34 ms·

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 wo

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.

lucaswoj 6y ago
This is Moderna's goal https://www.modernatx.com/mrna-technology/mrna-platform-enabling-drug-discovery-development https://www.modernatx.com/mrna-technology/mrna-platform-enab...
strbean 6y ago
Seems to be working well so far for COVID vaccines. We're about to witness a very large scale test though.
flobosg 6y ago
> 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.
- deleted 6y ago
  [deleted]
- elcritch 6y ago
  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.
  - flobosg 6y ago
    > 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.
    - elcritch 6y ago
      > 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.
      - flobosg 6y ago
        > 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.
kens 6y ago
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.
arrosenberg 6y ago
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.
tboyd47 6y ago
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)?
- fabian2k 6y ago
  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.
  - tboyd47 6y ago
    Is aluminum not toxic?
- raducu 6y ago
  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.
theophrastus 6y ago
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?
ryanianian 6y ago
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?
- raducu 6y ago
  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.
- delecti 6y ago
  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.
  - dharma1 6y ago
    Not related to mRNA therapy, but retroviruses use reverse transcriptase to attach their RNA to the DNA of the host cell
    - delecti 6y ago
      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".
- mamon 6y ago
  > how do we effectively convince people this new type of vaccine is safe long-term? Same as always: do a long-term clinical trial and look for any side effects.
hirenj 6y ago
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).

lucaswoj 6y ago

This is Moderna's goal https://www.modernatx.com/mrna-technology/mrna-platform-enabling-drug-discovery-development https://www.modernatx.com/mrna-technology/mrna-platform-enab...

strbean 6y ago

Seems to be working well so far for COVID vaccines. We're about to witness a very large scale test though.

flobosg 6y ago

> 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.

deleted 6y ago
[deleted]
elcritch 6y ago
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.
- flobosg 6y ago
  > 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.
  - elcritch 6y ago
    > 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.
    - flobosg 6y ago
      > 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.

kens 6y ago

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.

arrosenberg 6y ago

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.

tboyd47 6y ago

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)?

fabian2k 6y ago
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.
- tboyd47 6y ago
  Is aluminum not toxic?
raducu 6y ago
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.

theophrastus 6y ago

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?

ryanianian 6y ago

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?

raducu 6y ago
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.
delecti 6y ago
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.
- dharma1 6y ago
  Not related to mRNA therapy, but retroviruses use reverse transcriptase to attach their RNA to the DNA of the host cell
  - delecti 6y ago
    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".
mamon 6y ago
> how do we effectively convince people this new type of vaccine is safe long-term? Same as always: do a long-term clinical trial and look for any side effects.

hirenj 6y ago

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).