It's interesting that they did not just undo the inherited disease. I assumed that, especially with Sickle Cell where we have a good understanding of how it works, they would go into Chromosome 11 and put it back how it "should" be with CRISPR. But instead they apply a workaround, ensuring continued fetal haemoglobin production.
The article does not mention whether that's because putting Chromosome 11 back with CRISPR is harder, or whether for some reason that wouldn't fix the problem.
That's also what struck me as odd, but having maintained legacy systems for a long time I can see why it's sometimes preferable to use a proven if inelegant workaround than going in and try to fix the actual defect, especially if you have limited debugging options.
It actually follow a common pattern in evolution. Doing big changes are hard, difficult and risky. Tinkering and doing small changes over time works for most things and any legacy system, as long they are not directly harmful, can remain as a byproduct. There is even a word for it in biology called spandrel.
Analogies to IT and development aren’t that appropriate here tbh.
This isn’t a legacy system, if you want to keep the IT analogy this would be failing over to a different system or replacing an existing solution that doesn’t work with a competitive alternative rather than fixing all your bugs.
It is much easier to wreck things with Crisper (in this case the regulatory region that turns of fetal hemoglobin) that to really go in and alter one or a couple of specific base pairs. What they did is nice but the latter would be the holy grail.
If the holy grail is only a few years away, then yes. Normal CRISPR editing rely on non-homologous-end-joining (NHEJ) which is not an absolutely exact process. However, there are now base editors (look up prime editing) that edit a single position with very high specificity. Takes a few years from basic research to the clinics but they will be everywhere soon.
"Holy grail" not because of how it would work on this particular disease, but because it would allow basically limitless editing of any gene in any living human, allowing us to fix all hereditary genetic diseases, and do a whole lot of other things besides.
One reason may be that a general fix that produces good hemoglobin is much more efficient than attempting to fix the original problem. People can have a near-limitless number of mutations that lead to defective proteins, so creating fixes for all those "bugs" can be very expensive. A general fix that works around the "bug" is cheaper, consistant, and more scalable.
Another way to look at it: Would a per-patient fix be possible? Maybe. Is it worth debugging and fixing everyone's crappy DNA to do that? Probably not.
That’s true even if the mutation is the same it’s hard to actually fix it, while reactivating or over-expressing a gene that already exists and works is much easier.
For this specific case it’s also better because lesser coverage might still produce sufficient results since fetal hemoglobin out competes adult hemoglobin.
I think in general CRISPR would be patch over rather than a point fix.
This is such mind-blowing success, it makes me contemplate switching fields. Is it reasonably feasible to switch from IT to Biotech/Medical Research in the mid thirties?
I had a friend with Fukutin-related limb-girdle muscular dystrophy R13 and am wondering if CRISPR could be the solution for her.
You don't even need to switch fields. There are plenty of biomedical companies (and what isn't a tech company these days?) and projects that could use some passionate technical people.
I mean, they are a pick and shovel play. They don't make drugs? Plus, sequencing is great but it's getting saturated. Plus, ideas like direct sequencing using nanopores and chemical modification of nucleic acid to make the nanopore signal stronger may disrupt.
Reading a lot of 10-Ks, you get the impression that many if not most biotech companies want to appeal to investors who find "pick and shovel" companies appealing. Even companies that are basically drug companies often try to portray themselves as having a revolutionary "platform".
I'm not saying your attitude is obviously wrong, but there must be a lot of people whose imagination is captured by making tools and the potential of that to change the world. The development of a tool like optogenetics, for instance, makes me feel like amazing things can be accomplished. It's leverage.
Yea sure, I love pick and shovel plays. I think they're the ones you make the easy money from like ThermoFisher, Becton Dickinson, EMD/Milipore, Sigma-Aldrich, etc. I was thinking more like FAANG companies that are huge, pay awesome, and make the final product, though I guess you could say advertising is a bit of a pass-through income generator.
Maybe you and I have different definitions of 'platform' company? I define as a way to iterate to get new products, like Regeneron uses their humanized mice to crank-out mAbs, or Genetech/Amgen use recombinant molecular biology to make mAbs, or Vertex uses their in vitro ion channel conductance screening method to make new structure correctors for CFTR...
