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CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV an

CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV and 7 for Lentivirus. Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR. I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real future. It just didn’t get the same news cycle, for whatever reason.

anovikov 4mo ago
Bingo! CRISPR has an advantage of being relatively easy to describe to a layman, giving it a PR advantage.
- fragmede 4mo ago
  So is the "idea" of microchips in vaccines. Should we just give up and let everything else have the PR advantage
mondomondo 4mo ago
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fastball 4mo ago
Viral vector delivery is indeed harder to sell with PopSci, what with movies like "I am Legend".
- jvanderbot 4mo ago
  Great first half of a movie, by the way. Up there with Sunshine for "Sit down for a great hour-long ambiance". I usually end Legend after the mannequin trap, and end Sunshine after the transit of mercury.
spligak 4mo ago
You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound. Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.
- GaggiX 4mo ago
  I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?
  - spligak 4mo ago
    There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other. The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet. The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse. As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
    - im3w1l 4mo ago
      Naively, I would deal with this by deciding how many cells I want to kill each day and then figure out a dosing schedule that achieves that. Or maybe it's better to do one dose every few days. But yeah either way.
roncesvalles 4mo ago
CRIPSR was a game-changer for genetics research. A lot of gene knockout studies use CRISPR. However, it was always weirdly overhyped for clinical use from the beginning and this was obvious to anyone with a genetics background. The public in general doesn't have a good understanding of basic genetics and I blame high school science curriculums for not covering it well enough. Too much time is wasted on Mendelian genetics without covering the Central Dogma. You basically cannot "edit" your somatic DNA in a meaningful wholesale way since every single cell in your body has a copy of the DNA, and it's a foolish endeavor. What you can conceivably edit to good effect is your germline DNA, stem cell DNA, or modify mRNA expression (e.g. retinoids; yes putting retinol/adapalene cream on your face is "gene therapy"), or introduce foreign mRNA for your translation machinery to co-opt (e.g. mRNA vaccines).
- Bjartr 4mo ago
  Edit every cell? No. Edit enough cells to impact health outcomes for a meaningful period of time? [Yes](https://www.youtube.com/watch?v=J3FcbFqSoQY https://www.youtube.com/watch?v=J3FcbFqSoQY)
  - shevy-java 4mo ago
    This approach can work for some genetic diseases such as blindness based on some cells in the retina or partial blindness. For others this is not really a cure. If you want to cure people with progeria, does curing 20% of the cells really help? Perhaps 100% is not necessary, but it would seem strange to cure only some cells but not others. You'd have a mosaic of cells where some would work and others don't. Cells interact; timing also plays a role in development. I don't really see that aiming for anything but a very high number of cells cured, can work.
- projektfu 4mo ago
  I disagree that it's "gene therapy" to affect the natural regulation of mRNA production. If that were true then the term "gene therapy" loses its meaning, as just about everything changes the expression of mRNA. You can probably do so somewhere just by thinking really hard about it. Expressing mRNA that doesn't exist in the genome, that would be gene therapy. Or just a virus.
ramraj07 4mo ago
Devils advocate, I also vehemently shat on RNAi therapeutics a decade back. We do have RNAi therapies in market now though. I do think Crispr will find its place similarly.
jagged-chisel 4mo ago
“Virus” - that’s why.
perlgeek 4mo ago
CRISPR is foremost a research tool. Calling it "extremely overhyped" without restricting it medical treatment seems disingenuous. The CRISPR-Cas9 gene-editing tool was developed in 2012, so I don't find it surprising that merely 14 years later, there's only one approved treatment. From discovery to approval, drug development often takes 10-15 years, and often much longer for novel techniques. So I'd say it too early to call it overhyped for treatments. Finally, I think we'll see a lot of treatments that don't use CRISPR-Cas9, but related gene editing techniques, but it'll take another 10 to 20 years. Take a look at https://en.wikipedia.org/wiki/MRNA_vaccine#History https://en.wikipedia.org/wiki/MRNA_vaccine#History for how long another novel technique has been in development before it became really widespread with the mrna-based covid-19 vaccines.
- shevy-java 4mo ago
  Why does it take 20 years? Except, of course, that it does not work nowhere near as well as it is being promoted - aka hyped. mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different.
  - perlgeek 4mo ago
    Let's see... first of all, 14 years ago was the discovery of the base mechanism, not of specific treatments. So specific treatments need to be developed, delivery systems need to be developed, side effects reduced. Then you need safety tests and efficacy tests. > mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different. And yet it took more than 30 years after the first mRNA experiments to develop a successful vaccine. Why it should be so much faster for CRISPR & Co?
  - ufmace 4mo ago
    One of the reasons is, you don't get really good data on how something works until you start running clinical trials for it. It's all very time-consuming - having to plan how the trial is going to work, getting approval for it, finding subjects who meet the criteria (here, a specific type of cancer at a specific stage probably) and sites near them willing to work with you, manufacturing and shipping the treatments, and only then can you start gathering data. If it didn't work, you gotta start over, And it all costs a boatload of money too.
JumpCrisscross 4mo ago
Do mammals have a CRISPR analog?
- spligak 4mo ago
  Background on this question: CRISPR-Cas is a naturally occurring process in bacteria that is used to adapt to viral attacks. We've coopted the system for use in mammals. As far as I know a few labs in this space are operating under the basic question, "why haven't viruses killed everything by now?" So this category of research is more or less the answer. > Do mammals have a CRISPR analog? Not exactly. There are things like https://en.wikipedia.org/wiki/Ribonuclease_L https://en.wikipedia.org/wiki/Ribonuclease_L that nuke cells and are stimulated by interferons. This might be why interferon injections are common chronic therapeutics for diseases in this space. The closest thing we have is probably whatever adaptability B or T cells can muster on their own? I'm sure someone lurking in the comments has a better answer.
tty456 4mo ago
You're confusing the beurocratic FDA stamp of approval with safety and effectiveness. Those are not the same thing.
WhitneyLand 4mo ago
I would guess you did not first write “CRISPR is an overhyped approach”, then after careful reflection decide, I don’t think that quite captures the intensity, better go with “extremely overhyped”. The comparison is kind of a category error. One is a DNA editing technique and the others are deliver platforms. I recall the hype mostly being how revolutionary it could be, not comparing it on a timeline to specific technologies that are at different levels of the stack.
- make3 4mo ago
  it's revolutionary in genetic research, allows us to observe cells with specific gene knockouts, over activations, etc. it's just very hard to deliver to a whole system
tstactplsignore 4mo ago
This comment doesn't understand why CRISPR is such a big deal in science. While Cas-as-a-therapeutic is easy for the public to understand, and therefore often emphasized in popular science, the primary use of CRISPR Cas systems is in modifying genes in the lab. Tens of thousands of papers have made important scientific advances using it successfully and CRISPR-Cas methods are used routinely throughout almost all of biology. This is like calling PCR "overhyped" because PCR-based infectious disease diagnostics are limited.
epihelix 4mo ago
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anovikov 4mo ago

