Schizophrenia, Hubris and Science
blogs.discovermagazine.com
blogs.discovermagazine.com
When I saw the report, and then saw people I respect heralding it as a huge breakthrough, it seemed over-the-top.
But I'm no scientist or medical expert, and I'm bored of emotion-driven debates about medical science between myself and other scientific laypeople, so I kept my thoughts - and the results of my own hunt for further details - to myself.
But as the report says, evidence and details of genetic mechanisms in schizophrenia (and other mental and neurological disorders) are not new.
Sure this discovery may add some substance to the understanding of the topic, but it's not revolutionary.
The real revolution will be when science figures out exactly why and how some people with a given genetic predisposition for an illness will develop that illness, whilst others do not.
As discussed in this article about the 2003 book The Gene Illusion [1], the 50% rate of identitical twin concordance for schizophrenia is widely cited as evidence that it is a genetically deterministic condition.
But whether or not the figure is really 50% or something lower, that still leaves at least 50% room for non-genetic factors.
We'll only start making real progress in curing these kinds of illnesses when we form a deep understanding of whatever is going on in that very large component that we already know is not purely genetic.
You have zero clue regarding what you are talking about. Your comment is just meaningless combination of platitudes. Even if we find a target and develop a drug that treats 20% of the cases, it still counts as a real progress if not a revolution. Look at the other comment in this thread by Chris Patil.
As you say in your "But I'm no scientist or medical expert", yes that's the reason why you find an obviously flawed blogpost appealing. Since the post was written/designed to make you feel better about your pessimism/skepticism.
This trend of "Contrarianism for the sake of contrarianism" is a sophisticated version of click-baiting where bloggers/commenters displaying classic case of dunning kruger spread FUD about any new discovery/result.
Commenters on Reddit/HN quickly lap up these articles/comments since it resonates with their sense of technological pessimism, often disguised as skepticism. As a result its now fashionable to criticize every new discovery/progress and get guaranteed pageviews/upvotes. It helps if its in form of a scary slideshow or contains assertions or scenarios that are not under question.
Whilst I have no medical qualifications, my skin in the game is that I've experienced debilitating depression, anxiety and an apparent auto-immune fatigue illness for at least 15 years (but with evidence of the early stages of these conditions tracing well back into childhood), and I've witnessed people close to me succumb to other mental illnesses including schizophrenia and bipolar.
I desperately want all these illnesses cured.
In the absence of the medical profession's capacity to identify and treat my conditions, I've had to become "my own physician" and have spent much of the past 10 years researching the topic very deeply.
As a result, I've been able to find a system that seems to be succeeding in reversing these conditions. I've also been doing whatever I can (within a very limited budget and access to diagnostic facilities) to gather data that might demonstrate physiological changes - e.g, inflammation markers, antibodies for known chronic infections linked to auto-immunity, hormone levels.
My research and self-experimentation has given weight to the notion (which I derived from a number of medical researchers who have solid credentials but whom I suspect you'd find contemptible) that having a genetic predisposition for a chronic illness (which I seem to, given that other members of my family exhibit similar symptoms) doesn't necessarily condemn you to experiencing that illness, and that you can reverse or avoid the condition by altering your environment or your perception of your environment (I.e., epigenetics).
This is why I find it relevant to point out the data (<= 50% identical twin concordance) that indicates that the genetic predisposition is just that - a predisposition, not a sentence.
So when you say it would be major progress if this discovery led to the development of a drug that helped 20% of sufferers, I say sure, but wouldn't it be more revolutionary if we could understand precicely why these genetic predispositions express in some people and not in others, then use this knowledge to develop techniques to resolve or prevent the illness in 100% of people?
I'm genuinely interested in your thoughts on that.
For what it's worth I think I'm the bigger optimist here. I think we are in a position to be able to cure many of society's most burdensome illnesses by understanding and addressing their environmental triggers. I believe that because I'm doing it myself with good success, and I believe the same kind of technique would be beneficial for other auto-immune illnesses, of which - according to this very research - schizophrenia is one.
Yes it needs a lot more validation and research, which is what I'm hoping to see, and am indeed doing what little I can to facilitate.
As a side note, your comment is quite personally abusive, which is against the HN guidelines. The guidelines seek to promote civility and substantiveness above all else.
This is a topic that is personally important to me and important to the world and is one I'm pleased to discuss at any opportunity with others who are knowledgeable and well-intentioned about advancing their understanding of it, and that can only happen when people are civil and respectful.
