It has the same BTC address as the usual sci-hub pages (12PCbUDS4ho7vgSccmixKTHmq9qL2mdSns) so I'd say yes. And please don't give them any ideas. The domain issue is hard enough it seems. Thank god there's hundreds of TLDs now :p
It's up for me. You may be in an area, or using an ISP, that is blocking access to that domain. Unfortunately I don't have any info to hand on alternate access methods, but I know they exist.
I would love to know (to assuage any family members' doubts) --
Are there any possible long term side effects of using such an mRNA drug that are yet unanticipated? All the short term side effects are known / will soon be. Anything beyond that, we haven't had enough experience to know?
Probably not. There was about 20yrs of research on using mRNA for gene therapy before the CRISPR/Cas9 discovery. It was abandoned as a route for gene therapy specifically because it wasn't long lasting. The mRNA isn't incorporated into the DNA, so it isn't reproduced by the cells and eventually breaks down. Things inside of cells are flying around at high speeds and constantly colliding, so it's not a very stable environment.
There are people that this was tested on still hanging around with no lasting negative effects (to my knowledge).
My partner, a biochemist, has mentioned the potential possibility of RNA viruses causing the RNA of the vaccine to stabilize as some sort of DNA structure. Normally RNA is quickly broken down by RNase, but apparently RNA viruses have a mechanism to defend against this, that it's possible to imagine having an interaction with an RNA vaccine.
I don't know anything about biochemistry, and I'm aware that the above is just remote speculation. It is meant as an example of food for thought. But I do wonder when a whole field of scientists state "there is no possibility of unexpected long-term side effects" to a therapeutic tool that has never been used at anything resembling this scale.
Would love to hear more experts discuss why this is considered sufficiently long-term safe to make the decision of vaccinating a billion people after nine months of testing. Am I missing something, or is it just a question of the precautionary principle in this case being considered too costly?
There could certainly be a logical error in play here, but considering this is mRNA, and not DNA, it seems like it would be fairly amazing for it to spontaneously form into DNA. Similar to a load of parts spontaneously forming into a bicycle.
That's not to say it isn't possible, but many things are possible but sufficiently unlikely that we take those risks. We eat, drink, and breathe many things every day that we don't fully understand the ingredients or impacts of.
From the responses you’d think I was talking about brain chips injected by Bill Gates, but I suppose this is the result when a layman attempts to explain something unfamiliar to other laymen.
The thing that all biologists fundamentally understand is that none of this stuff has been designed. Every process in the body happens due to chemical reactions that do happen spontaneously. The replies above don't seem to get this and instead consider a human body to be the product of design like a car or something. You can't just throw metal at a car and hope to invent a new type of gearbox. But throwing stuff at living things is exactly how change is driven. If we were immutable we wouldn't be here.
The part about parts spontaneously forming a bicycle is a nice soundbite, but reverse transcriptase (an enzyme) is used by RNA viruses to do just that.
Spontaneously, yes - fairly amazing. But what if the person treated with the mRNA vaccine happens to be infected with another RNA virus that is producing reverse transcriptase enzymes to convert its own RNA into DNA?
To prevent an immune response and degradation, the mRNA vaccine nucleosides are modified from normal human mRNA. It's possible that RNA virus reverse transcriptase may not be able to work on these modified nucleosides.
Given that this pandemic has killed millions, shut down the world economy, and caused untold long term damage to children due to lack of stable schooling: yes, it’s because the precautionary principle is too costly.
Edit: sorry, my comment may have sounded snarky, which was not my intention. World-wide vaccinations do carry a risk. It’s just that such a risk clearly pales in comparison to the very known downsides of the current situation. I am in no way a vaccine expert and cannot comment intelligently on why long-term risks are considered to be low.
You mean million that died, had a positive PCR test at some time. There are still less people dying in 2020 than in 2018 in most countries even though population gets older and therefore more people are dying every year on average anyway.
It killed a million because it's novel. The flu also has killed millions, but because it's been around a while there's a lot of herd immunity to the flu. As time goes on, Covid's severity naturally decreases. Same as it has always been. And kids being kept out of schools despite being 99.999% immune is ridiculous.
Kids are being kept out of school so they don’t get the virus and spread it to somebody else. They aren’t immune, as far as I know. Just less likely to die from it.
> Would love to hear more experts discuss why this is considered sufficiently long-term safe to make the decision of vaccinating a billion people after nine months of testing. Am I missing something, or is it just a question of the precautionary principle in this case being considered too costly?
FDA approvals aren't a black and white affair. Some drugs are approved as orphan drugs through trials designed to be much cheaper than Phase 1-3 trials when they treat diseases that wouldn't be profitable for pharma, for example, and there is a path for preliminary compassionate use approvals and accelerated development for stuff like chemo where the disease is terminal anyway. The FDA works with each company to tailor the process to their needs (although, obviously, they stick to a strict standard unless there's good justification).
Likewise, the vaccine rollout won't be all or nothing. We won't even have a billion doses for a long while and the focus will (likely) be on vaccinating those for whom the benefits outweigh the extra risk like front line medical staff and the immunocompromised or elderly. I don't expect the world to get vaccinated at gun point, although the rules for schools and other institutions will quickly accumulate to cover most of the population.
Personally, I'm not going to be taking the vaccine for a while since no one in my family is at risk and we're (mentally) preparing for several years of varying levels of isolation and other precautions. I have faith in the system for the most part since I've worked on an FDA application before (clinical diagnostics, not therapeutics), but the kind of geopolitical and economic pressure its under right now is unprecedented and should keep epidemiologists up at night (hell, it probably does). It's going to be up to each individual to balance their risks and obligations at least until we get more data.
That's the most level-headed response I've heard yet. Most people just equate my worries to those of an antivaxxer and move on.
These new vaccines have a 90% efficacy. It's probably a no-brainer to give them to someone in their 70s or 80s with a high likelihood of having an adverse covid case. But a 20-year-old?
Out of a purely selfish wish of having a more normal world, part of me wants to suppress these thoughts and think "I'm probably excessively cautious, it's a good thing that the economic pressures will probably ensure that most are vaccinated in a year or two". But I do worry that many healthy people don't have a complete view of the potential for unknown unknowns when they decide to take it.
The selfish part of me is thankful that someone else does the dirty job for ensuring that those thoughts aren's spread wider. I'm really hoping that the authorities know what they're doing, and I'd definitely be lying awake at night if I was in that role.
I probably won't take it myself - there, I said it - but rather wait and get more data, or maybe go as far as seeing when one of the protein-based vaccines are ready.
This was one of the questions someone posed during the FDA approval of the pfizer vaccine. I'm paraphrasing here, but you can look up the exact question on one of the youtube videos or read the transcription:
"Suppose someone was infected with a retrovirus, could reverse transcriptase embed that rna into the dna? This could be especially worrisome if we're talking about a pregnant woman and fetus undergoes rapid cell division... etc.."
I would be surprised if I did not mangle up some terms & concepts in the paraphrasing above. Someone who knows more can correct me or just watch/read the fda hearing.
Another thing that was mentioned in the FDA hearing was that pfizer also tested it on HIV positive people. HIV is a retrovirus which also carries the reverse transcriptase enzyme. I don't want to draw any conclusions from this because I don't have any medical knowledge. Maybe someone here with more insight could comment.
> Would love to hear more experts discuss why this is considered sufficiently long-term safe to make the decision of vaccinating a billion people after nine months of testing. Am I missing something, or is it just a question of the precautionary principle in this case being considered too costly?
I think, generally, it has been discussed. There's lots of research on mRNA vaccines going back decades at this point, though they haven't made it to market until now. I see people saying "it's not being discussed" often on this site, but really, anyone saying "no, this is safe" has the implicit support of all that research behind them.
