[HN Gopher] CRISPR Editing in Primates
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CRISPR Editing in Primates
Author : jwcooper
Score : 114 points
Date : 2021-05-20 16:31 UTC (6 hours ago)
(HTM) web link (blogs.sciencemag.org)
(TXT) w3m dump (blogs.sciencemag.org)
| PolandKid wrote:
| Reminds me of a story from Ursula Le Guin's Changing Planes short
| story collection - Porridge on Islac.
| [deleted]
| [deleted]
| LatteLazy wrote:
| So 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.
| entee wrote:
| My 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]
| carbocation wrote:
| For 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
| alextheparrot wrote:
| Lipid 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 wrote:
| What are some good books to learn more about this? Thanks.
| alextheparrot wrote:
| Sadly, 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 (General
| review 1)
|
| [1]: https://www.frontiersin.org/articles/10.3389/fmolb.2020.
| 5879... (General review 2)
|
| [2]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498813/
| (PCSK9 target again, but via siRNA actuator)
|
| [3]: https://genomebiology.biomedcentral.com/articles/10.1186
| /s13... (Example of cell-specific CRISPR integration)
| ChaitanyaSai wrote:
| Thanks 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?)
| victor106 wrote:
| > 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 wrote:
| If 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 wrote:
| I feel this pain, especially since I'm hoping to get my PhD
| over the next 6 years.
| Obi_Juan_Kenobi wrote:
| > 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 wrote:
| This 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
| Turing_Machine wrote:
| Some years back there was a guy who did an online experiment
| living on monkey chow for a period of time, logging his
| results as the experiment progressed.
|
| Jerry Pournelle, the late science fiction author, mentioned
| on his own blog that there was a period of time as a
| psychology PhD student when he, too, lived on monkey chow.
| However, he did it out of poverty, not out of a spirit of
| scientific inquiry.
| mushishi wrote:
| How about the top minds build monetization systems that give
| a percentage of ads/subscriptions stream to science? Build
| patron-esque systems that are dedicated to specific science
| projects and for slow but fundamental research.
|
| How about one could opt-in to be taxed in state so that money
| goes out to science. (Where I live there is a tax for a de-
| facto church if one belongs to that church)
| robotresearcher wrote:
| Science is largely paid for by taxes with budgets
| controlled by elected representatives. Top minds like
| Alexander Hamilton created this revenue stream already.
|
| Vote for science.
|
| Earmarked taxes are exactly how we get funds favoring
| religion. Let your representative represent, but choose
| them wisely.
| mushishi wrote:
| Sure, I'm all for taxes.
|
| As an individual after I've voted, and I still want to
| contribute some of the earnings I've made, how do I go
| about that? Is it the best just to start political
| influencing. Why not directly give money to specific
| areas of science. Making science a little bit transparent
| to general public might give motivation for people spend
| some money that is not distributed similarly as tax
| payers.
|
| Currently people are supporting e.g. musicians through
| patron-like systems, why not scientist. I think there
| could be a risk in that scientist would need to start
| wasting their time managing some kind of public display
| of what they do.
|
| There definitely should be a really solid financing from
| tax only, and it would be horrible if a system was
| created to undermine that so that you would need public
| collection of money for projects. I'm not saying that.
| robotresearcher wrote:
| There are many charities funding research. They tend to
| be medical, but not always.
|
| The Royal Society funds basic research, and is funded by
| donations. It's been running since 1660.
|
| https://royalsociety.org/about-us/funding-finances/
| pvarangot wrote:
| I have some experience with academic policy and stuff like
| that.
|
| While I don't philosophically agree with the sentiment what
| someone making actual policy will tell you is that scientists
| are, in average, already being payed way more than the
| "value" they add to "the economy" in their lifetime. There
| doesn't seem to be a supply crunch for people wanting to
| pursue a career as a biomedical researcher and the field is
| highly competitive, as most people on it can tell you.
|
| To change that, being completely blunt and with no nuance, I
| think three things can help:
|
| - As a society scientists get "moved out of the market". They
| kinda already are "out of the market" if you think that most
| of the money they make comes from strategic government grants
| backed by monetary emission or by discretionary allocation by
| "illuminated" boards that are sitting on a stash of money
| that patents from a very small percentage of previous
| "science" makes.
