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On July 1st. the journal Nature, published three reports that described genetic differences between people with schizophrenia and the rest of us. Nature held a big press conference, at the World Conference of Science Journalists, Many of the individual institutions involved in the studies also issued press releases. As so often in press releases, descriptions like “landmark”, “major step forward” and “real scientific breakthrough” were used liberally.
In short, there is no simple genetic basis for schizophrenia. The pooled results of the three studies gave 8,014 cases and 19,090 controls. A huge amount of genetic analysis was involved. Many thousands of small genetic differences were found between the schizophrenics and the controls, but no single mutation alone had much effect. There could be even more, because it is still not possible to sequence the entire genome of so many people. . In total, the effects of the many small differences might account for 30 percent of the disease risk. That’s more than the few percent that could be predicted before, though it’s still well short of the 70 or 80 percent figure that is often quoted for the genetic component of schizophrenia.
What is observed is a correlation between differences in the genome and having schizophrenia. The results don’t tell us directly about the cause of schizophrenia, and they don’t even (so far anyway) tell us much about the mechanisms that give rise to schizophrenia.
The reporting of this event makes a fascinating contrast in styles of scientific journalism. I’ll compare only two of the reports. One is by Steve Connor in the Independent (he of the recent contretemps). The other is by Nicholas Wade in the New York Times.
The headline sounds pretty hyped up to me, but headlines are often written by sub-editors, not by the author of the article. The article itself seems to be a pretty straight account that uses mostly quotations from the press releases. And it is accompanied by an irrelevant picture of a brain image, that’s alleged to show areas of the brain that contain dopamine receptors, though the work being discussed shows exactly that It’s not just a matter of a disorder in a transmitter system.. So the article is OK but it doesn’t contribute anything itself.
The fact of the matter is that the results of the gargantuan effort put into this study is to show how enormously complicated the problem is and just how little we understand, The prospect of inventing ‘cures’ looks almost hopeless in the face of such complexity. Nobody said it would be easy, but it has turned
out to be even harder than pessimists guessed. I would prefer a report that conveyed this reality better than the press releases do, and better than most of the hundreds of newspaper reports based on the press releases. There is one such report, that in the New York Times.
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The journal Nature held a big press conference in London Wednesday, at the World Conference of Science Journalists, to unveil three large studies of the genetics of schizophrenia. Press releases from five American and European institutions celebrated the findings, one using epithets like “landmark,” “major step forward,” and “real scientific breakthrough.” It was the kind of hoopla you’d expect for an actual scientific advance. It seems to me the reports represent more of a historic defeat, a Pearl Harbor of schizophrenia research. The defeat points solely to the daunting nature of the adversary, not to any failing on the part of the researchers, who were using the most advanced tools available. Still, who is helped by dressing The principal news from the three studies is that schizophrenia is caused by a very large number of errant genes, not a manageable and meaningful handful. The rationale behind the long search for schizophrenia genes was entirely justifiable. Since schizophrenia is highly heritable, it must have a strong genetic component. And it has long seemed possible that the responsible genetic variants underlying most common diseases would also be common. Natural selection gives us strong protection against diseases that strike before the age of reproduction. But its power to eliminate harmful genes is thought to wane sharply thereafter. So bad versions of genes that are bad only late in life could build up in the population, explaining why the common diseases that strike later in life are so common. And if researchers could identify the few major variants assumed to underlie each of these common diseases, from schizophrenia to heart disease to cancer, they could devise drugs to offset the genes’ effects. But nature is often a lot more complex than assumed. It now seems that the arm of natural selection is far longer than thought. It has reached way beyond our reproductive years and zapped most harmful genetic variants before they could get to be common in the population. That leaves relatively uncommon variants, lots and lots of them in each case, as the genetic cause of each common disease. In the last few years gene hunters in one common disease after another have turned up a few causative variant genes, after vast effort, but the variants generally account for a small percentage of the overall burden of illness. With most common diseases, it turns out, the disease is caused not by ten very common variant genes but by 10,000 relatively rare ones. Today it’s the turn of schizophrenia researchers to make the same discovery, though one perhaps more to be expected since schizophrenia is not good for reproduction. Schizophrenia too seems to be not a single disease, but the end point of 10,000 different disruptions to the delicate architecture of the human brain. Yes, that discovery is a landmark. The kind that says you have 10,000 miles yet to go. The march of science is not direct but two steps forward, one step back. This was the step back. But it was a completely necessary one. So the press release writers could have cast it as a noble defeat, were words like defeat a part of their vocabulary, or frankness their masters’ priority. |
This account may sound a bit pessimistic, but it also seems to me to be the most realistic of the lot.