It's not really that many decades of research. This tech is from the 90s. This is the very first mRNA vaccine to be deployed on a mass scale. Does it cause cancer 10, 20 years from now? Does anyone know that for sure? It's not like we have a perfect scientific statistical sampling of people who received mRNA vaccines 30 years ago and we can evaluate those long term effects.
Exactly — and I rely upon the many hundreds of thousands of years of experience and direct “winning” to beat adversaries.
This statement cuts both ways — if this recent pandemic was human made we need human solutions... only IF the virus is insurmountable.
As someone with direct experience with a large N, this virus is nothing to exponentially increase long term and second order risk with human “solutions” ... UNLESS the long term effects for asymptomatic cases are severe and under reported.
Again... too many variables outstanding to be certain, but highly cautious
Viruses do it all the time. It can indeed cause trouble, but a random mutated rhinovirus is more likely to do so (allergies, typically) than a vaccine which was developed specifically to not cause any damage.
This idea that "We are not gods." Such a peculiar argument. If something is capable by a mortal man what makes you think it has god-like qualities? To me it is the opposite. Also since you're using the word "gods" are you referring to polytheism? Where did you decide you were capable of determining a "god-like" thing? You. Are. Confusing. Me.
No it doesn't. Viruses have been around longer than humans have, so NOTHING HAS CHANGED. We have been through SMALLPOX, TUBERCULOSIS, SPANISH FLU, PLAGUE, AIDS, and many, many other pandemics and NEVER, EVER has anyone been insidious enough to suggest a vaccine as a prerequisite for human rights. You need to reevaluate your logic and life choices. This disease already has a 99.9% survival rate for the general population and much higher in certain demographics.
At any rate, government tyranny has killed millions and millions more than viruses have. And I won't stand for it. Medical tyranny will never be tolerated. If YOU want the vaccine, you get it. That's how liberty works.
Uhm, the Spanish flu infected 500 million people (6.5 times more than covid19) and killed about 50 million (33 times more than covid19). And if you consider that the world at that time had just about 2 billion people, a modern Spanish flu would have killed 175 million people (100 times more than covid19), and probably more since denser population makes it easier for viruses to spread.
Now, we have the (repeatedly) proven ability to avoid such a disaster, and you argue we should not? You really think protection from disease is not a basic human right?
I've mostly given up on HN as a forum for free discussion, because the mods' endorsement of downvote-for-disagreement results in comments like yours (reasonable, historically informed, advocating liberty and actual human rights) being downvoted to obscurity, while the comments full of manipulative, Orwellian word games ("You don't want to take a vaccine? You're refusing basic precautions and infringing upon my human rights!") are prized.
So, while I used to write comments like yours, myself, I don't bother anymore. I'd have to spend years toeing the line to build up enough karma to not get shadowbanned for it.
Anyway, I sign in here to say that I'm with you. I think it's important to show that this point of view is not the minority view in this country, and maybe even the world, despite all the media does to make it look like it is.
It looks like China's already started World War 3 in terms of "Unrestricted Warfare" (China's term, not mine): financial, biological, psychological, political. Just regarding COVID, they told the world COVID wasn't infectious between people, they held a 40,000-person potluck dinner in Wuhan while the virus was spreading and then let people travel out of the city, they threatened to turn ships around and withhold masks and medicine produced in China...how can anyone look at what China's done and not recognize their malicious intent? At the same time, they're building up their military around the world, indebting poor African nations, pushing their troops into Nepal and India (and actually killing Indian soldiers)...the list goes on and on. We have to wake up before it's too late.
[Of course, the 50 Cent Army is active on HN. Watch my comment fade away...]
Has there ever been an instance of genetic transformation as a consequence of a mRNA vaccine? Saw this listed as a potential risk in a paper[0], but I have no expertise at all to judge if this a possibility or not.
If you are referring to the following sentence in the introduction, I understood it to mean the opposite:
> Moreover,
mRNA vaccines induce transient antigen expression, while DNA vaccines provide a long-lasting
expression, thus mimicking an acute viral infection. Although a transitory gene expression might
be desirable as it minimizes potential risks of genetic transformation, this inevitably affects mRNA
potency, thus necessitating a dose increase.
This means that mRNA reduce the risk of genetic transformation compared to DNA vaccines, but it comes as a price because you have to deliver a larger dose of mRNA.
Yes that was the sentence. The expression "minimizes potential risks of genetic transformation" implies that there is a non-zero risk, and I'm curious how minimal it is.
Biology is about finding a productive exception to the rules.
This means that when circumstances say no you cant, biological entities find a work around.
as a cover your ass practice, even the smallest chance of occurence means non zero chance.
in this case an mRNA would have to be captured by a reverse transcription system most likely due to co-infection with a retro virus, that complex would have to be functional and would have to be transported into the nucleus.
this is a very remote chance but non zero, thus :
"minimizes potential risks of genetic transformation"
Would this be an accurate summary:
„There is a slim chance the mRNA is incorporated into the DNA if there is an ongoing infection with a retro-virus during vaccination“?
the RNA must interact with retroviral reverse transcriptase in a manner that makes a functional complex or it will just be snipped apart and decycled like garbage.
RNA will fold and produce 2' structure this has interesting consequence. catalytic RNA, structural RNA, stabilizing or protective RNA..
from the paper [3] above:
"Reverse transcription
initiates after binding of a cellular tRNA primer (in HIV-1, tRNA Lys,3 ), to the primer binding
site (PBS). The PBS is a sequence of 18 nucleotides, located downstream of the 5’-end of the
genomic RNA. The viral RNA that serves as template for reverse transcription is flanked by
repeat (R) sequences at its 5 ́ and 3 ́ termini."
the vaccine mRNA does not meet these requirements.
retroviral RNA is configured to function with the reverse transcriptase.
Promiscuity to include other RNA is exceptional not common.
virally infected cells also undergo changes that exclude further infection so they have the cell to themselves.
i would like to say zero chance, but life is in the business of sidestepping the rules to its advantage, however you have a much greater chance of being attacked by a shark while hiking the sahara dunes.
What do you think about one of the Australian Vaccine that got everybody in the study to test HIV positive. I don't think researches know enough to claim it save without long term tests. I also heard that HIV can hide in mRNA from your Immune system. I would call that long lasting.
Rubbish. It did not cause HIV. The reason they cancelled the project was that uninformed people would go around claiming that it caused HIV. Also, other vaccines are now available.
"This is a reference to trials of a vaccine being developed by the biotech company CSL and The University of Queensland which used a fragment of a HIV virus protein as a component to stabilise the vaccine (here). Production was halted after trials showed that antibodies generated in response to the protein fragment could lead to false positives on some HIV tests (here)."
Some clinical work has been done with mRNA vaccines as treatments for other diseases, including cancer. Nothing has made it to Phase 3 yet (other than for Covid-19), but on this page you'll find links to a slew of clinical trials over the years.
A handful of studies are currently recruiting for Phase 2, so that means there was a successful Phase 1 some years ago. So those people would, I believe, be the longest-surviving patients to have received an mRNA vaccine.
Yes, and also a number of non-Moderna clinical trials dating back to 2008. [1] The largest of those trials enrolled around 200 participants — not Phase 3 sized but still significant.
The difference to "traditional" vaccines is really not significant with regards to risk.
The mRNA is translated to a protein, which is the actual target your immune system then recognises as foreign, attacks, and remembers.
In a sense, it's a lot like a prodrug, which is a "traditional" small-molecule that is turned into the actual drug by some interaction with your body–your stomach acid, for example.