Anecdotal, but my cousin did exactly this. I will note, he is probably the most exceptional person I known of, beyond those classic geniuses everyone knows.
comp sci in prestigious european uni. Moved to us in early 2000s. Big nationwide datacenter stuff. Decided to become doctor. Did doctory stuff and floated around medical for a while before switching to psyc. Currently forensic psych for infamous US prison. Found that rather than patient hop in regular psyc practice, or drug up people in asylums, with trial cases spanning years you can really deep dive a person and do good work.
I think you need to pause before considering this route. Are you that exceptional? This level of intelligence is incredibly rare and unless you're 100% sure you're capable of this, I wouldn't do it.
The guy has brains to burn of course, but tbh, it's simply about motivation. Medicine is a grind, more than an intellectual exercise. If you have the brains for actual tech there's no doubt you have the requisite intelligence. The only barrier is the stamina for the grind. I know I couldn't do it. Not as I am now. Maybe in the future. I couldn't say for sure, given I'm not clairvoyant.
I agree that you should give serious pause. Probably the most serious pause of your life, but still. I wouldn't shy away too quickly. When you know, you know.
Very true. Not to discount MD training or doctors, but it's less about connecting disparate dots or learning how to solve problems and more about working out the brain like a muscle.
It’s worth knowing there are very few diseases that can be cured with singular gene edits. Many diseases involve multiple genes, cascades of gene expression, or complex physiological pathways. Oh, and not to mention epigenetics and environmental factors.
The strategy they used speaks exactly to your point. The diseases were not "cured" in the sense that these people were brought back to a generic baseline. That very well may have required a complex series of edits that are well beyond what is currently possible. Instead, they focused on a clever workaround that was simpler to implement, reactivating fetal hemoglobin. That's how they were able to cure two different diseases with the same gene edit.
So you have a much larger pool of genetic and non-genetic diseases that can be cured now. For example if someone had low lung function due to lung scarring, this might be an interesting treatment to look at.
My family has one of the well-known single-site cancer-causing mutations; we know what the specific site is, even. It would be immense to "fix" (I am not a geneticist) that single site. Even just for my kids.
Why would you prefer the risks of editing versus the risks of preimplantation screening? Editing would be strictly riskier unless there’s really no alternative (unlikely but possible)
Preimplantation screening isn't an option for me or any other of my family members who are long past implantation. I'm not saying I'd hop on stage 1 clinical trials of a potential editing cure, and we'd have to see what the data on risk looked like to compare it with the risk from cancer without editing.
Actually, there is a couple thousand monogenic Mendelian diseases, so work isn't short, also not people, just money. However, you won't treat a developmental delay with a gene edit, that only works for non-working enzymes etc. without too much permanent damage.
As an other commenter wrote, if you know some software engineering, you are already valuable to all biotech companies, so it's probably better to go there as an engineer first and pick up the biology on the side than to go back to school and waste 5 years of your life without providing real value.
>The remaining bone marrow cells are killed by chemotherapy, then replaced by the edited cells.
Interesting that they need to kill the remaining bone marrow cells. I wonder what happens when they skip that step. Do the modified cells still reproduce, resulting in a partially effective treatment? Are they targeted by the immune system and eliminated? Are they just out-reproduced by the normal cells and fade into irrelevance?
That depends on the nature of the genetic disease.
If the original gene produces a protein that actively causes an issue in the body, versus if the gene produces a broken protein that simply fails to do its job.
In the first case, a partial replacement means that the original active protein continues to cause the disease.
In the second case, a partial replacement means that the repaired protein begins expressing itself.
In either case, there may or may not be a linear correlation between the percentage of fixed proteins and the severity of the disease, and that relationship probably isn't well understood in most disease cases, but a partial replacement is likely much more beneficial in the second case, rather than the first.
That is why these initial test are done on chemo patients, so that we can isolate testing of the method of treatment without needed to know what amount of the original tissue needs to be replaced.
There is still a long complicated road ahead. Not a lot of organs get fully replaced in other procedures.
More than likely I'd imagine it's the last option. They can only produce so many of the edited cells. The body is going to have orders of magnitude more of the original ones present before the treatment that I think they'd just overwhelm the new ones. If you remove the original ones the new ones have a place to thrive and eventually get to normal levels
If you don't kill off the existing bone marrow, you end up with a couple problems:
1. You only give the patient a small number of edited cells. You want those cells to multiply and replace the existing cells. If you don't remove the existing cells, the edited cells aren't going to reproduce very fast because the body has a feedback loop and is saying "we have enough bone marrow cells now, so no need to make more".
