What mRNA is good for, and what it maybe isn’t(blogs.sciencemag.org)
blogs.sciencemag.org
What mRNA is good for, and what it maybe isn’t
https://blogs.sciencemag.org/pipeline/archives/2021/06/29/what-mrna-is-good-for-and-what-it-maybe-isnt
151 comments
What happens to the unactivated mRNA in that case? I was under the impression that it was typically the actual use of the mRNA by the ribosomes that broke them down generally, but I could be off base there.
The same mRNA can be used by multiple ribosomes. More info and "photos": https://biology.stackexchange.com/questions/54752/can-mrna-b...
Sure, it isn't destroyed immediately and the mRNA is used multiple time, but that's still ultimately the ribosomes damaging the mRNA from use. My question is around how they break down if there aren't ribosomes involved (ie. if the capsules above aren't opened because they weren't exposed to the light trigger).
Eventually the capsule will break down, be filtered out or be destroyed by the immune system and any RNA left will be broken down by RNAse.
More info about RNA destruction and RNAse https://en.wikipedia.org/wiki/Ribonuclease
This is one of the most amazing things I've read lately (apart from mRNA based vaccination itself). Thanks for sharing.
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I wrote a long essay about the same topic and came to similar conclusions as Derek Lowe: https://trevorklee.com/are-mrna-therapies-the-future-of-phar...
One thing that I'd like to emphasize is how unbelievably tiny mRNA therapeutics have to be. It's probably around 30 mg, and it's hard to do it more than once every few weeks, at least judging by siRNA therapeutics (which have similar immune issues).
30 mg is really tiny. It's hard to come up with a meaningful therapeutic in such a small amount of material. People have been hyping up self-replicating mRNA as a solution, but that's still in its infancy, and has its own problems regarding the "compilers"/polymerases that need to be packaged with it.
One thing that I'd like to emphasize is how unbelievably tiny mRNA therapeutics have to be. It's probably around 30 mg, and it's hard to do it more than once every few weeks, at least judging by siRNA therapeutics (which have similar immune issues).
30 mg is really tiny. It's hard to come up with a meaningful therapeutic in such a small amount of material. People have been hyping up self-replicating mRNA as a solution, but that's still in its infancy, and has its own problems regarding the "compilers"/polymerases that need to be packaged with it.
I think you meant 30 µg (micrograms).
And it is indeed tiny. Even for LSD "the only drug measured in micrograms", a typical dose is around 100µg. Most drugs (both the legal and illegal kind) are in the tens of milligram range.
And it is indeed tiny. Even for LSD "the only drug measured in micrograms", a typical dose is around 100µg. Most drugs (both the legal and illegal kind) are in the tens of milligram range.
I don't think it is correct to say only one drug is measured in µg.
Levothyroxine (for underactive thyroid) is typically administered in µg doses - but patient confusion with the more common mg means most medical staff will translate any mg dose a patient claims to be taking to µg automatically.
It may be atypical, but it's certainly not rare for drugs to be µg doses.
Levothyroxine (for underactive thyroid) is typically administered in µg doses - but patient confusion with the more common mg means most medical staff will translate any mg dose a patient claims to be taking to µg automatically.
It may be atypical, but it's certainly not rare for drugs to be µg doses.
I think the earlier commenter meant ‘drug’ as in street drug. But though that may have once been true, these days there are plenty of other designer drugs that come in tiny doses, many of them not as friendly as LSD.
I don't understand why both are called drugs in English. My language also has the word "drugs" but it's used exclusively for street drugs.
Drugs having to be government approved is a relatively recent development.
Perhaps about a hundred years, give or take. See https://en.wikipedia.org/wiki/International_Opium_Convention
The English language just hasn't caught on, yet. At least not completely.
In eg German, people generally differentiate between Medikamente and Drogen, but they still have a Drogerie which is essentially the same as a drug store.
Perhaps about a hundred years, give or take. See https://en.wikipedia.org/wiki/International_Opium_Convention
The English language just hasn't caught on, yet. At least not completely.
In eg German, people generally differentiate between Medikamente and Drogen, but they still have a Drogerie which is essentially the same as a drug store.
> In eg German, people generally differentiate between Medikamente and Drogen, but they still have a Drogerie which is essentially the same as a drug store.
To add a little additional context 'Drogerie' mostly sells hygiene products, supplements and the like. They only sell 'Medikamente' which are allowed to be sold over the counter in Germany, which basically is Aspirin and everything that is even more harmless. You will not find the kind of drugs you typically get in a CVS in a German Drogerie.
Every serious drug is only sold in what is called 'Apotheke' = pharmacy.
In Germany Apotheke (pharmacy) and Drogerie (drug store) are very different. I think there is no real distinction between drug store and pharmacy in English, but I'm not sure. There is also Reformhaus which is pretty similar to a small Drogerie with a focus on healthy living.
EDIT: I checked my claim about the Aspirin and it seems I'm wrong. They are not even allowed to sell that. But it kind of reinforces my point: Drogerie doesn't really sell drugs in the sense the word is used in English.
To add a little additional context 'Drogerie' mostly sells hygiene products, supplements and the like. They only sell 'Medikamente' which are allowed to be sold over the counter in Germany, which basically is Aspirin and everything that is even more harmless. You will not find the kind of drugs you typically get in a CVS in a German Drogerie.
Every serious drug is only sold in what is called 'Apotheke' = pharmacy.