"mRNA" might sound scary. But it isn't going to change your genome or anything like that; it's strictly downstream from DNA. Any virus, bacteria, or salad you eat contains far more mRNA in addition to DNA or RNA, and the first of those really does come with mechanisms to insert itself into your cells' DNA and has evolved to defend itself against your defences, and to slowly take over your body in some way or other.
There are some short-term risks on the order of, say, eating lobster for the first time. Allergies, for example, which can be quite severe and even deadly. But those are exactly the risks the trials would have uncovered, and the people possibly at risks of such things would already know they are susceptible.
There is no known mechanism for any risk that would not manifest within the first day or two.
Then you should be truly horrified about all the proteins from the hundreds of billions of bacteria and viruses, and of course, cancer cells, that are currently roaming your veins, because said bacteria or viruses did not even try to make them safe for their hosts.
Of the difference in scales of the bad things are six orders of magnitude, yes, probably.
If you think it's a risk, quantify and measure it, and compare it to the risk of not doing anything. People love to grouse about vaccines, bit they never seen keen on doing the math. (Because it consistently does not support such an argument.)
*if I viewed all proteins as equal... I take solace knowing that if said virus creates something truly catastrophic to the human race - its way beyond the realm of caring for we shall be dead soon. However, its evolutionary time scale factored by its probability of being that horrible means I’m better off waiting to win the lottery.
HOWEVER, knowing we as humans tried to replicate the exact “key card” into our cells that makes this virus so potent (aka the spikey bits with the ACE receptor end) worries me greatly. That’s not on evolutionary time scales or mutations... that sounds like IVF and diabetes.
I work with RNA, but not in medicine. mRNA is not a long-term molecule in the body, so its difficult to imagine direct long-term effects. Of course, immune responses can cause long-term damage. So the question is: should we wait to find out?
The doses have 30-100 ug. Assume 1)this is pure RNA, and 2)the molecules are about the same size as the spike protein sequence. With these assumptions, a dose gives you 10^10 RNA molecules. Average sputum samples show about 10^6 molecules/mL; max samples show 10^9/mL. I don't know how vaccines dilute when you inject it into somebody's shoulder, but it doesn't seem unreasonable to say the final conc will be between 10^6 and 10^9 RNA/mL.
So RNA is going to be in us, whether we want it or not. The question is, do you want the whole genome, or part of the genome. I'm picking the one that doesn't make more virus.
Would you perhaps be able to answer a question I've been wondering about?
Is this way of injecting mRNA really any different from just injecting someone with a virus? Not in the sense that it makes you ill but in the sense that a virus would do the same thing just with more harmful mRNA.
In this case, the mRNA just gets your body to produce a part of the spike protein that is on the virus. Once the spike protein is floating around in your body, your immune system recognizes the spike protein and starts an immune response. The spike proteins themselves cannot actually replicate and attack the body. They are just a small part of the virus structure.
If you inject with virus, presumably the virus would begin to replicate and attack your body.
It's RNA to make the spike protein, so your immune system becomes infuriated and produces a reaction to kill cells that turned into factories for that protein.
You don't want the virus RNA, that would be presumably all that plus more!
The answer to your question is, it's a subset of the virus.
>Are there any possible long term side effects of using such an mRNA drug that are yet unanticipated?
I'm not sure but I strongly assume yes.
The MAIN reason for this skepticism is that if it was just possible to introduce RNA such that we could have a net positive benefit against coronavirus, a virus that has existed for almost as long as mammals have, we'd have naturally evolved this ability.
The reason we haven't is because it will introduce more problems than it solves down the line.
It could very well be that with a limited understanding of human immune system, we have stumbled upon a solution to a problem that has affected us for millions of years. So, I think some people should try it. But forcing it on the masses is a terrible idea.
This take implies that no medicine for deadly diseases can work because otherwise we would have evolved the medicines ourselves.
Also, COVID-19 has not been around "for millions of years." Other coronaviruses, such as the common cold, have. The evolutionary benefits of defense against the common cold are fairly different than benefits against COVID-19. And immunity against one coronavirus doesn't grant immunity against all other coronaviruses.
>This take implies that no medicine for deadly diseases can work because otherwise we would have evolved the medicines ourselves.
That is true. Most of them don't work, not without creating worse problems down the line. Specially, if it's something as simple as creating some proteins that the body can already produce (which is what happens when mRNA vaccine is given). If the solution was as simple, evolution would have found ways to do that.
Currently, some deadly diseases do have some treatments that work... but that comes at HUGE expense i.e. a LOT of energy has to be spent for little gain. It is only possible because there is huge inequality among people and the rich class can afford to spend enormous energy and manpower to treat those diseases. If and when the world becomes more equal, this will no longer be possible (you'd think that "robot slaves" working off of "free energy" would solve that... I don't think that's going to happen but that's a different discussion).
>Also, COVID-19 has not been "around for millions of years."
We can't know that. It could very well be that COVID-19 had infected mammals before and we naturally god rid of it in a few generations. When infections come about, "weaker" individuals die and those with stronger immunity survive and reproduce and the species of COVID-19 might have died out. Some coronaviruses continue to live with us because they don't cause major problems... but there must have been many more which caused major problems and we had had to deal with them differently... and one of them could have been very similar to COVID-19.
But yeah, it could also be that this is the first time we're encountering it. So, let's go with that. My argument doesn't change.
>immunity against one coronavirus doesn't grant immunity against all other coronaviruses
True. However, in millions of years, our immune system has encountered many species and strains of coroviruses, and trained on that data and come up with a much more generalized and long term solution. I'd rather trust that than some random know it all people who think that have a better solution with very limited knowledge of what is going on.
Having said that, I'm not against testing new solutions. It's the scale that bothers me.
Two points, the most effective treatments we have for deadly diseases are vaccines which are effective precisely because they rely on our naturally evolved defences. Antibiotics are a runner up but are eventually rendered ineffective by evolution of bacteria they target. Second, Covid-19 is only new to humans, given time it will adapt to us and will likely attenuate.
> The MAIN reason for this skepticism is that if it was just possible to introduce RNA such that we could have a net positive benefit against coronavirus, a virus that has existed for almost as long as mammals have, we'd have naturally evolved this ability.
We'd have naturally evolved the ability to train our immune systems against specific things it hasn't seen before? How would that POSSIBLY work?
The novelty of this particular coronavirus is sort of the problem here, since people don't already have immunity, so your "millions of years" thing is completely off base.
You seem to be arguing against the possibility of a "universal vaccine" for all viruses but that's entirely not what this is. It's very specifically targeted and the idea that we'd evolve the ability to target things specifically without actually being exposed to them in the same way is plainly nonsense.
Actually, the ability to respond to never-seen-before threats is the whole purpose of the adaptive immune system [1].
> How would that POSSIBLY work?
Through a process called V(D)J recombination [2]. Essentially, every lymphocyte gets a different receptor of random shape, and purely by chance there will be a few lymphocytes with a receptor that matches the shape of the invading viruses (in most cases).
> Actually, the ability to respond to never-seen-before threats is the whole purpose of the adaptive immune system [1].
But the poster I was responding to was claiming that our immune system should have evolved the ability to not respond to those threats, but anticipate their specific forms without seeing them. That vaccination as a concept is hogwash because if it was useful, we'd have done it through evolution. But that's plainly nonsensical - we wouldn't need a system that functioned by random variation if we evolved the ability to know what the real targets would be, but we couldn't do that without specific knowledge, which we can't get without being exposed to the things, by which time ... it's too late to have then already built the specific defenses.
And during the time that takes you're suffering the consequences of a viral infection. Majormajor was replying to a comment suggesting that it might somehow have been possible to evolve the equivalent of a COVID-19 vaccine, which allows your immune system to adapt without experiencing a viral infection. What couldn't possibly work is for your body to already naturally be immune before experiencing the virus.
