For people interested in Crispr, Rich Horgan started a non-profit called Cure Rare Disease working to fast-track customized therapeutics for his brother and other families with Duchenne Muscular Dystrophy using in-vivo gene editing.
"...some of the patient’s hematopoietic stem cells... [are] harvested for gene editing outside the body. After these cells are removed, the remaining bone marrow is destroyed with chemotherapy to allow space for the repaired and reinfused stem cells to grow."
EDIT: This is apparently the same procedure as conventional bone marrow transplants in SCA patients. CRISPR is just slotted into that workflow to synthesize a transplant, without needing to find a donor.
Even with the amount of hype around CRISPR, that is... incredible. Turning patients into their own donors feels magical.
I suppose in this instance, the patients wouldn’t need immunosuppressants after their treatment, as I’d expect standard care patients currently need for life?
I think it's an open question. After this treatment, the patient's red blood cells will be producing a new protein that they have never produced before. This protein only differs from the previous one by one amino acid, so the question becomes how sensitive the immune system is to such a change. Given that the immune system has some difficulty recognizing cancer cells with multiple protein-coding mutations in them, I think it's likely that a single amino acid change will fly under the radar and not require any immune suppression, at least for the vast majority of recipients of this treatment.
Bone marrow transplant (BMT) recipients can still experience graft versus host disease (GVHD) which is when the transplanted marrow produces healthy cells that start to attack the host body.
Besides GVHD, it is like you said. BMT patients are one of the few transplant types that can eventually come off of immuno-suppressants with a successful transplant. The patient's original bone marrow is supposed to be wiped out by chemotherapy (and sometimes some radiation) to make room for the new marrow transplant.
Can we take a moment to appreciate the straightforward naming of graft-versus-host disease? I couldn't find the history of its discovery beyond this (https://www.sciencedirect.com/science/article/abs/pii/S03014...) and even there, I couldn't find any indication of how it came to receive that name specifically, but it's much better than "[scientist's name]'s disease/syndrome" that we keep running into because people want credits at the expense of accessibility of knowledge.
Yes, but T-cells learn to distinguish self from non-self in the thymus, and I don't believe this treatment alters the hemoglobin gene sequence in the thymal epithelial cells. Of course, the thymus, like the rest of the body, will be served by red blood cells containing the new hemoglobin gene, but I'm not sure if this alone is sufficient for immature T-cells in the thymus to learn it as a self protein.
All the antigens would be identical except those derived from the modified gene. This tiny difference probably is pretty likely to escape detection, but not 100% guaranteed.
The fundamental idea of using the donor's own stem cells is known as an Autologous Stem Cell Transplant and has existed for a while. It is used as therapy for a fair number of blood cancers (e.g. multiple myeloma or a few leukemias).
I think some small number of autologous HSCT recipients require immunosuppressants, but from what I remember the number is very very small. (Allogenic HSCT recipients, who receive cells from a different person, are _much_ more likely to require lifetime immunosuppressants.)
It's super cool that they're able to treat genetic diseases this way!
Sickle cell anemia can be "cured" by inducing expression of fetal hemoglobin (fHb). You don't need to shut off the defective gene and the disease is effectively "cured" if you replace enough scHb with fHb.
So you remove bone marrow from the patient, modify the cells, put them back in. The modified cells produce fHb at a high enough level that symptoms of Sickle Cell go away.
Not that different than the already approved CAR-T therapies (with the exception they don't use CRISPR for the genetic modification).
That's what I get for not reading the article. But the point stands on correcting genetics for hematopoetic cells. It's possible to fix a small number of cells, then reimplant (often depleting the cells in the person first) and they will replicate.
Easier than trying to fix the cells in a solid organ.
Because this is a blood based disease, I’m guessing they would extract blood from the patient or extract them from bone marrow (more likely), treat the cells outside the body, and then transfuse the modified blood cells back onto the patient to try and engraftment them in the bone marrow.
All of the hard CRISPR stuff is likely in vitro.
However, I don’t know anything about what the specific plans are though, this is just speculation.
