Cryola, in all colors

Existential angst

We've already posted some on this (here), but we've been thinking some more about last week's reports of revisions to the formal categorization of psychiatric diseases, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Given the reordering and recategorizing done in this revision, many people will have woken up last week no longer having the disorder that they had just the day before. That's difficult enough, but the deeper question is what it means that diseases can come and go at the drop of a 943 page tome. 

Science magazine has a piece (subscription required) on this.  They write about co-morbid conditions, in which mental disorders don't exist in their 'pure form', but instead categories overlap, and, for example, substance abuse and anxiety tend to ride along with other mental disorders, particularly depression. 

DSM-IV, currently in use, gives a menu of nine symptoms for "major depression," a diagnosis that afflicts about 17% of the population at some point in life, according to the U.S. National Comorbidity Survey. (Bipolar illness—depression alternating with mania—affects another 1%.) Missing from the list is anxiety; yet, says Fawcett [psychiatrist at the University of New Mexico School of Medicine in Albuquerque, and chair of the DSM-V work group on mood disorders], anxious depressives are at greater risk for suicide, and there's a "staggering" fivefold difference in response to antidepressants, with nonanxious depressives doing much better. Fawcett's group is therefore recommending that "mixed anxiety depression," a condition that has been residing in the Appendix of DSM-IV, be promoted to a freestanding diagnosis.

But giving anxiety a higher status within depression raises other categorical questions. The "anxiety disorders" are currently a separate category that includes generalized anxiety disorder, phobias, and panic, as well as obsessive-compulsive disorders and post-traumatic stress disorder. The symptoms defining the latter two are far more varied than those associated with depression and anxiety.

The piece further reports:

Indeed, DSM-V authors are debating whether the relationship between anxiety and depression is so close that they should be subsumed into a supercategory of human hopelessness, fear, and existential angst.

Don't we all feel this at some point, to some degree, whether or not we meet the criteria for diagnosis and treatment for a disorder? This is not to say that some people don't suffer terribly from depression or anxiety, by any means. These are very real conditions, and can be utterly debilitating.

But much of this is about medicalizing what used to be considered normal, driven at least in part by pharmaceutical companies out to make huge profits by selling medications that people will take for life. Watch commercials by these companies and you'll never feel normal again: shyness has been turned into 'social anxiety disorder', and of course there's a medication for it. And similarly, baldness or erectile dysfunction or toenail fungus can all be treated now, and while this might be welcome news to sufferers, it's much more welcome to the keepers of the pharmaceutical bottom line.  Indeed, the BBC reports that 'experts' say that 'pain should be viewed as a disease in its own right' and treated appropriately.    

We've written before about the need for science to be based on trust. Is the struggle to categorize anxiety and depression going to bring us any closer to a 'truth' about mental illness, and to easing the pain of the sufferers, or is all this recategorizing primarily about further enriching big pharma?  What should we believe?

And of course this category creep makes studies of causation even more difficult because the more heterogeneous the cases, the less likely they'll share a cause, be it genes or environmental factors or a combination of both. 

Crayola Deficit Syndrome

In that same light, we were interested to read the story in the NYTimes last week about families in which occupational therapists are now being hired to help children improve their handwriting.

These days, many little fingers are being drilled. Twenty-five years ago, pediatric occupational therapists primarily served children with severe disabilities like spina bifida, autism or cerebral palsy. Nowadays, these therapists are just as focused on helping children without obvious disabilities to hold a pencil.

So even handwriting difficulties are being medicalized. Parents desperate to have their children hold their Crayons right! If not, they need therapy, lest they become Signature Challenged adults! To qualify for that, a diagnosis! Crayola Deficit Syndrome!  

This a push-pull situation that is either good for everybody or bad, depending on your point of view.  The parents pull for diagnoses that can make them feel better (a label seems to make the worrisome scrawls understood and qualified for treatment, and even curable), and the various professional interests push (to expand their client base, drug customers, special-ed teachers). 

The reality is more continuous, a spectrum of variable traits. At the extremes, no one would argue that diagnosis and treatment aren't meaningful. But we're pushing rapidly from the extremes toward the middle. Maybe some day being 'average' will be considered a diagnostic trait, since if your kid is 'average' s/he is behind other kids and you'll demand a diagnosis and a therapist to fix this.

