The big problem is that the CRISPR would need to be delivered to 100% of infected cells. And as far as I know (I'm a biologist) nobody has a method that can achieve a delivery rate of 100% in vivo.
There are specific latent reservoirs the HIV hides in. It wouldn’t need to get every cell in the body, just have a favorable probability distribution to hit the reservoirs.
If you can get a reasonably high percentage then this might not be a problem. Include something in the crisper treatment that acts as a marker that protects the cells to which the treatment is successfully delivered. Then kill everything without the marker. I don't know what fraction of of your CD4 cells you need to maintain a healthy immune system, but I imagine even a double digit percentage reduction is probably tolerable, especially if the reduction is only temporary.
In-vivo is hard but there are many talented teams working on this. In animals, a company called Verve has discovered how to make in vivo CRISPR work via nanoparticles to the liver which achieves >80% delivery at certain concentrations of nanos. Pretty fascinating
I'm thinking more of a mutation already present that has less treatable traits but can't spread because neighbouring cells are already infected. But then when the treatment is delivered, it isn't cleared because of the difficulty of the delivery mechanism, but the treatment does clear up the surrounding cells, providing fresh ground for the mutated strain to reinfect.
(This is an active research area I've read about in cancer treatment, where it's been suggested that being too aggressive with clearing certain cancers encourages reservoirs of already mutated aggressive variants to be unleashed after treatment whereas before the avenues they had to spread were already infected with the less aggressive variant).
This doesn't make sense. HIV virus is generally not "substrate limited"/competing with other virii in its propagation in patients in (temporary) remission -- that's basically all of them that don't have AIDS. HIV retro integrates into host DNA and sporadically resurges on a stochastic basis, the drug cocktails in use inhibits this process.
Generally the viral load of a patient with HIV is miniscule but must always be kept in check.
Note that the point of a crispr treatment is that it would delete dormant HIV sequences that are hiding in the host DNA and not currently producing virii but threatening to pop up at some time in the future.
Obviously this too is subject to evolutionary pressures but almost certainly not the ones you are thinking of.
Evolutionary pressure is present in any situation and is unavoidable. It still has an effect even in cases where treatments are effective with a success rate of 100%: the selection of diseases for which there is no cure.
Entertaining such a perspective can lead to an extreme and undesirable conclusion, that the only logical outcome is to do nothing and dismantle the entire modern medical practice.
Other posters have explained why my concerns aren't warranted for this situation, I'm asking the questions to learn a little.
>It's not very constructive.
>Entertaining such a perspective can lead to an extreme and undesirable conclusion, that the only logical outcome is to do nothing and dismantle the entire modern medical practice.
Disagree, if you read my parent comment in this thread, I talk about the research going on in cancer to account for evolutionary pressure, and the conclusion they arrived at is nowhere near "do nothing".
It is instead a change in treatment protocols to aim for less aggressive treatment, the clinic in questions motto is for the patients to die from something other than their cancer by having them on a protocol that has them live permanently with their cancer under the thesis that aggressrive attempts at eradication risk a stronger variant resurging.
Obviously it's not applicabale for all types of cancer which is why it's research, and why I'm not telling anyone that evolutionary pressure is a concern here, but am simply asking the question to learn if there are similar concerns between cancer and hiv disease treatments.
If we assume that the treatment needs to reach the HIV cell to effect it, and that the danger is not 100% of the cells are reached, would it produce evolutionary pressure? The survivors aren't interacting with whatever got its buddies, right?
That itself is an evokutionary pressure. Whatever allowed them to get missed would get amplified by reproduction. Only if it's entirely utterly and only random chance and not something like the method doesn't target certain cells would it not be applying pressure
You're viewing the cows in isolation here. Replace the cows with cancer cells with different mutations and it doesn't work anymore.
There's research going with certain types of cancer where the doses of cancer-killing drugs isn't intended to eradicate all cancer cells, but to keep it at a level that's manageable with future treatments.
The theory being that if you go too far, cells that are left with a "lucky" mutation can grow without competition, leaving the patient in an even-less treatable state down the line.
you're talking about cows in a HIV discussion, so I could have said "cows and napalm? we're talking about HIV!", but I'm charitably engaging with your analogy to show that evolutionary pressure is an active research area in disease treatment.
But there's a chance that any survivors learn to hide from planes and you've now given an evolutionary pressure to cows to hide when hearing airplanes or helicopters. Along with that a pressure that makes the ones that blend in less likely to be spotted to be bombed. So yes, you're right you probably won't get cows that can survive napalm itself but now you've got cows with camouflage and an instinct to hide.
