Of course it's possible to use this sort of therapy to prevent disease, by knocking out single genes associated with the development of disease.
It's just as possible to silence single genes that, when silenced, may elicit substantial positive effects in healthy adults. Part of George Church's list, by no means comprehensive, is:
MSTN -/- Lean muscle growth
SCN9A -/- Insensitivity to pain
ABCC11 -/- Low Odor production
CCR5, FUT2 -/- Virus resistance
PCSK9 -/- Low coronary disease
SLC30A8 -/+ Low T2 Diabetes
There are many others. Knocking out ACTN3, for instance, might remodel skeletal muscle for better endurance performance, and certain athletes don't express the gene.
Sadly, that's not how most phenotypes work. While some diseases/undesirable phenotypes are indeed simple mendelian, and some diseases/undesireable phenotypes can be "fixed" by knocking down a gene, in real life, gene therapy of any kind is actually extremely complex, determined by the interaction of many genes/gene products/regulatory regions/environment, with non-linear combinatory effects.
Church has been selling some fairly naive ideas for some time, and he knows better.
It's clearly how things work on rare occasion, which is self-evidently obvious in MSTN knockout animals, and certain other gene knockout phenotypes.
It's the exception rather than the rule, of course, as many if not most traits -- like, most famously, height and IQ -- are polygenic and mediated by a network of many genes of small effect.
There's still a lot you can do by silencing certain individual genes. I wouldn't dismiss it out of hand.
Even knockout phenotypes of single-trait genes can be awfully complex (if your goal is to engineer a health solution). I don't think than HN comments are a particularly useful place to litigate the faults of genetic thinking, but let me give an example from my own personal experience:
When I was a postdoc at berkeley, my advisor gave me a project to work on. A lab down the road at Stanford working with yeast had done a series of knockouts, precisely eliminating one gene at a time. They reported a number of fatal knockouts in genes that previously had no known function (or a non-necessary function), concluding that the genes presumably had some sort of necessary function for viability (such as housekeeping genes, but not in an obviously necessary way).
Since I'm a DNA nerd I spent time looking at the nature of the genes that were knocked out, and did a bunch of analysis. First I categorized the genes in various ways and didn't see any patterns. But, in the past I'd heard of overlapping genes, and mostly for fun/edification, I taught myself some CS I didn't know and created a data structure and algorithm that allowed me to find all the pairs of 'overlapping' genes (https://www.nature.com/articles/s41576-021-00417-w) in the yeast genome and found that for every single gene they had newly identified as necessary, it overlapped an already known housekeeping gene (overlapping genes were not, in the early 2000s, widely appreciated).
I spoke to my advisor and told him that I reasoned that the authors had made a mistake: in every case where they identified the gene as being necessary, they had accidentally disabled a housekeeping gene that was already known to be necessary for viability, and incorrectly concluded that the gene they knocked out intentionally was the cause of loss of viability. I hope that makes sense- it's basically a "false positive" that had another explanation: they had knocked out two genes when they thought they had knocked out one.
My advisor agreed and I sent my results to the authors, who never responded. Their subsequent paper explicitly mentioned my observations, without crediting me.
Since then, I've come to believe that much of what we believe about genotypes and phenotypes, even in cases where the outcome seems quite straightforward, linear, and single-cause, is instead an error of preconcieved assumptions. It greatly reduced my confidence in geneticists (I'm a biophysicist- highly quantitative, interested in the molecular cause-and-effect) ability to make strong statements.
I don't work in this area any more (it's more lucrative to move data for biologists than it is to be a biologist) but I strongly suspect that I if enabled my OCD bit and spent more than a month analyzing MSTN knockouts, I would find that something which is "self-evidently obvious in MSTN knockouts" is in fact much more complex and subtle than the narrative in the literature.
> Treatment of mice with antisense oligonucleotides (ASOs) targeting the Prnp transcript decreases expression of PrP and extends the survival of mice previously infected with misfolded PrP (6); however, the limited efficacy of ASOs and the requirement for chronic intrathecal dosing highlight the need for a more potent therapy.
"…new epigenetic editor that can silence the expression of prion protein (PrP) in the brains of mice and offers a fresh approach to the treatment of neurodegenerative diseases."
Wonderful news, let's hope it lives up to expectations.
Here's a thread breaking down showing how it they managed to get the viral transporter to self-regulate and "turn itself off" after target gene silencing in the brain: https://x.com/cureffi/status/1806404934658892013
And for further context, this work came out of the Weissman Lab at MIT and a collaboration with a group called CureFFI. In particular, there are two scientists there who have had an utterly incredible story. I don't like it when VCs and such try to attach onto someone else's shine, but seeing their story develop and constantly push forward after getting a start on a little website that I helped to create has been one of the most awesome things in my life. For over 10 years they've been going and going and going. The incredible sci-fi technical achievements here aside, it's also just an amazing human story of tenacity and curiosity. It's hard to talk about them without getting emotional once you read their story.
Alzheimer's, Parkinson's, Huntington's, etc. Will be exciting to see what's next.
Of course it's possible to use this sort of therapy to prevent disease, by knocking out single genes associated with the development of disease.
It's just as possible to silence single genes that, when silenced, may elicit substantial positive effects in healthy adults. Part of George Church's list, by no means comprehensive, is:
MSTN -/- Lean muscle growth
SCN9A -/- Insensitivity to pain
ABCC11 -/- Low Odor production
CCR5, FUT2 -/- Virus resistance
PCSK9 -/- Low coronary disease
SLC30A8 -/+ Low T2 Diabetes
There are many others. Knocking out ACTN3, for instance, might remodel skeletal muscle for better endurance performance, and certain athletes don't express the gene.
