The only thing that people can be really sure of, for all patients, and all disease conditions, in general, is that some things are NOT safe (like: literal poison or just peanuts for someone allergic to peanuts) and something are NOT effective (like: homeopathy or chemotherapy for something other than the relevant kind of cancer).
The entire concept of a legal declaration that a drug is totally Safe(tm) and totally Effective(tm) is basically just marketing.
The thing that actually makes things safe and effective is that the doctor diagnoses you correctly and prescribes the right thing at the right dose without causing complications FOR YOU. Sometimes some problems happen despite the best guesses and efforts (because every human is a snowflake), and this is just how biology is: extremely complicated in general.
(
Something to note is that antibiotics and vaccines are insanely more important than heart valve replacements and boob jobs, in terms of making life for humans possible under modern conditions. For basically all of human history cities were net death traps, full of disease, where the excess people born in the country went to have sub-replacement numbers of kids and then die of smallpox or whatever. If we can’t make new communicable disease treatments fast enough… this is what cities will go back to.
However the REST of medicine is often nigh unto homeopathy itself?
Perinatal care, and gunshot trauma treatment, and setting bones, and insulin for type I diabetics work, but these are unusual.
A lot of stuff “treats” the thing you went in for… while causing a new problem. Making all cause mortality go down is HARD. This paper argues that ignoring all cause mortality is fine. I think it is fine if the goal is to give people quite a bit of make-believe-medicine that causes them to feel cared for and helps doctors pay off their med school debts.
The real experiments are the early patients. If the patients are smart and have a good doctor and the cost-benefit-analysis for THAT patient in THAT situation pencils out… then the risks are worth the benefits and you take the bet and get your outcome. Then the doctor learns something.
That’s how medicine gets better in real life. The more clinical experience that builds up, the better a judicious clinician can make this determination. To pretend otherwise is crazy.
There have been a LOT of people taking the vaccine. Empirically, it seems to help more than it hurts. For a very large “clinical N”.
there’s a vaccine for a previously unknown virus made with completely new technology (granted, mRNA wasn’t discovered yesterday, but it’s never been used like this before), in an astonishingly short time, which is also safe and effective. How probable would this sound to someone completely ignorant of all the media and the whole Covid-19 thing?
Personally, I think that the thing that happened was: Moncef Slaoui (and Kushner?) did an end run around The Evil Ones?
Clinical practice reveals, over and over and over, that things approved by the FDA as “safe” actually weren’t “safe” and should maybe be recalled (or maybe they were safe if used properly and doctors weren’t using them properly, and so someone decided that rather than let people get hurt, and rather than purge the doctors of incompetence, they should purge the legal drugs of things that were being mis-used a lot)?
This is the fundamental lie of the FDA: they REALLY can’t do, during clinical trials, what they claim to do, and they get in the way of the people who MIGHT be able to do it for real eventually by just trying shit and repeating what works.
I’m not entirely against trying random shit on consenting old people who are going to die anyway.
SUPPOSE that things are hopeless… then why NOT try something that is likely to fail? It MIGHT work?
The right argument against such experimentation is more complicated and more about economics than medicine: how many bits of information about what parameters of various biological systems are you really buying when you try something new in medicine and is that worth it to whoever is footing the bill compared to their alternative uses for the same money.
However, the FDA also forbids this in general. Experiments should be as cheap as possible to get as many of them as possible. And it is NEVER cheap right now!
In order to try such an experiment you’d first file a New Drug Application (NDA) which is like $1M a pop.
So you can’t just notice that you have a weird disease, and are basically gonna die no matter in the near future for a predictable cause… and then “just try something that your doctor thinks MIGHT work based on first principles medical reasoning and wikipedia”. You you have to get permission from people in DC first.
Sometimes I wonder if they are INTENTIONALLY holding off medical innovation in general because like… abortion and transsexuality and cures for venereal diseases are already out of pandora’s box… what else is in there? Maybe immortality? Maybe EXPENSIVE immortality? So maybe they are outlawing “medical innovation in general” to the best of their ability? And they pretend that their destruction of medical innovation is actually in support of “safe and effective and scientific” medical innovation because… they think we’re dumb enough to believe their lies? (And maybe they are right?)
So, turning off some of the dumber laws momentarily enabled us to invent a new and effective vaccine.
And this isn’t surprising to me because science works. The thing in the US that’s broken is our political economy, not our actual physical sciences (yet).