Bingo! CRISPR has an advantage of being relatively easy to describe to a layman, giving it a PR advantage.

fragmede 4mo ago
So is the "idea" of microchips in vaccines. Should we just give up and let everything else have the PR advantage

mondomondo 4mo ago

[dead]

fastball 4mo ago

Viral vector delivery is indeed harder to sell with PopSci, what with movies like "I am Legend".

jvanderbot 4mo ago
Great first half of a movie, by the way. Up there with Sunshine for "Sit down for a great hour-long ambiance". I usually end Legend after the mannequin trap, and end Sunshine after the transit of mercury.

spligak 4mo ago

You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound. Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.

GaggiX 4mo ago
I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?
- spligak 4mo ago
  There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other. The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet. The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse. As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
  - im3w1l 4mo ago
    Naively, I would deal with this by deciding how many cells I want to kill each day and then figure out a dosing schedule that achieves that. Or maybe it's better to do one dose every few days. But yeah either way.

roncesvalles 4mo ago

CRIPSR was a game-changer for genetics research. A lot of gene knockout studies use CRISPR. However, it was always weirdly overhyped for clinical use from the beginning and this was obvious to anyone with a genetics background. The public in general doesn't have a good understanding of basic genetics and I blame high school science curriculums for not covering it well enough. Too much time is wasted on Mendelian genetics without covering the Central Dogma. You basically cannot "edit" your somatic DNA in a meaningful wholesale way since every single cell in your body has a copy of the DNA, and it's a foolish endeavor. What you can conceivably edit to good effect is your germline DNA, stem cell DNA, or modify mRNA expression (e.g. retinoids; yes putting retinol/adapalene cream on your face is "gene therapy"), or introduce foreign mRNA for your translation machinery to co-opt (e.g. mRNA vaccines).

