, with a great deal of precision, what will occur in any given situation.

By 'strictly numerical', he meant that one need not understand what the genes were, in chemical terms, or how they worked. The rules of inheritance were made manifest through the relative numbers of different types of offspring of a given set of parents -- which Mendel first showed, and others built upon.

But Morgan didn't suppose that all traits were due to single genes. He was aware that most were due to many genes, and that it was likely that most genes do more than one thing.

A man may be tall because he has long legs, or because he has a long body, or both. Some of the genes may affect all parts, but other genes may affect one region more than another. The result is that the genetic situation is complex and, as yet, not unraveled. (The Theory of the Gene, p 294).

And, these early geneticists also knew about the fundamental contribution of the environment. Morgan ends the paragraph above with this sentence: "Added to this is the probability that the environment may also to some extent affect the end-product."

A student of Morgan's, A.H. Sturtevant, in his A History of Genetics (1965), says:

With Johannsen [who introduced the words "gene", "genotype" and "phenotype" in the early 1900's] it became evident that inherited variations could be slight and environmentally produced ones could be large, and that only experiments could distinguish them.

And:

In 1902 Bateson pointed out that it should be expected that many genes would influence such a character as stature, since it is so obviously dependent on many diverse and separately varying elements. This point of view was implied by Morgan in 1903 (Evolution and Adaptation, p. 277), and by Pearson in 1904.

This is among other early examples he offers. Even the most widely used genetics textbook in the 20s and 30s, a book in fact that helped school the Nazis (and a chilling read today), described variation in traits that were due to environmental factors. That book was Human Heredity, by Baur, Fischer and Lenz, first published in Germany in 1921, and revised a number of times. Two of their examples of traits with environmental contributions, are pictured to the left. The pigs in the top photo to the left are from the same litter. The smaller one was poorly nourished, while the larger one was well-fed. As for the rabbits:

Among rabbits, for instance, there are two somewhat similar races, one of which is pure white with pink eyes, while the other (the "Himalayan" rabbit) though mainly white and whit pink eyes, has very dark fur on the ears, paws, tail, and nose. The colour of the fur in this latter race is modifiable by temperature. If an area of its skin be kept cool, which can easily be effected simply by shaving a part, all the new hairs that grown upon the cooled area have a dark tint. Fig. 6 shows how a patch which had been thus shaved has been covered with dark hair. But as soon as the fur has regrown, so that the area of skin is now protected by it from the cold, all the new hairs which subsequently grow in the area are white, as before, so that the dark tint of the shaved area gradually disappears. It would be easy enough, by shaving the whole surface of the body, to provide one of thees rabbits temporarily with a dark-tinted fur throughout... P 33-34.

So, how did this broad view of genetics become so much narrower as the field matured, so that genetic reductionism that now predominates to a great extent? Indeed, the Human Genome Project and its ongoing sequels epitomize this approach, as its supporters promised that knowing our genes would lead directly to disease prediction (and prevention, and even dramatically increased longevity as a result). Whether this was truly believed, or was cynical spin to get funding -- in fact, it was a mixture of both -- even the intellectual forebears of today's geneticists knew it was wrong.  Or was the early view never as broad as it seems?

In our next couple of posts we'll have some ideas on this. You may disagree, or have other ideas, and if so, we'd love to hear them.

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This post was stimulated by work on a paper about the developmental genetics of complex traits like the mammalian skull, and by interactions Ken had on his recent trip to the University of Minnesota, with two philosophers of science Ken Waters and Alan Love.

Vegetables and you

Today's big health news (or, at least, headline)? A vegetarian diet prevents cancer! A study of 60,000 people in the UK, published in the British Journal of Cancer, reports that vegetarians get less cancer of the blood, bladder and stomach. Of 100 meat eaters, 33 will eventually get cancer, while of 100 vegetarians, 29 will do so. If we feel a need to point out that this difference is rather unimpressive, the study does seem to have been independent--at least, it was not paid for by the carrot and broccoli industry! But, vegetarians are more than half as likely to get cancers of the blood and lymph, although the actual number of most cancers, in this sample, was quite small.

The protective effect of the vegetarian diet isn't always true, however--cervical cancer is higher among vegetarians than in meat eaters, though the number of cases was very small, and bowel cancer was slightly higher among those who don't eat meat (contrary to decades of reports that meat-eating, for various reasons having to do with bacterial metabolism of animal fat, increased colorectal cancer).

What mechanism do the authors suggest to explain their findings? Perhaps there are viruses or mutation-causing compounds in meat, or protective compounds in vegetables. Indeed, at least stomach and cervical cancers are known -- and this knowledge does seem to be real! -- to be caused by viruses.

However, something that at least the BBC write-up of the story doesn't point out, a notorious problem with these kinds of studies that should always be pointed out right at the top, is the problem of environmental confounding, in which one measure is correlated with an unmeasured factor. In that case, it is wrong to attribute causation to the former.

It should be clear even to the most obtuse that vegetarians and meat-eaters probably have different life styles in all sorts of ways, which may increase or decrease their risk of exposure to causative environments, having nothing at all to do with diet itself. In this case, diet is merely a marker of life style and risk, not a causative factor, and indeed the study does nothing to control for any such differences. Maybe the dedication of vegetarians to things like Zen meditation affects cancer risk!

Most interestingly, one of the authors of the study was interviewed on the BBC radio program, Newshour, this morning with a fascinating lead-in. Owen Bennett-Jones, the interviewer, pointed out that dietary findings come and go, often being contradicted by subsequent findings--red wine protects against cancer, or it doesn't, dietary fat causes breast cancer, or it doesn't--so why should we believe the results of the vegetarian diet study?

The author himself acknowledged that the findings are not earth-shattering, and may eventually be contradicted, and may only apply to vegetarians in the UK, and these were small numbers of each cancer anyway. He quite burst his own balloon, albeit with the help of his interviewer. His rationale is that after smoking, everything else is a minor risk factor. But, apparently this shouldn't stop researchers from spending large amounts of taxpayer money to look for these minor effects anyway. And hyping them to the media. Hmm. Maybe the vegetable industry should pay for this research!

Bennett-Jones played this story well. He had a science journalist on along with the scientist, and he asked her why so many unreliable stories appear in the media. She said the explanation is very easy--health news sells, especially when it's scary and about cancer. She blames the hype on scientists for wanting to publicize their iffy findings, the industry for wanting to promote the latest food that will prevent cancer, and the media for having to fill the papers and airwaves on deadline. Literally every day, she said, she gets calls from the food industry, or scientists, wanting to tell her about their latest findings.

So, follow a vegetarian diet if you choose to. But don't do it because of the promise that it will prevent cancer.

Fittingly enough, there's a story in the New York Times today, by Gina Kolata, updating us on yesterday's big health news, which suggested that c-reactive proteins, a marker of inflammation, cause heart disease. People were already developing tests for CRPs, counting on the promise that CRPs, rather than cholesterol, were causative and thus were going to need to be tested for in everyone, multiple times. But a new study in the Journal of the American Medical Association, suggests that, yes, CRPs are associated with heart disease, but are not causative.

Interestingly, this study uses a relatively new epidemiological method called Mendelian randomization to show that some people are genetically predisposed to make more CRPs than others, but that CRPs levels themselves aren't associated with heart disease. This is an appropriate use of genetic data.

Well, we have to go now. It's time for lunch. We wonder what's on the menu today.....