This may seem rather silly, but not for the reason you think. We would not want our progeny to be Signature Challenged, but after all, when our kids grow up, there won't be any signatures or handwriting. It will all be by bar-scans, keyboards or voice recognition. The really savvy parents will be checking their kids voiceprints, not their scrawls. So, relax! There's no need to Cryola over misspelt 'milk'.

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**Louis Menand expands on many of the same points we make here in a fine review of a book on the history of depression and another on the history of the drug industry in the March 1 New Yorker.  He says, among other things, that the redefinition of traits that were once considered normal, such as shyness, has 'juggernaut effects'.  Scientists then get grants to find 'the gene for shyness', and build research institutes to study it, 'even though there was never any evidence that the condition has an organic basis'.  

Evolution for real, and for keeps

Of all the things we should be spending research funds furiously on, infectious disease should be at or near the top of the list. Yet another story has appeared on the proliferation of antibiotic resistant species that are causing death and disease, mainly in hospital patients at present. But there's no reason to expect this to stay contained. And here we face real instances of genetic and evolutionary determinism. Since proper nutrition and exercise would also be a way to avoid massive numbers of otherwise early deaths, because hale people have at least better chances of surviving infection, we should refocus effort, away from luxury and made-up 'genetic' disease to these major societal problems.

There is, in fact, evidence that an increasing number of supposedly old-age, lifestyle-related diseases are going to turn out to be related to infection after all--either directly, or indirectly. Here we are learning from many avenues of research, including, yes we're free to acknowledge it, from GWAS approaches (case-control studies that searched for regions of the genome whose variation was associated with risk). Some cancers like stomach and cervical, among others, turn out to be due largely to bacterial or viral infection. Some heart disease is like that, too. But the genes identified by some of the more successful GWAS turn out to have connection with inflammatory gene networks. These include problems with intestinal, eye, and even psychiatric functions.

Direct infection may cause the disorder (the GWAS would be identifying genes whose variation somewhat protects, or makes one somewhat more susceptbible to the disorder). Or in a substantial number of diseases, the effect may be indirect: autoimmune diseases in which the immune system, after a real infection, mistakes your own cells for attacking bacteria; or perhaps infection in which the successful immune response then leads to chronic inflammation that itself may be damaging (these are called autoimmune disorders).

In genetic studies susceptibility variants may be brought detectably to the fore by the strong point-cause effects of infection, and that could explain why a disproportionate fraction of detected genes--of GWAS genomic 'hits'--seem to be involve the immune system. Since the susceptibility variants are not nearly fixed in the population--it's the fact of their variation that makes them detectable by association studies--they are probably not the result of a history of widespread or very serious infection with strong natural selection effects. And the signals usually only account for a small fraction (usually very small) of what are complex traits involving many contributing genes and environmental exposures.

But antibiotic resistance is a kind of classic Darwinism. Pathogens have simple genomes, huge population sizes, and rapid generational turnover. Antibiotics slam them with a sledgehammer kind of very strong selective effect. This is a cocktail of factors ready-made for the rapid evolution of the favored few--the lucky bacteria or viruses whose makeup makes them resistant. The wipe-out of their susceptible peers leaves an open field for the resistant ones to proliferate, and the rapid turnover and great population growth rate favors quick fixation of the new genetic variant in the population. Further, the dense population of very similar food items (humans, particularly hospitalized humans, at least so far) favors rapid growth and spread of the pathogen population, too.

Here is where evolutionary and genetic theory meet in classically relevant ways. The standard deterministic models work well, because the signal can be so much stronger than the statistical 'noise' of chance events in the lives and times of individual bacteria.

Whereas genetic susceptibility to disease in the host (us) is fairly similar in most individuals, we represent in a sense a standing target for the bugs to adapt to. We do have an immune system designed to evolve as fast as microbes do (it's called our 'adaptive' immune system, and is too intricate to go into here--but it is covered in our book and of course in many sites on the web), even this system may be unable to cope with the hardy pathogens that evolve in survivors of our antibiotic assault.