2. Host versus graft disease. The old immune system will attack the new immune system cells.
Fetal hemoglobin binds stronger to oxygen than normal hemoglobin, so that a fetus can "steal" oxygen from its mother's blood. But if the mother has been crispred to also have fetal hemoglobin, then this won't work right? Meaning it's a male only treatment?
Hi. I do research pertaining to this disease and can answer your very thoughtful question. It is in fact safe for pregnant women to have high levels of fetal hemoglobin. There is a condition known as Hereditary Persistence of Fetal Hemoglobin (HPFH) in rare individuals who express near 100% fetal hemoglobin into adulthood, and they are able to undergo pregnancy perfectly normally with no harm to mother or child. While it is true that HbF has a mildly higher affinity to oxygen, it has not been shown in population-based studies that having higher levels of HbF by itself causes any actual clinical adverse events.
Because of accidental pregnancies, there are some treatments denied to all fertile women regardless of choice. Ussually they are those that cause horrible birth defects (limb reductions etc) or make pregnancy deadly to the mother. Given the links between oxygen and injuries like FAS, this hemoglobin treatment may be one of that group.
Example: Acutane was once used to treat acne in teenagers. Many/most doctors didnt give it to teenage girls regardless of whether they were sexually active or on the pill. Mistakes happen. That drug would do horrible things to a fetus.
... Or all the women who do not want any (more) biological children or find this side effect better than the disease? Making babies is not a raison d'etre in modern civilization.
I like how evolution if you can call it that figured out first that fetal haemoglobin mitigated the problem.
The fix used CRISPR (and a gene engine?) to implement the fix on other people.
It's like version 2 of what human bodies figured out first naturally.
This sounds like something that my dad or other people with COPD/IPF could use. If fetal haemoglobin could grab more oxygen it would benefit people with low lung function. Sort of like Star Trek "Trioxin" they loved to use.
I wonder since fetal hemoglobin has stronger binding with oxygen which means the blood can oxygenate faster if this can be used for other issues as well like reduced lung capacity and performance enhancement.
But will the drug approval agencies allow genetically engineered therapies for anything disruptive? For example, they've been blocking the caries vaccine for decades.
As long as someone is willing to pay the $1-2B for the formal testing, and wait a few years for the paperwork to go through, I assume it'll work like any other procedure.
yes. here’s an extreme example, but i’d say that every monoclonal antibody therapy on the market today (11 of the top 20 biggest drugs this year) qualify.
There are no details to give, there never was a successful caries vaccine it’s just always been stuck at being worked on.
Big dental isn’t blocking it we just don’t have a good enough model and yes there isn’t a sufficient financial incentive to develop it really either.
Caries isn’t a big problem these days, it’s not then major cause of tooth problems as people grow older, dental hygiene and more importantly fluoride in water pretty much solved it for those population that were affected.
There is no financial reason to block a caries vaccine as it’s not going to have any impact on the industry, cosmetic and corrective procedures would still be just as in demand and gum disease is by far a bigger factor for tooth loss in adult patients than caries.
Not to mention that quite a lot of the “vaccines” weren’t traditional vaccines but rather replacement therapies where lacto acid producing bacteria would be replaced with strains that cannot produce it but can outcompete the lactobacillus flora in your mouth, these treatments are let’s say problematic since we have had little to no experience in flora replacement therapies and can’t predict or model the outcomes well.
Dr. Jeffrey D. Hillman invented it in the 1970s-1980s at Harvard under NIH grants (https://grantome.com/grant/NIH/R01-DE004529-10). Swab inoculation and you're done. It worked perfectly in animals and humans.
In the 1990s, he founded Oragenics, to try to commercialize it. The FDA gave them the runaround for about 20 years before they finally mysteriously gave up. In 2016, he got a 17-year patent, so I guess it'll be shelved until 2033 at least.
There's something fundamentally wrong with this picture. Why should a simple application of genetic engineering from the 1980s take 50+ years to make it to market? It's either a complete scam or a conspiracy.
The article does not mention whether that's because putting Chromosome 11 back with CRISPR is harder, or whether for some reason that wouldn't fix the problem.