In Germany Apotheke (pharmacy) and Drogerie (drug store) are very different. I think there is no real distinction between drug store and pharmacy in English, but I'm not sure. There is also Reformhaus which is pretty similar to a small Drogerie with a focus on healthy living.
EDIT: I checked my claim about the Aspirin and it seems I'm wrong. They are not even allowed to sell that. But it kind of reinforces my point: Drogerie doesn't really sell drugs in the sense the word is used in English.
> I think there is no real distinction between drug store and pharmacy in English, but I'm not sure.
This is... oversimplified, at least. I'm sure usage differs by region, even within the United States, but where I am a "drug store" is a convenience store which either contains or historically contained a pharmacy (in the latter case, there appears to be a decent chance the store is an historical soda fountain/cafe). A pharmacy is a place where one buys prescription medications, often only being a section/counter of a larger store. I would never use the terms interchangeably: one does not buy household goods at a pharmacy, nor does a place become a "drug store" by the filling and sale of prescription medication.
This is... oversimplified, at least. I'm sure usage differs by region, even within the United States, but where I am a "drug store" is a convenience store which either contains or historically contained a pharmacy (in the latter case, there appears to be a decent chance the store is an historical soda fountain/cafe). A pharmacy is a place where one buys prescription medications, often only being a section/counter of a larger store. I would never use the terms interchangeably: one does not buy household goods at a pharmacy, nor does a place become a "drug store" by the filling and sale of prescription medication.
Now that I read you comment I remember having seen this pharmacy within the drug store thing. I also remember that the lady there gave sort of medical advice to the customers and that I wondered if she was an MD or not.
That's a whole other discussion about the nature of pharmacies too. The pharmacists themselves have specific degrees and I always assume they're more knowledgeable about things like drug interactions than even the prescribing doctors, if that's the kind of medical advice you mean. One probably works with pharmacy technicians at the desk though; I'm not sure about their qualifications. At the very least the techs can help me find the right OTC medicine if I want it as drug stores tend to locate those strategically near the pharmacy.
But many US pharmacy chains also have RNs onsite providing services, part time, for vaccines and such. That's not quite the same as an MD but it's different than pharmacology.
But many US pharmacy chains also have RNs onsite providing services, part time, for vaccines and such. That's not quite the same as an MD but it's different than pharmacology.
In Germany, pharmacies have specific legal monopolies, and weird regulations, eg that forbid running a pharmacy chain. (It's a bit like unit banking in the US of yore.)
The pharmacists' lobby always defends them with 'oh, you need a proper pharmacist in a pharmacy to give people proper advice'. But whenever some intrepid journalist goes and tests the actual advice given by pharmacies in some bout of investigative journalism, the majority of pharmacies tested always fail dramatically.
The pharmacists' lobby always defends them with 'oh, you need a proper pharmacist in a pharmacy to give people proper advice'. But whenever some intrepid journalist goes and tests the actual advice given by pharmacies in some bout of investigative journalism, the majority of pharmacies tested always fail dramatically.
'Medicine'? 'Medications'? 'Prescriptions'? I'd say 'drugs' does lean quite strongly towards the illicit kind.
If a doctor asked me if I was 'taking any drugs', I would assume they wanted to know in confidence about anything recreational; not prescriptions/off the shelf medicine.
If a doctor asked me if I was 'taking any drugs', I would assume they wanted to know in confidence about anything recreational; not prescriptions/off the shelf medicine.
Yes, it depends on context.
Eg if your wife asks you whether you've taken your drugs yet, she means the same thing as meds.
Eg if your wife asks you whether you've taken your drugs yet, she means the same thing as meds.
Same in France. "Médicament" is what you get from your doctor and "drogue" is what you get from your dealer.
As for the shops, the one that sells prescription and over-the-counter drugs is called "pharamacie", the next tier is "parapharamacie", which sells vitamins, essential oils, hygiene products, etc... "Drogueries" are actually hardware stores.
As for the shops, the one that sells prescription and over-the-counter drugs is called "pharamacie", the next tier is "parapharamacie", which sells vitamins, essential oils, hygiene products, etc... "Drogueries" are actually hardware stores.
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> LSD "the only drug measured in micrograms"
Carfentanil is probably more potent then LSD, here is a lethal dose:
https://mediad.publicbroadcasting.net/p/wosu2/files/styles/x...
"For pain relief, a unit of carfentanil is one hundred times as potent as the fentanyl, five thousand times as potent as heroin, and ten thousand times as potent as morphine, despite having only 14 to 135 times the affinity for the mu receptor."
Carfentanil is probably more potent then LSD, here is a lethal dose:
https://mediad.publicbroadcasting.net/p/wosu2/files/styles/x...
"For pain relief, a unit of carfentanil is one hundred times as potent as the fentanyl, five thousand times as potent as heroin, and ten thousand times as potent as morphine, despite having only 14 to 135 times the affinity for the mu receptor."
That carfentanil looks like about a milligram, but impossible to say without knowing its density.
"The New York Times warns that a particle of carfentanil as small as a grain of salt or piece of dust can be deadly and that the drug is lethal in a dose as minuscule as 0.02 milligrams. "
so about 1/50th of a milligram is deadly... not sure what's the maximum dose before it kills you
so about 1/50th of a milligram is deadly... not sure what's the maximum dose before it kills you
1.0 µg of carfentanil is equivalent to 10 mg of morphine
Read through some of the links in the linked article it must be micrograms.
