7 ms·
CRISPR Editing in Primates
- deleted 5y ago[deleted]
- alextheparrot 5y agoLipid nanoparticle delivery vehicle is really simplifying a lot of therapeutics. Looking forward to seeing Moderna and Acuitas continue to build out the platform for more targeted or effective actuator delivery.
- ChaitanyaSai 5y agoWhat are some good books to learn more about this? Thanks.
- alextheparrot 5y agoSadly, I don't have a book to recommend. Most of the targeting today is happening through antibodies, but the majority of LNP delivery at this point is done passively without targeting mechanisms on the LNP (Needle injection point aside). That's actually one advantage of CRISPR over just injecting mRNA - you can target specific cell-lines (Even if you change the genome of many cell types) by using cell-specific promoters for the edits you make instead of relying on surface affinity based targeting of the LNP. Interesting resources: [0]: https://www.nature.com/articles/nrd.2017.243 https://www.nature.com/articles/nrd.2017.243 (General review 1) [1]: https://www.frontiersin.org/articles/10.3389/fmolb.2020.587997/full https://www.frontiersin.org/articles/10.3389/fmolb.2020.5879... (General review 2) [2]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498813/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498813/ (PCSK9 target again, but via siRNA actuator) [3]: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-015-0715-0 https://genomebiology.biomedcentral.com/articles/10.1186/s13... (Example of cell-specific CRISPR integration)
- ChaitanyaSai 5y agoThanks for the pointers! A big fan of birds-eye-view books that let readers then follow individual trees. I guess these take time to put together and some fields (like genomics / genetic engineering, are too fast moving now?)
- mncharity 5y ago> A big fan of birds-eye-view books Not a book, but the News Features in Nature have a similar flavor, eg [1]. And for following up with the motivating article... well, there's sci-hub, for now. [1] "The mysterious microbes that gave rise to complex life" https://www.nature.com/articles/d41586-021-01316-0 https://www.nature.com/articles/d41586-021-01316-0 in https://www.nature.com/nature/volumes/593/issues/7859 https://www.nature.com/nature/volumes/593/issues/7859 .
- Duller-Finite 5y agoThe Code Breaker by Walter Isaacson is a recent biography of Jennifer Doudna, who won the Nobel Prize for her pioneering work on CRISPR, that you might enjoy
- alextheparrot 5y agoI’ve been recommending The Gene to people who are just generally interested in this sorta thing
- deleted 5y ago[deleted]
- xvilka 5y agoIt's hard to judge even as a PoC in a sample of 4 and just one gene. I hope the research will expand into statistically substantial samples and various different genes.
- cblconfederate 5y agowell there's also 2 infants in china
- teataster 5y agoYou meant to say: "at least two infants," right?
- cblconfederate 5y agothat we know of
- billiam 5y agoThere are a lot of unexplored consequences of potentially editing out a gene as important as PCSK9. Some of the compounds it is making are essential to brain and liver development. They'll have to study that for years.
- ellimilial 5y agoQuite possible. Nobody wants another hERG fiasco.
- whymauri 5y agoDid someone try editing out hERG?!
- ellimilial 5y agoA fair amount of drugs inhibiting it had to be recalled after https://pubmed.ncbi.nlm.nih.gov/16554806 https://pubmed.ncbi.nlm.nih.gov/16554806 and subsequent regulators actions.
- whymauri 5y agoOh, OK -- right hERG inhibition liability is a candidate killer. It's just since the topic was gene editing, I thought someone had experimented with editing hERG somehow which had me really confused.
- tibbydudeza 5y agoether-a-go-go-related ... LOL
- 9dev 5y agoTIL gogo dancers are probably named after a legendary rock club named „Whiskey A Go Go“, which inspired the name of a gene that causes the legs of anesthetized flies to shake similar to once-popular dance moves in said club. Fascinating.
