> helping cells produce tissue to heal from events such as cardiac arrest
> beyond simple vaccines [...] mRNA therapeutics might be tailored to instruct a person’s immune system to fight their specific type of cancer, or target protein deficiencies in specific organs, and without the toxic side effects of traditional medications.
> “My personal moonshot is snake venom, and antivenoms for snake bites,” he says. [...] “You inject it into a person, and within hours the protein that you wish is being expressed,” he explains. The final product of such research, he imagines, would be an antidote that could work for the most lethal species of a specific area, delivered in a way that can be preserved for long times in very remote areas—for instance, a powder that can be stored for long periods of time and reconstituted quickly.
This is literally all the info I found that is actually relevant to the interesting headline. The rest of the article is about this person's career and what funding vaccine companies got in 2020.
When you say anyone, do you mean anyone with massive funds to finance a big effort with mRNA? Because that would also be wrong. This comment is either just wrong, or at least missing some very important context.
There’s a massive amount of research about mRNA. Gene therapy, vaccines, lots more. And there was money already sunk in to have mRNA vaccines at a proof of concept stage before the pandemic. There just never was the urgency to use mRNA in a vaccine until the last 15 months.
But mRNA research is all over the place, and not just in vaccines.
Moderna has a public development pipeline. It shows they are working on, among other things, an HIV vaccine and vaccines/therapies for multiple types of cancer.
> mRNA vaccines [...] generate a much stronger immune response than responses that are generated to the protein in a normal flu vaccine [...]
> One limitation of the current flu vaccines is that they take about six months to develop, meaning scientists must choose which strains they think will be prevalent in the next flu season — even before the current one is over. So by the time the vaccines are ready for distribution, a different strain may have emerged as the better target.
> An mRNA flu vaccine, on the other hand, can be developed in about a month or so, giving researchers much more time to determine which strains to protect against.
The flu vaccine seems to me to have a better chance of working than an HIV vaccine because we have been trying for decades to come up with one for HIV, without any success at all. I'm not saying that their attempts won't work either, but it's more of a bet than a flu vaccine. An iterative improvement on the existing flu vaccines would still be very helpful.
It seems like with HIV they can simply sequence the prevalent evolutionary outcome in your body within a month and give your body the blueprint to destroy that version
What typically happens with HIV is that the body kills most of it initially, but the remaining ones keep rapidly evolving until an iteration evades your immune response, this takes about 12 years. Seems like an mRNA vaccine could be done every 3 years for individuals and either completely eradicate the HIV presence in the body or do it once every 12 years for a reset
Let me know if I fundamentally misunderstand something
That's not quite true - HIV of course mutates but in-patient mutations are generally considered to have a negligible effect on outcomes/have a negligible effect as a driver of morbidity .
What is the big driver of HIV is in the name, it's a Immunodeficiency virus - it kills CD4+ T cells and other cells of the immune system. At a certain point you don't have enough CD4+ T cells left and you lose your adaptive/cell-mediated immune system and then you're in big trouble. Essentially it's a war of attrition and unless you're part of some tiny proportion of people who have either a form of immunity against it or an immune system that for whatever reason is able to continue waging war on it then you will succumb
There are subtypes of each. Influenza A and B cause the seasonal flu. The subtypes are named by their hemagglutinin (H) and neuraminidase (N). E.g. H1N1, H5N9, etc.
"There are four types of influenza viruses: A, B, C and D. Human influenza A and B viruses cause seasonal epidemics of disease (known as the flu season) almost every winter in the United States. Influenza A viruses are the only influenza viruses known to cause flu pandemics, i.e., global epidemics of flu disease. A pandemic can occur when a new and very different influenza A virus emerges that both infects people and has the ability to spread efficiently between people. Influenza type C infections generally cause mild illness and are not thought to cause human flu epidemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people."
"Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1 through H18 and N1 through N11, respectively). While there are potentially 198 different influenza A subtype combinations, only 131 subtypes have been detected in nature. Current subtypes of influenza A viruses that routinely circulate in people include: A(H1N1) and A(H3N2). Influenza A subtypes can be further broken down into different genetic “clades” and “sub-clades.” See the “Influenza Viruses” graphic below for a visual depiction of these classifications."
So the answer is: 198 possible strains, 131 that actually occur. That explains why they have to pick and choose.
I don't think that's quite right. Even if you have a flu strain with a particular name (H1N1) there are a number of variants within the H1 and/or N1 proteins that the vaccine will be targeted to as well, so the number is quite a bit larger than 198/131.
It's not that hard to make a new vaccine, the process for flu is very accelerated because they're just a variation on the original theme which has been proven to be safe (though unclear on effective until AFTER the flu season hits). If you think about it, we make a new flu vaccine every year, and develop it in 6 months. Each one contains a few guesses as to which of the flus are going to be an issue, it's not just one antigen in the vaccine. Those guesses are just that, an informed prediction, which is why the vaccines tend to be fairly ineffective (40-60%) at preventing disease altogether, though perhaps better at preventing serious disease.
Moderna is claiming to be quicker, so they'd have a more accurate read on what the REAL flu strain this year is going to be, and so it should be more efficacious. The key variable will be dosing. mRNA vaccines can only deliver a certain amount of mRNA so it might be impractical to deliver very many antigens at once. Also delivery issues, the current flu vaccine is super easy to make and deliver to patients, mRNA vaccines with their complicated cold chains aren't. Obviously it's not an impossible problem, but it's less convenient.
It would be especially worth it to have approved mRNA flu vaccine in hand for the next pandemic flu. You'd might be able to actually vaccinate your way out of it.
It seems they could pre-make vaccines for all 131 extant types and then mix the flu shots based on the current season. Though, likely that wouldn’t be economical.
It does raise the question of why they couldn’t just put a bit of all 131 subtypes in the vaccine. Or if that’d overload the immune system, say, the X subtypes most likely to makeup say 99% of probable flu season strains.
