My guess about why diseases are so hard to model is that all biological systems are self-organizing and thus quite stable (as systems can't really self-organize without navigating some staunch thermodynamic principles). When we want to model a disease, we think we can impose a different order externally, and the body is quite resistant to that change, as there can be redundant systems several times over. So we have to makes "super" versions of genetic mutations to make them the dominant force in the system, which is of course going to be far stronger than the "natural" mutations, because those mutations are a greater or lesser part of a multimodal failure. I think that brain organoids' main contribution to neuroscience will not be clinical but rather in helping us to understand the underlying organizational structure by which the brain grows (and I'm not disparaging the work even a tiny bit, for the record; this would be no small achievement). The best we can hope for in regenerative medicine is to set up conditions in which the body can recapitulate its own developmental growth program.
For our last discussion today, we're going to be talking about this recent schizophrenia GWAS paper. At the end of Monday's class, the teacher took a few minutes to talk about the fundamental challenges to that field of research. Namely that despite the high heritability of the disease (48% for monozygotic vs. 4% for dizygotic), all genetic evidence points to it being a highly polygenic disease. The best link so far gives only a 20% increase in risk. So either the rest of the genetic risk is complex and due to many interwoven factors, or due to extremely rare mutations. Both of which suck to find and follow up in any animal even remotely mammalian. His logic for iPSC-derived organoids was that they would capture the exact web of mutations in any given individual. But unless the disease is really rooted in what early development the organoid can capture, this just kicks the can down the road to super-star tissue engineers. But who knows. Alzheimer's organoids get plaques, so maybe schizophrenia organoids will get <insert vague theory of the month on disease etiology>.I think that brain organoids' main contribution to neuroscience will not be clinical but rather in helping us to understand the underlying organizational structure by which the brain grows (and I'm not disparaging the work even a tiny bit, for the record; this would be no small achievement).