> 30 mg is really tiny. It's hard to come up with a meaningful therapeutic in such a small amount of material.
I'm going to echo others and ask what you mean here. A lot of drugs have effective doses lower than 30mg. Are you saying that 30mg is an unusually small dose for a pharmaceutical? Because I don't think that's true.
I'm going to echo others and ask what you mean here. A lot of drugs have effective doses lower than 30mg. Are you saying that 30mg is an unusually small dose for a pharmaceutical? Because I don't think that's true.
micrograms
Everyone seems to be focusing on your first comment at the dose must to be limited to 30 µg to avoid lipid toxicities. But the second issue is an even bigger issue—-the immune system will remove cells expressing proteins not found in the patient’s genome.
Under what circumstances does this occur? Is this something the cell itself signals to the immune system?
it's one of the most extraordinary details I've learned in biology. The thymus expresses cell types from around the body and trains the immune system to not recognize them as foreign:
https://en.wikipedia.org/wiki/Central_tolerance
it's not for genes, but for epitopes
https://en.wikipedia.org/wiki/Central_tolerance
it's not for genes, but for epitopes
> 30 mg is really tiny
Not really. For example the amount of beta blocker I take for my heart problems is 5mg per day - the pill size goes down to 2.5mg.
Not really. For example the amount of beta blocker I take for my heart problems is 5mg per day - the pill size goes down to 2.5mg.
Not to mention LSD, which is a well below 1mg thing.
Also not sure why it matters at all, if it's under 1g you can administer it pretty much any way you need to.
Also not sure why it matters at all, if it's under 1g you can administer it pretty much any way you need to.
Pretty sure they meant micrograms, not milligrams.
Then they should not have used the SI milli- prefix.
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This sort of mRNA work isn’t immune-driven at all, in theory, and if you need your target cells to keep producing your desired protein, you’re going to have to keep telling them that by sending them more mRNA. Once a day? Once a week? Who knows? That’ll need to be worked out by experiment.
This doesn't seem like a problem from the point of view of those who are in the business of selling mRNA :)
This doesn't seem like a problem from the point of view of those who are in the business of selling mRNA :)
> mRNA can only be used to make the body make proteins that, well, the body can make. This might seem obvious, but it’s a pretty key part of where Moderna’s “software of life” analogy falls flat. It’s a limited software with limited toolkits. You’re not going to use mRNA in humans to make, say, an antibiotic that’s naturally produced in fungi.
Hmm? I keep hearing about plants and bacteria that have been genetically modified to secrete e.g. animal proteins. Do fungi assemble their proteins from a different set of amino acids than animals do?
Hmm? I keep hearing about plants and bacteria that have been genetically modified to secrete e.g. animal proteins. Do fungi assemble their proteins from a different set of amino acids than animals do?
A protein is often not just amino acids, but also a bunch of so-called post-translational modifications(PTM). These could be carbohydrates that have distinct functional roles, e.g. targeting. Members of different kingdoms have distinct PTMs which makes it difficult to just make a bacteria produce human protein. But bacteria you can modify genetically, human - not so much.
> I keep hearing about plants and bacteria that have been genetically modified to secrete e.g. animal proteins. Do fungi assemble their proteins from a different set of amino acids than animals do?
You're correct that the genetic code is _almost_ universal, and we do use mammalian expression platforms without problems. However, using a live human to express a protein that we normally never do is a bit of an ethical problem due to the associated risk. You don't want a partial expression or maybe a protein gets cleaved and turns into a toxin, or is misfolded and then ends up killing the host or causing a fatal disease (hello prions!), etc, etc.
(Source: Just stuff I picked up at work, I'm not an expert on these topics)
You're correct that the genetic code is _almost_ universal, and we do use mammalian expression platforms without problems. However, using a live human to express a protein that we normally never do is a bit of an ethical problem due to the associated risk. You don't want a partial expression or maybe a protein gets cleaved and turns into a toxin, or is misfolded and then ends up killing the host or causing a fatal disease (hello prions!), etc, etc.
(Source: Just stuff I picked up at work, I'm not an expert on these topics)
> using a live human to express a protein that we normally never do is a bit of an ethical problem due to the associated risk
Wait, so are you saying there's an ethical problem with triggering the expression of a strictly viral protein known to cause damage in and of itself?
Wait, so are you saying there's an ethical problem with triggering the expression of a strictly viral protein known to cause damage in and of itself?
>Wait, so are you saying there's an ethical problem with triggering the expression of a strictly viral protein known to cause damage in and of itself?
:) We're discussing the expression of therapeutics. But, it is true that if you could control the process there would be no ethical problem. But it never is so simple. The cute analogies and diagrams (I do think they are useful for beginners) don't convey the real risks of the technology. Its really hard to wrap your brain around it, at-least for me, even after working in vaccines for close to a decade now I can only grasp a very limited amount of the complexity of our internals.
:) We're discussing the expression of therapeutics. But, it is true that if you could control the process there would be no ethical problem. But it never is so simple. The cute analogies and diagrams (I do think they are useful for beginners) don't convey the real risks of the technology. Its really hard to wrap your brain around it, at-least for me, even after working in vaccines for close to a decade now I can only grasp a very limited amount of the complexity of our internals.
There is, which is why it took so fucking long for these vaccines to get approved, they needed to be strenuously tested for safety and efficacy among tens of thousands of volunteers.
The same way nine thousand women can make a thousand babies in one month, right?