They could - but up until recently no one cared enough, both for R&D spend and to get or mandate enough shots for it to work at it’s stated goals.
We’ve had people even recently refusing to give their kids polio, tetanus, or measles vaccines - and even 5 minutes of honest research or questions to a doctor will make quite clear how bad an idea THAT is. Getting 100+ flu vaccines, all which would have to go through a pipeline taking nearly a decade, when ‘nothing bad has happened’ on that topic for a hundred years?
Ain’t nobody going to pay for that.
We’ll see how the calculus is different soon. I for one would rather my tax dollars go towards figuring something like never having the flu again than blowing up some random middle eastern country a couple more times.
There’s got to be a large market for that given the entire elderly population is offered a flu shot every year. Doing that as a one off would be a huge cost saving.
Not sure it would pay for itself even in 100 years if you use that metric.
$20 (likely current retail cost of a flu shot) x the 46 million older adults in the US is a hair less than a billion a year. Making 131 or so effective flu vaccines and getting them through the process with the prior known and effective process? (including all the failed attempts)
That would be ideal - we also have no evidence that is possible at all, or desirable with immune system behavior/interactions.
We'd need try to find out, which I personally think would be way better for everyone involved than many other things we spend money on. So take that as my vote for trying?
One more piece of this is they endlessly mutate, I don't think in reality there is a limit. Most mutations probably don't help the virus proliferate, might cause it to not be effective. Eventually the shape of a new one, what your body is looking for in it's remembered virus history will change enough that it can't be detected. We see this in real time with the cv19 variants. My mental model of this (I am in software so I welcome corrections to the applicability) is it's like antivirus in software - the bad guys making viruses keep trying new variations on old ones, switching what the protection software is looking for so they can get around detection methods, as well as trying to find new holes.
The lead time for pushing new "virus definitions" is a lot shorter once the vaccine is adopted and manufacturing chain is established. A central lab can download the new variants genome from labs all over the world, select some markers and push changes to manufacturing facilities through e-mail or even Git.
One theory about the 1918 flu us that it hit young people harder because older people had encountered a similar flu already, before the younger generation were born.
But in general, being exposed to (say) seasonal flu every year might not help you at all when a new strain of pandemic flu shows up. The 1918 flu tore through young healthy people.
this are theory on case of allergy rising, no? child in early times exposed to more, played in dirt, strong immune system. child today play with i pad, use school antibacteria soap, weak immune system, allergy.
I'd also like to know where I can read further on discussions on this. My understanding is that it's the same for chickenpox - that lack of frequent natural exposure now requires artificial exposure with boosters to prevent shingles. Feels like vendor lock-in to me - often valuable but with some downsides that need to be evaluated on a case by case basis.
From my layman's reading (start from https://en.m.wikipedia.org/wiki/Shingles#Epidemiology), I think the chickenpox vaccine is potentially somewhat the inverse of vendor lock-in: that giving the vaccine to children decreases the possibility of shingles complications later for them, while studies potentially show an increase in the prevalence of complications among unvaccinated older folks, thus making it relatively worse to not vaccinate for it, as you get older, and as others opt into it. Since there's also multiple shingles vaccines now, this sounds to me more like a typical network effect from vaccination?
To make up an unrelated tech example of that, my impression was this would be like picking a Blackberry phone, while all your friends have Windows phones. You weren't forced to pick a Blackberry by vendor lock-in, but you may miss out on being in some social circles. Changing that group dynamic would require everyone to switch, not just on a case-by-case basis. But in this example though, the Window's phones (aka vaccination) have strictly more features than the Blackberry (aka kills you less often), so if you can afford to (aka you have an average immune system), it would be more logical to get a new phone yourself and join the network, than to ask all of your friends to get new phones.
Now that mRNA is productionized (or at least on the path towards it), and has been used in hundreds of millions of people without apparent major negative short term effects, the barrier is lower for other targets which no longer have to prove the whole technology is safe, effective, and producable.
We have two examples of safe (so far), effective and mass produced mrna vaccines; so it's probably easier to get funding to research and test other targets. HIV is a popular target, although it's also very difficult.
Do you ever read what you write before posting it and do a basic morality review?
I’m sure there are many valid points to debate which diseases to go after next, but you only consider the money. I’m a capitalist and love making money, but come on!
Questioning the choice to go after HIV because the primary people benefiting are too poor or gay? That is insanity.
you are misinterpret of this. i am not say that such would be good, but it are true that company tend for to do this, to mostly go fore money. so why moderna is go after hiv?
That's an answer right from the 80s and it's completely wrong and against the same statistics you link. In the US heterosexuals account for more than 25% of AIDS infections, not accounting bisexuals and undetermined infections.
i think it are support since 75% still gay and gays is very small section of population. this vast disproportination mean it mostly is still "gay disease". i counter your unacounted factors by my say that maybe some in "straight" population with disease are not wanting to disclose gay. i am wonder if maybe bi sexual are worst because they "leak" disease back into straight population. they are like persons travel between two "bubble" in coronavirus pandemic.
Many cancers exhibit immunosuppressive qualities that allow them to co-exist in a healthy immune system. It seems possible that mRNA-based therapies could be used to interfere with those mechanisms (eg binding to PD-L1, etc).
The delivery mechanism for the mRNA appears to be the primary innovation and I wonder if it would be possible to target it at specific cells. In the cancer context if you could differentially target the mRNA delivery to cancerous tissue, the 'payload' could be more generally cytotoxic but only affect tissue proximate to cancer cells.
This seems like it's on the order of CRISPR for potential to change the landscape of medicine in the next 50 years.
I agree. It's easy to overstate things, but over the next several decades I could easily see a computational personalized approach to fighting cancer: read the unique immunosuppressive markers, sort out what's tractable and what's not, then deliver a mRNA payload for that particular cancer for that particular person.