In terms of safety, the argument for LONG TERM safety of this vaccine technology is not, and never could be, empirical. To verify the safety empirically you’d… have to wait a long time for results.
Instead the thing you do is… guess. Just like with masks. Based on reasoning about reality?
So far as I’m aware the key idea here is Kariko’s work with things like pseudouridine. That’s what made this new kind of mRNA vaccine work where the old mRNA vaccines had unacceptable side effects.
Honestly, it doesn’t seem totally impossible to me that having a lot of this in your body might do… something? (Keep in mind though: water is poison at the right dose.)
But it empirically hasn’t done much yet now that it has been rolled out to millions. Like with masks… you reason about reality directly to the best of your ability, and ask for peers to check your thinking?
One central comforting thing for me (if you click through to Kariko) is that the clever chemistry ALREADY EXISTS in our bodies. Human biology makes chemical adjustment to the backbone and microstructure of mRNA, then looks for these adjustments actively. Then viruses either have to also attempt this (which is very hard for many of them) or else the lack of these adjustments in certain cellular compartments can work as a trigger of certain kinds of “kill it all with fire” immune reactions.
So the current clever mRNA vaccines are giving “viral code” with “human-like chemical signatures” to dodge this reaction, and thereby sneak viral protein manufacturing instructions “deeper into our cell’s machinery with less trauma” for at round of protein manufacturing, in a way that gives us “pieces of virus” (for our immune system to learn to recognize), but no second generation of virus (to be an actual infection), while avoiding some innate immune side effects.
I personally think it would be foolish to say that it can’t possibly hurt in any way ever at all. The best medicine is the ancient stuff like aspirin (ie the active ingredient in willow bark tea which is 4000 year old medical tech with mentions in Sumerian and Egyptian texts). Time allows information to accumulate <3
I just think that the bet seemed to be worth it. I have two doses of Pfizer. I got them as fast as I legally could because the testing on the old people seemed like “enough” basically? Also both parents got the vaccine, and presumably they have the same genes as me more or less, so if they didn’t specifically have a reaction then I wouldn’t either most likely?
Empirically: pretty safe and decently effective (for N>millions) over months against the strains that are out there right now.
Theoretically: clever and probably pretty similar to what human bodies already have in them.
Surprisingly: generated “unusually fast” because heroes started ignoring a bunch of catastrophically stupid laws.
Now I realize there’s another: the mRNA vaccines are not that new, they simply never made it public before. Just something that dawned on me.
Early papers on mRNA therapeutics date back to the late 1980s/early 1990s, with a number of small scale tests and trials starting by the late 1990s. Making custom arbitrary mRNA has been affordable/feasible since at least the mid-2000s. BioNTech was founded in 2008, and Moderna was founded in 2011, which means the relevant tech at that point was already far enough along to warrant founding companies that were going to need a lot of funding to bring anything to market. But instead of making vaccines targeting infectious diseases, they both mostly targeted cancer immunotherapy. I assume that’s because those are the treatments they were able to get funding for, even though it’s a much harder problem technically.
I don’t know when the first year was they they could have designed a successful vaccine against a novel virus in a day and a half, but the odds of that happening just before covid hit are obviously very low, especially since more recent trials and studies are showing that we can also quickly develop (better) vaccines against the flu and malaria, and the success with covid was not an unlikely outcome.
I don’t know when the first year was they they could have designed a successful vaccine against a novel virus in a day and a half, but the odds of that happening just before covid hit are obviously very low, especially since more recent trials and studies are showing that we can also quickly develop (better) vaccines against the flu and malaria, and the success with covid was not an unlikely outcome.
I did not get this part (maybe there’s a missed word or something. Are you implying that they had all tech in place to successfully manufacture such vaccines quickly?
So, to sum up:
mRNA has been studied and used (?) for about 30 years now
Moderna and BioNTech have been around for a while, and their past research has built up their scientific base.
Out of 18 mRNA vaccines developed around the world only 3 made it to clinical trials, and two made it to production
Manufacture? No. Use? Only at lab scale, in animals or a few patients for small studies. Design? Yes, and the design process did not require any additional new tech nor the resources of a large pharmaceutical company.
Yes, old school vaccines have a lot more history behind them and large organizations were more familiar with them and so they were better equipped to get them through trials and scaled up for deployment. But the mRNA vaccines that did make it through seem to be more effective than those old school vaccines.