>We'd have naturally evolved the ability to train our immune systems against specific things it hasn't seen before?
See my response to another comment. We must have dealt with countless species and strains of coronaviruses already. So, our genes have a lot of training they need. Even if we haven't trained for this particular strain or species, we will most likely fare better than the solution that has never been tried ever.
What if the children of those vaccinated turn out to be much weaker against other common antigens start dropping dead? It will set humanity back by a lot.
>since people don't already have immunity, so your "millions of years" thing is completely off base.
We do. Most people are completely unaffeted by the virus. It's a relatively small percentage that has severe problems. To endanger EVERYONE because a small percentage is affected is downright retarded. Having said that, I'm not at all against trying different things out. The best way to roll it out would be to do it over a VERY LONG PERIOD, spanning generations. And most importantly, keeping significant number of people completely unvaccinated. This has not been a problem until now because big enough population chose to be unvaccinated. However, the scale of current problem might mean that this could change... which is terrifying.
Look, I'm more willing than most to agree that forcing a medical procedure on the masses is a terrible idea. I'm even more willing than most to agree that not every vaccine will have a sufficient cost/benefit trade off for everyone. I have low-exposure and low-risk to COVID so I'm content to wait a while for the vaccine. I have questions in my mind about how we're so sure that a big shot of mRNA can't somehow cause a risk of birth defects, etc. But...
>> The reason we haven't is because it will introduce more problems than it solves down the line.
This is just not sound reasoning, and it's a terrible argument against the vaccine. Have you ever taken antibiotics? Or have you ever benefited long-term from anything medical that we didn't "evolve" through natural selection? Because I sure as hell have. How does this not apply to other vaccines, which have clearly saved an astonishing number of lives, and have, almost without exception, not produced the kind of long-term existential threats to humanity you seem to be hinting at.
>How does this not apply to other vaccines, which have clearly saved an astonishing number of lives, and have, almost without exception, not produced the kind of long-term existential threats to humanity you seem to be hinting at.
It does apply to all vaccines. Vaccines bias the immune system, which has evolved to be general enough to deal with problems that generally come our way. This bias caused by vaccines results in better performance against those specific viruses but comparatively worse performance against most of anything else. This can also result in auto immune disorders down the line:
Generally, this bias also happens naturally when viruses infects populations. But the tradeoff is mostly worth it when the virus is still at large... and the natural population is optimized for wide variety of attacks because the immune systems are biased in many different ways in the first place, so even after a pandemic, the resulting population will still have a varied enough immune systems.
Large scale vaccinations bias the population in a very few particular ways. When vaccines for multiple viruses are given to everyone, the immune systems become more and more similar than it would ever happen naturally. So, mass vaccinations make us more fragile as a species against future pandemics, not to mention the autoimmune disorders that also happen as a result.
Given that vaccines have unintended consequences, you probably agree that targetted vaccinations are effective i.e. what if we could vaccinate exactly those who will get infected right before they get infected? That way, we could help them fight the infections better while not affecting anyone else. Right? That is how the immune system already works. It starts the fight right after it detects the infection.
Sometimes, the immune response is not appropriate and can cause more problems than it solves. The same can happen with vaccines.
Sometimes, the immune response may be appropriate but is not sufficent to save the host. The same can happen to vaccinated individuals. It can be argued that the headstart that one gets because of early vaccination might make it worth it... but you also have to consider how many will be vaccinated even though they never really get infected and how many will be missed anyway... and there is also a cost to determining these things. So, overall, it is highly unlikely to be worth it.
Okay, layman's speculation: Given we can co-opt cells to manufacture proteins for us like this, and given we can predict what shape of protein an mRNA strand would produce, does this open up all sorts of potential in medical treatments? Tear it apart, HN.
I'm not sure I understand the question, as that's the point of the article. Clinical trials are currently testing mRNA to produce proteins to treat cystic fibrosis, heart failure and various obscure conditions. There are various problems, such as ensuring the the protein is created in the right cells, requiring repeated doses so the protein is created over a long time, handling side effects, and increasing the amount of protein created. So mRNA isn't an easy solution.
Yeah, that's basically what the article discusses. It will be easier for non-targeted treatments that can circulate the whole body. This tech (by itself) doesn't really solve the issue of delivering site-specific medication.
> given we can predict what shape of protein an mRNA strand would produce
For therapeutic proteins you usually work the other way around: You design the shape and try to get a sequence that folds as intended. In other words, the inverse folding problem.
The parent is referring to the recent DeepFold success in predicting protein shapes from DNA/RNA, which means it appears to have solved the inverse folding problem for many proteins (modulo more exotic protein “features”). I haven’t read the article (yet), but presumably being able to go from desired protein shape to plausible nucleotide sequences to mRNA to produce them would enable a lot of drugs to be developed that were cost/resource prohibitive previously. Presuming you can get access to DeepFold and the compute time to run it on semi-random sequences until you get matching shapes.
> it appears to have solved the inverse folding problem for many proteins
While this is true, DeepFold’s algorithm is only applicable to extant proteins having enough evolutionary information, which is arguably a small fraction of the theoretical sequence space. Fortunately, machine-learning approaches for de novo protein design are being actively developed as we speak.
> While this is true, DeepFold’s algorithm is only applicable to extant proteins having enough evolutionary information,
Didn't the challenge include predicting previously unseen/unsolved proteins? Based on that, I would wager that what DeepFold learned is an evolutionary "language" that maps out a large useful subset of the entire possibility space. Natural evolution tends build upon previous successes so it seems probable evolution has mapped out a fairly useful "language" of patterns for useful protein shapes. Especially given only a portion of the shape is critical to function for many proteins.
But agreed, de novo protein design based on DeepFold's successes probably will outperform a naive approach by orders of magnitude. But why wait if even a naive approach is already orders of magnitude better than current methods?
Either way, I'm excited to see who comes up with the first custom protein(s) to catalyze industrial processes! Get some yeast/bacteria to mass produce a protein based alternative to platinum catalyzer's for fuel cells using an active site with organically available (and cheap) metals. Design half of it to stick to a polymer so it coats nicely. Bam, no more trying to get some weird polymer/perovskite with the right properties. Not sure mRNA is needed at that point versus CRISPR, but maybe it's more effective.
> Didn't the challenge include predicting previously unseen/unsolved proteins?
All protein sequences in the competition lacked a published solved structure, but they had enough effective (remotely) homologous sequences to predict coevolution-derived interresidue distances and contacts. All those sequences were already present in databases and therefore within the known protein universe.
> Based on that, I would wager that what DeepFold learned is an evolutionary "language" that maps out a large useful subset of the entire possibility space.
This might be true, depending on how “foldable” the unexplored space is. A reverse DeepFold would give some clues on that.
> Natural evolution tends build upon previous successes so it seems probable evolution has mapped out a fairly useful "language" of patterns for useful protein shapes
This is already known. The structural and functional diversity we see in existing proteins originated from a relatively limited repertoire of conserved protein domain folds, or even subdomain-sized fragments in some cases.
> Either way, I'm excited to see who comes up with the first custom protein(s) to catalyze industrial processes!
Same here! Especially since the de novo design of enzymes has been progressing slowly but steadily.
> but they had enough effective (remotely) homologous sequences to predict coevolution-derived interresidue distances and contacts.
Ah, I see what you're saying a bit better. Makes more sense to how the the possible "design" space for novel proteins could be limited. Designing novel active sites could be especially tricky, more than it'd seem at first glance. A folded structure that'd effectively transfer electrons from one target species to another in a catalyzer protein could likely be outside the explored "vocabulary" of extant proteins as it'd require specialized pathways and precise positioning. Chlorophyll is pretty unchanged in evolution as I understand it.Thanks, interesting background! I'll keep an eye out for the de novo design algorithms.