For the incredibly small amount that I know, it looks like a game changer. (Like everything else, though, there's a long road from theory to practice. Implementation is going be very tough)
I think this is precisely what BioNTech has been doing with melanoma. Not in a few decades, they already had living patients with personalized vaccination against their own melanomas in 2019:
If this immunotherapy gets developed further, the next generations of humanity may look at cancer in the same way that we look upon bacterial diseases: unpleasant, the threat of treatment resistance is there, but not the fearsome serial killer that they used to be.
Although given how we've squandered (and continue to squander) antibiotics, future generations may view bacterial diseases the way past generations did.
i think necesity here is for to block third world from acquisition of new antibiotic drug. there is where new superbug are arise. maybe it kill many there, but it also save many American here in longer term.
in such 3world country, misuse/overuse of antibiotic are make for development of resistant. then poor sanatation are make for it easy for to spread to other persons. https://wwwnc.cdc.gov/eid/article/5/1/99-0103_article
"Developing Nations" or "Developing World" is better.
"Third world" contributes to exactly the kinds of stereotypes that this comment reinforces — the backwardness of poor countries, where doctors don't know better, science is ignored, etc. It's just not accurate; medical knowledge and competence is on the rise all over the world, among both professionals and volunteers.
no. i am not stopping. i disagree. i see not any inaccuracy. i do not work for AP and do not care what it say in style book, AP change style book many time for to please the pc persons. example, AP change style book for to say singular "they" are now ok: https://www.apstylebook.com/blog_posts/7
i have not in previous heard it "offensive" and am not changing because some person sayes it. i have been to many nation, those i call "third world" are backward. improvement you describe make them moving away from third world, not make term wrong, this is move to second then to first. i will not call different word because somebody say so.
Dude, it's not developing country misuse of antibiotics that's the problem. It's pouring it into animal feed in factory farms. It's doctors in wealthy countries giving their patients an antibiotic prescription for a viral infection because their patients expect them to "do something." You're not getting downvoted for using "third world" you're getting downvoted for speaking from a position of ignorance.
> in the same way that we look upon bacterial diseases: unpleasant, the threat of treatment resistance is there
Those treatment resistances are quite different. Resistant bacteria spread to other people, while cancer is almost always limited to a single patient. So it the treatment works for a certain fraction of cancers, it'll stay at that level, unlike bacteria which become increasingly resistant over time.
(I guess that in the very long term that might not be true, since natural cancer resistance will offer less of an evolutionary advantage. But that assumes that humanity will remain in a similar state as currently, which seems unlikely.)
I know, it is an imperfect analogy. But thank you for noticing and explaining my shortcut to other readers.
Cancers are very patient-specific, and the main threat with immunotherapy is that the targeted cancer adapts quickly enough to escape the immune system again.
>Cancers are very patient-specific, and the main threat with immunotherapy is that the targeted cancer adapts quickly enough to escape the immune system again.
(I'm just an interested party and don't have any formal training on the subject.) I'm sure there are technical terms for it, but from what I've read the lack of regulatory features in the replication process of cancer cells tends to accumulate more mutations and genetic damage through each generation. PARP-inhibitors, for example, help fight cancer by suppressing DNA repair enzymes and letting the cancer cells get into non-viable states more often than healthy tissue.
In general though, this genetic entropy/volatility creates a scenario where adaptations can happen quite quickly.
I was thinking about this very subject this morning, and I realised the mRNA stuff actually isn’t the exciting part.
It’s the packaging in lipid particles that is much more interesting. We can get away with this approach for vaccines because we (largely) don’t care where we deliver the payload to, just as long as we get mRNA to a cell where it can make the protein. Not sure about current formulation, but I read most LNPs end up in the liver from circulation.
The next level of tech is targeting the particles, and then it gets as tricky as other contemporary techs, because you want your targeting mechanism on the prticles to be something resembling a receptor ligand (protein/carbohydrate).
Manufacturing of those (and putting them on a lipid particle) is still a slog. If we figure out nice ways to do that (without reasonable purity) then it doesn’t matter what is in the LNP (e.g put gold particles inside cancer targeting particles and zap your cancer cells dead).
An alternative approach would be to learn enough to make mRNA “programs” that once inside a cell could determine cancerous vs healthy cells. There’s been research on computations using DNA, and many natural pathways do similar “calculations”, that it seems feasible to create a “if specific xyz protein/carbohydrate/etc in cell exceeds threshold trigger cell death pathways”. Then injection in a tumor mass should be sufficient. The mRNA program might only need to be partially accurate to be more effective than many chemotherapy’s.
From what I’ve read both are options. There’s benefits to getting the immune system to target cancerous cells
Such as ongoing protection. Directly killing the cells is a good way to reduce tumor mass by direct injection however. The first t-cell immune treatments almost killed the patients due to liver/kidney overload from cellular debris as the immune system reacted too strongly, so being able to in cull tumor mass in a controlled fashion likely has merit as well. Either way the “detection method” would need to be very well tested and robust I imagine. Though the first treatments could be for “last chance” treatments that’d enable testing the safety of the particular detection method.
Possibly naive question: if you can differentially target any particular thing to cancer cells specifically, why not just deliver poison to kill the cells directly? I.e. chemotherapy but without any of the nasty side effects.
Not naive at all. I didn't word my question well as my interest is broadly if this new technology gives us any more ability to differentiate the delivery, either by selecting for cancer cells or by only 'activating' within cells that are cancerous.
In general there are a number of 'targeted' therapies being developed that don't specifically target the cancer cell, but try to make life more difficult for the cancer by broadly impacting a cell's ability to hide, replicate and accumulate...features that the rest of a healthy human tissue is less dependent upon.
I'd prefer to have the poison not have to be in the same process as the detection? The detector likely needs to enter or interact with the cell regardless of whether it's cancerous
One version of what you are describing is called an antibody-drug conjugate. There are about a dozen ADCs approved and many more in various stages of development
There are a lot of folks excited about mRNA as a "programming language" for the body. And it kind of is, but it's more complicated than that. The critical thing is that mRNA is extremely immunogenic -- that is, it provokes a strong immune response. Makes sense, since evolutionarily when we had little particles delivering RNA strands to our cells, they we viruses.