I was super pumped for this tech to start being used in human clinical trials, but a couple of years ago, there was a study[0] that raised some key concerns about CRISPR therapeutics increasing the risk of cancer due to some edited cells self-destructing once their genomes have been modified, leaving behind cells with a higher risk of cancer due to not being as sensitive to genomic edits. Have these challenges been overcome yet?
Woah! So the cells that accept the CRISPR modifications do so because they have dysfunctional p53 gene activation. This most likely means they are specifically the cells most likely to become tumors if they undergo any mutations triggering carcinogenesis as p53 and its helper genes are mainly responsible for killing off cells that become cancerous among other things.
This means that you can use CRISPR to selectively kill these cells only since they would be the only ones that easily accept and express the CRISPR modifications. This could be ground breaking if it is not already tried.
Hasn't Vertex already run an experiment on people and cured sickle cell disease using CRISPR last year? What's new here (except that the organizations are different)?
Health, intelligence and facial symmetry do seem to be linked to the absence of deleterious mutations so yes it may well be that the children of wealthy people benefit, in the farther future. I don't foresee any particular harm, since the standard arguments apply: what starts as luxury eventually becomes accessible to all with the rich having paid the development costs.
Also consider that since the industrial revolution child mortality in the West has declined tremendously (thankfully), so it's possible that our genomes have accumulated mutations presently unknown which will need to be deleted at some point. Better done via gene-editing tech than via the cruelties of natural selection or eugenics.
Road to hell is paved with good intentions. In this case, creating super-humans that lack any weakness, sickness and are just ideal of what can human being be without those is putting them already way above everybody else.
One doesn't need an x-ray vision or flying around to be to have superhuman status.
I understand your optimism because it sounds properly awesome. But we humans always, without exceptions, fuck up everything that is even theoretically fuckable and often even the rest. If you don't see potential for evil with this then I guess you lack a bit of imagination.
For every great discovery to help humanity there is always some powerful idiot thinking how it can we weaponized, used to gain advantage above others, the non-conforming, the unknown, or simply the weak.
> But we humans always, without exceptions, fuck up everything that is even theoretically fuckable and often even the rest.
Yet science has allowed us to live longer, healthier, freer of disease, less likely to be poor (and far less likely to be extremely poor). Its easy to complain about how terrible everything is when you’re not dead of tetanus at 5 years old or have gone blind due to lack of vitamin A.
> Helping people with severe diseases is still far away from creating the perfect humans.
Not as far as it looks. Honestly, it looks closer, than real self driving cars.
> You turning this positive into a negative is distasteful.
I'm incredibly happy that we, as humanity, are advancing with science - the mRNA vaccines are also incredible. The part that is not incredible is that we, as society, are in most cases still behave like we did in the stone age: greedy, selfish, narcissistic. Because of this tech that should be used to help those in need is most commonly used to "help" those with enough funds or means.
Cheering for science advancements that are far out of reach for the majority leaves a bitter taste.
EDIT BTW, Gattaca is a temporary time. Once it's passed - one whole generation, so say ~80 years - that world would be wonderful, but that limbo time, when the movie plays out, is the nasty part.
> Cheering for science advancements that are far out of reach for the majority leaves a bitter taste.
Yes. Damn that new fancy tech of farming that only the rich can afford!
Seriously. Think about what you're saying for a second. Tech that is only for the rich becomes affordable for the masses faster and faster every year. Computers were for nation states in my parents life time. Today there are computers more powerful than the first computers in cheap toys.
We cheer for tech that only the rich can use now because it will be for the masses soon. Tech that never exists for the rich, will not exist for anyone ever.
>We cheer for tech that only the rich can use now because it will be for the masses soon. Tech that never exists for the rich, will not exist for anyone ever.
Realistically however, this kind of area falls squarely in the healthcare field which is increasingly becoming a thing for the rich and indentured servitude for the rest.
People vastly overestimate our understanding and ability to produce reliable phenotypic changes. Being able to change the tiny percent of diseases that have a straightforward and simple genetic connection is a far cry from designer humans. I think Richard Dawkins said it well.