Of those 18, how many actually failed trials vs. other reasons for not having come to market (didn’t get funding, didn’t have the pre-existing expertise needed, didn’t move fast enough relative to competitors)? Also, four of those 18 were BioNTech, and counting that as a success and three failures seems like a mistake when it’s the same company trying multiple things initially and then proceeding with the best one.
How many old-school vaccine development efforts didn’t pan out, or only got approved because of extensive government support in their countries of origin?
My take is that we have had, for at least a handful of years, the ability to design a new mRNA vaccine against a novel virus in a matter of days, test it in a matter of months, and scale it up in less than a year. Instead, the companies founded to develop that kind of technology had to go in a different direction (targeting cancer), and without the pandemic they would have languished much longer without bringing any mRNA therapeutics to market at all. The pandemic cut through enough bureaucracy that they got a product out and built manufacturing capacity, and now that they have done that, they’re quickly able to repeat that success for other diseases.
I do not expect the pandemic to lead to a flurry of other new traditional vaccines, because those haven’t suddenly gotten easier or cheaper to develop, we just threw more resources at them for covid.
As far as I can tell, if we had had better regulatory and research policy, we could have lived in the world where Moderna or BioNTech had been working on infectious disease mRNA vaccines all along, and launched an improved flu vaccine back in 2016 or so, so that by early 2020 they already had some manufacturing capacity and supply chains in place that they could expand and replicate (with at least the medical community knowing this was a thing that had been used millions of times). I do not believe that that world ever had to have made any technological advances that ours didn’t make, yet they would have been able to mass produce our most effective covid vaccines much, much faster than we did. They would know that they knew how to fight a virus.
Edit to add: I worry that many people (1) think this is what a worst-case-scenario pandemic looks like, and (2) think that next time there’s a new disease, the solution will be to mask up and shut down indefinitely, instead of immediately designing an mRNA vaccine, conducting large trials as fast as possible, and pre-emptively manufacturing hundreds of millions of dose so they’re ready to go ASAP, with an expectation that all relevant regulatory agencies will work round the clock to remove all unnecessary roadblocks to approval.
The only thing that people can be really sure of, for all patients, and all disease conditions, in general, is that some things are NOT safe (like: literal poison or just peanuts for someone allergic to peanuts) and something are NOT effective (like: homeopathy or chemotherapy for something other than the relevant kind of cancer).
The entire concept of a legal declaration that a drug is totally Safe(tm) and totally Effective(tm) is basically just marketing.
The thing that actually makes things safe and effective is that the doctor diagnoses you correctly and prescribes the right thing at the right dose without causing complications FOR YOU. Sometimes some problems happen despite the best guesses and efforts (because every human is a snowflake), and this is just how biology is: extremely complicated in general.
(
Something to note is that antibiotics and vaccines are insanely more important than heart valve replacements and boob jobs, in terms of making life for humans possible under modern conditions. For basically all of human history cities were net death traps, full of disease, where the excess people born in the country went to have sub-replacement numbers of kids and then die of smallpox or whatever. If we can’t make new communicable disease treatments fast enough… this is what cities will go back to.
However the REST of medicine is often nigh unto homeopathy itself?
Perinatal care, and gunshot trauma treatment, and setting bones, and insulin for type I diabetics work, but these are unusual.
A lot of stuff “treats” the thing you went in for… while causing a new problem. Making all cause mortality go down is HARD. This paper argues that ignoring all cause mortality is fine. I think it is fine if the goal is to give people quite a bit of make-believe-medicine that causes them to feel cared for and helps doctors pay off their med school debts.
Keep in mind: something like 80% of the dollars spent in medicine are spent in the last few months or weeks of life, and they are often miserable, and pointless, and not what anyone sane would want for themselves or their loved ones… but many people are not sane
)
The real experiments are the early patients. If the patients are smart and have a good doctor and the cost-benefit-analysis for THAT patient in THAT situation pencils out… then the risks are worth the benefits and you take the bet and get your outcome. Then the doctor learns something.
That’s how medicine gets better in real life. The more clinical experience that builds up, the better a judicious clinician can make this determination. To pretend otherwise is crazy.
There have been a LOT of people taking the vaccine. Empirically, it seems to help more than it hurts. For a very large “clinical N”.