Schizophrenia is not alone in proving to be a lot more complicated than one would have hoped. One of the most interesting outcomes of the genomic age has been to show that far simpler conditions than schizophrenia turn out to be not so simple after all. The simplest genetically transmitted diseases are those caused by mutation of a single amino acid in a single protein of known function. For example, one of the best understood receptors is the type of acetylcholine receptor that is responsible for transmitting an impulse from a motor nerve to a muscle cell, Curare blocks them and so paralyses voluntary movement, A rare form of muscle weakness, slow channel congenital myasthenic syndrome (SCCMS), is caused when one of the amino acids in the protein mutates. But it has turned out that there is not just one mutation. It would be nearer to the truth to say that each family that suffers from the disease has its own mutation. Each of the mutations has a rather similar effect on the function of the protein, but there is not just one SCCMS but dozens.
The same is true of mutations in the glycine receptor that cause the rare congenital condition, ‘startle disease’ (posh name, hyperekplexia), The glycine receptor mediates inhibitory actions in the spinal cord. It is blocked by strychine, Strychnine causes exaggerated reflexes and eventually tonic convulsions: your muscles tighten so you die with the risus sardonicus. Mutations in the glycine receptor that stop it working so well have an effect rather like strychnine. But rare though the disease is, at least 15 different mutations, each in a different family, have been found to produce similar effects. There is just one startle disease, but many.
Cystic fibrosis is even more complicated. Mutations in a single protein, with a function that is now quite well understood, can cause the disease. But every patient does not have the same mutation. Around 1500 mutations have been found in the 20 years since the gene was sequenced. And to make it still more complicated, the symptoms shown by two patients with the same mutation may not be identical. The effects depend, it seems, on the rest of the genetic make-up of the individual. There is a nice account in ‘The promise of a cure: 20 years and counting’..
The same pattern is repeated again and again. Schizophrenia is just a very extreme example of a common phenomenon Not so long ago it was the dogma was that the future of drug discovery lay in genomics and high-throughput screening, Richard Sykes, when head of GSK, put the vast resources of GSK into this approach. It did not really work (which might explain why he left GSK to become rector of Imperial College). Now we know why.
It turns out to be a bit more complicated than anyone had foreseen, and one suspects it will take a long time to sort it out.
Follow-up
There is some comment on the reports on the Nature web site.
As so often, there is a first class level-headed account of the facts and what they mean on the NHS Choices site.
6 Responses to Schizophrenia: hoopla, disappointment and science journalism
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Dear DC,
Another great post; nice comparison of the hype-vs-reality reporting of science in main-stream media.
Thanks & keep up the great scientific debates.
This study does indeed provide a ‘reality-check’ for the now creaking belief that discovering a ‘responsible gene’ is just around the corner. What should be of even more concern, however, is the assumption upon which not only these expensive studies but also its criticism (here & elsewhere) is based – because it is this ongoing assumption that will allow us to throw away even more billions of dollars. Nicholas Wade states it boldly: “Since schizophrenia is highly heritable, it must have a strong genetic component.”
This is not established. And there is good reason to say it might never be.