Yes, and no. The principle is there, but it is important to understand that each cell type is essentially a specialist factory to produce proteins, and the drug may be produced best when you get exactly the right factory to produce the protein (I’m thinking about PTMs). If your body is flooded by inferior product from the wrong factories, the effect of the superior product may be inhibited of diluted.
That said, I can imagine once we figure out how to deliver the mRNA to precisely the right targets, this would be a lot easier (eg engineering receptor ligands onto the mRNA lipid delivery particles).
On face value, it sounds less risky than the standard vaccine development route, which may involve introducing immortalized (i.e. cancerous) cells or artificially stimulating an immune response with known toxins (adjuvants).
I still have questions about the mRNA vaccine concept. Maybe some well-informed HNer can shed light?
1. If the goal is to get the desired protein inside the patient's body, why is injecting mRNA that produces the protein more effective than simply introducing the protein itself?
2. How does the patient's immune system know to treat this protein as unwanted if it's being produced by the body's own cells?
3. How do vaccine developers avoid creating an over-active immune response in the patient (i.e. an allergy)?
The simplistic answer is that the immune system tries out new antigen-detecting cells in a safe environment before letting them run around with a loaded gun. Any cell that activates in that safe environment is destroyed, as it recognized one of your own antigens.
The other mechanism is that the immune system doesn't react only to foreign antigens, there also needs to be some general activation of the immune system in that area for a real response.
The full answer is that this is really, really complex like pretty much everything involving the immune system. And auto-immune diseases indicate that the immune system doesn't always get this right.
there is a system homologous to machine learning 2factor authentication.
in very loose terms both keys must be presented while the immune system is in training, the instances where protiens are expressed with out cell surface recognition molecules in proximity are invalid thus foriegn, and memory immunity to this "failed login" is maintained. when both factors [protien plus recognition] are present constituitively over the course of development the immune response is squelched.
1. A single rna can produce multiple times the protein, because it is like the proverb about giving someone fish and teaching them fishing.
2. Someone already said, but a protein has no marker saying "local produce". It is either allowed or not and the body reacts or not when detecting it.
3. They hope. Measure the dosage and adjust. As it was reported, some people getting the vaccine have an allergic reaction, but hopefully it will be rare and under control. So far there are only a few cases reported.
Adjuvants are not toxic, they're simply known to enhance the immune system response (so they are something that indicates danger to the immune system). The immune system is incredibly dangerous and destructive, and you really don't want to trigger it without reason. So injecting something unknown might not be enough to get the immune system fully alarmed, that's why some vaccines add adjuvants to produce a stronger response. RNA can be an adjuvant by itself, as it's also a typical component of viruses and the immune system reacts to that.
So the trick really is to design the RNA and the delivery system so that it produces an immune response of the right magnitude. Too weak and it doesn't work, too strong and it's harmful.
Antibodies that bind to your own proteins are filtered in an earlier stage in antibody production. Real viral proteins are also produced by your own cells, so that is never a factor by which you could distinguish friend from foe.
1. I guess for smaller batches it is easier to develop the mRNA. Otherwise, we would have monoclonal antibodies and not a vaccine(the vaccine has other benefits, it trains the T-cells and the B cells remain dormant even after no abtibodies are detected in the blood).
2. The imune system knows all your protein already, t cells are evolved in the thymus gland, if they attack anything "self", they get destriyed.
the vaccine doesnt contain fetal cells, in the case you are providing the vaccine is an attenuated virus approach.
the cells are used to manufacture quantities of the virus in an extremely weakened form. This gives a chance for the immune systemto mount a response before the pathogen initiates systemic disease response.
the cells in question are not freshly harvested from a foetus, the progenitor cells are harvested and kept in continual culture for use. the reason immortalized cells are used is to escape the "expiry date" of a normal cell.
>>Some vaccines currently available were developed using cell strains cultured from two fetuses aborted for other purposes in the 1960s.[6]<<
A layman's speculation followed by a layman's (at least in terms of immunology) question: introduce a novel mRNA, cells produce novel protein, it is presented to the immune system as something to foment a defense again: vaccine. But the article talks about using this mechanism to replace a functional copy of a genetically missing enzyme. How is it assured that this will assume the opposite goal and not become another target for the immune system to guard against?
On the opposite side: how do we effectively convince people this new type of vaccine is safe long-term? I'm not a biology person, so I trust the biology people when they say it's safe, but many don't.
My intuition is that many cancers can start when proteins are mis-copied, and mRNA therapy seems to rely on copying to work very reliably. Does introduced mRNA increase the risk or impacts of mis-copying?
Is there an ELI5 intuition for why mRNA therapy is safe and won't lead to cells becoming cancerous?
Cancers start when DNA is mis-copied. Typically DNA is copied to RNA, which is then used to generate protein, and there isn't usually a mechanism for that RNA to go back a step to become DNA again. I don't want to say it's impossible, or that there's no conceivable negative effects, but cancer seems like an implausible result from mRNA therapy.
Thank you, that's a good addition. I knew it didn't happen with mRNA, but also knew that there was _a_ route from RNA to DNA, though I couldn't remember what. That's why I hedged my statement with "usually".
I don't think mRNA spreads from cell to cell, the mRNA enters a limited number of cells and those cells start producing certain proteins the mRNA tells them to.
I'll state upfront that I'm not a biologist, but here's my attempt at the explanation.
The ELI5 version:
Think of the cell as a factory for proteins. The blueprints for all of the different kinds of proteins it can produce are encoded in DNA and stored in the foreman's office. When the cell wants to make a particular protein, the foreman copies the instructions from the blueprint onto slips of paper (mRNA), and sends them to the assembly line workers. This type of copying happens all the time, and is pretty reliable -- and even if it's not, the end result is just some wasted time and a junk part. The blueprints are unaffected. mRNA vaccines sneak some unauthorized instructions to the workers, who then run a ghost shift to produce the protein we want to cause an immune response to.
When we need to create a second factory, we need to photocopy all the blueprints for the new cell. This uses a totally different process (a photocopier assembled specifically for the job of copying whole blueprints onto more blueprint paper, and not the work-order slips sent to the assembly line). The photocopier is pretty reliable too, but occasionally it introduces artifacts, and eventually, enough of these errors can build up to create mistakes in the blueprints. The blueprints have instructions on how to deal with errors in a new factory (by blowing it up), but if enough of those failsafe instructions are obscured by copier artifacts, you now have a potentially cancerous cell.
The foreman's office doesn't usually make changes to the blueprints based on work order slips. It's possible with a special copy machine -- this is how HIV works, by sneaking that machine in -- but without a work order slip to blueprint copier, it doesn't matter how many fake work order slips we pass into the cell. They will only affect the production line, not the foreman's office.
The more detailed, and almost certainly wrong-in-the-details version:
There are three types of encoding for genetic material: in DNA, in RNA, and in proteins.
In order for the information encoded in genetic information to be active in a biological system, it has to be expressed as a protein -- a physical manifestation with binding sites and the ability to interact with other molecules. Ribosomes, a component of the cell, do the "assembly" part of transferring genetic information to a protein. This is called "translation".
DNA is the long-term storage of the information eventually expressed as proteins -- it's a collection of templates in long term storage. So there has to be a process to get information from the long-term storage of DNA, in the nucleus of the cell, to the ribosomes elsewhere in the cell.