First if you think my reply which merely pointed out that your remarks were meaningless or that you were unqualified (as you yourself pointed out) was "Abusive". You ought to re-read the article which is an open political attack, along with a photoshopped image mocking a researcher.
""" So when you say it would be major progress if this discovery led to the development of a drug that helped 20% of sufferers, I say sure, but wouldn't it be more revolutionary if we could understand precisely why these genetic predispositions express in some people and not in others, then use this knowledge to develop techniques to resolve or prevent the illness in 100% of people? """
The issue with such statements/questions E.g. "But wouldn't it be great if we could prevent cancer instead of curing it?" or "But it will be more awesome if achieve true AI instead of just some game benchmark" or "Wouldn't it be great if achieved faster than light space travel". Is that at best they are meaningless from point of view of scientific inquiry. They offer no benchmark, or even a reasonable plan of action. At worst they are often used to mislead from real scientific achievements.
Such statements are feel good equivalent of "World Peace!" or "End Hunger!" or "All you need is loveee!". While most users on this site would be able to quickly figure out the futility of "World Peace now" they don't recognize it when the similar statements are formulated in medical / healthcare domain.
To conclude this, what the researchers found regarding schizophrenia is awesome, they published in Nature, and as other comment points out most of the scientific community thinks its amazing if not revolutionary. There is no reason to dismiss it by quoting a politically motivated attack by some blogger and citing impossible to achieve goals without any feasible roadmap.
- The main reason I engage in discussions like this is to test how much of a "clue" I in fact have about these topics, and identify what gaps in my knowledge need to be filled. This one has been as valuable as any in that regard. (FWIW I found Chris Patil's response to the post most insightful, as well as researcher Kevin Mitchell's followup comment.)
- It's untrue, your implication that pointing out the importance of the non-genetic component in the development of illness is a pointless diversion. There are compelling hypotheses around this (some going back decades) and promising studies in this area [1]. Yet they are often marginalised or contemptuously dismissed by the segment of the scientific community that remains fixated on genetic determinism (e.g., Richard Dawkins' recent public attacks on epigenetics - based not on any evidence but on his own ideology and ego). The point is that there could be much more progress in resolving these illnesses if researchers/institutions were less focused on fanning their own egos with over-the-top claims, less constrained by the existing commercial model for medicine (we can use this to make new drugs!), and more open to other researchers' insights and discoveries that could help to complete the whole picture.
- It's no big deal to me as I can handle it, but you were abusive in a way that is outside HN guidelines. Your perception of the tone of the original article doesn't change that. When I couched my comments with "I'm no expert", as a point of modesty and a disclaimer, that didn't warrant such a confrontational assertion as "You have zero clue regarding what you are talking about", followed up with a string of accusations that seem to be grounded in your own grievances with other people who engage in this topic, but were not evident in anything I wrote myself. Like I said, I can handle it, but if you make a habit of that style of commenting, you may attract the attention of the mods and other participants who value HN as a place where people treat each other with politeness and respect (HN is very deliberately not Reddit).
- HN has a password recovery feature FYI. And you can email the mods at hn@ycombinator.com for help with this or any other aspect of the site.
Thanks for the discussion.
[1] Prominent researchers and advocates in this area include Harvard medical professor Rudy Tanzi, former Stanford researcher Bruce Lipton, and general physician Lissa Rankin. I comfortably concede they all suffer the propensity to align themselves too much with the new age woo industry - though that is partly due to their banishment from the scientific mainstream for having non-conformist ideas that question genetic determinism (Lipton in particular). FYI My personal quest is to gather hard data as I apply their hypotheses in an attempt to completely cure my own illnesses, then work with professional researchers to investigate these hypotheses more widely.
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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.
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.
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.
The Sekar et al. discovery in Nature connected the human genome's largest influence on risk of schizophrenia with a molecular mechanism that would explain the age of onset and major pathological observations. That'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.)
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).
The press release doesn’t say that Sekar et al identified the “first schizophrenia risk gene”, but rather that it was "the first time that the origin of this devastating psychiatric disease has been causally linked to specific gene variants AND 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' 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.
Beyond that, I'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).
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.
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.
> As for the “excessive synaptic pruning” model, it’s very far from new: it was proposed in 1983 and has since been discussed in 3580 papers. So it’s simply untrue to imply that Sekar et al. are the first to shine light into a biological “black box”
Yeah, people have been running their mouths for a century proposing hundreds of radically different schizophrenia theories. It's different to propose yet another one, and to show that one out of the hundreds is genuinely part of schizophrenia!
Contrarianism for the sake of contrarianism.