Yeah, we don’t even need to get every cell at that point, just a sizable number of the CD4 cells that are relatively easily accessible. The HIV would destroy every CD4 that isn’t CCR5 by itself. The antibodies would clean up the rest of the virons. Theoretically that would work as a cure too if you could excise the hiv and insert the CCR5 widely enough.
Does it need to be 100%? We have dormant viruses that are domant and would only activate when conditions are good, like colds, and we have ways to deal with it. It’s an analogy, for aids we would deal with it with meds and press it back there by turning it into a sort of nuisance like colds. The issue is cost and stigma of passing it. I for one still wouldn’t want aids to be as prevalent as the cold even if it’s super easy to deal with.
Science by press release. The results aren't even preprinted yet. Only some methods in a 2022 preprint. Looks hyped up, I'd ignore.
> This press release is based on abstracts P0004 P0006, P0013, P0026 and P0004 at the
European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). The material
has been peer reviewed by the congress selection committee. Only material from P0004 has
been published in a preprint article. The other three have not yet been submitted to a medical
journal or as preprints.
Way out of my depth here, but I'm guessing the main hurdles to turning this into a drug are encapsulation in a way that survives injection (or better yet, ingestion) as well as either targeting of infected cells or at least ensuring that even if it touches every cell, it only affects HIV DNA?
There's a sickle cell therapy that uses CRISPR. I don't know the specifics but if one has been successful then a second can be too. I'm looking forward to getting more information in the future. Cell culture vs cure is a long road but at least there's hope. The big drawback is that these therapies are super expensive but time and experience in the past have proven that the costs can be lowered.
"Sickle Cell Disease Approvals Include First CRISPR Gene Editing Therapy"
Yup Casgevy & Lyfgenia! These sickle cell (and now also approved for beta thalassemia) CRISPR therapies basically work in the following way:
- Blood stem cells are removed from the patient and the CRISPR Cas9 protein outside of the body is injected to cut the gene responsible for suppressing fetal hemoglobin production (even people with sickle cell have healthy fetal hemoglobin, their adult hemoglobin gene is what causes the deformed red blood cells)
- Chemotherapy is used to kill all living bone marrow and remove all previous unedited stem cells.
- New edited stem cells are inserted, and patient recovers with new blood production being of healthy red blood cells.
I'd say a huge step forward was FDA and EMA approval, but figuring out a way to remove previous unedited stem cells with chemotherapy would be a step change in the patient experience.
It's both extremely sci-fi and incredibly terrifying that one of the steps for a cure is to quote unquote kill all living bone marrow. Modern medicine is fascinating in how advanced it can be.
Yeah it's a spectacular transplant procedure, though it's really not that modern medicine, it has been developed since the 50s! The step where you irradiate or apply chemo to kill off the existing bone marrow had to be done at first because the patients had leukemia so you had to do this anyway. An interesting thing is that if there are still cells left in you, they will be wiped clean by the new transplanted immune system in a so called graft-vs-host response that also sounds like a horror-movie concept :)
not sure if you need to kill absolutely all living bone marrow. Unlike cancer having 5% sickle cell red blood cells is probably fine. That makes the chemo probably way less bad than what you would need for cancer.
"- Chemotherapy is used to kill all living bone marrow and remove all previous unedited stem cells.
- New edited stem cells are inserted, and patient recovers with new blood production being of healthy red blood cells."
It's very likely HIV could be cured similarly. I believe all the people who have been cured so far are bone marrow transplant recipients in which the marrow had a specific gene or genes.
It's very different, you only have to fix some of the bone marrow to help someone with sickle-cell, but you have to eliminate all reservoirs of HIV to cure AIDS.
I was under the understanding that HIV attacks only immune cells, white blood cell, only. All the issues that eventually kill are due to the body not being able to defend itself. So it seems like a cure would be very much similar to a sickle cell cure. Is that not the case?
A good video explanation of that too via Sci Show. It's quite complex; chemo, lab work and takes a long time and not always successful but the majority of the time it is successful.
mRNA vaccines are about getting mRNA into just a few non-specific cells which then instructs the cell to produce Corona Virus Spike Protein. This gets identified by the immune system which then makes antibodies targeting the spike protein.
So the mRNA only needs to get taken up by a few cells to produce an immune response.
The HIV CRISPR-Cas technique needs to target several orders of magnitude more cells in the body, and is performing a far more complicated procedure than simple transcription like with an mRNA vaccine.
And that Bill Gates wants to use the vaccine to depopulate Earth, and that the vaccine includes a 5G enabled microchip to coerce you into adopting SDGs. It's really bullshit all the way down.
crispr also makes mistakes. The kind that lead to cancer, disability and death. It’s not a magic wand. Being able to do something in cell culture is interesting but very far away from a therapy.
