Vertex set the price of Casgevy at $2.2 million
Patients must spend weeks, even months, in the hospital before and after the therapy is administered.
Yoiks. So how many actual people are going to be able to get this treatment?
Vertex set the price of Casgevy at $2.2 million
Patients must spend weeks, even months, in the hospital before and after the therapy is administered.
Yoiks. So how many actual people are going to be able to get this treatment?
Ohalo (the company Dave Friedberg is now CEO of) recently got approval for a potato edited by CRISPR:
Ohalo had two RSRs under consideration this year for its potato, one which focuses on higher concentrations of beta carotene – enhancing the overall health and nutrition value of the potato – and another which results in reduced glucose and fructose content in the potato, which, according to Ohalo, will reduce the adverse side effects that lead to significant spoilage during cold storage of potatoes.
https://thespoon.tech/gene-edited-food-startup-ohalo-emerges...
I would have bred them for more potato protein. It's a very close meat protein substitute by essential amino acids. Might be why it tastes so good. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245118/
Of the ten plant-based proteins included in the current analysis, potato protein is the only protein source containing the WHO/FAO/UNU requirements for all essential amino acids. Thus, when consuming potato protein as the only dietary protein source at the recommended adult protein intake level of 0.66 g/kg/day, sufficient amounts of all essential amino acids should be consumed. It remains to be investigated whether the ingestion of a single meal-like amount of potato protein has the capacity to stimulate muscle protein synthesis.
Anyone know about vegan protein profiles and best ones now?
I supplement protein, filtered for vegan because my body doesn't like whey, and Pea protein is pretty solid. It's a "complete" protein and doesn't require any complicated processing steps, just drying, pulverizing, and a centrifuge step to spin out the fiber.
Are you sure that's all they do? Peas aren't even close to 100% protein, so you'd be eating a very high-carb powder if that were the case.
Yep, here's an article [1] describing the process. Here's some youtube video I found showing the various steps [2].
They don't have to use any chemical solutions more exotic than water and air. I bungled the explanation with "centrifuge", it's more complicated than that, but the fiber content is removed in that step.
[1]: https://gogood.co.nz/blogs/news/how-is-pea-protein-manufactu...
I'm assuming that's the point of the centrifuge?
Hence the "spinning out the fiber" bit. Likewise, whey protein is a byproduct of cheesemaking where fat gets separated from milk, otherwise it'd be a very high-fat powder.
Not quite vegan, but I like cricket protein.
Cricket protein is still insanely expensive though.
Cricket protein can trigger shellfish allergies, fyi.
1. Soy, brown rice, pea, corn, and potato all hit their EAA/total protein cut-off.
2. I don't see how amino acid % of total protein is a useful way to gauge a food's protein especially in this context. Wouldn't you want to look at protein per calorie or EAA per calorie?
For example the paper's chart might make you think that you should eat potatoes and corn if you want to maximize plant-based protein, but that's not the case at all.
- 500 calories of potatoes boiled: 10g protein (650g of food)
- 500 calories of rib-eye steak: 54g protein (200g of food)
- 500 calories of soy chunks (TVP): 75g protein (btw hits all EAA objectives for the day) (150g of food)
- 500 calories of wheat gluten (seitan): 101g protein (135g of food)
Potatoes are dense in other nutrients and a great part of a healthy diet, but you definitely wouldn't use potatoes as a "meat protein substitute". Even broccoli is 3x as protein dense as potatoes.
On the other hand, seitan, tofu, and TVP are the trifecta of plant-based protein that can actually substitute for meat.
Wouldn't you want to look at protein per calorie or EAA per calorie?
PDCAAS is a reasonable standard to use, pro-rated against total calories.
https://en.m.wikipedia.org/wiki/Protein_Digestibility_Correc...
Don't compare whole potato, it should be to potato protein extract.
I skimmed the article but it seems to contradict itself:
Soy, brown rice, pea, corn, and potato protein have essential amino acid contents that meet the requirements as recommended by the WHO/FAO/UNU (WHO/FAO/UNU Expert Consultation 2007) (Fig. 2).
and another which results in reduced glucose and fructose content in the potato,
That's pretty amazing. Imagine if we can change apples to produce Aspartame instead of sugars!
Unless you are diabetic, aspartame is much worse for you than sugar. It causes metabolic issues, such as reduced metabolism (leading to more weight gain than a subjectively equivalent amount of sugar), migraines in some people, interacts with drugs, is bad for your digestive tract, and probably has other side effects.
Even if you are diabetic, you can already eat apples. They have a low glycemic index.
* reduced metabolism (leading to more weight gain than a subjectively equivalent amount of sugar),*
Doesn't that mean aspartame somehow contains more energy than sugar?
I mean, assuming the increased weight is fat, that is stored extra energy.
There is some evidence that artificial sweeteners increase insulin resistance: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014832/
I have also heard that because artificial sweeteners increase insulin levels without increasing blood glucose to the same extent that sugars would, this leads to a blood sugar drop which induces increased eating.
The idea works longterm. You take aspartame, which has a sweet taste but no energy. Your body starts all kinds of digestive functions and gets confused. After a lot of aspartame it doesn't know how to respond to sweet food anymore.
Extraordinary claims require extraordinary evidence. Can you back any of this up, or provide a reason I should believe what you’re saying? Because it directly contradicts decades of research on what is perhaps the most scrutinised and studied dietary supplement in the world.
Aspartame is safe, and very well tolerated.
You’re spreading misinformation.
Decades of research have found rare, but still very mildly negative health results from aspartame, and an overwhelming flood of direct evidence for strong negative health effects from sugar.
Back up what you are saying with some studies. Because what you are claiming is going against a LOT of modern medical knowledge.