There's a point to be made that we are pushing the vaccine into millions of arms without knowing the long-term effects of them. Having studied them for over a year, all of the data points to the vaccines being safe for 99.999% of people who take them. It would be great to have some kind of time compression machine and be able to see the long-term effects -- say 10 years out -- but at some point the evidence of safety is strong enough that we decide pandemic risk >> vaccine risk.
> that we decide pandemic risk >> vaccine risk.
"We"? I don't remember deciding that. Who gets to decide that for me?
"We"? I don't remember deciding that. Who gets to decide that for me?
Nobody is forcing you to get vaccinated.
It's not the same problem because getting sick doesn't take nine months. They give X people placebo and real vaccines and then wait for enough of the placebo group to get infected living their regular lives.
Antibiotics are not necessarily proteins but can be arbitrary ‘small molecules’ which could require a suite of enzymes instead of just one enzyme
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I don’t see that exact quote, but the article seems to be a list of many of the reasons just inserting the same mRNA sequence may not work as desired. To compare contextually also, researchers now spend substantial effort to teach simple monocellular organisms to produce various proteins of interest, because the pathway and other influences in the cell can influence whether it is translated and how the protein folds.
I believe this a reply to klevertree's comment, rather than the article: https://news.ycombinator.com/item?id=27682445
Ah. It's not really a response to klevertree's comment, but it is a response to the article klevertree links, rather than the article at the head of the page.
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Plants and bacteria lack an immune system like the human‘s. Fully fledged immune systems with antibodies, T killer cells and B memory cells is something mammals „invented“.
Your point of course stands, but from what I can tell (as someone very much not an expert, i.e. glad to be corrected), the history of the adaptive immune system is far more continual and definitely precedes mammals, with the "fully-fledged" versions found in early vertebrates and some mechanisms preceding that as well.
The abstract here seems quite well-written: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919748/
The abstract here seems quite well-written: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919748/
the statement as written is not specific enough to be useful. We certainly have moved genes and entire synthetic pathways between organisms.
Derek Lowe's articles during covid have been a huge help trying to navigate the coronavirus hellscape we have been in. It's great to see him start to talk post-covid applications of medicine as things maybe wind down a bit. Delta+ willing
His "Things I Won’t Work With" articles are really informative and entertaining.
https://blogs.sciencemag.org/pipeline/archives/category/thin...
For example: Things I Won’t Work With: Dioxygen Difluoride https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th...
https://blogs.sciencemag.org/pipeline/archives/category/thin...
For example: Things I Won’t Work With: Dioxygen Difluoride https://blogs.sciencemag.org/pipeline/archives/2010/02/23/th...
Reminds me of the excellent book "Ignition!" by John D. Clark:
https://archive.org/details/ignition_201612
> If the paper weren’t laid out in complete grammatical sentences and published in JACS, you’d swear it was the work of a violent lunatic.
Favorite part of a good article. Although it seems to me these experiments need to be repeated, for science.
Favorite part of a good article. Although it seems to me these experiments need to be repeated, for science.
We could retarget the mRNA batches tonight if it wasn't for the FDA not taking this seriously.
Retargeting is one of those things that everyone is 99% sure it's safe. But 99% sure in millions of people means thousand of problems and perhaps deaths. So before signing any authorization it's better to wait until the clinical trials are done instead of using gut feelings. (Waiting too much is also bad, so it's a tradeoff.)
> Retargeting is one of those things that everyone is 99% sure it's safe. But 99% sure in millions of people means thousand of problems and perhaps deaths.
You seem to be assuming “99% sure it is safe” means “sure that its 99(.9)% safe”. They are...not equivalent.
You seem to be assuming “99% sure it is safe” means “sure that its 99(.9)% safe”. They are...not equivalent.
I know... I know... You are right.
But a simple calculation sometimes is better than a correct long calculation in an online discussion :)
The correct calculation is to ask them "How sure are you that is at lest safe for X% of the persons?" The replies are like
100% sure that it's safe for 90% of the persons.
Also 100% sure that it's safe for 99% of the persons.
97% sure that it's safe for 99.9% of the persons.
93% sure that it's safe for 99.99% of the persons.
87% sure that it's safe for 99.999% of the persons.
...
Now you take the derivative of the function (or the inverse of the function?), multiply by -1 if necessary and get a gut feeling probability distribution to use to calculate the integral and get the expected values of deaths of using the new version without a clinical trial.
Anyway, you need a lot of 9s, because a FDA approval means almost automatic approval in a lot of countries. There are like 10 vaccines now and 7.000 million people in the word, so my guess that it will be used in 500-100 million people.
But a simple calculation sometimes is better than a correct long calculation in an online discussion :)
The correct calculation is to ask them "How sure are you that is at lest safe for X% of the persons?" The replies are like
100% sure that it's safe for 90% of the persons.
Also 100% sure that it's safe for 99% of the persons.
97% sure that it's safe for 99.9% of the persons.
93% sure that it's safe for 99.99% of the persons.
87% sure that it's safe for 99.999% of the persons.
...
Now you take the derivative of the function (or the inverse of the function?), multiply by -1 if necessary and get a gut feeling probability distribution to use to calculate the integral and get the expected values of deaths of using the new version without a clinical trial.
Anyway, you need a lot of 9s, because a FDA approval means almost automatic approval in a lot of countries. There are like 10 vaccines now and 7.000 million people in the word, so my guess that it will be used in 500-100 million people.
What has the FDA done to start gathering this data?
