[HN Gopher] An epigenetic editor to silence genes
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An epigenetic editor to silence genes
Author : Teever
Score : 120 points
Date : 2024-07-02 19:50 UTC (1 days ago)
(HTM) web link (www.science.org)
(TXT) w3m dump (www.science.org)
| ProjectArcturis wrote:
| Very impressive work. Just in mice so far but this looks very
| promising for Huntington's in particular.
| dluan wrote:
| Eric and Sonia are incredible human beings hellbent on a mission.
| Awe inspiring.
| dluan wrote:
| 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...
| knodi123 wrote:
| > 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/
| flobosg wrote:
| 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.
| Zenzero wrote:
| > requirement for chronic intrathecal dosing
|
| Well that's a pretty wicked drawback if I've ever heard one.
| hilbert42 wrote:
| _" ...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.
| teeray wrote:
| I wonder if this could be used to neutralize HIV genes that have
| been reverse transcribed in.
| Kalanos wrote:
| How fleeting are the modifications? How specific are they?
| Wouldn't it makes more sense to deliver a gene that produces
| RNAi?
| A_D_E_P_T wrote:
| 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.
| dekhn wrote:
| 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.
| A_D_E_P_T wrote:
| 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.
| dekhn wrote:
| 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.
| WhitneyLand wrote:
| >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.
| the__alchemist wrote:
| Does anyone have a linky? The usual route is not working, maybe
| due to it being new.
| woliveirajr wrote:
| 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...
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