So, that's great for vaccine production. Not so great for other diseases. Cystic fibrosis, for example, the body fails to make one specific protein. We (probably) can't just program it to produce that protein, because it would also train the immune system to target that protein. The best non-vaccine targets are probably cancer, where you want to get the immune system revved up against a tumor.
I thought they solved that by replacing U by 1-methyl-3'-pseudouridylyl in mRNA vaccines? I can imagine it's not great for vaccines either, you want the immune system attack the spike the mRNA codes for, not destroy the mRNA before it can do it's thing.
> We (probably) can't just program it to produce that protein, because it would also train the immune system to target that protein.
I am not a scientist but my understanding is that the immune system targets only what it is trained against. It doesn't target anything which is non-self without being trained beforehand.
IMO if it was otherwise there would be no need for vaccine.
So I think that it is quite feasible to make a cell to produce a new protein, for example Zolgensma [0] works that way: It creates a new gene (hence a new protein) to replace a deficient one.
Immunology is wildly complicated so my description is going to fall short of reality, but my understanding of the role of the adaptive immune system as it would relate to mRNA therapies is different.
Lymphocytes, or T cells & B cells, are immune cells which have receptors on their surface that recognize a specific, tiny chunk of protein. For any given lymphocyte, the type of receptor on its surface is fixed for its life and that receptor is able to recognize exactly one distinct protein chunk.
Through some very cool mechanisms, very early on in life we all develop a massive number of lymphocytes, each of which recognize different protein chunks. I've not read any research which quantifies the scope here, but it's not unreasonable for the sake of a thought exercise to the assume that at one point we all have a lymphocyte receptor repertoire that's capable of recognizing every conceivable natural protein. Through what I consider one of my top 10 most jaw-dropping biological mechanisms [0], we cull the population of lymphocytes that recognize self, leaving us with a cell population capable of recognizing and responding to every non-self protein conceivable. No training is needed here, each of us at this exact moment has several T cell and B cell populations ready to recognize proteins produced by the next novel pandemic causing virus, whatever future protein mRNA vaccines might make, and whatever proteins these future mRNA therapies might produce.
What you refer to as training is probably more like immunological memory, which allows for a ramping up of the immune response on a quicker timeline. We give vaccines where it's generally not safe (or survivable) to wait out an effective immune response, because the disease causes so much havoc in the meantime. This doesn't really apply for the introduction of novel, useful proteins.
Your point about Onasemnogene abeparvovec is a very interesting one. I'm truly only guessing here, but people with SMA almost universally produce functional protein via SMN2, but very little of it. It's not enough to serve its function, but is perhaps enough for effective self-tolerance. I'm also not entirely sure about the timeline of self-tolerance development, it's possible Onasemnogene abeparvovec is given young enough to allow effective tolerance development!
You're not changing anything (your DNA) and whatever you're making is temporary and limited (especially because you can't have anything too complex or long as mRNA without that breaking up).
I think this is not just because of viruses, but also healthy autoimmunity. Finding even your own cell internals in the bloodstream would mean there is work to do for the immune system. E.g. auto-antibodies may increase with tumor burden, as cell rupture caused by apoptosis, or necrosis attract immune cells and cascade recruitment of more, which is usually a good thing.
Anyway, AFAIK the mRNA breakthrough wasn't with the mRNA itself, but rather the delivery vehicle to avoid said immune response. I don't think your example of cystic fibrosis, and generally chronic illnesses, are prime targets for mRNA based therapy, as the genetic defect isn't causally targeted by mRNA tech. You would force all cells (with non-discriminatory vehicles) to produce the missing protein repeatedly. Much better target for gene therapy.
I don't think people see the future of mRNA in substituting into the delicate machinery of the cell continuously. I think the possible therapy target are of the type raw, simple one-hit wonders. Very much alike traditional medication approaches, with the twist of excellent drug delivery avoiding extracellular pharmacokinetics, e.g. vitamin C has very different, even antagonistic roles in the intra- vs extracellular space, and of course liver-fistpass and immunological clearance. mRNA tech is not gene therapy (although, there is of course effective overlap).
Depending on your defect, CF can either under-produce CFTR, produce deficient CFTR, or produce no CFTR. I’d imagine each of these scenarios has different viability for mRNA theraputics.
HIV is a virus, so it would seem to be a good candidate for mRNA since you'd want to make it generate an aggressive and early response to the virus. I can't even guess though what challenges would arise given that HIV likes to target the immune system itself.
I am so excited for the prospect of mRNA treatments, especially in the field of auto immune conditions like multiple sclerosis. Those scientists are heroes.
You're correct, doctors/biologists still do not know the root cause of IBD (UC/Chrons). In fact, most autoimmune diseases are quite poorly understood due to the vast dimensional space that can influence the human immune system. If there is evidence that it could be controlled via an mRNA vaccine, it would give me much hope for the future of controlling autoimmune diseases without consistent drug intervention or surgery.
How would the treating of auto immune work? In my understanding you can trick the immune system into putting yet anther protein on the "kill on sight" list, by forcing the protein's mRNA blueprints into the production pipeline of some cells and... waiting, assuming that the immune system does its thing. So far so good. But isn't an autoimmune problem an entry on the "kill list" that shouldn't be there? I understand how we can append to that list (through a fascinatingly elaborate stack of indirections), but how can we revoke an entry?
They target signaling mechanisms that the immune system uses.
I think I don't understand it very well, but it seems one approach is to have the vaccine cause cells involved in an auto immune disorder to put a bunch of 'friend' markers on their surface. So the technology is that they can trigger protein expression and the medical approach is to get cells to express proteins that lessen immune activity against the cell.
I work in a pharma company, and I have been working with the animal model they use for this paper regularly for the past 4 or 5 years. I am not an mRNA therapy expert by any means, so I'll only comment on the results from the MOG35-55 and PLP EAE models.