Personally, I think that the thing that happened was: Moncef Slaoui (and Kushner?) did an end run around The Evil Ones?
Clinical practice reveals, over and over and over, that things approved by the FDA as “safe” actually weren’t “safe” and should maybe be recalled (or maybe they were safe if used properly and doctors weren’t using them properly, and so someone decided that rather than let people get hurt, and rather than purge the doctors of incompetence, they should purge the legal drugs of things that were being mis-used a lot)?
This is the fundamental lie of the FDA: they REALLY can’t do, during clinical trials, what they claim to do, and they get in the way of the people who MIGHT be able to do it for real eventually by just trying shit and repeating what works.
I’m not entirely against trying random shit on consenting old people who are going to die anyway.
SUPPOSE that things are hopeless… then why NOT try something that is likely to fail? It MIGHT work?
The right argument against such experimentation is more complicated and more about economics than medicine: how many bits of information about what parameters of various biological systems are you really buying when you try something new in medicine and is that worth it to whoever is footing the bill compared to their alternative uses for the same money.
However, the FDA also forbids this in general. Experiments should be as cheap as possible to get as many of them as possible. And it is NEVER cheap right now!
In order to try such an experiment you’d first file a New Drug Application (NDA) which is like $1M a pop.
So you can’t just notice that you have a weird disease, and are basically gonna die no matter in the near future for a predictable cause… and then “just try something that your doctor thinks MIGHT work based on first principles medical reasoning and wikipedia”. You you have to get permission from people in DC first.
Sometimes I wonder if they are INTENTIONALLY holding off medical innovation in general because like… abortion and transsexuality and cures for venereal diseases are already out of pandora’s box… what else is in there? Maybe immortality? Maybe EXPENSIVE immortality? So maybe they are outlawing “medical innovation in general” to the best of their ability? And they pretend that their destruction of medical innovation is actually in support of “safe and effective and scientific” medical innovation because… they think we’re dumb enough to believe their lies? (And maybe they are right?)
So, turning off some of the dumber laws momentarily enabled us to invent a new and effective vaccine.
And this isn’t surprising to me because science works. The thing in the US that’s broken is our political economy, not our actual physical sciences (yet).
In terms of safety, the argument for LONG TERM safety of this vaccine technology is not, and never could be, empirical. To verify the safety empirically you’d… have to wait a long time for results.
Instead the thing you do is… guess. Just like with masks. Based on reasoning about reality?
So far as I’m aware the key idea here is Kariko’s work with things like pseudouridine. That’s what made this new kind of mRNA vaccine work where the old mRNA vaccines had unacceptable side effects.
Honestly, it doesn’t seem totally impossible to me that having a lot of this in your body might do… something? (Keep in mind though: water is poison at the right dose.)
But it empirically hasn’t done much yet now that it has been rolled out to millions. Like with masks… you reason about reality directly to the best of your ability, and ask for peers to check your thinking?
One central comforting thing for me (if you click through to Kariko) is that the clever chemistry ALREADY EXISTS in our bodies. Human biology makes chemical adjustment to the backbone and microstructure of mRNA, then looks for these adjustments actively. Then viruses either have to also attempt this (which is very hard for many of them) or else the lack of these adjustments in certain cellular compartments can work as a trigger of certain kinds of “kill it all with fire” immune reactions.
So the current clever mRNA vaccines are giving “viral code” with “human-like chemical signatures” to dodge this reaction, and thereby sneak viral protein manufacturing instructions “deeper into our cell’s machinery with less trauma” for at round of protein manufacturing, in a way that gives us “pieces of virus” (for our immune system to learn to recognize), but no second generation of virus (to be an actual infection), while avoiding some innate immune side effects.
I personally think it would be foolish to say that it can’t possibly hurt in any way ever at all. The best medicine is the ancient stuff like aspirin (ie the active ingredient in willow bark tea which is 4000 year old medical tech with mentions in Sumerian and Egyptian texts). Time allows information to accumulate <3
I just think that the bet seemed to be worth it. I have two doses of Pfizer. I got them as fast as I legally could because the testing on the old people seemed like “enough” basically? Also both parents got the vaccine, and presumably they have the same genes as me more or less, so if they didn’t specifically have a reaction then I wouldn’t either most likely?
Empirically: pretty safe and decently effective (for N>millions) over months against the strains that are out there right now.
Theoretically: clever and probably pretty similar to what human bodies already have in them.
