5 ms·

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

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.

fintler 6y ago
It did start in the 70s! https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/
- CharlesW 6y ago
  Another easily-searchable fact is that the COVID-19 vaccine is not the first RNA-mechanism drug.
deleted 6y ago
[deleted]
jfarlow 6y ago
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. [1] https://www.labiotech.eu/in-depth/gene-therapy-history/ https://www.labiotech.eu/in-depth/gene-therapy-history/ > 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.
- johntb86 6y ago
  Wouldn't an adenovirus be delivering DNA? mRNA can't be incorporated into the genome (barring some crazy mixing due to a retrovirus) because it's RNA.
  - flobosg 6y ago
    mRNA is not the only type of RNA that can be delivered. Another type could be interfering RNA targeting endogenous coding or non-coding RNA molecules.
- armada651 6y ago
  Can we please not spread the misinformation that mRNA can somehow integrate into the genome? It feeds crazy conspiracy theories around the vaccines.
  - jart 6y ago
    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.
    - deleted 6y ago
      [deleted]
- usrusr 6y ago
c54 6y ago
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.
iscrewyou 6y ago
It’s not new. Work had been happening on mRNA. But the vaccine, I assume, is humans working under pressure and finally making it happen. I found this video (from 2013) in the other thread today about the vaccine Moderna Vaccine taking two days to make: https://news.ycombinator.com/item?id=25468959 https://news.ycombinator.com/item?id=25468959
LetThereBeLight 6y ago
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.
- rolph 6y ago
  PCR, the Polymerase Chain Reation. https://en.wikipedia.org/wiki/Polymerase_chain_reaction https://en.wikipedia.org/wiki/Polymerase_chain_reaction 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]. https://en.wikipedia.org/wiki/Artificial_gene_synthesis https://en.wikipedia.org/wiki/Artificial_gene_synthesis liposomes are manufactured via biochemical-mechanical process. https://en.wikipedia.org/wiki/Liposome#Manufacturing https://en.wikipedia.org/wiki/Liposome#Manufacturing
  - innomatics 6y ago
    > 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.
    - rolph 6y ago
vlovich123 6y ago
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.
- Narretz 6y ago
  I think you mean BioNTech not Moderna.
- maxerickson 6y ago
  Pfizer worked with BioNTech, not Moderna. 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).
  - denimnerd42 6y ago
    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.
dragonwriter 6y ago
> 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.
iskander 6y ago
>take[1] some mRNA[2], inject it [3], have in translated as the antigen in the body[4]. Poof, that's it. 1) Develop synthesis technique for large scale high purity mRNA without base errors or truncations. 2) Discover pseudouridine modification to decrease innate immune response. 3) Discover and optimize lipid nanoparticles for encapsulation of mRNA to prevent its degradation. 4) Optimize LNPs and miRNA sites in UTRs for localization to desired cell type and to prevent aggregation in undesired or dangerous cells/organs. Poof, that's it!
kennywinker 6y ago
> it isn’t exactly high-tech or clever Read the history section of the rna vaccine wiki: https://en.m.wikipedia.org/wiki/RNA_vaccine https://en.m.wikipedia.org/wiki/RNA_vaccine 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: 1989 - injected rna maybe goes into cells 1990 - proof injected rna creates proteins 1994 - proof injected rna creates immune responses Then: “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/ https://www.statnews.com/2017/01/10/moderna-trouble-mrna/)
- denimnerd42 6y ago
  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.
  - kennywinker 6y ago
    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.
inglor_cz 6y ago
"Poof, that's it." 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.
deleted 6y ago
[deleted]

fintler 6y ago

It did start in the 70s! https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC433302/

CharlesW 6y ago
Another easily-searchable fact is that the COVID-19 vaccine is not the first RNA-mechanism drug.

deleted 6y ago

[deleted]

jfarlow 6y ago

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. [1] https://www.labiotech.eu/in-depth/gene-therapy-history/ https://www.labiotech.eu/in-depth/gene-therapy-history/ > 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.

johntb86 6y ago
Wouldn't an adenovirus be delivering DNA? mRNA can't be incorporated into the genome (barring some crazy mixing due to a retrovirus) because it's RNA.
- flobosg 6y ago
  mRNA is not the only type of RNA that can be delivered. Another type could be interfering RNA targeting endogenous coding or non-coding RNA molecules.
armada651 6y ago
Can we please not spread the misinformation that mRNA can somehow integrate into the genome? It feeds crazy conspiracy theories around the vaccines.
- jart 6y ago
  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.
  - deleted 6y ago
    [deleted]
usrusr 6y ago

c54 6y ago

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.

iscrewyou 6y ago

It’s not new. Work had been happening on mRNA. But the vaccine, I assume, is humans working under pressure and finally making it happen. I found this video (from 2013) in the other thread today about the vaccine Moderna Vaccine taking two days to make: https://news.ycombinator.com/item?id=25468959 https://news.ycombinator.com/item?id=25468959

LetThereBeLight 6y ago

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.

rolph 6y ago
PCR, the Polymerase Chain Reation. https://en.wikipedia.org/wiki/Polymerase_chain_reaction https://en.wikipedia.org/wiki/Polymerase_chain_reaction 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]. https://en.wikipedia.org/wiki/Artificial_gene_synthesis https://en.wikipedia.org/wiki/Artificial_gene_synthesis liposomes are manufactured via biochemical-mechanical process. https://en.wikipedia.org/wiki/Liposome#Manufacturing https://en.wikipedia.org/wiki/Liposome#Manufacturing
- innomatics 6y ago
  > 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.
  - rolph 6y ago

vlovich123 6y ago

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.

Narretz 6y ago
I think you mean BioNTech not Moderna.
maxerickson 6y ago
Pfizer worked with BioNTech, not Moderna. 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).
- denimnerd42 6y ago
  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.

dragonwriter 6y ago

> 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.

iskander 6y ago

>take[1] some mRNA[2], inject it [3], have in translated as the antigen in the body[4]. Poof, that's it. 1) Develop synthesis technique for large scale high purity mRNA without base errors or truncations. 2) Discover pseudouridine modification to decrease innate immune response. 3) Discover and optimize lipid nanoparticles for encapsulation of mRNA to prevent its degradation. 4) Optimize LNPs and miRNA sites in UTRs for localization to desired cell type and to prevent aggregation in undesired or dangerous cells/organs. Poof, that's it!

kennywinker 6y ago

> it isn’t exactly high-tech or clever Read the history section of the rna vaccine wiki: https://en.m.wikipedia.org/wiki/RNA_vaccine https://en.m.wikipedia.org/wiki/RNA_vaccine 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: 1989 - injected rna maybe goes into cells 1990 - proof injected rna creates proteins 1994 - proof injected rna creates immune responses Then: “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/ https://www.statnews.com/2017/01/10/moderna-trouble-mrna/)

denimnerd42 6y ago
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.
- kennywinker 6y ago
  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.

inglor_cz 6y ago

"Poof, that's it." 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.

deleted 6y ago

[deleted]