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Comment by foxyv | Hacker News Reader

This is absolutely awesome. I look forward to finding out if this has an effect on the germ line as well. Imagine, ending genetic illnesses like these for the rest of human history. I look forward to forgetting these diseases even exist, except in the archives of medical history.

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We could eliminate heart disease, which is still the number 1 killer of men, women, in the US, and globally.

https://www.wired.com/story/a-single-infusion-of-a-gene-edit...

That trial was specifically for familial types of hypercholesterolemia, which are strongly genetic. Not clear that it would also work for run-of-the-mill high cholesterol, although it is possible.

Fair point. I subscribe to the idea that LDL causes heart disease:

> Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel https://pubmed.ncbi.nlm.nih.gov/28444290/

The trial inhibited PCSK9, and this study says "other PCSK9 mutations result in unusually low concentrations of plasma LDL cholesterol and a reduced risk of atherosclerotic disease". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ I'm optimistic about this.

There are other things that also cause heart disease.

As far as I know, ApoB is the only "necessary but not sufficient" molecule, and that's mostly in LDL. There's also IDL and VLDL, but AFAIK those are in insufficient quantities to have clinical significance - please LMK if you know otherwise. There's also Lp(a), but PCSK9 inhibitors also work there:

> For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/

I hate to sound like I'm only focused on PCSK9i - there's also ezetimibe/bempedoic acid/statins, but AFAIK only PCSK9 has been shown to be a viable target of CRISPR. Perhaps that's your point, but I wonder what would happen if we flattened ApoB starting at age, say, 25. Perhaps the residual Lp(a) wouldn't be enough to cause any MACE.

It is known that infection plays a role in some cases and increasingly suspected that it is a risk factor generally.

Up to 45% of people with chronic infections develop heart disease 10–30 years after the initial illness, which can lead to heart failure.

https://en.m.wikipedia.org/wiki/Chagas_disease

...gum disease can be caused by 20 to 30 different types of bacteria... and it is increasingly thought that gum disease is probably an independent risk factor for heart disease.

https://www.heart.org/en/news/2021/03/19/how-oral-health-may...

What do you suggest is the mechanism of action behind that? I submit ApoB. Same reason why high blood pressure leads to ASCVD.

Note that risk factor is not causal. I.e. not exercising is a risk factor.

Notably it seems like you can't drive LDL too low https://www.health.harvard.edu/blog/ldl-cholesterol-how-low-...

Infection chewing on the heart is a problem.

I don't know why I'm being asked to explicitly state that.

Infection: "not a good thing."

...I feel like we're on different levels so let's just stop here before you start to condescend.

I'm not condescending. Chagas disease is a class of trypanosomiasis which currently the medical establishment doesn't know how to treat. It's due to a parasite. Parasites living in your heart and feeding on the tissue is not a good thing independent of whether or not it is related to fatty deposits in the vessels.

I'm genuinely baffled that in a discussion of heart disease, actual infection is being handwaved off as irrelevant and only another possible means to cause fatty deposits.

I'm sure our backgrounds are really different. I'm a knowledgeable layperson and a lot of people are dismissive of me because of that.

It doesn't mean your "level" is somehow implicitly above mine anymore than one language is inherently "superior" to another. Language is a tool. Its purpose is communication. If one chooses language that fails to adequately communicate with the target audience, the failure is on the speaker.

Let me add that while I clearly am not as well versed in fatty deposits in the circulatory system as you are, I am leery of any plan to globally suppress any class of molecule.

The brain has the most cholesterol of any organ in the body. If we suppress fats globally to "prevent heart disease," what might this do to the brain?

Bone marrow is fatty. It's a critical part of the immune system where white blood cells are produced. If we suppress fat globally, what does this do to our immune system?

They invented antibiotics not that many decades ago and announced "the end of disease." Fast forward to today and we are wrestling with antibiotic resistant infections and drug shortages.

I'm leery of any claim that "this one neat trick will be the end of this entire class of disease." In this case, I readily know of actual diseases that specific one neat trick wouldn't help at all which are pertinent to the category known as heart disease.

> I'm not condescending.

I encourage you to reflect on your prior statements.

> I'm leery of any claim that "this one neat trick will be the end of this entire class of disease."