|
| - We low the barrier for someone to be able to do the
| "science" we need. Like with music production. A lot of
| people will be able to self-finance. This is happening with
| lab equipment but it will likely never happen with research
| trials and human experimentation.
|
| - More money is thrown to whatever "science" we want in
| general. Like what happened with space exploration or AI.
|
| I hope a little bit of the three keep on slowly happening and
| maybe eventually we will reach a breaking point where
| everyone has access to personalized cutting edge
| medicine/diet/exercise plans. I don't find it likely but I
| hope we make progress torwards that in my lifetime.
| Teever wrote:
| > This is happening with lab equipment but it will likely
| never happen with research trials and human
| experimentation.
|
| I bet that we will see some form of this. In some way we
| already do in the form of recreation drug users, body
| modification hobbiests, fetishists, and nutropics users.
| xvilka wrote:
| It'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 wrote:
| well there's also 2 infants in china
| teataster wrote:
| You meant to say: "at least two infants," right?
| cblconfederate wrote:
| that we know of
| billiam wrote:
| There 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.
| SV_BubbleTime wrote:
| I am aware of the potential promises and discoveries.... and I
| still think "stahhp" when it comes to gene editing primates.
| We've made it thus far, let's just not open the box before we
| really know what's in it.
| Turing_Machine wrote:
| Someone with cystic fibrosis (or the parents of a child with
| CF) might well disagree, though.
| teachingassist wrote:
| And they might well _not_ disagree.
|
| I doubt that an average person with CF would want testing
| on primates to be done in their name.
|
| Justifying your ethical position by name-checking a
| disability group is kind of gross, especially given that
| animal testing is not a mechanism which typically results
| in improved treatment.
| bigcorp-slave wrote:
| Hi, not using a throwaway so you know I'm sincere. As
| someone with a serious and currently incurable
| disability, I would support testing on one hundred
| billion non-human primates if it gave me a 5% chance of a
| cure.
|
| I'm sure you'll find people who don't feel that way. But
| I can't overstate enough how horrible it is to go from
| being a functional adult with all the joys and sorrows
| that brings to being a much less functional person in
| pain every day. That is reality for millions of people. I
| don't feel that what GP did was gross. I think it
| reflects reality for people who suffer on a daily basis,
| and whose loved ones do.
| sidlls wrote:
| There are tons of biomedical research groups testing
| things on animal subjects. A lot of discovery and
| progress has been and will continue to be made with that
| system.
|
| And I'd have any number of them tested on if it meant
| progress toward a cure for any number of conditions
| afflicting human beings. I don't think that's "gross."
| SV_BubbleTime wrote:
| Yep. I agree. It's a luxury for me personally, but... I do
| assume there are people with things this could solve that
| also understand the risks and lean on the side of greater
| sacrifice/altruism.
|
| Here is the thing, this is probably moot. The genie is
| probably already out of the bottle.
| elihu wrote:
| I'm not an expert so maybe someone can give a better response,
| but I've understood CRISPR as something that doesn't
| necessarily edit all the targeted cells, just some proportion
| of them. So, maybe if one doesn't want to eliminate the
| production of a compound entirely, one sets the dose low enough
| to to only edit the genes of, say, half the targeted cells.
|
| If I'm interpreting the article correctly, though, it sounds
| like in their trials they think they may have edited nearly all
| the targeted cells.
| carbocation wrote:
| There is at least one example of a healthy adult who is
| compound heterozygous for loss of function in _PCSK9_ [1].
|
| Also note that in the study linked in the main post, the gene
| itself is being base edited in the liver, not globally.
|
| 1 = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1559532/
| ellimilial wrote:
| Quite possible. Nobody wants another hERG fiasco.
| tibbydudeza wrote:
| ether-a-go-go-related ... LOL
| 9dev wrote:
| TIL 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.
| whymauri wrote:
| Did someone try editing out hERG?!
| ellimilial wrote:
| A fair amount of drugs inhibiting it had to be recalled
| after https://pubmed.ncbi.nlm.nih.gov/16554806 and
| subsequent regulators actions.
| whymauri wrote:
| Oh, 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.
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