- victor106 5y ago> The actual therapy is a long mRNA encoding the sequence of the base editor (with all the appropriate modifications to make it express well – this is very much like making an mRNA vaccine, just with a very different payload. The mRNA vaccines just make an antigen protein, but this one will of course produce a functional enzyme that is itself capable of modifying DNA. That mRNA and the guide mRNA (to tell the newly produced enzyme where to go) are encapsulated in a lipid nanoparticle formulation (again, similar to the vaccines and the existing RNAi therapies). This is mind blowing stuff. I wish our best and brightest put their mind on this rather than working on online ads
- whymauri 5y agoIf we paid scientists even half what engineers building ads at FAANG make, we might get our wish here. I was once jokingly told by a mentor that if I got too hungry as a research assistant that I should eat some of our lab rodents :) Yeah, I'll get a job instead, lol.
- stanford_labrat 5y agoI feel this pain, especially since I'm hoping to get my PhD over the next 6 years.
- Obi_Juan_Kenobi 5y ago> PhD over the next 6 years. Bruh If you shoot for 5 it might take six. If you shoot for 6 it will take 8. I know you can't read too much into such a short comment, but do some serious introspection. You're setting off like every alarm bell for someone that's about to get absolutely hosed by a doc program.
- rflrob 5y agoThis is really program dependent. The NSF actually publishes statistics on all kinds of aspects of degree programs. Life Sciences (which doesn't have the reputation as a super speedy science program) has a median time in PhD program of around 5.5 years. Obviously the distribution is going to be skewed, but some fields have had a push towards really reducing the time to graduation. I'm all for doing serious introspection before (and during!) a PhD, but the comment is way too short to set off many alarm bells for me. https://ncses.nsf.gov/pubs/nsf21308/data-tables#group7 https://ncses.nsf.gov/pubs/nsf21308/data-tables#group7
- entee 5y agoMy biggest worry with this would be the low level of off target edits and the number of recombination events that yielded an unwelcome product. Looks like those were very low, but with an N of 4, hard to know long term. The reason being that when you screw around with DNA you can get cancer. This has been an issue in a variety of cases with gene therapy, though is clearly getting much better. This is really cool though, exciting times!
- deleted 5y ago[deleted]
- carbocation 5y agoFor what it's worth, unlike earlier CRISPR technology which made DSBs at desired locations, base editing does not make double strand breaks. This is described pretty well, I think, in the journal manuscript[1]. 1 = https://www.nature.com/articles/s41586-021-03534-y https://www.nature.com/articles/s41586-021-03534-y
- PolandKid 5y agoReminds me of a story from Ursula Le Guin's Changing Planes short story collection - Porridge on Islac.
- LatteLazy 5y agoSo the actual tech here is: * mRNA and lipid nano particles to get the mRNA into cells * 2 pieces of mRNA. One codes for the change to break the gene for the protein being targeted and another to create a enzyme to edit the first piece into the genome * both bits of mRNA need to be in the cell, then the enzyme and gene are created and the enzyme edits in the gene So any cell where this works correctly (and its descendents) no longer produces the protein. It appears that about 60% of cells get hit successfully (based on a 60% drop on the protein level). They only targeted liver cells. That's good because the liver tends to soak up foreign materials from blood. But edits were found at low levels in other organs (spleen etc). That shouldn't make much difference as the protein in question is only produced in the liver. But beware I guess as a multi-use protein could be altered in multiple organs. Also, it looks like the edit was very accurate and didn't break other genes at anything like the rate it broke the target. This is pretty incredible stuff. The biochemical equivalent of keyhole surgery.
- BurningFrog 5y agoSo, if I understand the article, the possible medical effect of this specific thing is to change LDL cholesterol levels. Doesn't seem like that would solve any huge health problem, but the proof of concept that you can edit DNA in the liver fairly freely should be enormously fruitful
- nixarian 5y agoAh so that could explain how the West has survived so long, when we have all the markers of a society that should already be dead.
- hujni 5y agoOddly worded intro given human trials are "primate" trials. I'd be interested to see if there are different rules for using CRISPR on any person who could reproduce, vs those who can't.
- calkuta 5y agoCasual announcement of animal experimentation results. I wonder what cruelties are concealed within? Long-term imprisonment? Vivisection?
- equitablequal 5y ago"Tissue studies showed that the base editing took place almost entirely in the liver.. Modified sequences could be detected in the spleen and adrenal glands, and hardly anywhere else. Similarly, liver samples showed very low levels of off-target editing in their DNA sequences.." Yikes there is a lot of important information being glossed over here