They have good disease induction in their control groups, their targeted mRNA therapy shows pretty remarkable efficacy, and they show they can diversify a little bit with respect to the target.
These models are a little too "furry test tube" for me for this application. They work by injecting an antigen, either a short version of the myelin oligodendrocyte glycoprotein (MOG) peptide or the myelin proteolipid protein (PLP). The mouse makes antibodies against that antigen, and those antibodies also attack those antigens in their natural environments, leading to demyelination in the CNS. Well their mRNA for the MOG model makes more MOG peptide, giving the antibodies another target so they don't cause demyelination. In the human condition, there are multiple antibodies against multiple targets, so I'm not sure this is as relevant as they're suggesting, unless I'm missing something. I do want to add that this paper has a ton of work in it, and it looks pretty high quality as far as I can tell.
None of this is to say there's no value here, I'm just not sure what target they would make an mRNA for to treat human MS based on this paper or how they'd identify and test that target to get FDA approval to move into trials.
I'm not at all in the field, but that doesn't match what I got from the Nature abstract. I didn't see anything describing the mechanism as "giving the antibodies another target". What I read is that the introduced MOG caused regulatory T cells to retrain the immune system to stop attacking MOG.
They do bring up the multiple target problem. The glint of hope for that involves "bystander suppression", which they found some evidence for happening, but I don't really understand what that is.
Are there any online resources where I could learn more about what mRNA treatments could theoretically cure? Take Hashimoto's disease for example, a disease where your thyroid gland slowly gets destroyed by your immune system. If I understand correctly, mRNA could stop your thyroid gland from getting destroyed in the first place, but it cannot regenerate the thyroid gland if it has already been destroyed. Is that correct?
My mental model is that in the next decade or so mRNA treatments could be effective if a disease can be treated through the expression of a small number of proteins. These proteins could either have a direct function or stimulate an immune response. I think your example works.
What kind of proteins are important when you're looking at the immune system? Is there a protein that can attach to thyroid gland cells and signals to the body that it isn't a threat? Or is there some sort of memory of the immune system with non-threat cells, that mRNA could overwrite? I'm not a biologist, I'd love to read more about these specific inner workings without dissecting a whole undergraduate biology book.
If that's possible, curing type 1 diabetes would be on the horizon as well. There's some evidence that people with t1d have latent beta cells that could be reactivated to restore normal(ish?) insulin response. That would be incredible.
It's an indictment of something that we've had this amazing new tool for vaccine production in existence for a decade but we never even tried to use it for that until COVID because "vaccines typically don’t make much money" and "vaccines just aren’t that exciting" scientifically: "it’s nice and easy," to quote Rossi from the article.
If it really does turn out that effective mRNA vaccines can be created in a straightforward way for a host of new diseases, that's ten years of deaths and misery that we as a society just allowed to happen unnecessarily. I don't know how to fix that: maybe the market-based incentive structures that work for acute disease treatments aren't a good fit for broad preventative public health measures like vaccines.
Or focus on lowering costs. We learned in the pandemic how fundamentally broken the FDA is. There is no reason that things can't be faster that "operation warp speed" all the time.
Or re-focus the monetary models around either markets or patient outcomes. Right now, medicine is not a market, it's a strange game. The most money that can be made is finding a treatment that may provide a modest increased benefit over what is live, then sell it to medicare at "name your own price". This incentives high probability wins (which are typically things we already understand well).
By this model vaccines are sadly "too effective" on two counts:
- They are preventative. Americans are scared that regular people walk into hospitals and debt peons walk out. We are too sickly and scared for preventative medicine, and like our infrastructure which is never maintained to the point of being in "good working order".
- They are O(1) dose. The unity economics of once-and-done is bad. Better to sell something which makes a customer for life.
> There is no reason that things can't be faster that "operation warp speed" all the time.
Because money. Operation warp speed started mass manufacturing at the same time as clinical trials. 70% of drugs fail the 3rd stage of trials, so that would be a hugely wasteful endeavor to parallelize this when failure is the norm.
> There is no reason that things can't be faster that "operation warp speed" all the time.
Safety? I'm not wild about new vaccines requiring emergency use authorization and indemnity for the manufacturer. It worked out fine for COVID, but this is not a model I would _want_ to replicate.
We did not have this tool for a decade, it was still very much scientific work in progress, with a lot of practical problems to be solved. Those problems were only ironed out in 2017-2018.
You can absolutely kill or at least maim a new medical technology if you push it on the market too far and a wave of serious side effects hits you. As an example: death of Jesse Gelsinger [0] delayed genetic therapies by several years, possibly a decade or more. Scientists were afraid to touch the tools that killed a young man and produced a public backlash.
The science funding climate, at least in the US (I don't really know what goes on elsewhere) is in a really sad state. Projects with a low probability of success are really hard to get funded but that is precisely what you need to come up with really novel things. Curiously, science funding bodies don't seem to think of things in a probabilistic way.
The second issue is the same idea, but applied to industry. There is an activation energy that you need to surpass in order to make any business profitable. If we are talking about building a business around a brand new and unproven (in a business sense) technology like mRNA, the barrier is _huge_. You need entities with very deep pockets to accept year after year of losses before you can start getting a viable business producing cutting-edge products.
In both cases I think intelligent use of government funds could be a big help. I am not big on socialism, but I have long held that this is one of the most important things a government can and should provide: subsidies for risky research and business endeavors, not to mention large-scale infrastructure projects.
We do fund basic research decently well, but not development. That's mostly in agreement of the above, but leads to a few differences.
In particular, if we start funding the both research & development, the public sector starts taking on all risk, so there is 0 reason to reward the private sector with IP ownership. Do a drug bounty, and then public domain the IP. I would say have the state hold the IP and license it out with cost controls, but I think having medicare actually negotiate will do that well enough.
