Thread by @AutSciPerson

[Trigger Warning for eugenics, pathologization, treatment, cancer comparison]

I'm going to post quotes from that lecture Daniel Geschwin did that was posted on JULY 2021.
#Spectrum10K

The link is here -

Let's start at the beginning.

1/[25+]

“My focus regarding autism is translating genetic findings in autism into therapy. And today I’m going to give you a summary of genetic findings, where I think this is going” – Dan Geschwind

What kind of "therapy"? Likely treatment for autism, based on the rest of the talk.
2/

"At a level of a disorder like autism and other neuropsychiatric disorders, Having a toe-hold that’s genetic and more precise can also understand what we call disease pathophysiology, that is how disease actually occurs, what is the biological basis of disease."
3/

"Of special interest to autism, we have a California center for Rare Disorders in which we identify rare genetic disorders, so that helps diagnosis as well as clinical care and new innovative medicines."
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"Disease risks are unique and different. Identify genetic risk in populations..The hope is we identify new drug targets, in cancer this has been spectacular, as well as in autism. Prevention, diagnosis and prognosis, and optimizing treatment." - Daniel Geschwind
5/

Because of the invention of new sequencing technology, we’ve had a drop in the cost of genetic information because of this new technology that’s faster..and this creates big data. We have both huge cohorts of patients and big data on them, as well as all kinds of DNA,"
6/

"& we can combine..& operate on it with computer science. The result is millions of genomes sequenced & the power to analyze them. We’re at the beginning of..an explosion of genetic discoveries of across populations and a more accurate understanding of human disease."
7/

"One of the points I want to make – There’s no kind of gene that’s an “autism gene” per se. These genes disrupt brain development in a way that severely increases risk for autism as well as allied neurodevelopmental disorders, such as intellectual disability, seizures, etc."
8/

"So we have all this technology moving ahead & that’s been really really amazing to identify genes causing autism. & what’s interesting is that these genes identified to date are mostly rare mutations, but together they comprise a substantial portion of autism."
9/

"There are rare, causal major effect mutations. If you have one of these, it’s likely to be the cause of the neurodevelopmental disorder you have. There’s a whole other side of genetic risk, that is common genetic variation & it’s things we all share not just rare mutation"
10/

"& that can also increase autism risk. Again the way that it works is not one gene at a time. That’s additive, you need a lot of those small risk factors together."

11/

"But through the combination of association studies and whole exome and whole genome sequencing, we’re basically able to survey all types of genetic risk together now in a very cost effective way." - Dan Geschwind
12/

"One of the things that we knew, but we’ve kind of now learned even more that’s very clear is that there’s very many forms of genetic variation and modes of inheritance of autism. I mentioned rare and common."

Mentions de novo (non-hereditary) mutations & recessive genes.
13/

"There’s autosomal dominant where it’s actually passed down. That’s extremely rare, but does occur. And then there’s the common additive risk..for common variation because each effect is very very small, you need a lot of those different copies mixed together."
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"what we’ve learned is that genetic testing can currently identify ~20% of mutations contributing to autism. So we do clinical microarray, Fragile X syndrome, & exome sequencing, & that is clinically indicated. Insurance companies should pay for it but they don’t always."
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"If we compare ourselves to 2008 and then fast forward to 2016, 2020, we had a handful of genes, little understanding of mechanisms. Major pharmaceutical companies were withdrawing from the central nervous system disorders and had little interest in autism."
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"By 2016, more than 200 candidate genes, much clearer models. Because once we identify the cause that allows you to begin to understand how to treat it, and major drug development efforts in autism are now ongoing" - Daniel Geschwind
17/

Compares to gastric ulcers:
"We have a toe-hold now that we just did not have before. One example is gastric ulcers, we used to treat them by telling people to relax and don’t eat spicy food. Well that might help the symptoms but the ulcers never went away"
18/

"It was found in the 90s it was due to bacteria, it was an infectious disease at some level. Once we knew that we could actually treat the bacteria. So knowing the cause totally changed our notion of what the disease was, its mechanism, and then we were able to treat it."
19/

"Another piece of this, even though we’ve made extraordinary progress, most of this has been in European populations. So we’ve discovered many genes, maybe about 200 now. We predict there could be upwards of 500-1000 genes, they’re highly additive effects in many people"
20/

"but even the major genes don’t account for more than 1% of cases. So 1/5th of autism that’s caused by these kinds of mutations, these major genes, are basically lead to a collection of rare individual disorders."
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"And there’s something called strong pleiotropy which means that these genes don’t just cause autism, they contribute to epilepsy or intellectual disability, even schizophrenia in some cases." - Daniel Geschwind
22/

On race and ethnicity:
"But racial and ethnic diversity are critical to improve the accuracy of genomic testing, we’re beginning to understand that more and more. And so, one of the projects we started about 8 or 9 years ago was the Autism Genetics & Human Diversity Project,"
23/

"which is run out of UCLA but is a network of sites – WashU, John Hopkins, Emory, Einstein University. We’re actually recruiting families that are African American who have at least one child with autism, and this is ground-breaking work and very important"
24/

"because to truly understand autism we have to understand it in all populations, and there’s really a potential for health disparities as well as genetic misdiagnosis if we don’t do this." - Daniel Geschwind

[more quotes to come, have to send these tweets first]
25/

"But we expect, and we’ve started to, identify the mutations that cause autism in African Americans, Europeans, there are studies going on in Asian, that’s been very successful and they’re leading to dozens if not hundreds of genes."