> “Think of the body as a blanket, suspended from the ceiling by 100,000 rubber bands, all tangled and twisted around one another. The shape of the blanket — the body — is determined by the tensions of all these rubber bands taken together. Some of the rubber bands represent genes, others environmental factors. A change in a particular gene corresponds to a lengthening or shortening of one particular rubber band. But any one rubber band is linked to the blanket only indirectly via countless connections amid the welter of other rubber bands. If you cut one rubber band, or tighten it, there will be a distributed shift in tensions, and the effect on the shape of the blanket will be complex and hard to predict. In the same way, possession of a particular gene need not infallibly dictate that an individual will be homosexual. Far more probably the causal influence will be statistical. The effect of genes on bodies and behaviour is like the effect of cigarette smoke on lungs. If you smoke heavily, you increase the statistical odds that you'll get lung cancer. You won't infallibly give yourself lung cancer. Nor does refraining from smoking protect you infallibly from cancer. We live in a statistical world.”
>Cheering for science advancements that are far out of reach for the majority leaves a bitter taste.
Yet a random child born in the slums of Mumbai has a higher life expectancy than the wealthiest people on earth did 100 years ago. Just because the rich have it better than everyone else does not mean that scientific advancement has not led to vastly improved lives all over the world. Yeah, people are still greedy and mean and blah blah, but with 2 extra decades of life to live on average.
>BTW, Gattaca is a temporary time. Once it's passed - one whole generation, so say ~80 years - that world would be wonderful, but that limbo time, when the movie plays out, is the nasty part.
I don’t think you understand the point of the movie. The movie was about how we shouldn’t put total and complete faith in gene editing, because our genes are not the only thing that make us “us”. Jude Law is a genetic phenom but ends up not doing anything with his life of note because of his decisions, bad luck, and his lack of drive and motivation. Ethan Hawk was written off as a loser before he was a day old because of his genes, but he succeeded due to his decisions, good luck, and his drive and motivation. His genes said he had a statistically super high chance of dying because of his heart, but he didn’t, because a statistical likelihood is not a certainty. Ethan Hawk is allowed on the shuttle by the doctor, who’s genetically enhanced son is “not all he would have hoped”.
The message of the movie is that we need to be careful of using genes as a proxy for everything that makes up a person, and how that could lead to a dystopian society where people are pigeon holed based on one thing about them. That taking the shortcut of using a proxy, even one as complex as our genes, for something as complex as “human potential” is folly. The statistical nature of genes, epigenetics, and environmental factors cannot be ignored.
Two years ago, Chinese Scientist Dr.He JianKui did a very similar thing. He edited the genome of twin girls so that they will be immune to the HIV-virus. By all account the project is successful. The announcement of this breakthrough causes a lot controversies. People are shocked and dismayed. Here is the link:
https://www.nature.com/articles/d41586-018-07545-0
Using CRISPR to edit the genomes of human embryos because YOLO, is very different to using it in a modified version of an existing treatment for sickle cell anemia. Do you not see the difference in ethical scale and scope?
HIV is a very capable mutator, all he did was give it a chance in two hosts to mutate against. and then who knows the future danger of the kid's health. Dolly the sheep was cloned, but had enlarged organs. So not perfect. And what changes in these kids is a huge unknown and there was no way to predict it, because the doc just did because he could. Plus a whole eugenics program has a huge historical negative example in the last century because it lead to death camps.
Whoever does it, hopefully it is after evidence-based discussions to establish a framework for ethical and safe application. Just because the box can’t be closed doesn’t mean we just throw our hands up and say “well, nothing we can do to steer this in a responsible direction”. We don’t breed humans like dogs to produce super men, even though we theoretically could.
Bone marrow transplants as a treatment for SA are already a thing. All this does is make it so you can use the patient's own bone marrow instead of a donor, hopefully reducing rejection. There's no subtle point to be made, the question you're asking is a solved one, because it's just a modification of an existing therapy.
Now, compare that to editing human embryos in vitro then implanting them, just because you want to prove it's possible to use a gene editing technique to alter the genome of a person.
He JianKui's Project is not to build the superman. the parent of the baby girls is HIV positive. He did that so that Parent is not going to worry about their babies is going to get the disease.