Nothing.
NIH funded the trial for the Moderna booster.
NIH funded the trial for the Moderna booster.
A nice presentation by the FDA about why they're reluctant to let new treatments through without full phase 3 trials: https://www.fda.gov/about-fda/reports/22-case-studies-where-...
We don't do phase III trials for the flu vaccine every year. Instead we follow the same production formula for the new virus variant. Why not with COVID? The FDA agrees this is desirable but is just foot dragging.
Do you think there might be some difference in "changes each year for flu vaccine" and "changes for every other vaccine"?
Like perhaps, how much study the practice of flu vaccine changes has undergone, what the limited target constraints are, and prior field experience with the sterotypical changes to those specific targets?
Like perhaps, how much study the practice of flu vaccine changes has undergone, what the limited target constraints are, and prior field experience with the sterotypical changes to those specific targets?
Uhm, it is serious if you know anything about drug development history. It always is.
The current mRNA Covid vaccines have a pretty high incidence rate of ongoing rapid swelling and rashes (in the 1/100 to 1/1000 range), and it's still unclear what will happen to the hundreds of thousands of affected people.
Source: https://en.m.wikipedia.org/wiki/Pfizer%E2%80%93BioNTech_COVI...
Also to be found in the adverse reactions database (VAERS) by the CDC.
The current mRNA Covid vaccines have a pretty high incidence rate of ongoing rapid swelling and rashes (in the 1/100 to 1/1000 range), and it's still unclear what will happen to the hundreds of thousands of affected people.
Source: https://en.m.wikipedia.org/wiki/Pfizer%E2%80%93BioNTech_COVI...
Also to be found in the adverse reactions database (VAERS) by the CDC.
VAERS reports aren't sufficient to show causation, because they just show whatever people happened to report.
It's the same reason drugs show the thing they're treating as a side effect. People are reporting the symptom because they already had it.
It's the same reason drugs show the thing they're treating as a side effect. People are reporting the symptom because they already had it.
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Delta+ and the next variant after that just in time for school in the Fall and a bunch of unvaccinated kids.
> mRNA can only be used to make the body make proteins that, well, the body can make.
That's an important point we need to keep in mind: mRNA can be used to fix the body where it is broken/or not producing specific proteins when it would be needed. But it doesn't give us superpowers or change us into other beings than what we are.
That's an important point we need to keep in mind: mRNA can be used to fix the body where it is broken/or not producing specific proteins when it would be needed. But it doesn't give us superpowers or change us into other beings than what we are.
> So if you’re going to give patients an mRNA injection and you don’t want to set off alarm bells in the innate immune system, you’re going to have to carefully engineer your sequences at the very least.
Isn't that what substituting uracil by pseudouridine solves?
Isn't that what substituting uracil by pseudouridine solves?
No, that substitution helps, but it doesn't solve the problem. You're still introducing foreign mRNA into the body, and the body still has millions of years of evolution telling it that foreign mRNA = invader .
It solves the TLR problem, and process/purification solves the cytosolic dsRNA problem.
Worth noting that even if it's good for literally only infectious disease vaccines, we're still taking about an enormous breakthrough with the potential to save hundreds of millions of lives. Imagine vaccines for malaria, HIV, Zika, and many others.
While mRNA vaccines were great in the COVID situation, they have been in development over the last decade and I'm not sure an HIV vaccine will be as simple as putting HIV envelope protein into this technology. I'm not aware of attributes to the mRNA technologies that will dramatically simplify the development challenges. I believe the more substantial step for is that we (Pharma, Investors, Governments)now realize infectious diseases are a problem for people beyond the developing world. Will that commitment hold?
Totally! We are entering a golden age of vaccinology.
My newborn was diagnosed with Sturge–Weber syndrome and mRNA sounds like a potential solution.
The issue is it's rare and united States government approval is expensive and slow. Not something that works well with a degenerative disease.
I'm a bit insane right now admittedly, but given my background and wealth, I'm considering DIY. The technology is there, government is the hold up. Would you let your kid have seizures and cognitive problems because of red tape?
The issue is it's rare and united States government approval is expensive and slow. Not something that works well with a degenerative disease.
I'm a bit insane right now admittedly, but given my background and wealth, I'm considering DIY. The technology is there, government is the hold up. Would you let your kid have seizures and cognitive problems because of red tape?
mRNA is the ultimate biohacking tool. You can potentially use it for weight loss by improving metabolism without exercising and a few other things.
I won't be injecting any mRNA to loose a few kilos anytime within the next multiple decades.
Metabolism is complicated and there are some really nasty and weird metabolic diseases out there, based on some small regulatory feedback loop being broken. Don't fix a working system!
If your weight bothers you, just go for walk or a swim once in a while. Have a salad.
Metabolism is complicated and there are some really nasty and weird metabolic diseases out there, based on some small regulatory feedback loop being broken. Don't fix a working system!
If your weight bothers you, just go for walk or a swim once in a while. Have a salad.
> If your weight bothers you, just go for walk or a swim once in a while. Have a salad.
It is super annoying when people post crap like this, as though that's all it would take to address the obesity epidemic.
By the way, there is approximately zero effect on weight in response to "going for a walk or a swim once in a while".
It is super annoying when people post crap like this, as though that's all it would take to address the obesity epidemic.
By the way, there is approximately zero effect on weight in response to "going for a walk or a swim once in a while".