This is terrifying.
26/

"The challenge is that advances have identified many genes involved in susceptibility for autism, these genes provide targets for mechanistic understanding and therapeutic development, similar to the ulcer idea."

27/

"However these findings highlight extreme genetic heterogeneity even in rare disorders. Will we have to develop a specific treatment for each disorder, or will there be convergence in specific biological pathways, developmental stages or brain circuitry"
28/

"that allows us to do, you know not have to develop thousands of different treatments."

I skipped treatment potentials section – he talks about biological pathways/molecular pathways/circuits/etc.

This entire talk is only about autism btw. Not co-occurring conditions.
29/

"That’s been a lot of focus now, where and when is autism, you know, is a lot of the risk? We’ve asked this question started in 2013 and now we have much more data, it’s almost 8 years later. This remains very very solid." - Daniel Geschwind
30/

"Where and when are the genes that cause risk for autism are expressed? Mostly, at the highest levels, during brain development, during the time when neurons are born, so early development of the cerebral cortex. Neurons in L2 through 4."
31/

"These layers 2 through 4 on the top of the cortex are involved in connecting different regions to each other, including long-range connectivity. This connects in a way, what is shown in MRI research, which is long-range connectivity deficits in autism."

"deficits"
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"There also have been amazing advances that are helping us move this forward rapidly. We can take a patient’s skin cell or blood cell and now we can make brain tissue from a patient, brain-in-a-dish kind of models, and these are called induced pluripotent stem cells."
33/

"We took 22q11 deletion syndrome which is the major human genetics syndrome and it increases risk of schizophrenia and autism. We grew 43 lines..we were able to show that there was a calcium problem and identify a drug that would rescue it and show that we could rescue it"
34/

"and now there needs to be studies in mice and other animals, and perhaps we could move this toward the clinic. How about other mutations, are we going to be as lucky? I don’t know..1 is this connectivity..deep brain stimulation & other things to alter activity or enhance."
35/

"There is a change in the excitatory and inhibitory balance and different mutations cause different changes. And perhaps again we can physiologically intervene there are perhaps use drugs. We can modulate neuronal activity with a lot of drugs…Genes don’t act alone"
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"1 of the questions is can we target the network? I think yes. We can identify drugs that are predicted to reverse the pattern & test the drug & see if it has the induce physiological change. I’m very optimistic. I think it’s not going to be easy..this is uncharted territory"
37/

TW cancer comparison
"But we are beginning to move from an area where we were like ulcers in the 50s, and cancer in the 50s, to now being able to identify genes that cause a disease and target those mutations. So in conclusion, autism risk has a large genetic component"
38/

"but its causes, its etiology are multi-factorial and heterogeneous. I like to think of autism as The Autisms. Genetic studies have identified many dozens of risk genes, and we can capitalize on these genetic findings using convergent evidence from students in human brain"
39/

"and model systems to begin to elucidate the neural systems basis of autism. Autism risk genes converge to impact early fetal brain development and the development of the cerebral cortex. And what they do likely in many cases is disrupt long-range connectivity."
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"Genetic findings provide a starting point to create models in vitro, which is in a dish, or in vivo, in a mouse for example, to identify potential convergent molecular pathways for development of targeted therapies." - Daniel Geschwind

#Spectrum10K
#StopSpectrum10K
41/

"So thank you...it really has taken a village, funding from Hartwell, work with the New York Genome Center, of course funding from The Simons Foundation, Autism Research Initiative, and AGRE – Originally a program of Cure Autism Now and now is a program of Autism Speaks."
42/

"A lot of work connecting gene to function involves this large project called PsychENCODE and BRAINSPAN, and again, this speaks to the necessity for collaborative multidisciplinary research and consortium to really move this ahead." - Daniel Geschwind

[end of video]
43/43

If you're wondering why I don't have much commentary,

it's because I'm not sure I should have to say anything more after quoting most of that talk?

It's quite obvious that Geschwind is looking for gene therapy treatments specifically for autism. #BoycottSpectrum10K #Spectrum10K

This is a helpful, quick summary of his intentions:

https://twitter.com/AutSciPerson/status/1435288872867483654?s=20