“We are motivated to work toward a cure that can be accessible and affordable to patients worldwide,”
Sickle Cell is prevalent in some populations because the gene mutation is protective against malaria. (Probably only beneficial if you have one copy, not two.)
I hope they will keep this in mind and work to eradicate malaria hand-in-hand with trying to eradicate the genes that are protective against it when they look to take it global.
It's fine if they just figure out how to cure sickle cell anemia. Great even.
No one will force people in areas where malaria is endemic to have sickle cell anemia treated, and a treatment for sickle cell anemia won't slow down treatment/eradication of malaria.
It's certainly not impossible that governments of African countries would spend thousands of dollars per person to prematurely cure sickle cell anemia, but I think we can say that it's unlikely.
What other actors are going to give people unwanted bone marrow transplants?
I guess medical companies testing the technology might do things to get people to participate in trials, but I'm not real sure people with sickle cell anemia would be mad about having to use modern anti-malarials instead of suffering with sickle cell.
There was an island where they used poison to kill all the mosquitoes because it was a big problem. All the mosquitoes dies and then all the things that ate the mosquitoes died.
And then all the things that ate things that ate mosquitoes died. And it went through a few more layers of this, like some modern day version of the Biblical plagues.
That doesn't mean we shouldn't do it. It just means it is correct to not take the decision lightly.
(Unfortunately, I've never found a good write up of this true story on the internet. I read it long ago back when dinosaurs roamed the earth and I had a bright yellow rotary phone and got information printed on dead trees.)
The citation you provided elsewhere (for Sardinia) was for some DDT spraying - which was obviously not targeted exclusively at mosquitoes, and explains why lots of other things died.
Targeting the very small set of mosquito species (that carry malaria) with something that will wipe them out within a few generations (under 12 months) seems tremendously safe, because a) it's a small subset of the total mosquito population, b) you can test this in isolated (eg. island) environments, and c) by the very nature of this, rollback is easy -- once the species has died out locally, if needed you can quickly & safely re-populate with non-modified specimens.
It's not alarmist. Not by any stretch of the imagination.
I'm an environmental studies major and I have a genetic disorder. I'm getting healthier when that is supposed to be impossible and it's in part because I'm an environmental studies major and I think of the body as a complex ecosystem.
You kill one thing or change one thing and there are always myriad knock on effects. Always. Anytime you do anything that's actually at all effective, there is hell to pay.
I am getting better by trading short term costs for long term gains, the exact opposite of what Western medicine typically does. We monetize disease by trading short term gains -- that doctors can claim credit for, justifying their fees -- for long term costs which we politely admit to with multi-page warning materials included with all drugs and then normalize largely ignoring that stuff and taking it anyway. Then when your condition gets worse, they blame it on your genes instead of on the side effects of the harsh drugs they have been poisoning your system with for years and years.
It's possible to make targeted changes to an ecosystem, but it's not easy and even if you get it right, there are costs involved. Managing such change is hard and there tends to be hidden costs that the experts want to disavow responsibility for and they can generally get away with it because cause and effect can be hard or impossible to prove.
I hope they cure Sickle Cell. I hope they eradicate malaria. Parasitic infections are pretty awful.
I hope they do it in a way that doesn't involve millions of Africans being thrown under a bus so Westerners can feel like heroes while hand waving off the human costs for the locals which Westerners have a long history of running rough shod over on the excuse that we imagine we are superior to them or something.
> Always. Anytime you do anything that's actually at all effective, there is hell to pay.
Just the first counter examples that comes to my mind: "Western medicine" eradicated smallpox and polio; what was the hell price for those?
"Western medicine" really only means medicine based on the scientific method, and shouldn't be conflated with the profit maximisation mechanisms which are so prevalent in the US medical system.
Overpopulation is one of the consequences of actually solving problems. Birth rates fall after mortality rates fall. The result is a bump in population size.
This is a known phenomenon. It's very well documented.
It's not a reason to keep letting people die, but the transition comes with costs.
That's just reality.
Antibiotics were supposed to be the end of disease. Now we are brewing antibiotic resistant infections.
