There is little chance CRISPR will ever be widely used to directly treat disease | Hacker News Reader

There is little chance CRISPR will ever be widely used to directly treat disease

josiahzayner.com

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CRISPR is currently being used to treat human subjects in these clinical trials:

* Transthyretin Amyloidosis: https://news.yahoo.com/intellia-therapeutics-doses-first-pat...

* Lymphoma: https://www.healio.com/news/hematology-oncology/20201023/cri...

* Leber Congenital Amaurosis: https://www.retina-international.org/lca-10-clinical-trial-f...

* Thalassemia & Sickle Cell: https://geneticliteracyproject.org/2020/06/18/crispr-provide...

* Antibiotic Resistant UTIs: https://www.medpace.com/the-first-controlled-clinical-trial-...

Trials take a long time but some early results are pretty amazing. For example for the Thalassemia & Sickle Cell trial we actually have patients that have been treated with great results https://crisprtx.gcs-web.com/news-releases/news-release-deta...

Physicians running the trial claim that these diseases are basically cured in some patients: “I am encouraged by the preliminary results, which demonstrate, in essence, a functional cure for patients with beta thalassemia and sickle cell disease.”

This is just the beginning. The article is clickbait, or worse, totally misinformed.

> This is just the beginning.

A vaccines to eradicate smallpox was discovered in 1796. Since then 1 (one) eradicating vaccine has been produced.

I'd assume, in agreement with the headline, that the value of CRISPR has already been identified. That's how biological breakthroughs historically are.

Before I get to comments on the meta information of this article - I'll just point out that the article is complete hyperbole, CRISPR is being used in the clinic, thats not the only metric by which to declare "crispr is dead" anyway, and that the article makes some fundamental errors in the use cases for CRISPR (the 1% number cited used to be accurate for one subtype of crispr editing, has been superceded, and is not the type of edit that has its main clinical use today anyway). Theres a fundamental misunderstanding of the value of CRISPR that would take another article to correct.

This is one of those posts thats unfortunately inseparable from who its coming from. For those not aware, Josiah Zayner is, to put it mildly, a controversial figure. He's best known for injecting himself with CRISPR. I find it interesting that he now claims he knew about CRISPR being hype from the beginning considering how much money he made off if it in the meantime. There's this idea that the word "biohacker" describes people who are more style than substance, which is unfair, but also not unwarranted given the examples the public often sees.

I use CRISPR regularly to edit stem cells. While there is a lot of hype around it, this blog post is unfairly harsh.

In particular:

>In 2006, RNAi gene silencing was given the Nobel Prize. MIT called it the breakthrough of the decade. I remember everyone being so excited about it! It was the hot topic at conferences and even my graduate school interviews. While RNAi was and always has been a great benefit to researchers its actual application has been extremely limited. It’s taken 13 years from the RNAi Nobel Prize to bring something to the clinic and even then the two drugs have been a bit underwhelming. According to Google Scholar, papers even mentioning RNAi have been on the decline for the past 6 years. The drug approved in the past few years haven't even slowed the decline.

The reason RNAi has fallen out of favor, at least for research purposes, is that CRISPR knockouts are much better.

Holy clickbait, here's the meat:

> Despite claims by scientists and pharma companies there is little chance CRISPR will ever be widely used in the clinic to directly treat disease. That is because it suffers from all the same faults as its predecessors and maybe even more so. Gene editing has low efficiency in adult animals(yes humans are animals) no matter the technique used. For instance, if you have a disease that affects the brain you can probably only modify <1% of cells even using the best delivery techniques available. Really, the only way to get rid of genetically inherited diseases using gene editing is by modifying embryos.

> Misleading as it has been CRISPR can’t actually make specific changes to a gene easily in an adult animal. That is because it requires what is called a donor template, basically just a DNA template that cells can use to create the genome modifications. There is no efficient way to use donor templates in an adult animal so all genome edits would need to be gene knock-outs only i.e. you can only use CRISPR to destroy bad genes not modify them to make them good genes. As you can imagine this is very limited in scope when it comes to diseases that can and should be reasonably targeted using genome editing.

By the way, here is a nice read on the history of gene therapy and its dangers:

https://www.sciencehistory.org/distillations/the-death-of-je...

It also mentions CRISPR:

> Biochemist Jennifer Doudna, who later discovered the CRISPR-Cas9 gene-editing mechanism, remembers feeling the shock waves as a young researcher, even though her work had nothing to do with gene therapy or any kind of medical research.

> There is no efficient way to use donor templates in an adult animal so all genome edits would need to be gene knock-outs only i.e. you can only use CRISPR to destroy bad genes

"CRISPR can only knock-out bad genes" would mean a 100% efficacious cure for all prion diseases, because no prion disease can affect PRNP-negative cells.

Thanks—I've replaced the baity title with the sentence you quoted.

I'd add a question mark (standard moderation tactic when a title is divisive) but it's maxed out at 80 chars already.

I see no mention of what I thought was the primary obstacle to using CRISPR to modify whole organisms: pre-existing immunity to the CRISPR machinery.