Messenger RNA is the intermediary molecule which carries the genetic information from the DNA to the ribosomes. It's produced in the nucleus of the cell by a mechanism called "transcription", which copies a subset of a DNA molecule into a complementary RNA molecule encoding the same information. The DNA double-helix is "unzipped", a complementary RNA strand is assembled, and the double-helix reforms. The mRNA can then be transported to the ribosomes.
mRNA is a useful vaccine mechanism, because we're co-opting a late stage of the cell's protein production pipeline. We don't have to assemble the target protein by hand and figure out how to modify it make it stable for distribution -- a task that would need to be repeated for each protein we wanted to make. Instead, we can figure out how to synthesis mRNA, and we don't need to worry about either synthesis or stability for the end protein product.
When we talk about cancer and mis-copying, this is at a much earlier stage in the pipeline. When a cell splits into two cells through mitosis, we don't want a subset of the protein templates in the cell's genetic material; we want a complete copy. This is a separate biological pipeline, which involves the cell building up a mechanism to do the copying, dissolving the membrane of the nucleus, and ultimately producing and collating copies of all the DNA from the nucleus. This is an entirely separate process, and messenger RNA isn't involved at all.
There is a route for information to travel from RNA back to DNA, and this is the mechanism retroviruses use, and HIV is the most famous example. A complete retrovirus particle includes reverse transcriptase, an enzyme which allows them to transfer information from RNA back to DNA. This is the reverse of the normal DNA -> RNA pattern described above, hence the name _retro_virus. Without that enzyme or something like it, there isn't a pathway to convert RNA back to DNA, and human cells don't normally express an enzyme which has this function.
mRNA might not pan out for more general purposes (well, specialized for each use case) but it seems kind of crazy that the most significant pandemic, social upheaval, and economic crisis the world has known in 100 years could also lead to some of the most significant advances in medical science & therefore quality of & length of life as well.
I'm not trying to downplay the health issues or impact of COVID, just saying that it has the potential for one heck of a silver lining. Not least of which is that even if other mRNA uses aren't forthcoming, we're incredibly more prepared to fight another pandemic, especially other Corona strains, that could be more harmful.
Sure, Moderna alone has been working on things for 10 years, but not a whole lot of other "Big Pharma" resources seem to have been thrown at it previously. My guess is that will change now.
The situation reminds me of research into serotonin's role in depression. Like mRNA in its field, ideas about serotonin and a little bit of research were bouncing around for a few decades. The drug that was ultimately branded Prozac was developed in the early 70's, but not brought to market until the mid 80's. Then, it's ground breaking efficacy compared to prior drugs & for people not helped by those other drugs acted as a catalyst for research that now forms the foundation for modern treatment of mood disorders-- certainly far from perfect, but also far better than 30-40 years ago.
For example, Prozac's minor role as a norepinephrine reuptake inhibitor sparked significant research into that neurotransmitter as well, leading to yet another generation of new drugs, SNRI's like Cymbalta that which are not only a useful for depression & anxiety, but also for the treatment of certain forms of chronic pain & as an aid for quitting smoking.
It's too early to tell for sure, but I see the potential for the moment in history to be a similarly catalyzing event for mRNA research & subsequent treatments.
(Unless of course the vaccine produces a zombie apocalypse, the relatively small trials by chance not having anyone impacted by that potential "side effect" of zombie-ism, in which case I'll feel pretty silly sitting here a few months from now having to eat my words. And brains, lots of brains.)
This article is a great read. It is amazing what scientists have accomplished using mRNA. I have researched on the application of genome editing using the Cas9 protein in cancer therapy. There are many possibilities for utilizing mRNA and proteins. The future of medicine sounds exciting!
I think RNAs are great as a cell therapy. Not necessarily mRNAs, but other ncRNAs which can be used to silence enhancers. This would be great for many diseases.
mRNAs are great as a vaccine to trigger an anti-cancer response, combined with checkpoint inhibitors. The big challenge is to choose a good personalized mix of peptides (encoded as mRNAs) in a way that scales to thousands of patients.
I did some reading on this back when this was all announced, and wrote it down on Twitter. This tweet [1] links to a Nature paper that describes applying mRNA vaccines to cancer. If you scroll up, you'll also see pointers to other papers that I found along the way when I was learning about mRNA vaccines in general.
here it says that UK authorities advise that people with a history of allergic reactions may not get the mRNA based vaccine, as they may get an anaphylactic event. Now wikipedia says that this is a potentially serious condition https://en.wikipedia.org/wiki/Anaphylaxis
Now I am confused, https://www.aafa.org/allergy-facts/ says that some 50 million people in the US suffer from some kind of allergies, does that imply that 15% of the population can't get the mRNA vaccine? Now would that figure have any implications on the effectiveness of vaccination? Should people with allergies get a different kind of vaccine? Many questions remain.
Allergic reactions to vaccines of any type are somewhat normal, if rare. Usually those don't relate to the vaccination agent itself but accompanying chemicals that trigger your immune system (after all, the immune system won't launch an attack if you got stabbed with a needle) to go into attack mode. When you have an allergy to vaccines, this attack mode goes into overdrive and causes a widespread release of cytokines and other immune system agents. In some cases the reaction can be driven by the vaccination agent itself but from what I recall that is exceedingly rare.
The advice is actually for "serious" allergic reactions. There's a world of difference between hayfever and something life-threatening like nut allergies.
I have hay-fever and Asthma and you won't be able to stop me getting the vaccine. I see far more risk from COVID than the vaccine.
I have to question your motivations here. Your post is disingenuous at best.
The linked article mentioned 'allergic reactions', it further links to a cnn article [1] that mentions 'significant history of allergic reaction', both articles don't clarify the condition.
I think they should give some detailed clarifications on the issue to the public, as the producers of the vaccines can't be sued for damages, in the event that something goes wrong.
cell surface protiens go through a turnover in similar fashion to mRNA. protiens are chemically and phsyically more robust than mRNA however due to thermokinetic damages etc. protiens must eventually be decommisioned and replaced by new updates [likewindows10]. cell membrane turnover also occurs. this is a recovery of the cell toward its central tendency. in strictest terms the expression of the novel protien is damage, but not to the extent that the cell must be destroyed. Cells have timeline leading to proceedural, and also programmed cell death, this is a case of the needs of the many [tissues, whole organism] outwieghing the needs of the one or few.
there are many quotes regarding ~every Xmonths you are a new person.
The question is, how did this start just now? In 2020? How is the COVID-19 vaccine the first to use mRNA? Anyone with who has taken AP Biology could conceive of and understand the idea behind making vaccines rapidly: take some mRNA, inject it, have in translated as the antigen in the body. Poof, that's it. I feel like the development of mRNA drugs should have started in the 70's or 80's. It isn't exactly high-tech or clever.
Delivery of the RNA is hard. To the right cell type, not immediately degraded, not accidentally integrated into a critical part of the genome, with a payload that is actually effective, etc.
The original gene therapies (early 2000s) were essentially RNA therapies (adenovirus). And their unethical rush and subsequent failures caused a bit of a 'gene therapy winter' [1]. We've since made enormous progress on both the ability to safely deliver genes, but also our ability to generate/design new useful genes.
> In 1972, a paper titled ‘Gene therapy for human genetic disease?’ was published in Science by US scientists Theodore Friedmann and Richard Roblin, who outlined the immense potential of incorporating DNA sequences into patients’ cells for treating people with genetic disorders. However, they urged caution in the development of the technology, pointing out several key bottlenecks in scientific understanding that still needed to be addressed.
"incorporating DNA sequences into patients’ cells" is a wildly more dramatic approach than temporarily tricking a number of cells into manufacturing some protein with mRNA. It's almost like the difference between getting the browser to run your page's js vs a full remote code execution vulnerability.