I agree with your sentiment, but we also need to careful with hindsight bias (i.e. it's easy to pick the winners after the fact)! It's a tricky question!
A good chunk of that is that people had finally gotten a delivery mechanism to work in the past few years. The "for a decade" is misleading, because a decade ago it was an interesting idea nobody had gotten to work in a way that was useful. 2020 it was something with good promise and product development under way that could be sped up massively with more money and acceptance of it being a gamble.
This feels like a post-hoc rationalization to me. Of course it was less ready, and then more ready. But exactly how much of a gamble was it?
The upside is immense even considering just existing diseases, but we are really bad at pricing things that improve the status quo vs prevent bad things.
The theory, assuming a delivery mechanism is found, is rock solid---"if not when"---and I therefore wouldn't call it a gamble.
On the other hand, I don't know enough about the biology to speak to the difficulty and uncertainty around delivery mechanisms. Can we get more info on that? I suspect it wasn't too uncertain, though "oh, we change this base pair a bit and the immune system doesn't care" does seem like a relatively unplanned discovery.
mRNA vaccines have been undergoing active research for decades, and in particular the lipid nanoparticle delivery mechanism used in both the Pfizer and Moderna vaccines was first used in 2018 in a (non-vaccine) drug called Onpattro[2]. Without this technology, Moderna in particular was having issues with excessive side effects as late as 2017[1].
As such, the Covid-19 vaccines from Pfizer/BioNTech and Moderna could not have been developed pre-2018, and - absent a deadly pandemic that requires taking extreme measures (such as using very large trial groups) to hasten the timeline - normally vaccines undergo development over a period of many years[3] to collect sufficient data to ensure effectiveness and to ensure that the long-term side effects are well understood. Moderna in particular was, prior to the Covid-19 pandemic, working on developing vaccines to target cancer using mRNA technology[4]. Had the pandemic not occurred, one would therefore not expect to have seen any approved therapies until the mid-to-late 2020s at the earliest (and probably later, given how often vaccines and other drugs fail in human trials).
In short, the issue was not that pharmaceutical companies were disregarding the technology, so much as simply the last remaining breakthrough needed to be made - and now that mRNA vaccines have proven themselves to be safe and effective, there'll be no shortage of effort to apply them to new diseases.
I thought about a scheme where the years of patent protection in a particular field where there has been lack of progress is adjusted upwards, creating incentives for r&d in that particular space. The same obviously should also go into the other direction
I think patents are just a poor way to fund this stuff in general. Better to do drug bounties in which case the financing trickiness is only about who funds the human trials.
In more than medicine, there's a good argument that only monopolies can afford R&D (c.f. Bell Labs) and monopolies are also terrible, so I'm pretty down on leaving R&D to the private sector anyways. Remember we already publicly fund all the R, this just about the D.
Also, ownership, and IP ownership in general, far from being the natural order of things, is an extremely weird and hard to price financial instrument. I don't see the point of forcing it, and trying to make it work with e.g. adjustable patent lengths. That just feels like an epicycle that's very prone to regulatory capture.
That fact that we fund all this basic research, but then can hardly be bothered with the development part of "R&D" seems like a pretty strong anecdote in favor.
Scientifically and medically, vaccines seem extraordinarily exciting as a simple tool that can permanently eliminate problems. Treatments sound very exciting if I were running a business, but scientifically less so.
I'm really glad that we've developed these great mRNA vaccines, and I hope that a business drive for recurring revenue doesn't chase people back to merely looking for treatments.
Once drugs go off-patent, the subscription model is a lot less appealing. Even before then, allowing vaccines to sell for $200 per dose (I'm just making up this number) would encourage vaccine production. But you're right that this is an example of markets not doing the right thing, so it might take government, or even insurance company subsidies on vaccine development.
That’s not an outlandish number; retail price of the HPV vaccine in developed countries is about 200 euro a dose (though in practice usually paid by health services). They get a lot cheaper once out of patent, of course.
Permanently? I thought the standard of performance has become “reducing symptoms, maybe, we think, we’re not really sure. This is probably safe though”
The answer seems straightforward then. More research to better understand mRNA vaccines and their consequences plus an effort to communicate what is found in a way that is digestible for lay people.
I suppose that gets points for being easily digestible, but it is also from a source that has knowingly lied to the public about covid safety in the past year (masks), it doesn't address any specific concerns related to the vaccine, and this document itself is obviously wrong. For example, it calls the vaccine a "a harmless piece" of mRNA when side-effects to the vaccine that are fairly considered harmful (fever, feeling bad, malaise, etc) are well documented and commonly known.
If they wanted to do a good job, the information should come from a trustworthy source, it should present the best arguments against the vaccine, and discuss the merits and lack thereof of those arguments. It should genuinely present the risks and the benefits and a good analysis of the tradeoffs. This document clearly falls well short.
This honestly is highly concerning - if that can be done for species, the next step could be to target ethnicity. I feel like this is one of those Oppenheimeresque moments in human history.
As a Jewish genealogist who got involved in direct-to-consumer genetic genealogy testing very early on (14+ years ago), this is one of my biggest fears. Genetic signatures for endogamous populations, in particular, are really easy to pick out of DNA samples. It’s already openly discussed in Jewish DNA Facebook groups and blogs which chromosome segments tend to be Ashkenazi “pile up” regions, to separate true potential cousin matches from just plain endogamy. A bad actor, or nation-state, could easily do the reverse and look for those segments on purpose…
It’s been tried and done before via chemical and biological methods (if you don’t want to sleep for awhile, check out what has been declassified on THOSE topics and realize that is what they were OK releasing to the public!).
The problem of course is that in deploying it, you’ll inevitably kill a bunch of your own - no population is so consistent you won’t kill a bunch of senior leaders who had parents 3 generations ago who were transracial or whatever and lied about it - and it will inevitably turn everyone in the world against you.
Even states like NK or Iran need friends, and those friends would have enough casualties from anything like this there is no scenario I can imagine anyone would intentionally release something like that.