Sure, I overspoke. My usage of the word eliminate is strong - there are always edge cases in biology. And I should've been more specific with my language and specified ASCVD instead of the more broad "heart disease". That would, kinda by definition, scope what I'm talking about to fatty deposits. However, I think we're deep in pedantic territory and I hope you forgive me my excess. I didn't mean to enter "one neat trick' territory, though I can see how I came off that way.

> chagas

I'm also a layman and accept there are gaping holes in my knowledge, which is why I asked you a genuine question: "What do you suggest is the mechanism of action behind that?". My interpretation is that high levels of chronic inflammation leads to endothelial damage which leads to the formation of cholesterol plaques as the immune system attempts to fix the damage it caused. I'm going to assume here that "Infection chewing on the heart is a problem." means you think the parasite literally eats holes in blood vessels? I don't know what you think, which is why I asked. If you know the pathogenesis of heart disease with Chagas, I'd love to learn.

> I am leery of any plan to globally suppress any class of molecule.

A fair concern. I would note that healthy children have an LDL of 23.8 mg/dl https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529694/ and they manage to supply their greedy brains. Note too that circulating (blood) cholesterol is not "global" cholesterol:

> The body has four distinct “pools” of cholesterol, in which tissues have regulatory mechanisms to maintain their respective homeostasis. In order of size, these pools of cholesterol consist of: peripheral tissues, red blood cells, liver, and lipoproteins. It turns out that the brain synthesizes its own cholesterol and does not exchange cholesterol with the other aforementioned pools, which means that cholesterol concentrations outside the brain have no direct impact on brain cholesterol. https://peterattiamd.com/does-low-cholesterol-cause-cognitiv...

I watched a special on this and all interviewed scientists were drastically against any germ line edits (as in something that would then be passed to offspring) as we simply don't understand things well enough yet. Some groups will eventually do this in a less regulated nation, but for now we have to be very careful.

"Eventually" already passsed five years ago.

https://en.m.wikipedia.org/wiki/He_Jiankui_affair

I remembered that, but since it was an isolated incident chose to ignore it. I meant at some point China or some other country is going to just give a blanket approval or just not enforce any restrictions and then the game is on.

I imagine this wouldn't be a huge issue with women since they don't produce eggs after birth, but men continue to produce gametes for life. Is there a way to prevent the introduction of the CRISPR edits to spermatocytes? Or do you just have to bank sperm and sterilize as a condition for the treatment?

They’re targeting specialized cells that make blood cells outside of the body. Once they’re reimplemented they don’t move around.

Okay, so they modify outside of the body and then transplant. So that's why it's sickle cell first, because they can do self-transplantation with bone marrow.

Speaking generally, I think you could perform something like this on sperm stem cells. Sperm turn over (the full population dies and is replaced) fairly quickly, but the stem cells last a long time.

It seems more likely they would just, uh, collect a sample of a single sperm cell and treat that, then use it with a treated egg using IVF.

It seems like we should collectively decide on a reasonable pathway to germ line edits for single gene disorders. If we don’t and keep waiting, someone will do it somewhere. And once the taboo is broken things might get weird in a hurry of the global scientific and medical communities aren’t prepared.

> seems like we should collectively decide on a reasonable pathway to germ line edits for single gene disorders

Genuine question: why? Isn't the argument against germ-line editing one for diversity? If so, it seems fine to have some populations who ban it while others experiment with it.

The argument I have heard for CRISPR are if I recall correctly more about avoiding mutations from "accidental matches" and what that would do to patients and possible descendants.

These scientists could not publicly and unambiguously condone this for the fear of being singled out and picked out as "playing god" extremists.So they have to say the platitudes about "being careful" and ethical concerns.

However, when you suffer all your life from a genetic disease such as, say, the sickle cell or diabetes type 1, it is very obvious that it is any delay or hinderance in this direction that is deeply unethical, not the practice. Your germ line gets hundreds of random mutations at every conception, and your gamets get tons more mutations and errors as you age. It's not a dynasty hairloom.

No, this treatment would not - it does not act by "fixing" hemoglobin S (which causes sickle cell disease), but rather increasing production of hemoglobin F (fetal hemoglobin).

This particular treatment can't. They perform the gene editing on cells outside of the body before transplanting them back into the patient.

Editing the germline is a terrible idea. Governments should instead fund IVF with genome sequencing of the embryos so that you can pick an embryo that doesn't have the disease. Of course only for people with genetic diseases.

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