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.
We don’t have the ability to measure health yet. People who are by all metrics healthy fall over dead all the time, or have inflammatory/autoimmune problems that get written off as psychosomatic. There are a lot of things that are considered normal today that will later be recognized as diseases.
Ok I know what you mean, what you mean is that we don't have a formal definition. But I'd like to believe that a perceptive physician does know when people are unhealthy, i.e they observe the person physically, not merely look at numbers. Such physicians are a dying breed though.
I don’t understand your question. How do people make vaccines and drugs?
By the way, I would like to point out that your ilk have killed a great many people. For decades you have cracked people over the head with the idea that cholesterol is a health outcome and that saturated fat is bad for you. It turns out that cholesterol is a heuristic and that it’s been read wrong to boot. And it turns out saturated fat isn’t just not bad for you, it’s an important part of a healthy diet.
Dr. Shawn Baker and Dr. Paul Saladino ate nothing but red meat and saturated animal fat for two years and they had CAC scores of zero. There is testimony that someone’s CAC score went down after cutting out sugar and adding beef tallow.
Can you blame me for resenting the medical establishment?
My question about how one would ever go about developing drugs with "that perspective" is with regard to your statement that "We don’t have the ability to measure health yet." If you don't believe we can identify the difference between health and disease, how would you trust any process that is required for drug development?
Getting to your assertions about cholesterol, there is a chasm between "dietary recommendations for cholesterol" and "genetic and therapeutic modification of lipoproteins."
Re: dietary recommendations, which seems to be what you are referring to, I think that the evidence for or against specific dietary recommendations for many types of nutrient intake is hardly compelling. But it's also not an area of my expertise.
Re: therapeutic reduction of cholesterol, the results over decades are totally unambiguous: reducing LDL-cholesterol via statins and PCSK9 inhibition reduces cardiovascular disease and prolongs life. And those benefits are also conferred to people who have lower cholesterol throughout their life due to genetics.
If a healthy person is a person who is totally free of disease, then we do not have the ability to determine whether or not a person is healthy. That has nothing to do with developing drugs for and treating the subset of diseases that we know about because they present with obvious and intuitive symptoms relatively speaking.
I disagree about LDL. It’s not as simple as LDL. There are different kinds of LDL and some are worse than others as is pointed out in that link, I think. Medications that reduce LDL do other things too and it’s not clear that their effect on LDL is the real vector for their efficacy. And people with elevated LDL sometimes don’t develop the diseases that high LDL supposedly causes. It’s a broken model based on an overly intuitive interpretation of legitimate data.
I read a biochemistry textbook. The same one you guys read. The only time it mentioned ketosis, it was a brief footnote in effect saying “ketosis is a dangerous abnormality and results in diabetic ketoacidosis.” It was literally a sentence or two for the whole metabolic phenomenon of ketosis. A widespread textbook printed in the last 5 years if I recall. That’s when my eyes were opened to the possibility that the doctors have been making oversights. How could you blame a doctor for believing his textbook?
>Re: therapeutic reduction of cholesterol, the results over decades are totally unambiguous: reducing LDL-cholesterol via statins and PCSK9 inhibition reduces cardiovascular disease and prolongs life. And those benefits are also conferred to people who have lower cholesterol throughout their life due to genetics.
But if you look outside of the mainstream literature, it appears that that high LDL is protective. Also statins appear to cause more problems than they solve ( So has Aseem Malhotra been screaming about for nothing?). While I cannot quote 'studies' ( I do believe that you can find some if you searched ) , there are compelling anecdotes ( like that of Dr. Shawn Baker) which to me proves consensus on a topic need not necessarily mean that the view is correct. Ofcourse people quickly remind you that anecdotes are not data...
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.
> one sets the dose low enough to to only edit the genes of, say, half the targeted cells
Using the single-cell sequencing we’ve learned that disease is sometimes driven by a very small sub-population of cells(e.g. cancer treatment resistance). There’s no way of knowing how the organism will respond to a perturbation even in 1% of the cells.
There are people with defective PCSK9 genes that appear entirely healthy except for having very low cholesterol. I mean, that's how they discovered the PCSK9 class of drugs.
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.
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.
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.
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.
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.
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.
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.”
I dispute this - the results of animal research on therapeutic benefit are massively overstated.
Most animal research doesn't have therapeutic benefit as a goal or any prospects of contributing to any therapy. Pretty much none is successful on these terms.
Even so, animal research as a whole is still justified and gets public funds on these terms, without any evidence of results.