Surprisingly: generated “unusually fast” because heroes started ignoring a bunch of catastrophically stupid laws.
This essay of yours might be worth its own post :)
Your comment got me thinking about the probability of what I described once again:
Such miracles only happen in people’s imagination.
Previously, I noticed one simple explanation: the vaccine is not as safe / effective.
Now I realize there’s another: the mRNA vaccines are not that new, they simply never made it public before. Just something that dawned on me.
I’ll study the links and get back here. Thank you for your time and effort!
Early papers on mRNA therapeutics date back to the late 1980s/early 1990s, with a number of small scale tests and trials starting by the late 1990s. Making custom arbitrary mRNA has been affordable/feasible since at least the mid-2000s. BioNTech was founded in 2008, and Moderna was founded in 2011, which means the relevant tech at that point was already far enough along to warrant founding companies that were going to need a lot of funding to bring anything to market. But instead of making vaccines targeting infectious diseases, they both mostly targeted cancer immunotherapy. I assume that’s because those are the treatments they were able to get funding for, even though it’s a much harder problem technically.
I don’t know when the first year was they they could have designed a successful vaccine against a novel virus in a day and a half, but the odds of that happening just before covid hit are obviously very low, especially since more recent trials and studies are showing that we can also quickly develop (better) vaccines against the flu and malaria, and the success with covid was not an unlikely outcome.
I did not get this part (maybe there’s a missed word or something. Are you implying that they had all tech in place to successfully manufacture such vaccines quickly?
So, to sum up:
mRNA has been studied and used (?) for about 30 years now
Moderna and BioNTech have been around for a while, and their past research has built up their scientific base.
Out of 18 mRNA vaccines developed around the world only 3 made it to clinical trials, and two made it to production
9 “old-school” vaccines made it through the trials
This does sound somewhat realistic: old tech is better-known and had more successful attempts at.
Manufacture? No. Use? Only at lab scale, in animals or a few patients for small studies. Design? Yes, and the design process did not require any additional new tech nor the resources of a large pharmaceutical company.
Yes, old school vaccines have a lot more history behind them and large organizations were more familiar with them and so they were better equipped to get them through trials and scaled up for deployment. But the mRNA vaccines that did make it through seem to be more effective than those old school vaccines.
Of those 18, how many actually failed trials vs. other reasons for not having come to market (didn’t get funding, didn’t have the pre-existing expertise needed, didn’t move fast enough relative to competitors)? Also, four of those 18 were BioNTech, and counting that as a success and three failures seems like a mistake when it’s the same company trying multiple things initially and then proceeding with the best one.
How many old-school vaccine development efforts didn’t pan out, or only got approved because of extensive government support in their countries of origin?
My take is that we have had, for at least a handful of years, the ability to design a new mRNA vaccine against a novel virus in a matter of days, test it in a matter of months, and scale it up in less than a year. Instead, the companies founded to develop that kind of technology had to go in a different direction (targeting cancer), and without the pandemic they would have languished much longer without bringing any mRNA therapeutics to market at all. The pandemic cut through enough bureaucracy that they got a product out and built manufacturing capacity, and now that they have done that, they’re quickly able to repeat that success for other diseases.
I do not expect the pandemic to lead to a flurry of other new traditional vaccines, because those haven’t suddenly gotten easier or cheaper to develop, we just threw more resources at them for covid.
As far as I can tell, if we had had better regulatory and research policy, we could have lived in the world where Moderna or BioNTech had been working on infectious disease mRNA vaccines all along, and launched an improved flu vaccine back in 2016 or so, so that by early 2020 they already had some manufacturing capacity and supply chains in place that they could expand and replicate (with at least the medical community knowing this was a thing that had been used millions of times). I do not believe that that world ever had to have made any technological advances that ours didn’t make, yet they would have been able to mass produce our most effective covid vaccines much, much faster than we did. They would know that they knew how to fight a virus.
Edit to add: I worry that many people (1) think this is what a worst-case-scenario pandemic looks like, and (2) think that next time there’s a new disease, the solution will be to mask up and shut down indefinitely, instead of immediately designing an mRNA vaccine, conducting large trials as fast as possible, and pre-emptively manufacturing hundreds of millions of dose so they’re ready to go ASAP, with an expectation that all relevant regulatory agencies will work round the clock to remove all unnecessary roadblocks to approval.