For whatever reason even the adaptive immune system in vertebrates, including humans, may not have been exposed to environments so changeable as those we're likely to subject ourselves to in the near future if we're not careful. Whatever the reason, if we're slow to respond we're going to teach ourselves a clear lesson in evolutionary genetics.

Why does genetic determinism persist, in spite of the evidence?

What's so wrong with genetic determinism anyway? Isn't it just political correctness to claim that who we are isn't determined by our genes? Genes are the basis of every trait, aren't they? And, they follow rules so we can predict who'll have what. Lots of diseases are caused by mutational variants at single genes, so traits like behaviors and intelligence and skin color must also be reducible to single genes. And, indeed, we can even retrodict the reason that a given trait evolved, since, obviously, natural selection has molded all living things into what they are today, yes?

 Well, no, even if conventional wisdom is that we can predict pretty much anything from genes. And, people seem to believe it in droves; thousands are happily paying genotyping companies to have their disease risk determined, and at least 15,000 people have volunteered to have their whole genome sequenced by the 100,000 Genome Project. The predictions are often expressed in terms of probabilities, but vended and perceived as being causal -- if you're a regular here, you know what we think about this.

And genetic explanations for many traits, including behaviors, are being adopted far and wide. Just type "gene for" or "genes for" into Google, and see how many hits you get (hint: you'll find that it's close to 10 million, and Donald Trump has the genes for success). Delve even briefly into those results and you see that we now are being told by political scientists that how we vote is genetically determined, not to mention whether or not we vote, economists and psychologists tell us that 'the warrior gene' makes us aggressive (except when it doesn't) and influences whether or not we belong to a gang (if we happen to be male). The list is long and growing -- just do this same search again next week, and you'll see. (By the way, the selection against 'good genes' via the deaths of warriors while cowards stayed home dining well and having the warriors' women has worried societal thinkers from Plato through Darwin and the Nazis to the present. But if that was truly selective at the genetic level, why has society not become all cowards?)

Given how much we've learned about the complex polygenic, gene-by-environment nature of complex traits (e.g., see our discussion of GWAS vs lifestyle questionnaires as predictors of disease risk, and, indeed, a study of 19,000 women published in the Journal of the American Medical Association last week reports that risk of cardiovascular disease can't be predicted from genes identified by GWAS), why is determinism still so appealing? Especially given the potential risk (see our recent posts about eugenics, here and here).Why won't it loose it's grip on contemporary thinking (just as the other side of the pendulum, environmentalism, gripped the post-WWII generation)?

Certainly some of it is just momentum -- when the expensive infrastructure for genetic treasure hunting is built, be it in service to political science departments, psychology, epidemiology, anthropology or economics, it's hard to dismantle, even when the evidence against this approach mounts and the payoffs turn out to be slight. 

And too, it's all too easy to construct scenarios to explain positive results, even non-significant ones. Making selective, after-the-fact claims of success is just what homeopathic medicine, phrenology, and other nonsense therapies do. The temptation seems to be too great for many to resist, particularly in a field like anthropology, with its focus on human evolution and how we got to be what we are. It must be genetic, and it must be due to natural selection. And generally these stories can't be tested, so we can make up anything we want! So, we've got genes for long distance running in West Africans because of their history of cattle rustling, genes for opposable thumbs because, well, because of almost any explanation for why they make us human, and even genes for ping pong prowess in China (although the proposed adaptive reason for this escapes us at the moment, but there is one).

But hold on. These kinds of Just-So stories needn't be so rampant, if researchers would just ask themselves a few simple questions. First, when trying to explain the association of a gene with a trait is a researcher should wonder, if the trait of choice is really so adaptive, (meaning that people with the trait consistently had more children than those without, over many generations), why the trait still varies after so many generations of selective pressure. Perhaps selection wasn't all that strong, and the trait not so adaptive after all. Was the trait present in mammals before there ever were humans? If so, no human-specific arguments bear much weight.

Further, and this is just good science, how can the chosen evolutionary explanation be tested? How would we know why a trait evolved? We can't know enough about environmental pressures at the time the variant arose, nor about how it varied through time, to be truly convinced that we know how or why a trait is selected. So, if you've constructed an explanatory framework that involves assumptions about environmental pressures tens of thousands, or hundreds of thousands of years ago, how will you test it?  And, why should a complex trait like thumbs or language or head size be due to a single gene anyway? If not, what is its genetic and evolutionary basis?