Doesn’t mean a mad scientist type would cook it up accidentally in the garage, but there are always real world constraints stopping wide spread (physics sometimes, often effectiveness limits or the like).
Why do you bring Iran or NK into this? Let's get it straight: Until now, the only counties who have actually tried genocide on industrial scale, have performed inhumane tests on live subjects of other cultures or used Nukes on civilian targets have been mostly western. Heck, they were literally wiping each other out right until 75 years ago. They are also the ones actively ganging up and invading others TODAY. What delusion suddenly caused you to think it is again 'others' who are trying to wipe you out?
Huh? I guess that depends on your definition of western I guess, since Japan certainly had no issues genociding, testing chemical and biological weapons, and all that other stuff on a wide swath of Eastern Asia? Russia isn’t generally considered by anyone I’ve run across as a ‘Western’ country either, and they had (still may have) a massive program.
Near as I can tell, every industrialized power has gone through the phase.
The comment about nukes is weird, since I believe the US is the only power to ever nuke someone in anger - and near as I can tell, plausibly used it as little as possible and in self defense (though we could talk ourselves blue in the face on that point).
Nothing would have stopped the US from carpet nuking Japan for instance at the time, except some minor logistical hiccups.
My comment about Iran and NK is specifically because they’re consistently isolated by (and start fights/ideologically align themselves opposite) the bulk of countries.
They’ve been, and continue to encourage being ‘others’. I pointed out, they still have no incentive to wipe any groups out/start targeted plagues, wouldn’t start something like this, so why would anyone else?
Could somebody explain to me what a PVC (Personalized Cancer Vaccine) is? Like what is the personalized part in there? Is there really a realistic scenario in which we'll get some regular vaccination and then we'll be cancer free in the future?
Ok, so cancer is essentially a blanket term for describing that you have a group of cells in your body doing uncontrollable runaway mitosis (replicating themselves). But the thing is that it's caused by hundreds of different mutations to your cells in thousands of combinations. So developing a single way to combat all of this is super hard. But if we can identify your particular set of mutations and train your body to attack cells with those, we can get rid of your cancer and prevent it from returning. There are a few strategies for this and it's how some of the most incredible cancer therapies of the last few years work...those are just only applicable to certain very specific mutations.
Could mRNA injection temporary restore activity for loss-of-function mutations like p53 deletion in cancer?
The general, inherent hurdle in cancer treatment is discriminating individualist, misbehaving cells from cooperative, healthy ones.
From what I got, p53 isn't not expressed in healthy cells, but rather inactivated. Therefore it may be possible to systemically restore it in all cells, without inducing apoptosis in well-behaving cells.
This would be exciting, because it would enable cancer treatment avoiding selection based on cell signature, or "finding a target". Effectively restoring functionality of cell cycle guardians, which will then suicide the cancer cells seems like an attack vector very hard to evade for cancer cells. You wouldn't ask "who is misbehaving?", but rather shortly reign "everybody does as I say, now!".
Cancer cells can get rid of all the surface proteins (targeted by immunotherapy) and even gain root acce.. omnipotent stem cell characteristics (game over), they cannot shake the programmatic hallmarks of cancer, without stop being cancer. And the most important feature isn't rabid metabolism (targeted by chemo), but unchecked cell division. Chemo doesn't work well on indolent/non-aggressive cancers, as their metabolic signature is not discriminating. But who cares, if cells lost e.g. the p53 altogether, if we can force the machinery onto them regardless? No need to diff/patch the source, bring the bytecode to the compiler and fix the system until broken for good. All we want is them to "wake up" briefly and take responsibility for the mess they got at hand.
(Of course, it wouldn't be possible to flood the body with "activated p53", as that would probably suicide all cells (although it makes for a pretty scifi murder-agent), and the activation itself may offer an escape... until people figure out the whole shop.)
mRNA seems almost like a biological programming language; if you can determine how to build a protein that triggers the body's immune system to attack something you want to destroy it's just a matter of design and testing. I wonder if you could build a real language that you could use to design a sequence and automate the testing.
I still find describing anything in biology as a "programming language" to be a bit generous. It still feels more like fiddling with inputs to an ML model.
You could, but keep in mind mRNA occurs in 3D and thermodynamic and kinetic forces play a huge role in biochemistry, so it’s quite a bit more complicated than your average program.
Well, that is why it comes 50 years later than, say, Kernighan and Ritchie standard of C.
The know-how and hardware of today are just enough for the 1.0 of mRNA vaccines, so to say. How will the fourth or fifth generation look like, is probably beyond our imagination right now.
> Derrick Rossi doesn’t quite see it this way, but he kind of saved the world.
>
> In 2008, he began researching messenger RNA (mRNA), building on the long-ignored work of Hungarian researcher Katalin Karikó
What?! Katalin Karikó is an SVP at BioNTech, the lab that created Pfizer's vaccine.
I know it’s maybe pure vanity and I definitely wish to see cancer cured first but I think the psychological impact of hair loss, especially in young people (<25), is often underestimated.
For better or worse, it's not the importance of a disease per se that drives innovation, it's money. So assuming that hair loss is the kind of problem that would get people to spend money, then we might see some progress here.
There are many possible ways to quantify importance? And many many stakeholders with often conflicting ideas, demands, and influence.
If someone is spending money on something, they are voting that it is important FOR THEM - and more important than whatever else they would have done with the money.
If politicians/government aren’t spending money on something - despite saying it’s important - that is a very clear signal that their words and their actions do not align. We have words for that too.
If they don’t even bother saying words about it, then that is a clear signal not enough pressure is being applied to make it even a pretend priority no?
Funny story: finasteride was used to treat enlarged prostates (and decrease risk of prostate cancer) before it was observed to reduce male-pattern balding as a side effect.
* They're expensive (~4-8 dollars per follicle) with a single transplant being 1000-5000 follicles. Severely bald men may need multiple
* There is a finite number of follicles that can be transplanted.