All molecular genetic research into ‘schizophrenia’ is based on the findings of twins and adoption studies that have supposedly *already* established it as an inherited disease. There is now quite a large literature about this work ( – I list a few references below) that exposes the appalling ‘science’ backing it; psychiatric genetics has the same intellectual pedigree as intelligence genetics, behaviour genetics and criminal genetics, all of which has been a distorted and verificationist venture, on largely ideological grounds, depending (often wilfully, one might suspect) on a popular yet absolutely inaccurate reading of what heritability means – and especially of what the heritability coefficient h2 can actually tell us. ‘Schizophrenia as inherited’ is of course accepted benignly and in good faith by perhaps most clinicians, but a reading of the incredible history of research into twins and adoptees would be at times comical if it weren’t so sobering (and often heart-rending). Sobering indeed when one considers that (just as part of the picture), the most cited and authoritative review – Gottesman and Shields – quoted in proabably all psychiatric textbooks, still factors in data from the post-war work of German eugenicist, Franz Kallman, amongst dubious others.
Dependence on arguments about heritability seems to have played on the public’s (and policy makers’) ignorant assumption that it declares something about ‘heredity’ and ‘inheritance’. It does not. Heritability informs plant and animal breeders about the selectivity of evidently genetically-based traits in selective breeding programs. It is the measure (within a particular population, at a particular time and place) of the degree to which trait variation can be accounted for by genetic variance. This particular variance has to be genetic in plants because – aside from the environment – traits cannot be transmitted or obviously caused in any other way. Animal characteristics will likely also score highly for heritability, though of course even in some animal communities certain behaviours rely on being ‘taught’ somehow by parents. A trait then can be highly heritable but not simply or even genetic. That traumatised and troubled human beings beget children who in turn become traumatised and troubled is a sad but overwhelming fact about humanity. Of course, not all children brought up in adverse circumstances will suffer in this way, and not everyone who suffers in this way has had trauma or duress or has had to endure prolonged , emotive and debilitating no-win situations. But the sheer correlation of trauma, existentially-invalidating relationships, and poor mental health between generations (evident as a workaday fact in the clinic) is likely to produce a high heritability statistic when looking at poor ‘mental health’. Basically, if a certain amount of variance in psychotic people can be attributed familiarly, this does not tell us that it is genetic in origin. (It might actually be genetic, but heritability here won’t tell us. What we need is ‘the’ gene itself.) The hereditarian assumption interprets heritability only in this way, however, leading to a travesty in reading h2, the heritability statistic. If ‘schizophrenia’ (or any other diagnosed complaint) manages to achieve an h2 of 0.8, for example, the psychiatric hereditarian will conclude that schizophrenia (for any one person!) is 80% ‘caused by’ genes – and further, but curiously conclude that it is 20% ‘caused’ by the environment. Even then, that 20% is something of an embarrassment to the medical model – and thus the invention of the original stress/diathesis or stress/vulnerability model which suggests that schizophrenia is genetic through and through, but will only reveal itself as a genotype when placed under environmental stress. Any genetic or evolutionary analyst will tell you this is utterly bogus reasoning; a complete misreading and overreading of heritability – and they’d likely be quite animated in explaining all the fallacies involved. It is, however, accepted common sense for psychiatrists, much of the public – and most especially science journalists.
(A side issue is that straightforward heritability estimates do not address the possibly significant effects of genotype / environment interactions and covariations on trait variations – which are of course most pronounced of all in human beings.)
To add to this (in passing!) – the ‘schizophrenia’ diagnosis is reliable only because the whole world has a manual on how to diagnose it, and it has no validity as a disease concept at all (in terms of aetiology or prognosis or directing treatment). Treatment is a matter of experiment. Any argument for the ‘existence’ of ‘schizophrenia’ (rather than psychosis) is no argument at all but purely axiomatic. The history of the construction and acceptance of the concept (from Kraepelin’s strange ramblings to the committee-led edifice of the DSM) is also a tragi-comedy.
Even if a clear and actual genotype was found for ‘schizophrenia’, we would need a functional link (e.g, brain chemistry) to actual behaviour and experience. There is nothing to be found here. There are no chemical imbalances in psychosis, depression, mania – despite what the pharmaceutical ‘information sheets’ suggest – and certainly no physical tests. Certain neurodevelopmental differences may have been found but one might as feasibly (if not moreso) attribute this to the effects of protracted trauma on the growing child.