I don’t see how a plant is supposed to metabolize the aspartame for energy?
It would only be a successful reproductive strategy if some external actor decided to propagate the plants that were putting something not useful to the seeds into the fruit.
Hmmm. That second one reminds me of the Flavr Savr (https://en.m.wikipedia.org/wiki/Flavr_Savr).
More shelf life in exchange for likely worse taste...
Worse taste but probably healthier in this case.
Yeah potatoes will fill your stomach and better than starving but they aren't really healthy food. Eat them in moderation, and prefer sweet potatoes/yams.
On the contrary, potatoes are full of good stuff: https://www.mayoclinichealthsystem.org/hometown-health/speak...
Just make sure to go easy on the toppings!
That says,
“ true that potatoes are high in starch or carbohydrates, the nutrients that cause spikes in blood sugar. But pairing them with foods high in protein, fiber and unsaturated fats can slow digestion and lead to a steadier release of glucose into the bloodstream.”
Which suggests you should add toppings or else potatoes are not very healthy if eaten on their own. (I think they’re fairly high up on the glycemic index).
prefer sweet potatoes/yams.
Sweet potatoes, as you might expect, have more sugar in them. As do garnet yams.
The issue with potatoes isn't really their (low) sugar content.
thanks that's neat, although I wish it wasn't with a Solanaceae member. Do you know if they are working on other types of produce or are they just working on potatoes?
Are you concerned about off-target edits activating toxin producing pathways?
Maybe they are referring to the small percentage of people are sensitive to the whole family (potatoes, tomatoes, peppers, tobacco, etc) and find any exposure produces inflammation/digestion issues.
yes it's both actually! Potatoes are wildly toxic to humans when they have any green on them, and that can actually happen in the refrigerator if left to long and then consumed. They have the capacity to really F us up. Editing those strikes me as like threading a needle between hair triggers. You don't want to miss your target.
But also yes exactly, the whole family can cause inflammation and difficulties in people sensitive to them (which tragically because I love spicy food, includes me D-:). So that means that any cool stuff they do I won't be able to try.
Don't worry, once they figured it out they are going to put this stuff in every food and you won't be able to eat anything at the supermarket anymore.
monster-potato?
Pretty cool, I wonder if it changes the chemical composition of the soil in any way compared to a regular potato.
The gene that causes sickle cell anaemia actually provides partial immunity to malaria, which is why this gene has not been bred out of the population over time.
which is why this gene has not been bred out of the population over time.
Is that why? Or is it just the people with it aren’t sick enough to die before procreating?
It's a recessive/heterozygous thing. If you get the gene from neither parent, you're vulnerable to malaria. If you get the gene from either parent, you're immune to malaria and don't get sickle cell. If you get the gene from both parents, you get sickle cell. A hypothetical future person who's going to be born in an area with a lot of malaria would really want exactly one parent with sickle cell and one parent lacking the gene completely to guarantee the best personal outcome, or they'd want exactly one heterozygous parent (for a 50% chance of being immune to malaria with no downside), or they might settle for the gamble of two heterozygous parents (50% chance of immunity, 25% chance of sickle cell).
Can they do sperm (or egg) selection to change those odds for IVF?
Or add the DNA tests to dating apps.
In fact yes! https://punchng.com/value-of-ivf-in-elimination-of-sickle-ce...
But practically, it'd be a huge challenge. Nigeria's one of the main victims of malaria and, not by coincidence, one of the main victims of sickle cell. There are IVF clinics in Nigeria, but they're very expensive even before you consider sickle cell testing. It likely wouldn't scale to all of the births per day, and something like a quarter of the country would need it.
But it's not IMPOSSIBLE. You'd need to do maybe 75 or so per day to cover the 25% or so of the country that have the gene and would need it. Hard and expensive and impractical, but perhaps possible?
This sounds like Tay Sachs for Africans. Read that carriers of Tay Sachs might have defended them against tuberculosis, and they're also looking at gene therapy for it.
Prevention is the preferred method of passing this trait on however.
(You already know this but for the general audience)
The train doesn't make you immune to malaria but it does increase resistance after infection.
Without access to modern hospital treatments it is fairly normal to die very young from sickle cell disease - it causes 100k+ deaths a year.
An in-law of an ex has it, and regularly spends days in hospital during crises. Without access to a high quality hospital he'd have been dead a long time ago.
The average life expectancy for someone with sickle-cell disease in developed countries is 40-60 years, and serious crises tend to start from childhood.
That said, it's recessive, and so it's likely the reverse of what you think: It's not primarily the people with full-blown disease who contributes most to the long term survival of the trait, but that the trait alone confers fairly significant advantage in regions where Malaria is huge killer mostly without causing health problems. So across the combined set of carriers and those with the full disease, the life expectancy in Malaria stricken areas tends to be higher.
Pattern of change of the prevalence of the trait correlating with changes in prevalence of Malaria has been observed many places. E.g. the prevalence among US black people is significantly lower and dropping than in the areas their ancestors came from.
I think this is right, but just to spell out the recessive gene implications for readers, here's the Punnnett square[1] :
R | r
+----+----+
R | RR | Rr |
--+---------+
r | Rr | rr |
+---------+
The people who have some malaria resistance are all of the ones with "r". In particular, the "Rr" folks have the resistance, but not the anemia.
So basically, this gene screws over 1/4 of the population and benefits 1/2. In areas with lots of malaria, this tradeoff is worthwhile, evolutionarily speaking.
One of those harsh cases where evolution (if we personify it) does not care about individuals — only the species.
Worth noting punnet squares are kind of bunk: https://youtu.be/zpIqQ0pGs1E?si=SDRQP-PW2u_6Jq3d
Although sickle cell does seem to be one of the rare cases where they work out.