Can you name one therapy, confidently, perhaps even without searching, that has clearly come out of animal testing?
[To answer my own question, the only example that I'm immediately aware of is: thalidomide.]
Why, in any other circumstance, would we want to spend a precious resource in unlimited quantity on something that is expensive, unethical, and doesn't work?
There are significant problems with generalizing from from animal models to humans. There are also significant problems with the ways this research is authorized and conducted. This is true even if you discount all animal suffering that research creates.
However, to claim that animal research hasn't had a massive positive impact on the advancement of biological knowledge and healthcare is not based in reality.
Vaccines, cancer treatements, anesthetics, and so on. Could some or many of these have been discovered without the use of animals in research? Perhaps--but hindsight is what it is, and I'd rather do research on animals with known and well-trod methodologies to discover these now in parallel with developing new techniques to make these discoveries without the use of animal models; not eschew the models until we have alternate methods.
Animal testing has found hundreds of vaccines against HIV that work in primates, but none of them have worked in humans.
How is that a useful thing to spend time on? You have a model, and it's proven that your model doesn't work: I would expect you to throw away the model.
You could spend those excellent researchers and science budget on anything else, and expect better results.
(I get that all drugs have been tested on animals out of legislative requirement, but I hope it's clear we are talking about using animal models for de novo drug discovery).
For a business-oriented forum, I find it hard to understand why people see this as valuable.
I don't see how suggesting someone would rather not have a disability is "gross". These kinds of overreactions don't help the situation. Try arguing a point rather than coming from a place of emotion.
> Try arguing a point rather than coming from a place of emotion.
Arguing that someone with a disability should support this because they might benefit, without reason or evidence for that, is an appeal (only) to emotion.
I find it ableist, to use disabled people as an abstract hypothetical grouping in this way, only to support a point that is indefensible any other way.
If you don't want me to have an emotional reaction, don't set up an emotive point.
You know what I find gross and ableist? Using people like me as a tool to argue against the development of treatments that could help us. That is what you’re doing. You are so concerned with the suffering of animals that you are discarding the suffering of humans. You don’t have any evidence the other way either, you are exactly as guilty as the person you are responding to. Except you are arguing against performing research that can help people.
I agree that suffering is a risk that we should balance.
Your point in the other comment was that you would cause suffering to and sacrifice "hundreds of billions" of primates for a small chance to heal yourself.
That's clearly not balanced. I personally don't think that animal testing as it exists today, and given the complete lack of direct results that it has to show us, is balanced either.
Do you really value yourself, as a human, trillions of times higher than a chimpanzee? I don't and won't respect that. You saying that, out loud, only makes me wonder how much you internally value other humans.
> especially given that animal testing is not a mechanism which typically results in improved treatment.
The technique described in the article absolutely could result in not just "improved treatment", but an actual cure. We know what causes CF. We know what causes many other genetic diseases. Right down to the individual bad DNA segment.
And there is absolutely no way those treatments are ever going to be approved without animal testing. Sorry, they just aren't.
That's such a privileged thing to say. You most likely don't have a serious illness or generic issue. You also probably eat meat. Most people have no issues sending billions of animals to painful hellish lives on factory farms and slaughterhouses so that they can enjoy a juicy burger. If there was a small chance of curing a disease that caused you pain and suffering every day, in sure you wouldn't hesitate one second before greenlighting any and all testing on primates.
Why does everything have to be so polarized now? I fear it is because on the internet, people can join and leave an argument as they please.
The choice between 'No animal testing whatsoever' and 'greenlighting any and all testing on primates' is a false choice. The right answer is probably 'as close to no animal testing as is possible'. Learn to seek the middle ground with others, hint: try to see it from their point of view
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.
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.
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?)
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.
The 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
* 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.
"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
> 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
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 :)
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.
At least in Physics a big issue isn't so much the pay (you won't get rich, but you won't starve..) but rather the instability and uncertainty.
Due to the way Academia is structured there simply aren't enough jobs, and the more senior people can get stuck just writing grant applications instead of doing actual science.
I'd massively expand the number of National Labs and research institutes so it isn't such a pyramid scheme - and allow budget for some sort of "scrum master" figure to deal with the non-science bureaucratic stuff.
Expanding the grants budget would also help make it less desperate so scientists can focus on doing science and not begging for funds.
> 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.
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.
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.
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.
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)
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.
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.
So, 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
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!
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].
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.
Oddly 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.