As we say in The Mermaid's Tale, natural selection certainly happens, but in general it's weak, usually very very weak, among other things, rather than a steady, simple driving 'force'. And, the idea that complex traits are due to single genes or even a few genes has been shown over and over not to be so, even if there are determined efforts to make them genetically predictable. So, why do these selective genes-for scenarios persist?

We live in a fundamentalist age, and there's more than a hint of simplistic fundamentalism to these selective scenarios: Darwin was right, and it's heresy to question Darwin. Therefore, everything's due to natural selection -- even though Darwin himself cautioned against that kind of thinking. And, the legacy of success at finding single genes for many (rare, usually pediatric) diseases has lulled us into thinking that all traits should be due to a single gene, so why we're human and no longer chimps is probably due to a single gene, or at least a single trait (the use of language, brain size, uprightedness, thumbs, tool use, and so on), for which we'll surely find the gene. People may deny that their explanations are so simplistic, and say they recognize complexity, but look at what they say and how they act.

Fundamentalism is dangerous, no matter its form. And genetic fundamentalism, as the history of eugenics has taught us, is no exception. Throw in traits fraught with societal import, such as intelligence or criminality -- which can't even be defined meaningfully (does anyone ever look for genes for white collar crime?), much less reduced to single genes -- and it can be explosive.

The underlying problem is a hunger for simple answers to satisfy various desires, such as easy prediction, pharmaceutical bonanza, simple explanations of cause and origin. The scientific challenge is to understand the way genetic mechanisms and genetic variation, as part of a mix of causation, work and how traits affected by such a mix evolve.

 A lot hinges on the meaning of 'determinism'. The usual concept is the same as cause, in the sense that we say gravit y determines how fast something will fall, or temperature when something will melt or boil. But in genetics it can be a confusion of probabilistic association and physical cause. The problem is too great for a post, but probable association -- you have a 27% of being diabetic if you have such-and-such genotype --is a very different kind of determination. It usually is misleadingly simple in many ways, especially when many factors, measured and unmeasured, are involved. Rarely does it mean strict causation.

Lab on a chip

An example of a fine use of technology and research money -- medical labs on paper 'chips', at the cost of a penny each, of great potential use in places with little or no medical care.  We blogged about a similar kind of thing here.  (Showing you that we aren't complete naysayers!)

Nature's typical Big Mistake

Well, we had hoped it wouldn't happen, but in the media-hype age we guess it's unavoidable. Our copy of Nature arrived today, the issue with the genome sequences of Archbiship Desmond Tutu and several Khoisan-speaking 'Bushmen', (in the past, at least, it had become protocol to call them by the former cultural-linguistic rather than the latter originally potentially pejorative name), which we blogged about here . The cover, showing San individuals marching across open country, bows and arrows in hand, makes nice anthropology in classical National Geographic style, setting the stage.

The cover's main heading "Southern African Genomes" is fine. But the photo, and the subheading, are not and especially for a leading science publication which should know better. The subheading is "Genetic variance in the oldest known modern human lineage." That description is completely wrong, and in a way falls into classical colonialist thinking of people like the San as 'other', relative to our noble selves. The authors knew this because we'd talked to them about it (they're here at Penn State), so we presume the cover was Nature's editorial (or Sales Pandering Department) decision, not the authors'.

The San genomes are no older than any other human genomes, of course--including yours, whoever you are who may be looking at this post. We all go back to the same set of common ancestors. What the proper description should be is something to the effect that the San have humans' most divergent sequences, meaning that the San sequences are more different from each other, and have a deeper common origin relative to other populations; another way to put that is that it's been longer since they shared common ancestry. That reflects isolation of small local populations, the result of being displaced by the fairly recent Bantu expansions, and other demographic factors, but in no way are today's San 'ancient'. It's sad to see this misconception, with the accompanying picture, perpetuated here. But it's a persistence of classical thinking in our society.

Now besides calling them ancient, is it just gratuitous political correctness for us to object to the San being pictured on Nature's cover? Well, ask yourself why they didn't put a picture of Desmond Tutu (not necessarily nude) as their cover instead? Why the exotica of four naked arrow-toting San marching through the tall grass? This is classical gawking at the inferior 'other'.