Punnet squares are as "bunk" as Ohm's Law.
No the important part is that the mutation is recessive, but being heterozygous for it is enough to confer malaria resistance.
Africa wasn't colonized by Europe until vaccines and treatments were invented because of malaria and other tropical diseases. Quinine was one of the last ingredients needed to conquer Africa.
In regions where malaria was endemic, this mutation was selected for, as malaria kills children.
Malaria often kills people before they reach the age of being able to procreate.
Good point and thanks for being on-topic. Humans have three variants of the HBB gene and having sickling mutations in the variant expressed in adult is causal to SC disease.
The FDA-approved treatments reactivate the fetal HBB gene in adults and this change in gene expression control effectively prevents SCD.
Very cool and transformative work. Now we have to get the price tag down from seven figures to four or five figures so that it will be used widely. That may be a few decades. Let’s hope that more efficient alternatives are developed soon.
From an efficiency standpoint, I think having to harvest and modify the patient's stem cells is probably the biggest choke point, right? I would imagine that if you could inject something once and be done with it (I'm thinking like Zolgensma), you could mass produce it more effectively
That is true but even the unreliable malaria vaccines that are out there are more effective and reliable against malaria than sickle blood cells.
Correct, but if we have good treatments for malaria (e.g. hydroxychloroquine, atorvaquinone) then I would argue that we no longer need that partial immunity
Lots of AI content recently (and I am working on AI-adjacent stuff myself lol), but I am most excited for upcoming medical changes. Cure every disease, then let people have designer bodies if they like.
You might enjoy Cronenberg’s Crimes of the Future if that idea is appealing to you. Very curious execution of a disease-free bio-tech (organ-ic-tech?) future.
I just wanna be able to digest plastic
Speaking of digesting random things, I found myself bored in the shoe section of some store (I wanna say Nordstroms), and I was curious if I could eat the leather shoes. Beef is beef, right? Apparently you cannot digest leather due to the chemicals involved in the curing process.
I was curious if I could eat the leather shoes. Beef is beef, right?
This was a recurring theme in Lucky Luke [1]. The titular hero cooks and eats his boots when he faces starvation, usually when he gets lost in the desert.
I was wondering about new digestive capabilities recently and wrote this blurb:
https://clonk.me/nft/137/0x8abd8d9fab3f711b16d15ce48747db496...
If we could eat different things, we could give up agriculture and save a bunch of land and energy.
why digest plastic if you can photosynthesise
I'm a big Cronenberg fan but I haven't seen this one (these ones? as there seem to be two). Would you recommend the 1970 or the 2022 version?
Sorry, I wasn't even aware of 1970.
They are apparently unrelated, it is 2022 that I was referring to.
Excellent, thanks!
Why stop there?
Why stop there?
I can't wait to grow all those extra fingers and teeth!
I think we're pretty far away from designer bodies. We might solve a lot of cancer in our lifetimes though.
Lyfgenia’s approval came with a black box warning about the possibility that patients who receive the therapy might later develop blood cancer and should be monitored for that risk. Two patients in trials of the drug died of blood cancers, and studies concluded that the cancers were caused by the chemotherapy conditioning regimen for the treatment, not Lyfgenia itself.
the cancers were caused by the chemotherapy conditioning regimen for the treatment, not Lyfgenia itself.
I am certain some media group is going to conveniently leave this part out of the title of their article, and surely no one is gonna waste time reading the actual article and the rumors will take off.
The article says "patients must undergo a preparatory treatment with a chemotherapy drug to remove any native stem cells that might remain in their bone marrow." It doesn't make much difference to the patient if it's the Lyfgenia itself or the chemo drug, if the chemo drug is a requirement. Right?
Fair enough, but there remains the possibility of finding an alternate, safer chemotherapy drug.
Does anyone know if changing the drug would require a new FDA approval for the entire regimen, or could the protocol be easily changed?
Does anyone know if changing the drug would require a new FDA approval for the entire regimen, or could the protocol be easily changed?
The FDA-approved prescribing information will recommend a particular chemotherapy regimen, but clinicians will be free to substitute alternatives if they believe those are clinically superior. They won't need permission from the FDA or the manufacturer to do that; clinicians deviate from the FDA-approved manufacturer recommendations all the time ("off-label prescribing").
If the manufacturer wants to update the official recommendations in the prescribing information, then they'll need FDA approval for that. But it is possible for clinicians to publish their own treatment guidelines (e.g. in medical journal articles), independent of the manufacturer, and the FDA has no control over those.
What a weird system: there's something better, but the manufacturer isn't allowed to tell you about it. What if they, like, slide the journal article across the desk, whilst holding their finger alongside their nose and winking?
What a weird system: there's something better, but the manufacturer isn't allowed to tell you about it.
It is the way medicine works – not just in the US, in most countries worldwide. Not just about gene therapy, about all drugs and devices.
The FDA and its international equivalents (the EMA in the EU, the TGA in Australia, etc) regulate the manufacturers, not the clinicians. They control what the manufacturers sell and even what the manufacturers are allowed to say about their products (in product packaging, prescribing information, advertisements and marketing collateral). They don't control what the treating clinicians do with those products – to the extent that is regulated, it is the job of other regulatory agencies (e.g. professional licensing boards, civil courts hearing medical malpractice claims, etc)
What if they, like, slide the journal article across the desk, whilst holding their finger alongside their nose and winking?
What they'll do instead: there will be a conference where (among other things) the journal article author will present their findings/recommendations, and the manufacturer will sponsor (and hence help pay for) the conference. They never actually said anything, they just made sure you were there to hear about it.