Sadly, that's not how most phenotypes work. While some diseases/undesirable phenotypes are indeed simple mendelian, and some diseases/undesireable phenotypes can be "fixed" by knocking down a gene, in real life, gene therapy of any kind is actually extremely complex, determined by the interaction of many genes/gene products/regulatory regions/environment, with non-linear combinatory effects.
Church has been selling some fairly naive ideas for some time, and he knows better.
It's clearly how things work on rare occasion, which is self-evidently obvious in MSTN knockout animals, and certain other gene knockout phenotypes.
It's the exception rather than the rule, of course, as many if not most traits -- like, most famously, height and IQ -- are polygenic and mediated by a network of many genes of small effect.
There's still a lot you can do by silencing certain individual genes. I wouldn't dismiss it out of hand.
Even knockout phenotypes of single-trait genes can be awfully complex (if your goal is to engineer a health solution). I don't think than HN comments are a particularly useful place to litigate the faults of genetic thinking, but let me give an example from my own personal experience:
When I was a postdoc at berkeley, my advisor gave me a project to work on. A lab down the road at Stanford working with yeast had done a series of knockouts, precisely eliminating one gene at a time. They reported a number of fatal knockouts in genes that previously had no known function (or a non-necessary function), concluding that the genes presumably had some sort of necessary function for viability (such as housekeeping genes, but not in an obviously necessary way).
Since I'm a DNA nerd I spent time looking at the nature of the genes that were knocked out, and did a bunch of analysis. First I categorized the genes in various ways and didn't see any patterns. But, in the past I'd heard of overlapping genes, and mostly for fun/edification, I taught myself some CS I didn't know and created a data structure and algorithm that allowed me to find all the pairs of 'overlapping' genes (https://www.nature.com/articles/s41576-021-00417-w) in the yeast genome and found that for every single gene they had newly identified as necessary, it overlapped an already known housekeeping gene (overlapping genes were not, in the early 2000s, widely appreciated).
I spoke to my advisor and told him that I reasoned that the authors had made a mistake: in every case where they identified the gene as being necessary, they had accidentally disabled a housekeeping gene that was already known to be necessary for viability, and incorrectly concluded that the gene they knocked out intentionally was the cause of loss of viability. I hope that makes sense- it's basically a "false positive" that had another explanation: they had knocked out two genes when they thought they had knocked out one.
My advisor agreed and I sent my results to the authors, who never responded. Their subsequent paper explicitly mentioned my observations, without crediting me.
Since then, I've come to believe that much of what we believe about genotypes and phenotypes, even in cases where the outcome seems quite straightforward, linear, and single-cause, is instead an error of preconcieved assumptions. It greatly reduced my confidence in geneticists (I'm a biophysicist- highly quantitative, interested in the molecular cause-and-effect) ability to make strong statements.
I don't work in this area any more (it's more lucrative to move data for biologists than it is to be a biologist) but I strongly suspect that I if enabled my OCD bit and spent more than a month analyzing MSTN knockouts, I would find that something which is "self-evidently obvious in MSTN knockouts" is in fact much more complex and subtle than the narrative in the literature.
>gene therapy of any kind is actually extremely complex
Yet there’s people on YouTube self administering gene therapy to cure lactose intolerance.
Not an endorsement, just to say it’s interesting how easy it’s becoming to do these things.
I was reminded of this comment exchange from last May: https://news.ycombinator.com/item?id=40439379#40440171. TIL that, according to this paper, antisense treatment in the brain has some drawbacks:
> Treatment of mice with antisense oligonucleotides (ASOs) targeting the Prnp transcript decreases expression of PrP and extends the survival of mice previously infected with misfolded PrP (6); however, the limited efficacy of ASOs and the requirement for chronic intrathecal dosing highlight the need for a more potent therapy.
> requirement for chronic intrathecal dosing
Well that's a pretty wicked drawback if I've ever heard one.
Very impressive work. Just in mice so far but this looks very promising for Huntington's in particular.
"…new epigenetic editor that can silence the expression of prion protein (PrP) in the brains of mice and offers a fresh approach to the treatment of neurodegenerative diseases."
Wonderful news, let's hope it lives up to expectations.
Remembers me this book: https://www.goodreads.com/book/show/54120408-klara-and-the-s...
Although the main plot is about AI, the real reason why the protagonist exists is very interesting about epigenetic...
I wonder if this could be used to neutralize HIV genes that have been reverse transcribed in.
Eric and Sonia are incredible human beings hellbent on a mission. Awe inspiring.
Here's a thread breaking down showing how it they managed to get the viral transporter to self-regulate and "turn itself off" after target gene silencing in the brain: https://x.com/cureffi/status/1806404934658892013
And for further context, this work came out of the Weissman Lab at MIT and a collaboration with a group called CureFFI. In particular, there are two scientists there who have had an utterly incredible story. I don't like it when VCs and such try to attach onto someone else's shine, but seeing their story develop and constantly push forward after getting a start on a little website that I helped to create has been one of the most awesome things in my life. For over 10 years they've been going and going and going. The incredible sci-fi technical achievements here aside, it's also just an amazing human story of tenacity and curiosity. It's hard to talk about them without getting emotional once you read their story.
Alzheimer's, Parkinson's, Huntington's, etc. Will be exciting to see what's next.
https://www.newyorker.com/books/page-turner/a-prion-love-sto... , https://www.nytimes.com/2020/07/07/health/rare-diseases.html , https://experiment.com/projects/can-anle138b-delay-the-onset...
> it's also just an amazing human story of tenacity and curiosity. It's hard to talk about them without getting emotional once you read their story.
In their own words:
https://www.cureffi.org/about/
How fleeting are the modifications? How specific are they? Wouldn't it makes more sense to deliver a gene that produces RNAi?
Does anyone have a linky? The usual route is not working, maybe due to it being new.