On the other hand, the San live the way photographed and they supposedly gave 'informed consent' to being studied (and depicted on a magazine with worldwide circulation?). There happens to be a clear-cut historical relevance here. In the 1800s, leading European scientists brought a Khoisan woman, Sarah Baarteman was her 'western' name, and exhibited her (naked) for Europeans to gawk at like a museum specimen--and especially her large buttocks and breasts, and extended labia minora (the 'Hottentot apron') to titillate Victorians. She was dubbed the 'Hottentot Venus'.

Is this more of the same colonialist exploitation? It is hard to say it's not. Where does legitimate anthropology end and exploitation begin? It's not a new question. Nature is clearly being exploitive. They could have used the sampled San's faces (which were in the article itself). It's inevitably related to the power differential and the fact that it's us studying them. Would we agree to be studied if some of them, in their native state, arrived at our doorstep asking if we'd be in their study?

Whether and how anyone is harmed by this kind of thinking only the future will tell. Whether it's been detrimental to indigenous populations in the past is also debatable, because clear-cut exploitation need not be seriously affected by such anthropological things. Fortunately, these kinds of whole genome sequence data are rapidly becoming so common that their circus value will properly diminish. Soon, it'll just be science, and then how valuable the actual information gathered is or isn't will be determined by the usual, and proper, determinants of scientific impact.

'The' gene? For what?

There is yet another story in the news these days, about a diabetes drug that apparently raises the risk of heart disease. In this case, the chemical known as rosiglitazone binds to a receptor called PPAR-gamma in fat cells. Variation in a PPAR-gama gene has been found by several studies to be associated with higher risk of type 2 (adult-onset) diabetes, the form of the disease in which cells do not respond to circulating insulin, thus leading to elevated glucose in the blood, and to pathological consequences.

However, there is some evidence accumulating, according to the news stories, that rosiglitazone may increase the risk of heart attacks.

Whether or not this turns out to be true, it is but one of many stories about side effects. Indeed, as a follow-up story suggest, there are some boys-will-be-boys elements of questionable ethics--where the company was hesitant to accept or acknowledge at least one study that showed the elevated heart-attack risk--resembling many other stories of yielding to heavily vested interests, an aspect of the ethics of science that could use some serious scrutiny. Again, we see the news stories but can't claim to know what the preponderance of the facts are in this case.

Separate from any ethical questions, most drugs, if you read the small print, can have many side effects. The small print in drug inserts may contain several anti-lawyer rather than true biological effects of the drug, since if an effect is rare in a drug trial it will be difficult to prove a true casual connection.

Above is one image of one section across one stage (mid-gestation) of a mouse embryo, stained (purple) to show cells expressing PPAR-gamma. This is from the great gene-usage site GenePaint.org that shows the mouse mid-gestation expression of around 20 thousand genes. Go there and you can look at all sections in two different mouse embryos available for this gene (here's one).

The point is that even at one stage in one strain of animal, the gene is expressed in many tissues. Ironically, but not necessary atypically, the gene is not expressed in the heart at this stage. However this is part of a system of energy-related cellular functions that are used by most if not all cells, and the gene is in fact expressed in most cells at some level (see Wikipedia for PPARg).

Regardless of how the drug-reaction story turns out, it and many other like it show a point that we tried to make in The Mermaid's Tale, and that we were by no means at all the first to observe: many genes--probably the vast majority of genes--are expressed in several different tissues at different times or under various circumstances. Signaling and related cell-communication and gene-expression regulating systems (of which PPAR is an example), are often used in many different types of cells. It is not the gene, but the combination of genes, that has functional effects.

Thus, it is totally to be expected that a drug that targets a gene product can, or probably will, have multiple effects. The effect may be positive relative to disease in one type of cell, but harmful in other cells. Usually, doses are adjusted to minimize such effects, but humans and our experiences and cellular contexts are so variable that it is difficult to avoid some cost for a given benefit.

This is part of the way life is organized. It's how life evolved. It's how organisms with many different tissues and organs evolved--because an organism is the result of exquisitely complex and highly stereotyped cell-to-cell interactions.