I'm not a doctor but my mother is. When I was a teenager, she'd be invited to these free dinners at fancy restaurants paid for by pharmaceutical companies, and a couple of times they allowed her to take me along (she was allowed to bring her spouse/partner to some of them, so she just asked "can I bring my teenage son instead"?). During the dinner, some academic would do a presentation on their research into how wonderful one of the company's drugs was, and also do some Q&A. So the manufacturer wasn't technically saying anything, everything was said by some academic (whose research they were funding). I didn't understand it all, but I found it rather interesting. Still didn't follow her footsteps into medicine though (although my younger brother has).
But, she tells me the regulators have cracked down on free perks from pharmaceutical companies, so they are forced to be a lot less generous nowadays than they were back in the 1990s. (This is not the US though, this is Australia.)
It's reasonable to expect small improvements in the risk profile, but I think blood cancer is going to be a side effect for any drug following this basic idea. You will always need some chemo to destroy the defective blood-making stem cells before replacing them with the genetically-modified blood-making stem cells, and any chemo that is strong enough to kill all of the blood-making stem cells in your body is necessarily going to have a risk of damaging healthy cells and turning them into pre-cancer cells. So the risk can be reduced but probably not eliminated.
That makes sense. Thank you.
In theory, could a separate gene therapy target and knock out the stem cells that carry the mutation?
There is active research on doing gene therapy without requiring chemotherapy (or radiation) first. It has been shown to work in mice, and they may eventually get it working in humans too. It would likely require a significant modification to these gene therapies though, since one approach is to alter the method of growing the stem cells to produce a significantly higher number, and then transplant that, with the hope that the transplanted edited cells outnumber and outnumber the original unedited ones. So very likely the FDA would treat that as a new therapy requiring a new approval process.
https://med.stanford.edu/news/all-news/2019/05/radiation-fre...
There is also ongoing research into immunotherapy for killing stem cells, as an alternative to the existing methods of chemotherapy and radiation. Potentially, immunotherapy could have significantly reduced secondary cancer risk.
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-...
I was thinking more that it could poison the reputation of gene therapy by causing folks to falsely associate cancer with gene therapy. And that false stigma could carry on even if one day chemo was no longer needed.
Here's basically how the process works:
* Harvest stem cells from the patient.
* Prepare a DNA plasmid with the Cas9 gene, guide RNA for the desired genetic modification, and an antibiotic resistance gene.
* Electroporate the plasmid into the harvested stem cells. Grow the electroporated stem cells in antibiotic-containing nutrient media. Only cells with the plasmid (and thus antibiotic resistance) survive.
* Expand and freeze the genetically modified cells.
* Administer chemotherapy to the patient to eliminate defective bone marrow stem cells.
* Inject the modified stem cells back into the patient, where they repopulate the bone marrow with the CRISPR edits, aiming to correct the genetic mutation.
This process isn't new but one of the biggest challenges is propagating genetic modifications to all effected cells in the body. This is why it's much easier to GMO an egg / sperm because once the change is made there, it's replicated in every new cell thereafter.
Other techniques utilize harmless viruses to transfect genetic modifications to the body, but this has other trade-offs. mRNA vaccines don't propagate to every cell, but the cells which do successfully transcribe the mRNA are able to generate enough of the target protein that the body can recognize it and develop an immunity to it. Eventually, the modified cells will die and no cells will be left to produce the mRNA vaccine protein.
is crispr a big improvement here over AAVs or zinc fingies?
AAV or adeno-associated virus is a delivery method for getting cas9 mRNA (the code that says, make cas9 protein and do gene editing). Zinc finger nucleases are a similar class of dna editing proteins.
In this specific experiment they chose to transfect cells with plasmid directly rather than transduce with virus.
ZFNs are difficult and slow to engineer. There are certainly tradeoffs but the fact that almost the entire industry is using CRISPR-based approaches tells you where things lie on balance
Do you know why they're having the marrow synthesise fetal hemoglobin versus hemoglobin A(2)? (Is it simply because HbF is one molecule while HbA and HbA2 are two?)
Fetal hemoglobin has a lot of biochemical advantages for fighting sickle-cell disease on its own so this is leveraged in the CRISPR solution - e.g. create more of the cells that inhibit the disease in the first place.
https://en.wikipedia.org/wiki/Fetal_hemoglobin#Treatment_of_...
Pretty big news. I believe this is the first gene editing therapy approved by the FDA and theres a large backlog thats been in the works for many years. Id like to see the flood gates really open up for gene editing for diseases, preventative treatments, and even cosmetic.
Id like to see the flood gates really open up for gene editing for diseases, preventative treatments, and even cosmetic.
Me too, because it's fun to consider DNA as some code we can edit to get outcomes we want!
However, some people are ethically opposed to that - but piggybacking on the preference people have for having children should be able to move the Overton window!
It really is inspiring. Yeah I take the opposite side, ethically speaking. I think its cruel to not allow people to fix their bodies in the ways they want and in many cases need. Im in the max body-editing camp. Also this should resolve race issues once and for all which is fun to think about.
Also this should resolve race issues once and for all which is fun to think about.
I doubt it. One of the root causes of “race” issues is humans using prior probabilities. Unless that changes, then the priors will simply move on from being skin tone based. I would suggest they already have for some portions of the population.
some people are ethically opposed to that
Body autonomy may be a fundamental right requiring legal recognition. It curiously cuts across many protracted debates: abortion, vaccine requirements, transgender rights and now gene editing. (I suppose abortion and germ-line edits are a special case.)
Now comes the hard question, how will the US payer system afford it?
"An August report from the nonprofit Institute for Clinical and Economic Review found that the treatment and similar gene-editing therapies for sickle cell disease would be cost-effective if priced between $1.35 million and $2.05 million. In the U.S., patients with the condition and their insurers pay on average between $1.6 million and $1.7 million for disease management over the course of a lifetime." Source: https://www.politico.com/news/2023/12/08/fda-gene-editing-th...