It's common for diseases to jump species when adequately threatened. Organisms don't like being eradicated and will fight back.
You see more genetic mutations in diseases, fomenting resistance, when they are under pressure.
We've lost some of the medical best practices I grew up with. I have no idea if that's directly related to the eradication of small pox or polio. I haven't specifically studied those cases.
Change comes at a cost. That doesn't mean it isn't worth pursuing. It does mean that cavalier attitudes about how, clearly, this is all upside have a tendency to be dangerous.
There are cavalier attitudes on one side, and alarmist attitudes on the other side, and in my humble opinion saying that "Anytime you do anything that's actually at all effective, there is hell to pay" falls in the latter.
When I was growing up, medicine was more focused on social elements. It more explicitly recognized that people spread disease from person to person.
At one time, the way we stopped STDs was we took the names of all your recent hookups, contacted them and let them know they had been with someone who had just tested positive for a particular STD and offered them testing and treatment.
In my teens, the AIDS crisis hit. In the US, it was mostly associated with gay men and IV drug users. These populations had reasonable concerns about giving a list of contacts to authorities and pushed for drug research and stronger privacy policies.
My understanding is we largely no longer use this proven method of stopping the spread of most STDs.
I can also remember going to a doctor with a sibling and a couple of cousins and all of us getting treated so that the issue wouldn't just go round and round through the family. I feel like that was a fairly common practice at the time and we mostly don't do stuff like that anymore.
Historically, doctors did house calls and were one of the smartest, best educated people in town and towns were relatively small. They could address issues that helped contribute to your medical problem beyond just prescribing drugs and surgeries.
Now we act like human beings are specimens in a petri dish and like their physical health is unrelated to their lifestyle or the fabric of their life.
I think this is a big problem. The phrase "We've thrown out the baby with the bathwater" comes to mind but doesn't quite fit.
What we've done is tossed aside wisdom and context to worship at the alter of ooh shiny diagnostics. The high tech diagnostics are useful but the largely unnoticed loss of wisdom and context is a serious problem and we aren't even trying to solve it because we mostly haven't noticed that it matters.
> You kill one thing or change one thing and there are always myriad knock on effects. Always. Anytime you do anything that's actually at all effective, there is hell to pay.
I stand by my earlier claim.
While I acknowledge the potential of unintended consequences, and the often surprising interconnectedness of many elements within an ecosystem, I further dispute the claim that any change necessitates other, exclusively bad, 'hell to pay' changes.
Here I am, in rural Australia, and within a kilometre of me these are the pests that I would be ecstatic to get rid of, and that would have close to zero negative, and myriad positive, knock-on effects:
prickly pear, tiger pear, heliotrope, pattersons curse, foxes, rabbits, several species of med fruit fly & mosquitoes.
Almost all of these are guaranteed to have no negative knock-on effects simply because they were introduced here in the past two centuries.
Australia is like the poster child for unintended ecological consequences. All those introduced species you cite to refute my opinion I would cite to support it.
Though the camel being introduced to Australia seems like something of a silver lining. From what I gather, Australia is now like a haven for the species.
I'm interested in how you defend (if I'm reading that correctly) retaining those pests in Australia.
Further afield from my humble abode, yes, Phytophthora, lantana, black rats, blackberry, feral goats / pigs / deer, cane toads, camels, etc.
The reason we can export camels to the middle east is that when we imported them from there, we didn't import the various parasites that are now rampant in that part of the world.
Perversely this gives us an export trade and a massively out of control population of highly destructive and resilient beasts.
If we could remove all wild camels from Australia over the space of 10 years you'd be hard-pressed to identify any net negatives, and certainly it'd be impossible to identify any negatives that were detectable when mapped onto a graph of the positive effects.
They are invasive species that exploded in Australia due to a lack of natural predators. How you can cite their existence as a refutation of anything I've said baffles me.
I've been up excessively long. With any luck, I'll be asleep soon.
> They are invasive species that exploded in Australia due to a lack of natural predators. How you can cite their existence as a refutation of anything I've said baffles me.
I wasn't 'citing their existence', so much as declaring an eagerness to remove them.