I have lost 5 kg since january going from ~102kg to ~97kg. This has happened from two changes: going for a run 2-3 times per week and reducing the amount of cake I eat. I still have fries with mayonnaise with my hamburgers.
I acknowledge that there is an issue around cheap food being unhealthy food and people being forced to eat chips for lunch for financial reasons, but for anyone in the middle class or above I really don't understand why it's more complicated than 'move more, eat less'.
It's hard. But it's not complicated.
I acknowledge that there is an issue around cheap food being unhealthy food and people being forced to eat chips for lunch for financial reasons, but for anyone in the middle class or above I really don't understand why it's more complicated than 'move more, eat less'.
It's hard. But it's not complicated.
I'm not clear on one thing from this: early on the author states that mRNA treatments do not create a permanent immune system memory response and need repeated treatments for continued response.
But then when the author switches to the 'mRNA vaccines' section he instead refers to cancer treatment, finally circling back at the end to say 'infectious disease vaccines' are the low hanging fruit.
Is that still referring to mRNA? How are they getting long term immune system 'memory' from mRNA? I can't quite understand how the articles explains that among the forward looking prospects for cancer etc.
the theraputics part is different than the immune system response part. they said in the theraputics part you don't get to use the immune system memory because the immune system memory is there to make a foreign enough protein that looks like the virus receptors so the body learns how to kill those proteins.
a therapeutic doesn't want you to kill the proteins it creates because the proteins created need to be able to go and do work on other cells... so it needs to look somewhat like "normal" proteins that a body would create naturally.
a therapeutic doesn't want you to kill the proteins it creates because the proteins created need to be able to go and do work on other cells... so it needs to look somewhat like "normal" proteins that a body would create naturally.
Thanks. If I'm correct then the mRNA vaccine introduces proteins that reflect the virus and trigger the immune response?
I think I was reading the article as mostly focused on vaccines, but it was focused on cancer treatment, hence my confusion...
Kinda... the mRNA is the code for the cells to make the protein that resembles the virus. traditionally it was a virus or a part of a virus that was made that gets directly killed by the immune system for being different.
The article is talking about multiple possible uses for mRNA drugs, including prophylaxis and non-prophylaxis vaccines (you would not take a vaccine for a cancer before you get it, unless it is to prevent an infection that could cause cancer (HepB, HPV, etc)), and mRNA therapeutics, including ones from protein replacement. For protein replacement, you would have to take the mRNA often, because mRNA degrades. Your immune system has memory, but you won't keep making random proteins after the mRNA goes away.
You're about right. the mRNA vaccine introduces mRNA, which is taken up by cells. The cells then use the mRNA to produce the proteins of interest, which then can be presented to immune cells to start the immune response.
mRNA is sort analogous to code that compiles to proteins
mRNA is sort analogous to code that compiles to proteins
I am worried about the low level of intact mRNA in those vaccines, esp. as an IT guy.
https://www.medicalnewstoday.com/articles/early-concerns-rai...
25-45% randomly modified or defective mRNA doesn't sound safe. It's a bit like machine code with random errors, isn't it?
https://www.medicalnewstoday.com/articles/early-concerns-rai...
25-45% randomly modified or defective mRNA doesn't sound safe. It's a bit like machine code with random errors, isn't it?
RNA uses an error-correcting code, and if that fails all that should happen is that some of the proteins your ribosomes create will be misshapen. Your body is good at dealing with foreign proteins.
Except when it isn't. I'm sure this problem has been explored and ruled out, but as a general note, when I read that "all that should happen is some proteins will be misshapen", my mind immediately screams prions.
Prions need to be beta-sheet proteins with specific conformations. They're hard to generate, and certainly are not single-base substitutions - otherwise the biosphere would be riddled with them.
Thanks, this is quite re-assuring since I am worried about prions as well.
Could you please suggest a link for me to further educate myself on how unlikely this is ?
This isn't bad: https://www.scientificamerican.com/article/what-is-a-prion-s...
The basic punchline is that while prion diseases are terrifying, there's not a lot of them and they are quite specific - you have to have a protein which is already able to adopt that conformational structure, and it has to be a protein we already make natively, as prions only work with what's there.
We are probably still missing part of the picture as well: i.e. the prion diseases which cause problems are brain diseases, we don't see the same issue with other tissues.
It would be difficult to actually induce a prion disease in someone via genetic vaccine in the first place, since prion's notably don't have a genetic component - and in the case of vCJD the infectious and benign protein sequences are the same (i.e. the coding is already something we carry, they're conformational jumps).
The basic punchline is that while prion diseases are terrifying, there's not a lot of them and they are quite specific - you have to have a protein which is already able to adopt that conformational structure, and it has to be a protein we already make natively, as prions only work with what's there.
We are probably still missing part of the picture as well: i.e. the prion diseases which cause problems are brain diseases, we don't see the same issue with other tissues.
It would be difficult to actually induce a prion disease in someone via genetic vaccine in the first place, since prion's notably don't have a genetic component - and in the case of vCJD the infectious and benign protein sequences are the same (i.e. the coding is already something we carry, they're conformational jumps).
> the coding is already something we carry, they're conformational jumps
Aha, this is helpful. And I believe mRNAs are not known to trigger these conformational jumps.
Another fact-check article supporting your statement: https://www.reuters.com/article/fact-check-no-evidence-that-...
Aha, this is helpful. And I believe mRNAs are not known to trigger these conformational jumps.
Another fact-check article supporting your statement: https://www.reuters.com/article/fact-check-no-evidence-that-...