Attempts to target just one gene in one type of cell are a real challenge as a result. That's why even targeting a mutant gene in a given type of cancer has proved to be so challenging, as another story in the NY Times has discussed.

Would a new eugenics backfire?

Using genotypes to predict phenotypes is a coming activity that will only increase. In the past, traits that were assumed to be genetic were used to commit all sorts of offenses, minor or major, to the independence or well-being of individuals, and groups were targeted--assuming that individuals bore the traits assigned to their group.

This was the eugenics era and these measures were justified on darwinian and social grounds that the unfit were not worthy to live as 'normal' or 'fit' people do. The current era of genetic determinism does not seem likely to lead to mass executions the way the twisting of eugenics did in the 20th century. But what forms it will take, and the degree to which genetic information is used is probably unpredictable.

Whether it will be institutional (government policy, insurance or employment structures, etc., that are based on genotype), or whether it will be implemented by individuals, only time will tell. Clearly however, parents will be using such information in regard to their reproductive patterns--a matter of individual 'eugenics'. That is already happening.

If parents who carry dangerous mutations abort or prevent the birth of offspring with serious impairing disease, is this good for society? Here, we do not deal with the question of whether such persons deserve life or should be viewed as defective, any more than those of us who, say, wear glasses or are born with deafness are.

One subtle point was once known to all geneticists, but may have been forgotten, depending on how genetically-based abortion or in vitro fertilization (IVF) programs are carried out. It is called reproductive compensation, and it goes like this:

Remember yesterday's post, where we discussed a gene with a normal D allele and a recessive disease allele, d. Let's say that dd individuals have the disease and can't reproduce, so the source of the allele in the population are the Dd 'carriers' of the harmful allele. If screening is done to detect dd fetuses, which are aborted, then no more cases of disease will be produced. This would also prevent those two copies of the 'd' allele from being present in the next generation. Two Dd parents will produce 1/4 dd offspring, so a lot of 'd's will disappear in a single generation of screening, a rapid form of beneficial artificial selection.

But if the screening accepts Dd offspring, rather than aborting them, there will continue to be carriers in the population. Reproductive compensation occurs if parents selectively remove 1/4 of their offspring but, because they can do this kind of testing and prevention, allow the birth of more Dd carriers. In this case, the frequency of the 'd' allele can actually increase in the next generation, causing an excess production of carrier children by parents jubilant that they won't bear diseased children. In the long run, unless the screening program is always maintained, there can be an increase of disease at some point in the future. If we're doing this to countless of genes for which we develop screening tests, the total risk of such offspring could increase greatly. How serious this problem is, is a legitimate question. It was one that was discussed in the eugenics era and even afterward.

We don't happen to know how such screening programs handle the Dd conceptions. But if screening removes or prevents the birth of Dd as well as dd children then a true (and rapid) reduction of harmful alleles will occur. IVF might automatically do this, but if for people who can't afford or are not aware of the fancier and costlier technology rely on abortion, they would have to abort 3/4 of all their fetuses to prevent new copies of 'd' in their offspring, which they are most unlikely to do! This would mean an advantage for the wealthy and privileged....not exactly a new phenomenon.

A second issue is what the societal impact would be if, say, everyone decided to genetically engineer children to be good baseball players, or good guitarists (or fearless soldiers, or intelligent investors, or mathematicians). To each parent this may seem a good goal, but in society at large, it would likely be a case of the endless evolutionary rat race. All those brilliant mathematicians would not be particularly brilliant in the eyes of society. There will still only be so many jobs in math departments.

Instead, in a society of mathematicians there would simply evolve some new way of competing for resources and success. If there are too many born with Olympic sprinter genes, of course they can't all be on the Olympic team, or the Olympics would have to change. Or we'd just get bored with sprints. Or the best times would simply decrease with a similar proportion of winners as we now have.

The point is that of unintended consequences. Evolution works with what's present. If I dream of producing an Isaac Newton, and nobody else does, I might have a successful genius whose Nobel Prize I can boast of. But if everybody produces Isaac Newtons, society will simply have to develop different criteria for its prizes. It would be like grade inflation: like Garrison Keillor's Lake Woebegone, all the children will be Nobel Prizewinners!

In this sense, eugenic dreams can be illusions, or almost certainly would be illusions.