Schizophrenia, Hubris and Science
The top comment by Chris Patil gives an important counterpoint:<p>---<p>Neuroskeptic’s “shoulders of giants” metaphor betrays an astonishing ignorance of the state of despair around translational psychiatry, and the blogger completely misses the boat on the importance of these findings. If the purpose of this blog post was to argue for a more reserved tone in scientific press releases, and support that view by challenging the significance of a study described in such a release, the blogger made an absolutely awful decision in their choice of which paper to make an example of.<p>Drugs used to treat schizophrenia today have the same molecular mechanism as compounds discovered serendipitously 60 years ago. In the intervening time we’ve seen no innovative drugs, and no new biomarkers — a sad lack of progress at a time when we’ve made enormous progress in treatment of cancer and cardiovascular disease. At the same time, pharma companies have exited neuropsychiatry in droves – despite enormous unmet need – citing lack of scientific foundations.<p>Because, see, drug developers don’t just just count Google Scholar hit results; they need to have a real understanding of mechanism with a solid experimental basis. Neuroskeptic’s abstract-counting seems to imply that every paper in PubMed reflects a major advance, but this confuses quantity with quality. Others feel that the view from the “shoulders of giants” is not especially clear. While it’s true that thousands of papers about schizophrenia have been published, many of them followed false leads, described failed animal “models”, or told genetic ‘just-so’ stories.<p>The Sekar et al. discovery in Nature connected the human genome&#x27;s largest influence on risk of schizophrenia with a molecular mechanism that would explain the age of onset and major pathological observations. That&#x27;s a major advance. Many others (including NIMH Director Cuthbert, and well-known GWAS skeptic David Goldstein) also called it a major advance (e.g., see Goldstein’s News and Views in Nature.)<p>I agree with them. Given that this paper not only points the way toward a novel risk gene but provides convincing evidence of molecular mechanism, it should be considered an unprecedented advance. (Unless the blogger feels like well-studied, potentially druggable pathways have been implicated by recent work on this disease; if so, they were not mentioned in the original post).<p>The press release doesn’t say that Sekar et al identified the “first schizophrenia risk gene”, but rather that it was &quot;the first time that the origin of this devastating psychiatric disease has been causally linked to specific gene variants <i>AND</i> a biological process” [emphasis mine]. This isn’t just another lab reporting a locus identified in GWAS. Instead, this is a situation in which a team of (very) clever geneticists analyzed a (very hard to analyze) set of genetic variants and then showed that the protein encoded by the risk allele has a molecular activity pertinent to an established (but heretofore unexplained) disease phenotype. This paper is an interdisciplinary tour de force, and it is philistine to detract from the magnitude of the authors&#x27; achievement in the service of quibbling about the tone of a press release. In any case, the basic claim of that release is true: Literally no one else has published research like this.<p>Beyond that, I&#x27;m puzzled by the implication that major advances in an extensively studied field are less important because they confirm (or deny) widely discussed models. In any event, hypotheses are different from experimental confirmation. The idea that excessive synaptic pruning is involved in schizophrenia has indeed been discussed in many papers (although most of those 3000+ mentions are one-liners and asides that cite a handful of originating papers).<p>Pardon my caps, but THAT IS EXACTLY WHY THIS IS IMPORTANT. The idea that SCZ could involve excessive synaptic pruning is so provocative and exciting that thousands of authors have decided to mention it in their papers, but before Sekar et al, we had no idea about the underlying molecular mechanism. Now we have not just a candidate mechanism, but one that unifies a great many disparate findings and points the way toward both further genetic research and rational design of therapeutics.<p>The Internet makes it easy for us to nip at the ankles of giants, especially from behind the cover of a pseudonym, and lately it’s been fashionable to pile on Eric Lander for doing basically what any chair is supposed to do: popularize the work of scientists affiliated with his institution. Also, granted, press releases could be toned down. But this paper is the wrong place to plant that flag; this is the wrong hill to die on. This paper is gigantic, and it’s easy for me to see how it could go down in history as a turning point in what was once a hopeless battle.