On a further point about genes; the ‘machine’ model for understanding genes is wearing very thin. The idea of genes as ‘code’ is evocative but rather metaphorical when we realise how involved is the cell in the reading and use of DNA, and the deep interaction between DNA, organism and environment. (Evelyn Fox Keller also makes for difficult reading if one wants even to believe there is such a ‘thing’ as ‘a’ gene. Even ‘the gene’ is a kind of useful fiction.)
To assume that if a drug makes a difference then it must be targeting a biological process is simple fallacious reasoning. Psychotropic drugs are all versions of stimulants or sedatives – the kind of effect that they have on all of us can help mask or calm certain people with certain difficulties at certain times. They certainly don’t redress any ‘imbalance’. (I wait with interest for the day a patient asks their psychiatrist for a test to reassure them that the chemical imbalance is now ‘rebalanced’.) An ‘anti-psychotic’ is so-called not because it targets a certain biological process but because it was simply found, fortuitously, to make some wanted difference ( – wanted, usually by a medic). The disruptive effect of these chemicals when stopped or even tailed off are almost always rebound effects caused by the brain’s compensations for the drug – though this is often interpreted as the underlying disease process ‘coming to the surface’ because not controlled.
I speak as a consultant clinical psychologist working with psychosis. In the clinic it is rare to come across complex mental health difficulties where the person has not had often unbearable trauma – overwhelming loss or bereavement, child physical abuse, child sexual abuse, emotional abuse, crushing bullying, disorientation; sometimes not even known about by their families. There are numerous workable and psychologically understandable models that help explain how adversity can sometimes lead to psychosis – via normal cognitive and emotional processes. The search for the ‘schizophrenic poly-gene’ demeans such people and obscures how their very human problems can be addressed in meaningful and sometimes transformative ways, not merely (or even) technologically. It is also a colossal use of money that clearly serves the interests of companies and careers, and not the user of mental health services.
I am very rarely moved to comment over the internet, but I’d be very curious about what people think of these unfortunately trite points.
Careful Skeptic
Ned Block (1995) “How Heritability Misleads About Race”, The Boston Review, XX, no 6, January, 1996, p. 30-35
Mary Boyle (2002) Schizophrenia: A Scientific Delusion? (2nd Ed.)
Jay Joseph (2003) The Gene Illusion: Genetic research in psychiatry and psychology under the microscope
Jay Joseph (2006) The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes
Richard Bentall (1990) Schizophrenia Reconsidered
Richard Bentall (2009) Doctoring The Mind
Evelyn Fox Keller (2000) The Century Of The Gene
Richard Lewontin (2000) The Triple Helix: Gene, Organism and Environment
Richard Lewontin (1991) Biology As Ideology
Joanna Moncrieff (2009) A Straight Talking Introduction to Psychiatric Drugs
http://www.critpsynet.freeuk.com/CPNpublish.htm
The problem with ‘Schizophrenia’ research are even more fundamental than this – the ‘diagnosis’ itself! It, (like all Psychiatric diagnoses’) is a diagnosis by exclusion – the same two main symptoms listed as ‘diagnostic’ (i.e. delusions/hallucinations) can be caused by a host of other factors, including simple heat stroke, simple sleep deprivation, substance intoxication/withdrawal – and a host of others – given that no-one sent under Section to a Psychiatric hospital ever recieves a full workup for a competent DD, the rate of misdiagnosis is staggeringly high. It is impossible therefore to even reliably identify a cohort of patients who have ‘Schizophrenia’, let alone find any ‘gene’ to which their condition can be attributed.
Technically speaking, since a ‘diagnosis’ under ICD-classifications demands that symptoms endure for a different time period than the DSM (USA) classification systems, a ‘Schizophrenic’ patient could be ‘rediagnosed’ merely by travelling across the Atlantic – I can’t think of a single piece of research that shows gene expression/ mutation is caused by international air travel (but hey, maybe there’s a grant application in this hypothesis for someone?)
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