Your point is broadly correct (not sure about disability though), but I think it overstates the danger of what will happen in practice. Yes, if you picked a random target and blasted away, you probably wouldn't have a good time. But anything that even approaches clinical trials is going to get substantial engineering put into it to minimize (and characterize) all of the off-target loci. If there's meaningful editing near an oncogene then that's going to be a deal breaker for a particular guide. When the FDA was discussing the Casgevy application, they went into remarkable detail of how Vertex had measured the off-targets - the regulators really, really don't want to approve anything risky.
Frankly just getting it to work at all is the real hurdle in this case.
One thing I was confused by: why did Vertex choose to reactivate HbF instead of attempting to correct the mutation that causes sickle cell disease in the first place?
CRISPR, in the form used by Vertex, is not capable of directly repairing an existing gene. In the case of sickle cell this means directly changing the mutated nucleotide in the HbA gene. CRISPR is very capable of cutting the genome at precise locations. These cuts lead to lossy repair pathways that introduce mutations or deletions that disable the gene at the spot that CRISPR cut. So, the best you can hope for is that the CRISPR cut leads to a loss of function. It's possible to use CRISPR to introduce new sequences into the DNA, by introducing a new DNA sequence alongside the CRISPR proteins, then hoping that DNA repair "accidentally" uses the genetic sequence you put in to repair the break in the DNA. This is even less efficient than just cutting the DNA, and it would not fix the mutated HbA, so it's not really therapeutically relevant for sickle cell.
There are more recent techniques, notably prime editing, that use a modified version of the CRISPR system that can introduce changes to single bases (nucleotides) in the genome. These have some promise of directly fixing diseases caused by single mutations, but there are hurdles in terms of efficiently delivering the prime editor to the right tissues as well as efficiency of the actual repair.
We roughly know the space of possible mutations in the human genomes because we have so many sequenced genomes now: if we don't spot a mutation it's probably not good when it happens, survivorship bias.
The problem with CRISPR is that we cannot control where the off-target effects happen, we can currently only optimise the guiding RNA and the Cas enzyme to have as little off-target effects as possible (but not 0, yet). It would be cool to engineer guiding RNAs that bind in those high mutation-rate areas when they have off-target effects, stuff can mutate there and nothing will happen (probably).
> Frankly just getting it to work at all is the real hurdle in this case
This being the point. Many diseases have been cured dozens of times over in a tissue sample in a lab that never make it to actual therapies because the hurdle is elsewhere. The risks with crispr are as stated, especially flooding your entire body with it to target a virus.
How do Casgevy and Lyfgenia[1] avoid these dangerous mistakes? Is it something that can be generalized to other therapies, or does it need to be recreated for each "edit" that we want to turn into a therapy?
According to your link, both of those are applied to extracted stem cells which are then reintroduced. The ability to perform clonal expansion and DNA sequencing makes it possible that screening for off-target edits could be performed. Though I have no idea if it's actually done.
CRISPR is pretty complicated - I'd say it's not clear whether mRNA of such length could stably produce enough enzyme in enough places. It's great when you need an antigen to be presented, but not so much when you need an entire restriction enzyme system.
Probably not "the greatest day", but definitely a very very good day.
I think it's too easy to imagine Orwellian scenarios, but I think the real worries are much more subtle than people usually think, and they usually have more to do with how the world already works than with how it could change.
there's a million valid critiques of the news and this is the dumbest laziest one. people who comment "in mice" on all articles are more useful than your comment.
for example:
CRISPR is derived from bacteria so there is always the risk that the immune system targets the therapy
Fire or chlorine are far less dangerous than crispr.
Fire or chlorine are immediate and obvious. They can kill a person, but they can't modify one's behavior, identity (biometrics), or progeny, and all without either the victim or anyone else having any way to find out who did it or when, or even neccessarily detecting that anything was ever done at all.
Crispr is infinitely more dangerous than any gun.
It's equally powerful for good, but that just makes it worth it, it doesn't make the danger from unintended harm or intended harm go away, and the risk itself is a harm.
I am absolutely in favor of using crispr to fight hiv, or any other good purpose it can be used for.
But that comic was not necessarily inapplicable. As implied, what happens in a petri dish really doesn't mean much.
It also was not necessarily pointful because although it's true the petri dish doesn't really prove much, it's also true that you have to go through a petri dish stage before you can get to the actually useful human stage, and so there is nothing wrong with celebrating the potential stepping stone or milestone and nothing gained by shitting on it.
Sorry, can't hear you over a dozen ethical and legal violations I am in the midst of while throwing buzzwords like AI and Machine Learning.
It almost seems like with every technology there is a side that goes all in, risking mass suffering (i.e: AI, Crypto), and a side that abstains completely repeaing none of the benefits (i.e: banning GMO.)
It is almost like electing old, unqualified politicians doesn't yield good or speedy regulations.