The context was you started by saying:
> You kill one thing or change one thing and there are always myriad knock on effects. Always. Anytime you do anything that's actually at all effective, there is hell to pay.
I said that sounded alarmist, as there were plenty of contra examples - such as removing a dozen or so named non-indigenous pests from Australia.
You said:
> Australia is like the poster child for unintended ecological consequences. All those introduced species you cite to refute my opinion I would cite to support it.
I asked how that could sit alongside your claim that 'you kill one thing ... there is hell to pay'.
And here we are.
My point stands -- removing these introduced pests via a terminator gene or similar that targets precisely those organisms would be a fantastic result, and almost definitely have no negative effects, though of course I'd want that to be thoroughly evaluated.
You don't have to extinguish all mosquito species. It's enough to only target those which can carry diseases. Ideally one would engineer mosquitos to avoid humans because of their smell.
Modifying ourselves leads into the messy territory of bodily autonomy and consent. You can see this pretty well in the anti-COVID-vaccine crew. I feel like it'd be much more popular to modify mosquitos than apply some modification to humans.
Not to mention the ethical (regarding equity) concerns: disease from mosquitoes affects poverty-stricken areas the most, yet the people with the most access to these bodily modifications or procedures are going to be from wealthy countries.
There are few developed countries in the tropics. Singapore is one, and dengue is a concern here. I understand that the way it's mostly kept under control is through a lot of spraying, which isn't exactly great.
Mosquitoes are a rather distinct element in the natural world and it just seems unlikely that we are capable of understanding the full set of downstream effects of eradicating them entirely.
Right. There are thousands of species of mosquito, most of which don't carry human diseases.
Of the ones that do, many of are of African origin -- they evolved there along with us (and the diseases they carry). They are thus essentially invasive species in the rest of the world.
The nice thing about potentially using CRISPR-based gene drives to extirpate (e.g.) Aedes aegypti is that it would affect only that species, unlike our current pesticides which tend to kill insects of many different species indiscriminately.
Except there are multiple species of mosquito. Only 1 of them is a primary carrier for malaria. And if it disappears another mosquito in the family will replace it.
The eradication of malaria helped Sardinia improve its public health programs and also paved the way for socio-economic development. But at a huge environmental cost that is incalculable. Some farmers accused the DTT of killing their livestock, bees and also fish.
Common sense must tell people that whether we like mosquitos or not, they're part of the food chain. A food chain which is already stressed due to climate change.
Scientist who are eager to take out mosquitos sound more like kids who are eager to play with their new gene drive rather than consider the actual impacts.
No, scientists who are eager to take out mosquitos want to do it because it will save millions of lives. People have been dying of malaria for millennia—climate change has nothing to do with this particular issue/solution.
We're all very concerned, but we don't really spend very much money on Malaria treatments, relief and vaccines overall. Especially in the developing world. There isn't even really much urgency to do anything about it.
No operation warp speed to help save hundreds of thousands of lives a year. It's almost just like a fun topic to make people feel better about themselves.
I've read more about how transmission of malaria works and basically mosquitoes carry it from biting infected humans then pass it to other humans, it's not that mosquitos are evil, they don't even know what's going on.
I think there is a question of ethics involved personally, that's because if mosquitoes had the power to wipe us out, we wouldn't be that happy if they decided to go ahead with the plan.
While I agree it's likely, 'common sense' is also not science and we shouldn't take as a given that they are an integral part of the food chain. Pest species do exist.
Saving lives is generally a strong motivator, so it's worth considering the possibilities.
Avian malaria is endemic to Alaska, and both Finland, and Siberia formerly had endemic human malaria, especially the more southern regions. Something up there is definitely capable of being a vector for it.
But is malaria a big enough problem in the arctic to bother targeting the mosquito species there that could carry malaria? From a quick Google search, I'm guessing no.
Hopefully whoever decides to just go do it has the sense to only target mosquitoes that preferentially feed on humans. Much less ecosystem impact that way.
These days, introducing a known mutation via a CRISPR gene drive is engineering. The hard part is scaling it so your mutation doesn't die out, testing to ensure that it is actually propagating, etc.