* Permanent scarring in the donor zone.
The ultimate treatment would be either hair cloning (still a ways out, very expensive) or a way to reactivate the dormant follicles. Presumably if you could solve the latter you would become very rich very quickly.
It's still very costly, and carries a long recovery period. Your head will look quite gnarly. Of course we never see that because all the celebrities that do can afford to stay out of the public eye for extended periods.
I think that DNA methylation is a big factor in hair loss as well as hair color changes. There are other disease processes which are also driven by DNA/RNA methylation, so a treatment for any of these might also lead to treatments for all of them. (And I don't really know what I'm talking about and I hope someone with more expertise can add to this)
“The most worrisome part, he said, is that antibodies also can make subsequent infections worse, creating so-called antibody-dependent enhancement. Two vaccines — one against a coronavirus in cats and another against dengue, a flavivirus that affects humans — had to be withdrawn because the antibodies they induced caused potentially fatal reactions. If an antibody binds weakly against these viruses or falls to low levels, it can fail to “neutralize” the virus, but instead help it get into cells.”
Why would anyone down-vote a question asking if there is any merit to some concerns raised by a clinical researcher? The target audience is people working on mRNA vaccines who might be able to shed some light.
I dunno. The confluence of the interests of furries and Metal Gear/Deus Ex/Cyberpunk fans might make for a lucrative market leading into the widespread adoption of Anansization.
Jokes aside, I'm surprised at the rather negative response. As a medical problem, you're looking at not just cosmetic applications, but also treatments for not-uncommon disfigurement or injury, and the phasing out of existing, quite brutal, leg-lengthening surgeries. Philosophically, you have the issue of bodily agency, and the opportunity to remove that particular source of interpersonal disparity and discontent. Scientifically, I'd think it an interesting problem, one that seemed as implacable as death, except that it isn't, because we have brute-force methods to circumvent the proscriptions of the natural process.
Figured that would be something HN would be eager to chat about.
Well, it will treat everything. Soon it will be generic technology, accessible to any low-tier lab with "RNA printer". Any country will be able to download medication from internet. And in most places it is impossible to copyright naturally occurring RNA sequence.
I would love that the state sponsored research into chronic pain. Big pharma has no incentive to find cure, they want to push a suite of addictive pills that ruin lives or they spend money to block medical cannabis. Millions of people suffer with no way out.
Edit: why people downvote the truth? I guess none of you suffered this and I hope you will not, but silencing a voice like that is inhumane.
I didn't downvote, but if I had to guess, I suspect it's because your comment seems to have very little to do with the article (apart from the fact that the article is about medical research and you are advocating for a different sort of medical research). If there's a specific reason to think that mRNA could be used in treating chronic pain, including that could make your comment more obviously on-topic. (Not that your underlying point is a bad one! It's just hard to see how it fits in a discussion of this particular article.)
“Pain” is almost never the disease. (OK, maybe CRPS.) There’s a lot of things that cause pain, almost self-evidently, so it’s not one particular thing to attack, unlike a virus.
(Also we are at 36 states now with medical marijuana, so I think the “pharma wants to block this” ship has sailed, especially when you consider big-hitters like California and New York have full recreational marijuana now.)
Chronic pain is just a symptom. There could be million causes that needs to be treated first. And cannabis is just another form of "addictive pill", no better than opioids.
Meanwhile: Using a protocol of zinc, hydroxychloroquine or ivermectin and one antibiotic in combination with inhaled budesonide and/or intramuscular dexamethasone... The early ambulatory treatment regimen was associated with estimated 87.6% reduction in hospitalization and 74.9% reduction in death (p<0.0001): https://trialsitenews.com/texas-physician-researchers-case-s...
Please don’t play armchair medical researcher. The question you’ve asked is much larger 3 urls, one of which is an investigation into a single event among hundreds of millions of doses.
Your third link is not remotely relevant. The article is not discussing covid treatments, but rather the category of vaccine. Zinc isn’t going to cure cancer.
You can call me whatever names you want, but I believe the core disagreement is your approach is cure/treatment and I'm looking at the root cause/prevention. This is not to suggest zinc deficiency is the culprit, but various deficiencies in the American high calorie diet. From the NIH.gov website:
"Evolving and compelling evidence exists that proves that zinc is implicated as an important cytotoxic/tumor suppressor agent in several cancers. For example, that cellular zinc levels are markedly decreased in prostate cancer is well established" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291177/
" In addition, zinc contributes to the truncation of the Krebs cycle and inhibition of citrate oxidation, which further prevents cancer cell growth and proliferation, as well as inhibiting the invasion and migration of cancer cells" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216164/
"In conclusion, we found that highest category of dietary zinc intake can significantly reduce the risk of pancreatic cancer, especially among American populations." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463257/
How would an antibiotic help with a viral infection? Might as well start using some essential oils and homeopathy. If that regimen actually worked, we'd probably see it more widely used and studied.
They investigate each death reported to VAERS to see if it was actually vaccine related. Given how many millions of doses were given out, and especially to people that were already old or clinging on to life, 3,544 is not unexpected. None of those were directly attributable to the vaccine.
> helping cells produce tissue to heal from events such as cardiac arrest
> beyond simple vaccines [...] mRNA therapeutics might be tailored to instruct a person’s immune system to fight their specific type of cancer, or target protein deficiencies in specific organs, and without the toxic side effects of traditional medications.
> “My personal moonshot is snake venom, and antivenoms for snake bites,” he says. [...] “You inject it into a person, and within hours the protein that you wish is being expressed,” he explains. The final product of such research, he imagines, would be an antidote that could work for the most lethal species of a specific area, delivered in a way that can be preserved for long times in very remote areas—for instance, a powder that can be stored for long periods of time and reconstituted quickly.
This is literally all the info I found that is actually relevant to the interesting headline. The rest of the article is about this person's career and what funding vaccine companies got in 2020.