Classes coming to an end today, here's some fun facts I learned this semester: - Humans are more closely related to chimpanzees than mice are to rats: - Rats left together with a mouse will kill the mouse and eat its brains. - Mother mice will eat their young when stressed. - When left in a cage together, adult mice will fight to establish social dominance. The dominant mouse will then chew the whiskers off of the other mice. - There are no good mouse models of schizophrenia. However, in one of the few that exists, dominant schizophrenic mice will chew the entirity of the hair off the face of the other mice. Picture - One behavior of mouse models of autism is overgrooming leading to missing patches of hair. Coincidentally this is a behavior shared among several members of my family. - Mouse models suck. Seriously. Mice with Alzheimer's mutations do not get Alzheimer's. Mice with Huntington's mutations do not get Huntington's. - To remedy this, models have been generated with many more severe versions of those genes. For example, the 5XFAD mouse expresses five different copies of familial Alzheimer's mutations including one linked to onset around age 40. Many researchers question the relevance of these overloaded brains to humans. - Stem cells / brain organoids are great! It's a little telling about the current state of neuroscience that researchers put so much hope into them as the Next Big Thing going forward. But maybe that's just my environment's obsession with technology. It remains to be established how relevant an essentially fetal brain is to adult or aging diseases, but that's not going to stop anyone from trying. - Neuroscientists are impressive thinkers at very neuro-specialized topics, such as electrophysiology, learning mechanics, behavioral tests, and we've read papers with an extraordinarily methodical number of controls that can reduce a complex system into a clear set of roles for a few genes. Unfortunately, they tend to be not so good (yet) at larger systems-level analyses that involve many proteins acting in concert compared to, say, the fields of cancer or ecology. Hopefully this will change in the next few years. - Neuroscience has pretty figures:
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).
Amen. I am tired of hearing about how much more 'relevant' it is to stick a human tumor in an immuno-compromised mouse's brain, than it is to put a mouse tumor in a normal mouse's brain. Both models are less-than-ideal for obvious reasons, but I am never going to have a goat brain tumor and a thymectomy.Mouse models suck.
Huh. I wonder if our mouse is autistic, he has severely damaged his leg and will constantly gnaw at it, we got the infection under control but he is now bald there and limps.- One behavior of mouse models of autism is overgrooming leading to missing patches of hair. Coincidentally this is a behavior shared among several members of my family.