The parent was probably confusing RNA with adenovirus which IIUC does deliver DNA that integrates itself into the genome. There are dozens of COVID vaccines under development right. Many of them are in fact DNA vaccines. To date they've only been approved for vaccinating dogs of rabies. The mRNA vaccines that companies like Pfizer are making have the advantage of not permanently changing the DNA in the target cells. Even with DNA vaccine it's not the end of the world. For example, herpes simplex (cold sores) is an example of a natural virus that integrates itself in the DNA. But it's localized and it's not something that your children are going to inherit. Another interesting fact is that the Pfizer mRNA vaccine and others are delivered using lipid nanobots rather than adenovirus which I think is cool. But DNA vaccines have even potentially cooler applications since it means the medical field might for once be able to offer cures to illnesses, rather than charging you for a pill every day.
The number of [nucleic-acid-delivered] gene therapies in Phase II & Phase III trials right now is huge - because of this progress in delivery [of nucleic acids]. Gene therapies for the eye, for hemophilia, for sickle cell, many many cancer therapies all rely on the ability to 'deliver' nucleic acid payloads to cells. Of those, only 3 or 4 have been approved - and all in the past 2 years, but there are a huge number that are behind that tip of the iceberg - quite precisely because it's relatively straightforward to do 'same thing but with a different sequence' once the first one works.
The technology for synthesizing large quantities of specific RNA sequences has only been available recently. Same goes for forming the lipid nanoparticles that are used for encapsulating and delivering the mRNA. In fact if anyone has more detailed information on how these two processes are done I would love to learn more.
the emphasis in the wiki article is on DNA, the same basic principles apply with RNA.
for example you can start with RNA and use reverse trancriptase to produce a DNA sequence, amplify that sequence to a large copy number by repeatedly replicating it then transcribe the DNA to produce large quantities of RNA.
or you can start with the DNA [in large quantities of purity] then create many copies of the RNA by repeatedly transcribing the DNA.
The practice of artificial [in vitro] gene synthesis can create arbitrary sequences for input to the process[es].
> the emphasis in the wiki article is on DNA, the same basic principles apply with RNA.
This is not my understanding. PCR works to produce DNA because the DNA polymerase enzyme creates DNA copies from DNA templates, and those copies become templates themselves, feeding back into the chain reaction.
I'm not aware of similar enzymes capable of making RNA copies from RNA templates (RNA polymerases use DNA templates AFAIK).
I was imagining the RNA vaccines would have used a fully synthetic oligo production method, to get the extreme purity required. But it might be that some sort of PCR-like amplification process is used. Would love to read more if someone has details.
I was making reference to the process of cyclic amplification, in a manner palatable to non biology literate individuals
The same _basic_ principles
as can be read in the chempedia example the process of RNApol replication of RNA from RNA template is error prone, thus it is superior to create a large copy number of DNA template corresponding to the mRNA desired as DNA amplification is self correcting for the most part.
dependent upon experimental or procedural requirements it may be desirable to produce error prone replication variants of the RNA template, however it is quite possible to go from RNA template to RNA product with RNApol.
due to the fragile nature of RNA there must be some shielding or , a low cycle rate is used in conjunction with immediate harvest and stabilization of the product.
the sars-2 covid19 virus replicates by way of an RNA dependent RNApol [rdRNApol]
Thanks for the additional links. I guess you would need temperature stable viral RNApol to do direct 'RNA' amplification. Not sure if that exists or if it's even possible due to RNA instability. As you say not so worthwhile due to high errors.
Producing RNA from DNA amplicons (PCR products) makes sense, I'm curious if that is the source of material from in the vaccines, or if it's artificially synthesized?
when you have determined a sequence of RNA corresponding to a desired protien you may construct a DNA template with modification to suit your purpose.
the DNA polymerase used for DNA PCR is originally from a high tempurature tolerant organism, [thermophillic bcterium] and it is possible via searching high and low to find an organism that bears high temperature tolerant rdRNApol
Thanks for the Kary Mullis story. I performed thousands of PCRs and even made some batches of taq many years ago but never knew about its ideation! I knew some pretty out there biochemists though.
I'd like to know more about the potential for lipid nanoparticles to cross the BBB [1], and therefore consideration of long-term effects of mRNA and resulting proteins in brain cells. Am I alone in this concern? [1] https://pubmed.ncbi.nlm.nih.gov/29886842/
You’re right, we’ve understood that this could be done for a long time. Not quite the 70s, but.. at least the 90s. But believing something is possible and knowing how to do it are different:
“2005 they published a joint paper that solved one of the key technical barriers by using modified nucleosides to get mRNA inside human cells without setting off the body's defense system”
That kicked off a ton of research, but:
“Up until 2020, these mRNA biotech companies had poor results testing mRNA drugs for cardiovascular, metabolic and renal diseases; selected targets for cancer; and rare diseases like Crigler–Najjar syndrome”
But why did they spend from 2005 to 2020 working on mRNA drugs and not vaccines? Capitalism. Vaccines are not generally profitable (take once, you’re done) - so vaccines are not an appealing target for a startup with investors wanting big returns. (Source: https://www.statnews.com/2017/01/10/moderna-trouble-mrna/)
Yeah seems like vaccine development only started after the high profit objectives suffered failure. That doesn't mean we can't go back to working on those objectives in the future but they needed SOMETHING that would work to show mrna promise. Vaccines you only have to take once or twice so the side effects of immune response aren't too bad and you have an immune response to a vaccine anyways.
Even for the staunchest capitalist, covid has clearly outlined that we need medical research that is separated from market forces. After sars 1 was controlled, research in this area was all but dropped - despite virologists warning that it was just a matter of time before... well, this.
Medical research needs to be driven by what can help people, not by what can make the most money.
PPE too. We still don't have N95s for the public or in some areas even the medical professionals.
If we had a different administration in the USA we may have been able to conquer that quickly with sheer cash and coordination since the knowledge how to build melt blown N95 machines is there. For whatever reason we just didn't.
The immune system is incredibly dangerous to its own host if mishandled. By stimulating response, you are trying to light a cigarette using a white phosphorus flamethrower, so to say.
It took a lot of time to find the optimal way of mRNA delivery that a) really does something but b) does not provoke a massive, counterproductive response. This is a very narrow rocky ledge with precipices on both sides to walk.
I think the theory behind it is straightforward enough (and indeed, Moderna was founded 10 years ago with this sort of mRNA vaccine as their explicit goal), but the practice is more complicated.
Figuring out what sequence of mRNA will be the right one to get a cell to produce the right antibodies for the job, getting that sequence sliced out of the viral RNA, getting that all into a form where it can be absorbed by cells and not just instantly degrade are all nontrivial tasks.
The devil’s in the details: compare to the field of software or cpu engineering... seems straightforward enough to just have more instruction decoders, but due to complexities only ditching x86 has actually made it possible for Apple to do this.
> Anyone with who has taken AP Biology could conceive of and understand the idea behind making vaccines rapidly: take some mRNA, inject it, have in translated as the antigen in the body.
There was quite a lot of development on basic techniques of working with RNA necessary before that could even in isolated circumstances be easier than, or even competitive with, “isolate the antigen, inject it, done”.
> The question is, how did this start just now?
It didn't.
Getting a treatment to market isn't the start of application of a new technique in medicine; its usually something that happens many years, often decades, into work using the technique.
Given that Moderna is the first ever company to bring such a vaccine to market and they’ve been working on mRNA for the past 10 years, I imagine there’s a lot of technical complexity to actually deliver a therapy and then mass produce it beyond just the basic concept.
Reading how Pfizer and Moderna worked on it together, they needed detailed gene sequencing to understand how to design a potential vaccine. Even then they were left with a lot of potential options they still had to whittle down. Finally even with all that work they’re left with a vaccine with complex storage requirements.