Identification of preexisting adaptive immunity to Cas9 proteins in humans

https://www.nature.com/articles/s41591-018-0326-x

Immunity to Cas9 as an Obstacle to Persistent Genome Editing

https://www.cell.com/molecular-therapy-family/molecular-ther...

Evasion of Pre-Existing Immunity to Cas9: a Prerequisite for Successful Genome Editing In Vivo?

https://link.springer.com/article/10.1007/s40472-019-00237-2

I guess if you are looking at this solely from the perspective of using it for gene editing and "curing" disease, I would agree that practical applications might be over-hyped.

But it is still a great tool for research. Many model organisms are now opened to transgenesis due to crispr compared to traditional methods. There was a new paper that came out on cas3 recently that showed a cool application in studying minimal genomes (https://www.nature.com/articles/s41592-020-00980-w). And there are also potential in non-in-vivo usage of crispr for general sequence manipulation.

Just because it might not be immediately useful for one over-hyped application, doesn't mean it is dead for all other applications.

There are almost certainly homozygous recessive genetic diseases that can be treated if a subset of cells are able to replace the deficient enzyme.

Biopsy some cells, treat with CRISPR, return the cells.

I'm pretty on the record about CRISPR being overhyped, but to say nothing will ever be cured by CRISPR is too far.

This article is true in the kind of way if you limit crispr to crispr as it is now, and puts on blinders on imagination.

It's very similar to someone saying: The Penicillin Antibiotic will never be used widely to directly treat disease, while not knowing that in the times after its discovery, we would figure out how to mass produce this antibiotic, and then come up with whole groups of penicillin-like and non-like and synthetic antibiotics that today, are critical to the survival of the human race.

Just wait a few decades and this article would seem quaint.

5 hours ago I read an article posted here on HN regarding new innovations using this tech.

https://news.ycombinator.com/item?id=25094297

I am aware the article did briefly touch on this subject but still worth a mention here, considering the subject.

There is a high degree of truth in what was said - especially where site specific +content specific edis are needed to tissue associated cells. I think it has merit for areas where stem cells can be extracted and edited and then multiplied and the ones with site specific +content identified and the change then confirmed. These cells can then be multiplied and used to replace defective cells - as is done with certain blood cancers where the old stem cells can be killed to allow the multiplied cells to locate in the bone marrow and replace the defective cells. This has been done pre-CRISPR, by other methods - CRISPR will be of value here. In addition, it will be useable in somatic gene modification after all it's details are worked out. Work goes in this area, but is a few years from prime time application.

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This is horribly wrong. Josiah... what are you doing?!

So one thing I've been thinking about. Editing DNA is kind finicky, with off-target mutations and stuff.

But editing files, that is very easy.

So would you get higher quality results sequencing a genome, editing it on a computer, and then "printing" it back out to a DNA molecule?

How far along has DNA synthesis come? And when you have your DNA, how easy is it to insert into cells?

> editing it on a computer, and then "printing" it back out to a DNA molecule

That's kind of what Novavax claims, search for the interview with David Rubinstein on WEF. NVAX wants to print short fragments of virus's proteins, so the resulting vaccines supposed to be safer than those made by working with live viruses.

I guess this article is specifically hating on the Crispr method of physically cutting and joining DNA sequences and not the myriad of software tools built around this technology?

My knowledge of Crispr is very limited but it was my understanding that by lowering the cost and time needed to preform gene editing it opened up or democratized the ability to experiment to the masses rather than just the corporate giants, who may bury innovations in order to ensure their investment in drug and health research remains profitable.

I also hoped we might see some cool new flower colors and patterns but maybe that is totally different tech using gene guns.

The argument that everything has been done before is kind of like the "reinventing the wheel" argument, yet every year there is new wheel technology.

I am genuinely curious why anybody would think Crispr has any potential in mass-usage. We as a society already determined the highly-less invasive tactics of mass-Eugenics to be highly unethical, why would a clinical/basal attempt at the same idea resolve differently?

I’m not sure what you’re picturing it’s used for. It’s not to create genetic super heroes, it’s to cure genetic diseases like sickle cell.

Now. There is nothing stopping a rogue country or person from using it to develop super soldiers. Or better bio weapons.

Nothing except biology, chemistry, and physics.

I don’t think that we can produce a Homelander. We could have people that start producing designer babies. With enough time and low regard for collateral damage, we could have people designed to be highly intelligent. We could have children edited to be male or female. We could have children edited to not manifest African phenotypes regardless of parentage. The sky is the limit.

You don’t need CRISPR for sex selection—-it can already be done as part of the preimplantation screening for IVF.

For the other things, the best editing technique in the world is useless without a known and well-defined target. Intelligence is certainly partly heritable, but it’s not like there’s a single switch that needs to be toggled: genome-wide association studies find hundreds or thousands of linked genes—-and many of them likely have multiple functions. I would bet over-expressing any single one of them leads to many, many more problems than it solves.