Bjartr 4mo ago
Edit every cell? No. Edit enough cells to impact health outcomes for a meaningful period of time? [Yes](https://www.youtube.com/watch?v=J3FcbFqSoQY https://www.youtube.com/watch?v=J3FcbFqSoQY)
- shevy-java 4mo ago
  This approach can work for some genetic diseases such as blindness based on some cells in the retina or partial blindness. For others this is not really a cure. If you want to cure people with progeria, does curing 20% of the cells really help? Perhaps 100% is not necessary, but it would seem strange to cure only some cells but not others. You'd have a mosaic of cells where some would work and others don't. Cells interact; timing also plays a role in development. I don't really see that aiming for anything but a very high number of cells cured, can work.
projektfu 4mo ago
I disagree that it's "gene therapy" to affect the natural regulation of mRNA production. If that were true then the term "gene therapy" loses its meaning, as just about everything changes the expression of mRNA. You can probably do so somewhere just by thinking really hard about it. Expressing mRNA that doesn't exist in the genome, that would be gene therapy. Or just a virus.

ramraj07 4mo ago

Devils advocate, I also vehemently shat on RNAi therapeutics a decade back. We do have RNAi therapies in market now though. I do think Crispr will find its place similarly.

jagged-chisel 4mo ago

“Virus” - that’s why.

perlgeek 4mo ago

CRISPR is foremost a research tool. Calling it "extremely overhyped" without restricting it medical treatment seems disingenuous. The CRISPR-Cas9 gene-editing tool was developed in 2012, so I don't find it surprising that merely 14 years later, there's only one approved treatment. From discovery to approval, drug development often takes 10-15 years, and often much longer for novel techniques. So I'd say it too early to call it overhyped for treatments. Finally, I think we'll see a lot of treatments that don't use CRISPR-Cas9, but related gene editing techniques, but it'll take another 10 to 20 years. Take a look at https://en.wikipedia.org/wiki/MRNA_vaccine#History https://en.wikipedia.org/wiki/MRNA_vaccine#History for how long another novel technique has been in development before it became really widespread with the mrna-based covid-19 vaccines.

shevy-java 4mo ago
Why does it take 20 years? Except, of course, that it does not work nowhere near as well as it is being promoted - aka hyped. mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different.
- perlgeek 4mo ago
  Let's see... first of all, 14 years ago was the discovery of the base mechanism, not of specific treatments. So specific treatments need to be developed, delivery systems need to be developed, side effects reduced. Then you need safety tests and efficacy tests. > mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different. And yet it took more than 30 years after the first mRNA experiments to develop a successful vaccine. Why it should be so much faster for CRISPR & Co?
- ufmace 4mo ago
  One of the reasons is, you don't get really good data on how something works until you start running clinical trials for it. It's all very time-consuming - having to plan how the trial is going to work, getting approval for it, finding subjects who meet the criteria (here, a specific type of cancer at a specific stage probably) and sites near them willing to work with you, manufacturing and shipping the treatments, and only then can you start gathering data. If it didn't work, you gotta start over, And it all costs a boatload of money too.

JumpCrisscross 4mo ago

Do mammals have a CRISPR analog?

spligak 4mo ago
Background on this question: CRISPR-Cas is a naturally occurring process in bacteria that is used to adapt to viral attacks. We've coopted the system for use in mammals. As far as I know a few labs in this space are operating under the basic question, "why haven't viruses killed everything by now?" So this category of research is more or less the answer. > Do mammals have a CRISPR analog? Not exactly. There are things like https://en.wikipedia.org/wiki/Ribonuclease_L https://en.wikipedia.org/wiki/Ribonuclease_L that nuke cells and are stimulated by interferons. This might be why interferon injections are common chronic therapeutics for diseases in this space. The closest thing we have is probably whatever adaptability B or T cells can muster on their own? I'm sure someone lurking in the comments has a better answer.

tty456 4mo ago

You're confusing the beurocratic FDA stamp of approval with safety and effectiveness. Those are not the same thing.

WhitneyLand 4mo ago

I would guess you did not first write “CRISPR is an overhyped approach”, then after careful reflection decide, I don’t think that quite captures the intensity, better go with “extremely overhyped”. The comparison is kind of a category error. One is a DNA editing technique and the others are deliver platforms. I recall the hype mostly being how revolutionary it could be, not comparing it on a timeline to specific technologies that are at different levels of the stack.

make3 4mo ago
it's revolutionary in genetic research, allows us to observe cells with specific gene knockouts, over activations, etc. it's just very hard to deliver to a whole system

tstactplsignore 4mo ago

This comment doesn't understand why CRISPR is such a big deal in science. While Cas-as-a-therapeutic is easy for the public to understand, and therefore often emphasized in popular science, the primary use of CRISPR Cas systems is in modifying genes in the lab. Tens of thousands of papers have made important scientific advances using it successfully and CRISPR-Cas methods are used routinely throughout almost all of biology. This is like calling PCR "overhyped" because PCR-based infectious disease diagnostics are limited.

epihelix 4mo ago

[dead]