You answered your own question. The taxpayer already pays the same amount for lifetime treatment. This is just going to be the same except the person can lead a completely normal life after this. Also over time this will probably be much, much cheaper than the current lifetime treatment. There’s no reason a lot of the process can’t be easily automated.
No, I did not "answer my own question". These therapies are priced at $2.2 and $3.1 million, much greater than their calculated cost-effective price. And these are not small molecules that can be easily made generic, so not likely to get that much cheaper over time.
Plasmid production is pretty well industrialized. Lots of biotech drugs/treatments ferment plasmids as a step in their process (for example the Covid mRNA vaccines that cost $25).
I imagine an expensive part of this process is incubating the treated stem cells to increase their numbers, and then just the cost of the hospital time while the new cells establish and the patients immune system recovers from the chemotherapy.
Any new product is going to start out as expensive and this likely isnt a market realized price. This is the first of its kind. It probably still wont be cheap but its not going to be this absurdly priced in the future considering even the insurance companies likely wont pay for this.
And US patients won't be able to get it because they're going to be overcharged and drowned in debt to the point of bankruptcy.
Compared to similarly developed countries, Americans are actually in great shape when it comes to debt. See the OECD Data: https://data.oecd.org/hha/household-debt.htm
Don't be facetious. Parent was obviously referring to medical debt, which most first worlders never have to think about.
I wasn’t being facetious, I (wrongly) assumed you could infer the argument:
Americans have significantly less debt than Western Europeans. Their average appears to be 50% higher than ours. Including medical debt.
The idea, as per GP, that this treatment will inexplicably drive Americans to bankruptcy, is stupid. It’s offensively dumb. It’s the kind of uninformed doomer nonsense that runs rampant online progressive echo chambers, but has no basis in reality.
…which most first worlders never have to think about.
Those lucky bastards. With 50% more debt.
A very lazy reply.
Look at access to the cystic fibrosis therapies ($300,000 per year). The US (including Medicaid) were paying for them from launch in 2012.
The UK just came to an agreement for NHS to pay for it in 2020. 8 years later.
In Canada, only 5 of the 12 provinces/territories pay for it and only if your a child. Adults don't get it.
You actually stand the highest chance of getting it in the US.
I wonder whether in the future doctors have a visual designer(WYSIWYG) similar what programmers have in the form of Visual Basic/QT to alter DNA. It'd be pretty interesting if it happens
I wonder if they will have a natural language chat interface
Also terrifying in a sense. Instead of some wacko shooting up a school, he’s going to make an apocalyptic virus instead.
How do the edited genes replace the body's genes?
No replacement involved. The treatment edits and reactivates the fetal version of HBB gene that is inactivated after birth.
They technically never do the gene replacement within the body. They take the marrow alter it, grow and produce an external modified new marrow. Chemotherapy wipes out the old bone marrow out and the modified marrow is introduced instead.
As breathtakingly advanced and unprecedented as CRISPR treatment is, the execution is still radical and crude by necessity. Not to diminish the accomplishments but to note that we still have a great deal of room to grow.
Hopefully knowledge will eventually advance so that less extreme and unpleasant methods will take its place. But that would be a tough nut to crack.
Does anyone who's more familiar with exactly how this works know if this could be applied or potentially applied to thalassemia? From what I understand those are also related to genetically-driven misshapen red blood cells.
CRISPR Therapeutics also has a therapy for Beta Thalassemia in human trials that is up for approval in February 2024.
“Editing Humanity” by Kevin Davies covers the history and near future of CRISPR and includes a great chapter on describing both of these therapies.
could we have a CRISPR based penis elongation medicine in future? I would like to invest to that startup
Go for curing baldness first
My neighbor has 2 adult children with sickle cell. Its very tough watching what the have to go through. Frequent ambulance visits followed by multiple days in the hospital. Lots of pain in everyday life. The daughter is legally blind from complications.
The son tried for a long time to hold a job but couldn't because of how much time he would miss.
I hope they are able to get this.
Historic. This opens the door for CRISPR. Very exciting to have followed this in Science/Nature magazine till today.
Would be interesting if they could do this in embryos.
Yet another first. Approved, looking forward to more such products, in spite of everything and all the short-term issues, long term is an absolute game changer across the board.
Every time I read[1] about CRISPR there seem to be concerns about off-target editing, that might cause all kinds of trouble. Is this a solved issue ?
Note: I am not a doctor, but I do have a genetic condition that might benefit from CRISPR therapies, hence my interest.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034092/#:~:te....
This is such good news! I bet a lot of monogenic disorders are on the table now.
Recent and related:
FDA considers first CRISPR gene editing treatment that may cure sickle cell - https://news.ycombinator.com/item?id=38354939 - Nov 2023 (124 comments)
Any status updates on the next gen CHEWR?
The mechanism by which this treatment works is really neat (some notes in [0]). The treatment increases the production of a fetal version of hemoglobin. That fetal hemoglobin is unaffected by the sickle cell mutation. Presumably everybody who is alive (and not a fetus) has a good copy of this fetal hemoglobin gene and it "just" needs re-activated.
[0] https://sciencebasedmedicine.org/first-crispr-treatment-appr...
This is Day 1 so the price and how well it works today is almost certainly the worst it will ever be. Insurance will likely cover the cost. It's a very bad, painful, and outright deadly genetic mutation and $2.2 million is practically nothing compared to doubling someone's lifespan or giving them an extra 10 years.
More info I found relevant regarding cost for typical treatment and out of pocket estimated costs: https://www.hematology.org/newsroom/press-releases/2022/the-...