What error correction does RNA have? Are you just referring to the third base in the codons? DNA has some but I don't know of any for RNA, and it hardly seems worth it for most organisms to have RNA error-correction: it's better to just degrade the RNA and retranscribe it.
RNA and DNA essentially use the same genetic code, which is degenerate and thus somewhat error correcting.
You mean the degeneracy in the last base of codons that I mention? I wouldn't even call that an error correcting: would you count a file type that just skipped every third byte 'error correction'? I wouldn't. This isn't a robust system and most changes to any bases will change the protein sequence. Contrast that to DNA which does have error correction, since there are two strands instead of one and also two chromosomes with nearly identical information. Both are used to repair errors, at least some of the time. I'm not aware of such a system for RNA and it's not clear where it would get the information from - though maybe the most likely system would be a 'self-destruct' where errors are detected but since repair is impossible, the RNA is just destroyed.
I completely agree. I was addressing a confusion of the previous poster.
> Your body is good at dealing with foreign proteins.
Not always - Are you familiar with Prions diseases ?
Not always - Are you familiar with Prions diseases ?
Prions are not foreign proteins. They have to be misfolded native proteins to cause disease.
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That's why there are clinical trials. Humans testing to find out what happens.
All mRNA disappears from body in few days anyway.
All mRNA disappears from body in few days anyway.
I'm kinda surprised no one's talking about Robert Malone (the inventor of mRNA vaccine tech) mentioning the protein Spikes causing unexpected issues [1].
[1]: https://www.youtube.com/watch?v=Du2wm5nhTXY
[1]: https://www.youtube.com/watch?v=Du2wm5nhTXY
Of course now after the fact that mRNA vaccines are hugely outperforming other technologies in COVID, we know that they are our best bet for other infectious diseases as well (including having a much better flu vaccine), but Moderna+BioNTech got a lot of money last year to find it out, and this was not that clear 1 year ago.
What the article doesn't answer to me, is how to cure my 40 year old ex girlfriend with metabolic breast cancer. Sorry, but giving up on people just because it's technically challenging is not an answer to me. If the CAR-T or TIL therapies can cure her, I agree that the mRNA therapy route should be stopped, but right now trying all possible routes is my best bet to not be at her funeral.
What the article doesn't answer to me, is how to cure my 40 year old ex girlfriend with metabolic breast cancer. Sorry, but giving up on people just because it's technically challenging is not an answer to me. If the CAR-T or TIL therapies can cure her, I agree that the mRNA therapy route should be stopped, but right now trying all possible routes is my best bet to not be at her funeral.
mRNA vaccines are not "hugely outperforming other technologies in COVID". Sputnik V has around the same efficacy after 1 dosis that Biontech has after 2. That's 1-0 for Sputnik in my book.
Aaaaand here come the downvotes from the adherents of the religion of mRNA Technology :D Scientific objectivity is LONG GONE!
"With the Pfizer/BioNTech vaccine, protection against symptomatic COVID-19 was found to be 52% from 12 days after the first dose (immunity takes time to build). Protection then rose to 95% after the second dose." [1]
"Vaccine efficacy, based on the numbers of confirmed COVID-19 cases from 21 days after the first dose of vaccine, is reported as 91·6% (95% CI 85·6–95·2), and the suggested lessening of disease severity after one dose is particularly encouraging for current dose-sparing strategies." [2]
Dear mRNA-ists, how is 95 % after second dosis (mRNA) vs 91·6% after first dosis (non-mRNA) worth being called "hugely outperforming"?
And I didn't even go into the severe side effects of mRNA vaccines (AZ: Blood clotting in brain and/or lung; Biontech: Myocarditis, Anaphylaxia) vs virtual absence of side effects in traditional vaccines. But how dare I point those out, that's heresy, right? :O
[1] https://theconversation.com/covid-19-vaccines-why-its-import...
[2] https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
"With the Pfizer/BioNTech vaccine, protection against symptomatic COVID-19 was found to be 52% from 12 days after the first dose (immunity takes time to build). Protection then rose to 95% after the second dose." [1]
"Vaccine efficacy, based on the numbers of confirmed COVID-19 cases from 21 days after the first dose of vaccine, is reported as 91·6% (95% CI 85·6–95·2), and the suggested lessening of disease severity after one dose is particularly encouraging for current dose-sparing strategies." [2]
Dear mRNA-ists, how is 95 % after second dosis (mRNA) vs 91·6% after first dosis (non-mRNA) worth being called "hugely outperforming"?
And I didn't even go into the severe side effects of mRNA vaccines (AZ: Blood clotting in brain and/or lung; Biontech: Myocarditis, Anaphylaxia) vs virtual absence of side effects in traditional vaccines. But how dare I point those out, that's heresy, right? :O
[1] https://theconversation.com/covid-19-vaccines-why-its-import...
[2] https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
Perhaps because of https://blogs.sciencemag.org/pipeline/archives/2021/04/28/ru...
Also the adenovirus in SputnikV is apparently actually infectious.
https://twitter.com/angie_rasmussen/status/13873971863720058...
https://twitter.com/angie_rasmussen/status/13873971863720058...
AZ is not a mRNA vaccine.
> So mRNA-based techniques have a lot of power and a lot of promise. But there’s definitely a low-hanging-fruit area here, and that’s infectious disease vaccines. Beyond that the promise holds up, big-time, but the difficulties mount up as well. It’s going to be a long story with a lot of plot twists, but I’m glad we’re telling it.