> Hopefully whoever decides to just go do it has the sense to only target mosquitoes that preferentially feed on humans.
You have to repeat a considerable amount work for every single target species. I highly doubt they'd target more than one.
This particular treatment does not affect the germ line. i.e. it corrects the defect in the patient, but they can still pass it on to their children, who would be (malaria-protected) carriers.
> Probably only beneficial if you have one copy, not two.
One copy of the gene partially protects you from malaria; two copies of the gene make you very sick.
That's why even in Africa only a small portion of the population has the gene. The gene is an evolutionary advantage as long as the prevalence in the population is low. As soon as the frequency of the gene in the population goes up, it becomes a disadvantage because if both you and your partner have the gene your kid has a 25% chance of getting two copies.
That’s right, but the sad truth is that those who will afford gene editing and those who are at daily risk of malaria are two very different groups of people.
I've learned a lot about gene therapy. The immune system is a major bottleneck to wide spread gene therapy. If you modify the genetic makeup of cells in your body, the immune system will recognize the new antigens being presented by these cells and attack. Many gene therapy target point mutations that don't require significant alterations to correct that would alarm the immune system.
It’s also that we don’t have organism-scale models of how change in one gene will affect other body functions. We don’t know how to build these kind of models and we don’t have even 1% of the data to do that. Organoids are just emerging, but they aren’t 1:1 representation of what happens in real human.
1. Most point mutations won't result in significant changes, but if we are talking about gene therapy, the specific point mutation probably did effect protein folding or function
2. Proteins in each cell are broken down into unfolded fragments and presented on major histocompatibility complexes as antigen.
For those interested in CRISPR tech I'd highly suggest reading up on BEAM therapeutics. It's base pair editing which makes it much more precise compared to CRISPR which is editing DNA chains. They don't have editors for all base pairs yet but they have a couple and it looks very promising.
The Base Editor (and Prime Editor, etc.) _is_ CRISPR (Cas9) but with additional components fused to it that provide it additional features allowing it to edit in a more elegant way over the naked Cas9.
The technique sounds promising, since it avoids the typical problem of gene therapy, which is how to get CRISPR past the immune system into every cell in the body. With this technique you can do the CRISPR procedure in vitro.
A big downside to this treatment is that as far as I know this kind of chemo can make male patients infertile.
For my understanding: crisper works by cutting the dna at specific points surrounding the relevant part and then exchanging, right?
How likely is it, that in the whole DNA string there are other instances this “surrounding” matches and would be cut? How is this prevented / not causing side effects?
The nice thing about CRISPR is that you can use pretty long sequences for matching, so in theory you can just pick a sequence that doesn't occur anywhere else and cut there.
(Before CRISPR, you would use restriction enzymes with a short, fixed recognition sequence, typically 4-6 base pairs [1]. In that case it was a bit tricky to find the right enzyme that cuts the DNA in the right place, and not in an unwanted place. And you couldn't just cut the DNA in any place you want.)
If CRISPR can be bruteforced to change a significant number of cells for a whole organ/body then what is stopping us from rejuvenation?
(store your DNA in while not too old in a safe place fill this DNA in tons of virus vectors/CRIPRs and hop you can be rejuvenated!)
Probably not, killing off your bone marrow cells and replacing them is already pretty dangerous, and other organs would be way worse, because they have actual structure. Doing it with your brain would be impossible, for obvious reasons.
Yeah. My one and only concern is how tight regulation around genetic augmentation/editing will be. When will medical use cross over into cosmetic use and how do we regulate that?
The treatment is basically a bone marrow transplant, which would typically use donor cells from another person; CRISPR lets you use the patient's marrow instead, hopefully reducing rejection and other issues.
You extract marrow and CRISPR it to get rid of the problem gene. Then you kill off all of the bone marrow in the patient, and replace it with the new stuff. That's a cure.
A wild guess: million+. It’s supposed to be a once in a life time treatment, so pharma can’t milk you for life. It’s not that pharma is inherently bad, but rather that it costs billions to get this through all the stages of clinical trials.
https://cureraredisease.org/