I don't agree that it is nothing. 2 millions, if applied properly, could do good for many people. Take ten children from poverty, give ten children chance to get a good education, etc.
There is always a some kind of moral dilemma: should you spent millions to try to extend extremely I'll person or help with that money to some healthy poor children?
Such a crass statement. What if you're the patient? Would you spend 2 million to live 30-40 more years? It's so easy to step back and weight the lives of other as if you're making the decision for others.
What if you are on those 10 poor kids he mentioned ?
I don't agree that OP statement is "crass". It's a very pragmatic and important question we have wrestle with.
Except those 10 poor kids aren't spending their own money to save themselves. The patient is though which is the point.
if it's their own money sure.
But almost all care services end benefiting from some sort of subsidies. Even if just by increasing the cost of inssurance for the rest of the population
The $2M represents a certain portion of society’s productivity, which is not unlimited.
Yes, but spending it preventing debilitating disease that would cost about the same amount over the lifetime of the sufferer is a no-brainer, even in net econonic output, terms.
But it is so only for few countries with ridiculously high costs of medical services. What about other? If we are talking about someone from south America?
2m is much higher that either costs or economical output the treated person could deliver through lifetime.
Crass, sure.
Not sure it's really easier though, economics and emotional affect are often at odds. Ask people if a hospital administrator should spend 100k on either a single liver transplant for an 11 year old girl, or spread over 100 less expensive life saving interventions for 50 year olds, most people will say save the girl and demand the administrator be fired for even needing to think about it.
(Half remembered but apparently real scenario, though I'm not sure where from)
Why? The way health insurance works, all of those are profitable treatments. There is no "choose one or the other". Sick children/adults becoming healthy adults that can pay for health insurance is not a moral dilemma.
What are you asking "why" about, exactly?
The median income in America is a little under $40000 per person[1], so that $2.2 million pretty much represents the entire financial income of the average American over a working lifetime (55-60 years).
So in essence, you'd be trading the equivalent of one person's entire lifetime of productivity in exchange for the first generation of a radical new medicine whose outcome is unknowable.
I don't think it's crass to err on the side of caution for such a scenario.
[1] https://en.m.wikipedia.org/wiki/Per_capita_personal_income_i...
These people mostly do get treatment now, for decades, involving regular expensive long term hospital stays. So you're trading already expensive treatments that cut their earnings potential drastically both by cutting number of productive years but also due to extensive sick leave.
So if there even is an increase in the total cost of treatments, it's not at all a given it's a a net increase once account for decades of additional working life.
I see you are a fan of the MAiD program in Canada.
Of course I will do anything to prolong life of myself and my family, like any human being.
But as a society with limited resources we need to set priorities. I hope everyone will be able to receive treatment.
However, such treatment is only for rich people, or from rich countries.
Even some countries in Europe are not reach enough to pay for such medicine. Like Zolgensma, which also costs around 2 millions USD to cure SMA.
This is the effective altruism / utilitarianism insanity. If we only thought about "what the best use of $2 million is" we would still be living in huts.
Actually, utilitarianism and capitalism have been the strongest growth factors for human prosperity and welfare since forever.
Many societies with excessively strong opinions on morals however are literally living in huts.
Setting aside that the US government is deeply influenced by Christian conservatism and the culture by Puritan ideals, to the point that no American President can be elected without vocally professing faith in God, Christ, or being seen with a Bible in hand, and thus is the most moralizing culture within Western civilization by far (particularly where sex and gender are concerned,) which hut-dwelling societies are you talking about, specifically?
Here's a graph showing the negative correlation between "hut-dwelling" and "utilitarianism":
https://www.pewresearch.org/short-reads/2019/05/01/with-high...
The US can be said to be both. E.g. you won't find many "huts" along the northeastern coast, but search and you'll find them elsewhere:
https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...
I'll leave it as an exercise for the reader to determine where the most "huts" are found.
So it's flat out wrong to claim that some sort of perceived moral bankruptcy with regards to the value of human life has left our society in the stone ages, when all evidence points to the contrary.
Under utilitarian capitalism people are expendable, but in the meantime they are less likely to dwell in huts than morally superior societies.
Note that I've blatantly equated religion with moral here.
What about real people who are living in huts right now? With few million you can drastically improve thousands of lives.
Are they not worth saving? Because they are far away and have small purchasing power there is small sense to help them.
It's possible to do both :)
How? Society does not have unlimited resources.
Especially the one that extremely ill people need, humans.
People with sickle cell already cost the taxpayer a lot of money over their lifetimes. I wouldn’t be surprised if it cost more than this treatment.
Of course, in that case it is simple. I imagine dopa42365 was referring to a scenario where there was an alternative way to spend the money.
Possible in theory. But real life shows neither will be done in enough quantities.
I understand the dilemma, but many of those same children you are thinking of live in poverty in places such as Africa and with the misfortune of sickle cell disease.
If we prevented treatment because the money could be used elsewhere, we likely wouldn’t/won’t develop a drug that we could eventually[1] make cheap enough to cure these kids and give them longer lives too. We can do better!
[1] There is a cynical take here about drug costs, geopolitics, etc. but I am rejecting that cynicism.
As mentioned above—this is day 1.
How much did the first human genome sequence cost? (Effectively several billion dollars—now $1000.) How much did the first organ transplant cost? How much did the first electronic computer cost?
Yes, cost will slow widespread use but it will spur the. next wave of innovation—-some motivated by profit, some motivated by social altruism.
I wrote the OP :) I agree with you. What I was trying to highlight is that many of the people the person who originally responded to me was concerned about have the exact disease! And we need continued development with initial high costs to hopefully bring the costs down.