Very possible in the early stages. Given time we can probably improve. The only way to know is to experiment.

Super soldiers? Were that the issue, we could take LeBron James, Brian Shaw, or any number of intelligent athletes with various advantages and ask for sperm samples. You could have a couple thousand kids to mold from birth.

It turns out, as a society we haven't done that already, and neither has any other society. Conceptually, it's interesting to think an adult could have their genetics changed, but we have cheaper ways and we haven't even exploited those.

Even if it could be used to create genetic super heroes, there's nothing inherently compulsory about it, in contrast to eugenics.

what if everyone uses it (or other genetic treatments) for augmentation or design? there is a critical mass when compulsory loses its meaning, I think. you don't have to eliminate cash by law for example if no business will take it.

I think there is an essential difference between "you have to do X because it is mandated" and "you practically have to do X in order to keep up". For one, the latter scenario is essentially more democratic than the former, it first requires some critical mass of people voluntarily (in the strongest sense of the word) deciding that they are better off with X, whereas the former may only require a decision from a relatively small number of authorities. This puts strong restrictions on what X could possibly be: for example, you would never have people sterilizing themselves because some critical mass of other people are sterilizing themselves. I will also point out that your argument applies to technological progress in general and is not specific to gene editing.

EDIT: I may have misunderstood you, I interpreted your comment to be about the hypothetical scenario where most people have genetically modified themselves into being "super heroes" and now the people who haven't can't keep up with the rest of society, so it becomes a practical necessity without being legally required. On second reading though I'm not sure if that's what you meant.

A "non-binding eugenics guideline" has been considered highly unethical regardless, so no a non-compulsory solution here fails as well.

Could you please clarify what you are referring to by "non-binding eugenics guideline" and whom you are quoting? Also, could you explain directly why gene editing is unethical without making a vague analogy to eugenics? If the analogy is sound then you should be able to.

Eugenics literally means "well-bred" so any attempts to re-encode ourselves has a direct involvement of Eugenics, so I am not performing analogy here but invoking the principle of a fortiori. Particularly I am not claiming ethics of gene-editing or Eugenics in general, but that the public has no appetite for this as seen with the strong ethical claims against Eugenics.

By a "non-binding eugenics guideline" I mean something akin to "ex-convicts should not produce" or something, I mean there is absolutely zero state or national guideline that I know of that invokes arguments of eugenics, if you know of one then I am mistaken.

Ok, I think you are just playing word games here, using one very broad interpretation of the word eugenics when you say that gene editing is eugenics, and then a narrower interpretation of the word when you say that there are strong ethical claims against it. Things like forced sterilization are obviously unethical but the reasons have absolutely nothing to do with gene editing. Maybe we could make this more concrete if you gave some specific examples of the ethical claims against eugenics that you are referring to, which you think also apply to gene editing. Also, if you are talking about public appetite, I think it's worth observing that this is the first time I've heard someone compare gene editing to eugenics (I'm sure it's been done before, but it certainly doesn't seem common), and your comment is at the very bottom of the page.

society has no problem with mass-eugenics? see: abortion. or transgenderism. when you grow up in a digital world where everything can be manipulated effortlessly bringing that human agency and engineering into the real world is rather predictable. add the substantial profit motive in there and there is no end to what we might see.

How are abortion or "transgenderism" examples of "mass-eugenics"?

fetuses with down's syndrome are routinely aborted.

And if not for our medical system people with Down syndrome would die to natural selection.

> And if not for our medical system people with Down syndrome would die to natural selection.

I guess I don't understand your comment; what does natural selection have to do with it?

I'm making no statements here except that the abortion of Down-positive children is in fact eugenics. Parent's comment was asking specifically how abortion is "mass eugenics." Maybe saying abortion in toto is "mass eugenics" is overly broad, but certainly it's used for eugenic purposes--Down Syndrome being one such case.

Having an abortion after a prenatal diagnosis isn't the same as eugenics. Obviously, eugenicist or ableist beliefs could motivate an abortion after a prenatal diagnosis, but choosing to have an abortion is primarily a decision about you and your family.

I'm not sure what you're referring to with the transgender reference—any medical interventions trans people have are initiated by the trans person, making it completely unlike eugenics.

Edit: I should probably add that eugenics was widely popular less than a century ago in the U.S. and hasn't gone away completely. I think these examples are poor, however.

For me the motivation is rather important. A women terminating a pregnancy that's an obvious developmental train wreck is different than a political movement with some esthetic it wants to violently force onto society.

I have friends who are not having children despite wanting them because of a genetic defect. That is eugenics, and most would consider it the ethical choice for them.

Perhaps, but as time progresses such methods meet more resistance/grey areas. For instance there are gene sequences that have strong correlation with intelligence, and taking the same schema to avoid having a (nearly assured) kid of low intelligence would be more controversial obviously, or well similar cases 100 years ago of rapists and scum of the earth looking to have kids yes? Look not debating eugenics here, just pointing to any mass involvement of Crispr on child-rearing will meet to the same fate I am sure.

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