So it’s entirely possible that we just didn’t have the surrounding technical ability even if theoretically it was possible. The gene sequencing to sequence it quickly and share that across the entire world, the compute needed to do try different experiments at scale, the manufacturing capabilities, Moderna having invested in the space for the preceding 10 years, existing experience with developing a SARS vaccine, etc.
Moderna's vaccine is a great deal easier to store than the BioNTech/Pfizer vaccine (requires 'normal' freezers for storage, can be at refrigerator temperatures for a longer period).
BioNTech and Moderna both have links to Katalin Kariko so while they didn't explicitly work together on this the knowledge comes from similar research and sources.
Because the parent appears to have been downvoted (as of this writing), I'd just like to point out that according to the site FAQ, their question is perfectly acceptable on HN.
> It's ok to post stories from sites with paywalls that have workarounds. In comments, it's ok to ask how to read an article and to help other users do so. But please don't post complaints about paywalls. Those are off topic.
Why is that the next challenge? Why aren’t we using this on other diseases we haven’t been able to generate vaccines for and just continue to research it as a general therapy since that’s not yet an “engineering” problem?
HIV, Ebola certain cancers, etc. What about using it to train our immune system for more complex diseases like Malaria or various bacteria? What about investigating if the general techniques can also somehow combat simpler diseases like prions which don’t even have RNA.
Ebola, Malaria and HPV have working vaccines already, there's no particular need for new technology there. HIV would be interesting though.
And bacteria aren't in general limited by immune response. The immune system has zero difficulty detecting a bacterial infection, but it happens at a wildly different scale and can't be fought with a fundamentally chemical means like our bodies do with virii.
And the point about prions seems to misunderstand this technique. The way an mRNA vaccine works is by transmitting blueprints for a viral protein (but not the rest of the virus) into the body's cells, where ribosomes then synthesize the disembodied proteins, which get detected as "foreign invaders" and produce a lasting immune response which would then be effective against the real virus.
Prions, remember, are just misfolded versions of your body's own proteins. They have the same sequence of amino acids as "correct" proteins and just an incorrect shape. mRNA only transmits the sequence, not the shape. And in any case your cell's DNA already has the sequence encoded, because you're not dead.
The latin plural of 'virus' does not exist. It is a nebulous, uncountable concept to ancient rome. Like 'malaise' or 'ocean' (we can pluralize oceans in english, but hopefully you can imagine that a language would treat it as a concept for which the concept of pluralization doesn't make sense).
You'd think: Hey, it's `-us`, I know that one, it pluralizes to `-i`, but, no. There is no plural. It's a rare form that also ends in -us but doesn't work like most of the words you know derived from latin that end in -us.
But there is `vir`, latin for 'man', and the plural of that is viri.
So, 'viri', as in 'the latin pluralized form of virus', is dead wrong.
There is no -ii ending in latin. At all.
The plural of 'virus' in english is 'viruses'. Any other form is stupid. Sometimes language does that, but surely you'd agree that something like 'irregardless', whilst somewhat common, sounds very unprofessional. virii is the same way.
Should you mean no -ii ending to "virus" at all, it would appear to be a reasonable assertion. However if by "at all", you mean of any word in Latin, that is demonstrably false.
But that comment was written in English, not Latin, and such irregular pluralisation is better to be treated as a feature of the modern English. People generally do this not because they someway learned Latin incorrectly but because they noticed how other English speakers pluralise Latin looking words, and that is exactly how new grammar rules are adopted.
Also by referring to ancient Rome you treat Latin as some sort of a fixed, dead language, but English speakers do that irregular pluralisation to words borrowed from the modern languages descented from Latin too (see cappuccini), and so for example in Romanian plural of virus is virusuri, and in Neo-Latin it's vira. Personally I want to prefer virusuri just because it's the funniest one.
Prions can happen multiple ways. In familial (i.e. hereditary) CJD, a mutation in the PRNP gene (DNA) creates an abnormal misfolded protein, i.e. prion. In sporadic CJD, it's basically bad luck that the protein gets folded wrong. In acquired CJD, exposure to brain tissue with the prion protein causes it. Once there's a prion, it causes more of the protein to misfold, creating more prions and causing the disease.
In my understanding, a defect in the RNA that affected the protein would necessarily result in a different amino acid sequence. So for prions to form, they would have to be misfolded initially due to chance / environment or re-arranged afterwards through some process. The best known protein to form prions (PrP, Prion Protein) is known to convert from the well-folded form to a misfolded form upon interacting with the misfolded form, which could indicate that spontaneous formation of prions is due to interaction with something after the initial folding. I think this could also just be an indication that PrP just has lots of very close low-energy states, which would mean a higher chance of misfolding initially.
- Mostly lay person view (some bioinformatics experience)
That’s how they turn your brain into Swiss cheese right? I’m just wondering how they are formed, are they misfolded normal proteins or just alien like virii.
They are misfolded body's normal proteins, with a nasty side effect that they cause the normally folded copies of the same protein to also misfold in the same way. The result is a chain reaction of sorts.
The mRNA vaccines do also transmit the shape, as the encoded viral protein does get expressed in the cells. And the shape does get recognized by the immune system when that protein is secreted from the cell. But there is also a shape-independent mechanism that works on the sequence alone. The proteins in a cell are also chopped into tiny pieces and presentend on the surface. That part could not distinguish between different folded versions of the same protein like with prions.
I think I was misunderstood a bit. I wasn't proposing that mRNA in its current state (or even solely by itself) would somehow be able to cure prion diseases.
I was thinking more that research into biotech generally improves our knowledge. I don't know biology at all but I figured some evolution of technologies associated with CRISPR + mRNA + other things would be useful as a team in solving prion diseases. So maybe mRNA can become efficient enough that it's used to train the immune system to target the misfolded proteins themselves to try to limit damage while the treatment is ongoing. Futuristic now certainly, but is it definitely 100% impossible ever even as our knowledge & tech improves? Or maybe mRNA can exploit something in the prion process we don't yet understand. Maybe CRISPR could be part of the overall treatment therapy as you inoculate more of the body from whatever is propagating the bad code through your body which could be a time-consuming process (think vaccine at the genetic level - you potentially need to get it to every cell in the body).
Obviously this is all sci-fi stuff & some of it impossible & out there. I still like to imagine sci-fi is useful as potential roadmaps to brainstorm how we might solve impossible problems - even if we miss, we'll land somewhere useful.
The reason we don't have an HIV vaccine is because HIV embedds itself in the DNA of some cells and some of those cells don't start producing virions right away, the immune system can't detect them, you clear the visible infection, but just weeks after, those hidden cells start producing the virus and the infection starts over.
So the issue with HIV is the hidden reservoir of infected cells, afik.
> These drugs face the challenges of targeting mRNA to specific tissues and giving strong, lasting benefits without excessive side effects.
This innovation reminds me of Virginia Postrel's book The Fabric of Civilization: How Textiles Made the World [1]. Postrel describes several key technological innovations that propelled the manufacture of cloth from fiber farming to thread weaving to cloth weaving to cloth dying/decorating to distribution. Each innovation moved the bottleneck to a different layer in the value chain.
The mRNA platforms are ideal for vaccines but ultimately, the downstream safety/efficacy trials are the new bottleneck. There was a time when futurists obsessed about nanobots but these mRNA platforms are the ultimate nanobots, in my opinion. They can be configured to program biological cells to manufacture simple proteins in situ. This is a very powerful tool, but like the historical innovations in spinning and weaving, the technology can produced many orders of magnitude more potentially useful outputs than the rest of the value chain can use effectively (for now).
https://sci-hub.se/downloads/2020-12-18/44/10.1126@science.3...