Its very close to the lifetime average financial cost of medical services related to sickle cell disease for those with it, from things posted elsewhere in the thread. So its literally just paying the same (loosely) financial cost up front and then not having them suffer through the disease.
An incentive structure that encourages mostly making the wrong decisions on things like this when it comes to cost/quality-of-life is why the US has the most expensive healthcare system in the developed world on a per capita or per GDP basis, and doesn't have better-than-typical general outcomes to show for it.
To be fair, those incentive structures also encourage the development of what everyone knows going in will be—initially—absurdly expensive treatments.
Over-under on when the NHS agrees to pay for this?
I'm sorry but the "cure" for that requires political change involving the stepping over of some people's corpses. You can only do that once people are sufficiently angry.
Healthcare? People pay to be and stay healthy. The money was earmarked specifically for this purpose. Also, in the long run, you will be able to cure diseases even those "healthy" children have.
Sadly, unlike tech, the price of drugs doesn't always go down over time.
Collectively paying for rare but expensive treatments is literally the problem that insurance solves. This isn't wildly out of the expected range for this sort of thing. And it will surely get cheaper as it evolves.
Since the collective probability of rare, but expensive health issues is basically 100%, I would describe it less as insurance and more as wealth redistribution. Hence the (typical) requirement to purchase insurance and lack of ability to price it based on risk.
Of course, insurance and taxation can be viewed as similar things anyway, but it is different from things like term life insurance or motor vehicle insurance or home owners insurance.
Humm no... It's just risk amortization...
If it was just that (in the US), then there would be no need to prevent insurers from pricing based on health of the insured. Or legislating a 3x cap on premiums between highest and lowest premium. Or legislating out of pocket maximums.
The premiums are very explicitly a subsidy from young to old, which I view as a tax by a different name. Except instead of it being based on one’s income/wealth, it is based on age.
I do not follow the point you are making here. The regulation and legislation around health insurance do not change the nature of it.
I think you are assuming that insurers have perfect risk assessments power and thus regulating them should be unnecessary. But they don't and we have to.
You are just repeating your assertions here. I would love some arguments.
Sure, as long as we agree that is just your point view and nothing rooted in reality.
Sorry, I don’t really know how else I can explain it. The age rating factor itself is pretty self explanatory.
Instead of charging a sicker or older person $10,000 per month and healthier or younger people $100 per month because that is close to the expected loss in the calendar year for the insurer, they are mandated to charge younger/healthier people $1,000 per month so the older person can only be charged $3,000 per month.
Imagine a similar law for motor vehicles. The car insurance companies can only charge the worst and riskiest drivers 3x what the safest driver pays. Basically, you can keep getting into collisions and at some point your premium will stop increasing. Where will the money to pay for all the damages come?
I do not assume this. Insurance and tax/wealth redistribution is a spectrum.
Here what i am understanding of the point you are making :
When we offer a service to a group of person, and somehow mandate a flat price for that service. The people using the service less are subsidizing the cost for the people who use the service less.?
Yes, although I think you meant to type
Also, it is not a flat price, it is a capped price.
As an aside, think about how the optics would have been if the politicians were transparent that a significant portion of the tax liability to pay for the healthcare would be levied based on age.
Then think about older, rich people taking advantage of this and retiring early (between age 50 to 65), and because they can afford to have very low income (but a lot of assets), they qualify for even more subsidies during their most expensive years to insure, without negatively affecting their lifestyle.
https://www.healthcare.gov/glossary/premium-tax-credit
Yes, if you strictly view it from a short time horizon. If you think of it as an individual's risk over their whole lifetime, then it looks a lot better. A young person is "paying it forward" now, in exchange for having their own expensive treatments covered once they are old. This is the bargain that any social security or old-age pension system strikes.
The trouble is, as social cohesion breaks down, and demographic cliffs approach, people lose faith that long-term programs will still be there for them as they age. Perceptual time horizons shrink, and the arguments that you have made begin to resonate.
I don't have a good answer for either of those problems. Immigration solves the demographic cliff, but appears to threaten social cohesion. We can get into tedious and repetitious arguments about why that is, but let's please not?
What we in the US call "health insurance" is today very different from the textbook definition of insurance.
I don’t think any developed country in the world has an alternative “health insurance” model. I believe Switzerland and Germany require people to purchase health insurance and it is not priced based on health risk.
Health risks in general are very predictable and very high, especially as one ages.
Is it risk amortization because we just can't predict certain health issues? Let's suppose that we had a "health oracle" (or something not too far off) to predict medical issues in individuals. How would you structure health insurance in that case?
If we had a health oracle, what would be the point of health insurance ? I think with a 100% health oracle, health inssurance will become more like group buys for negotiating better prices with health providers.
That is why the industry term for health insurers in the US is “managed care organizations” (MCOs).
When you (or your employer) buys a policy from UNH, Elevance, Cigna, CVS, Humana, etc, part of what they pay for is access to the MCOs pricing services. And vetting services to minimize errors/fraud (a process which itself is ridden with errors/fraud).
Not really, no. Most people will die of something expensive, but not $2M expensive. A quick google says that per-capita lifetime health care expediture is ~$300k.
If you are referencing this
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361028/
That data is from the late 1990s, before the Affordable Care Act greatly expanded access to healthcare, and many new treatment options have become available since then.
What I meant, though, is that across a big population’s entire lifetime, there will be a ton of high healthcare cost events. And with technological progress, new treatments will always be coming out. Which is a great thing, just not what is typically thought of as an “insurable risk”.
Sorry, how does that follow? Insurance works any time you have a function with predictable average but high variance. Is the total health care expenditure across a relevant subscriber base in 2023 very close to 2022? Then you can make insurance work. It's just math.