Just want to emphasize the conclusion, because if you stop reading before the end, you might think that the article is dismissive of mRNA, its not, just realistic in the remaining challenges for some of the more ambitious outcomes of it.
Just want to emphasize the conclusion, because if you stop reading before the end, you might think that the article is dismissive of mRNA, its not, just realistic in the remaining challenges for some of the more ambitious outcomes of it.
It's not clear that mRNA holds any actual advantage for that low-hanging-fruit relative to other approaches though (e.g. protein subunit or DNA-based vaccines).
You're talking about opportunity cost, I don't know enough to speak to that, but that there is something else just as good or better doesn't make it any lesser.
At this point, the author of this article is more expert than I'll ever be, I'd assume that he has reasons to consider mRNA a low hanging fruit compared to existing tech like protein-subunit or adenovirus for infectious diseases.
And against DNA-based, well mRNA has beat it to the punch in being used at scale in humans, so that's possibly one advantage.
At this point, the author of this article is more expert than I'll ever be, I'd assume that he has reasons to consider mRNA a low hanging fruit compared to existing tech like protein-subunit or adenovirus for infectious diseases.
And against DNA-based, well mRNA has beat it to the punch in being used at scale in humans, so that's possibly one advantage.
I don't think he said that mRNA is low hanging fruit though. I think he said that vaccines for viral diseases are a low hanging fruit for applying mRNA.
Correct me if i am wrong but those highly effective mRNA vaccines were created in a few weeks and relatively inexpensively... and can other protein targets can be repackaged easily by coding the mRNA unit into the already encapsulated delivery mechanism. is that not better than the other alternatives?
No, the same advantages apply to the other alternatives I mentioned. If you have a target protein design ready, it can be readily plugged into mRNA, DNA, or protein subunit technology.
alright... thanks for that explanation. I thought it was more unique to the mRNA version that those but I was wrong.
“The mRNA vaccine seems to be highly effective, two doses of that vaccine against this variant,” Gottlieb said, referring to the Moderna and Pfizer/BioNTech vaccines. “The viral vector vaccines from J&J and AstraZeneca also appear to be effective, about 60% effective. The mRNA vaccines are about 88% effective.”
Higher efficacy does not have a 1-to-1 relationship with using mRNA technology. CureVac is an mRNA vaccine and is less than 50% effective. Novavax does not use mRNA and is more than 90% effective.
https://www.cnn.com/2021/06/14/health/novavax-covid-19-vacci...
https://www.cnn.com/2021/06/14/health/novavax-covid-19-vacci...
I'm talking about protein subunit and DNA-based technologies, not adenovirus viral vector. Protein subunit vaccines at least (e.g. the novavax and GSK vaccines) have proven themselves against COVID-19 as well.
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"The first distinction is between vaccines and therapeutics" LOL
This comment is dedicated to people downvoting me saying the same.
People is not even able to have argument on thing anymore.
Sad.
“The huge success of the mRNA vaccination platform”
Does anyone know what the agreed upon criteria for asserting the success of mRNA vaccinations is?
Aren’t we anticipating an uptick in cases in the US as we approach winter? Why are we assuming success already?
Does anyone know what the agreed upon criteria for asserting the success of mRNA vaccinations is?
Aren’t we anticipating an uptick in cases in the US as we approach winter? Why are we assuming success already?
I'm not sure what you mean by "agreed upon", but they are, blatantly, obviously, preventing (lots of) infections in lots of countries at this point.
> Why are we assuming success already?
I guess a combination of how little side-effects they've had at scale, and of how effective the data shows they are at preventing the first virus and the earlier variants, which is what it was designed for.
I think the uptick expected is with regards to unvaccinated people, and to new variants for the most part. You should also still see a 5% to 10% of cases in vaccinated people, as the vaccines show a range of effectiveness only around the 90%, so an uptick will still occur, but the overall numbers should be much lower in vaccinated people.
To conclude, success is not on our fight against Covid, though you can say it definitely helped a lot, but the vaccine technology has definitely shown success here.
I guess a combination of how little side-effects they've had at scale, and of how effective the data shows they are at preventing the first virus and the earlier variants, which is what it was designed for.
I think the uptick expected is with regards to unvaccinated people, and to new variants for the most part. You should also still see a 5% to 10% of cases in vaccinated people, as the vaccines show a range of effectiveness only around the 90%, so an uptick will still occur, but the overall numbers should be much lower in vaccinated people.
To conclude, success is not on our fight against Covid, though you can say it definitely helped a lot, but the vaccine technology has definitely shown success here.
Before hundreds of millions of people were vaccinated, the agreed on success was from the initial clinical trials, which saw virtually no infections in the vaccinated group, and hundreds in the unvaccinated. Now, with so many people vaccinated, more than 90% of new cases are in people who are unvaccinated (and virtually no COVID-related deaths).
Even if humanity wasn't able to manufacture 12b vaccination doses in time for the winter (success of the vaccination program), mRNA still undoubtedly proved itself as a technology (success of mRNA as a vaccination platform). mRNA vaccinations were faster to develop, easier to modify for new strains, and probably more effective than alternatives.
DaniloDias(4)
From the jump this article seems confused, considering to flag it.
https://www.pcibiotech.no/nucleicacids
This presentation has a lot of illustrations and explanations:
https://www.pcibiotech.no/s/PCI-Biotech-SMi-RNA-Therapeutics...