Insurable risk as in charging someone an appropriate premium that is based on their specific expected loss. Property and casualty, term life, etc.
Non insurable risk as in charging someone a premium unrelated to their specific expected loss (which is what health “insurance” is).
How exactly are health insurance premiums "unrelated" to care outflows (what you're calling "expected loss")? Are you saying that health insurers books don't balance and that they're losing money (they aren't) or making too much profit (not unless they're criminally hiding it)?
What you're saying doesn't make sense. There's no difference between health insurance and any other insurance in the way it works. You collect reliable and regular premiums from everyone, pay out unreliable/bursty (but statistically very predictable in aggregate!) losses as contracted, and pocket the remainder as profit. And it works.
Really, I don't know what you're talking about here. Health insurance is "expensive" in the US, sure. But it's not failing.
I meant the premium for a specific person is not related to their expected loss.
For example, if you carelessly drive and get into car collisions where you are at fault, your premiums go up, because your expected loss goes up.
In health “insurance”, it does not matter what you do, because your premiums are not based on your expected health costs. Hence it is more akin to a tax (or subsidy).
You're really not understanding this. That's got nothing to do with the insurance model. That's just a regulatory thing. All those choices do is change the specific population that gets insured in a single pool, such that their specific computed premiums are different. But for ANY such population, the total premiums paid == the total loss outflow + a reasonable profit. And you can tell that's true because the accounting for those companies appears in their SEC filings.
In practice, car insurers are allowed to partition their customers this way because it's felt to be "fair" and because it encourages safe driving. Trying to partition health insurance customers like that feels "unfair", and has minimal net benefit as health expenses aren't as controllable-by-the-subscriber as car accidents are. So we pass laws about how the partitioning gets done.
But again, "insurance" as a business model (and mathematical model) works EXACTLY THE SAME WAY. The only difference is how you draw the lines around who gets insured at what rate.
I do not dispute this. As I wrote in a sibling comment:
The Hep C cure was 100k USD when it released in 2014. 10 years later, it’s 25k USD max before insurance.
The price you see now will likely shrink in the coming years. Pretty good opportunity for an analysis on CRISPR pricing if you have a well-trafficked blog and are willing to track this for the next five years.
And much better than a liver transplant.
There are a lot of steps in between "acute HCV infection" and "requiring a liver transplant", and many insurers, even today, will require you to go through some or all of them before considering paying for HCV antivirals.
That's not a great comparison. There was a previous cure for hepatitis C before the first antiviral-based cure 2013, and the initial treatment regiment for the antiviral based regimen was a hybrid of the two, before they settled on a fully antiviral-based treatment.
The reason that the antivirals came down in price so quickly was because so many nearly-identical ones came on the market within a couple of years. That's due to the discovery of a particular protein and corresponding class of inhibitors some years earlier, which was not patented, opening the door for a flood of drugs which are all functionally identical in purpose and mechanism of action, but chemically distinct and eligible for separate patent protections.
That came at a time when political and other pressures made some private insurers more willing to approve treatment (usually after a few rounds of denials and appeals) - but again, with an emphasis on some, because there are large classes of people for whom it is difficult or impossible to get treated for HCV today. (They're just not the ones likely to comment on HN).
Contrast to this treatment, which is for a congenital condition that does not have the same political pressure to address, and for which a significant financial barrier to access is not merely the costs of the drug, but the cost of the associated care (chemotherapy, etc.) which is not included in the quoted price. In addition the patent laws function differently in this case, to the detriment of patients.
The history of hepatitis C and its treatment is fairly idiosyncratic and it would be a mistake to use the price trajectory of HCV antivirals as a predictor for any other treatment.
Indeed. The good news is, it actually turns out to be about the same or cheaper than ongoing treatment of a untreated sickle cell:
"""Each treatment is an individualized “one-off” treatment. For this reason, a single treatment for a single patient is expensive. At present it is estimated that in the UK treatment will cost £1 million or more. In the US the estimated cost is $2 million.
That may seem prohibitive, but we need to consider the overall cost-effectiveness of the treatment, which means comparing the cost of treatment to the cost of managing each disease without the treatment. Sickle cell patient require frequent hospitalization, which can be very expensive. One analysis found that Casgevy can be cost effective at £1.5 million or $1.9 million. This is in range of the estimated cost. Also, the longer the treatment benefits last, the more cost effective the treatment becomes. A lifetime of transfusions or hospital admissions adds up."""
https://sciencebasedmedicine.org/first-crispr-treatment-appr...
If I were a betting man I'd wager the house that the above is exactly why it costs what it does. 'Pay 2 million now, or pay 2 million over the rest of the patient's life as they suffer' is a pretty inarguable value proposition.
Of course once patents expire and processes refine prices will come down. The wheel of progress rolls on (more of less) as intended.
Not quite true: Identical twins/triplets/etc, can reuse the same cure.
i always find those prices unbelievable. What is the actual cost of all the expense and workhours for making the treatment
Throw that stone in the SaaS glass house. $100/m for 10c of compute and $1 of a devs time.
That's how technological progress works. The first version is expensive and not very good, so it isn't used much. But some use proves that it works, lets the kinks get worked out, and gives the makers funding and incentive to optimize the cost and quality. Give them time for a few iterations and it'll be cheap and plentiful. Just like the iPhone - the first one was super expensive, harder to get, and pretty limited. Now there's lots of cheap options and they're everywhere.
Sure. It's pretty typical for sickle cell patients to have to go to the hospital severe times per year for "sickle cell crisis".
If this is a cure (I haven't looked at the data), imagine the NPV of a lifetime of multiple hospitalizations per year. It's likely in the millions.
I'm assuming they're setting the price so high since insurance will only approve payment of a fraction of that