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Congratulations! The Chimeric Antigen Receptor (CAR) deployed here is very much unlike the standard 'small molecule' drug that 'disrupts a bad thing', and much

Congratulations! The Chimeric Antigen Receptor (CAR) deployed here is very much unlike the standard 'small molecule' drug that 'disrupts a bad thing', and much more like a rationally engineered tool using the body's very own technologies to overcome a particular limitation. In this case, it gives the patient's own immune system a notion of what the cancer looks like. If you want to build your own 'living drugs' we've built a digital infrastructure to allow you. Though we just made public our generic protein design software (thanks ShowHN! [1]), we're employing the same underlying digital infrastructure to build, evaluate, and manage CAR designs in high throughput [2]. The drug approved here was painstakingly designed by hand, while we think the technology now exists to permit many more such advances to be created at a much more rapid pace. [1] https://news.ycombinator.com/item?id=14446679 https://news.ycombinator.com/item?id=14446679 [2] https://serotiny.bio/notes/applications/car https://serotiny.bio/notes/applications/car Design your own 'living' protein drugs here right now: https://serotiny.bio/pinecone/ https://serotiny.bio/pinecone/ (and let us know what you think, and how we can make it better!)

skummetmaelk 9y ago
3...2..1.. Prion disease! Seriously though, how would you prevent such automated designing from having unintended side effects?
- jfarlow 9y ago
  The software is useful because it allows you to have some idea of the function of each component prior to their assembly. Further, at this point, the software is designed for R&D far far upstream of being put directly used as a therapeutic. Finally, if a design causes some problem, we want to know that - we allow that undesirable property to be discovered in the laboratory, annotated, and communicated so that others know to not use such designs.
  - skummetmaelk 9y ago
    Is it actually possible to construct proteins from functional components like we design digital logic and software? Don't the parts interact in highly complex ways that take a lot of compute time to solve?
    - jfarlow 9y ago
      If you're trying to compute from first principles (atom by atom), yes, exactly - that's a very hard problem. And if you're rearranging entire protein domains rather than point mutations - that's an intractable problem. And it is precisely the problem we are trying to solve - how can you have any idea what the function of a novel protein will be when you are swapping around hundreds of amino acids at a time? We've taken a different approach. A 'small data' approach, where we manually, and semi-automatedly ingest hard-earned empirical data about each domain, and make it computationally accessible. We give heuristics and logic to a biologist's intuition about 'this protein never seems to work when it's at the N-terminus', rather than trying to compute why it doesn't work by simulating the movements of 100,000 atoms over 10ns. And though many (generally synergistic) interactions won't be predictable in this manner, many will be. We help get you to those designs likely to work as quickly as possible. And the more empirical data ingested, the faster we think we can get you there. Further, even if it's not 100% effective at predicting the single best design, enriching the search space of a large (and expensive) screen is itself valuable. Life already mixes & matches DNA to create new functional all the time, we're just making that same process explicit and accessible. It turns out the function of any given protein domain is actually reasonably robust to being split up and rearranged. Especially when the goal is 'some function', or 'good enough', and you're not messing with or trying to tune a protein absolutely required for life.
- e40 9y ago
  3...2..1.. Prion disease! Can you explain that?
  - y2kenny 9y ago
    I guess OP was alluding to diseases caused by bad protein: https://en.wikipedia.org/wiki/Prion#Prion_diseases_and_their_transmission_properties https://en.wikipedia.org/wiki/Prion#Prion_diseases_and_their... A well known example is mad cow disease.
  - jfarlow 9y ago
    Prions are 'misfolded' proteins [1] that, in their misfolded form actually cause other proteins to also misfold - a physical viral cascade. A really crazy concept not too dissimilar from a kind of biological 'grey goo' - and in real life actually happens to cause diseases like 'mad cow'. The implication is that blindly engineering a protein might create such a physical virus. I would suggest that the likelihood of accidentally creating such a virus is very much like accidentally creating stuxnet. Possible, but extraordinarily unlikely. And further, would such a thing be made, we'd like to know about it while it's still in the lab and can be contained, learned about, and prevented in the future. [1] https://en.wikipedia.org/wiki/Prion https://en.wikipedia.org/wiki/Prion
- pishpash 9y ago
  Also a totally new class of bio weapons.
deleted 9y ago
[deleted]
snakeanus 9y ago
Is there any plan to open source the software?
- jfarlow 9y ago
  Not at the moment. We do love open source and have an interest in seeing what we can make open. But currently we simply don't have the resources to do so. There is the Synthetic Biology Open Language (SBOL) that is being developed to make this kind of information interoperable. The standard is young, eager and important work that we appreciate and follow. http://sbolstandard.org/ http://sbolstandard.org/
  - snakeanus 9y ago
    > But currently we simply don't have the resources to do so. Such as? I am unsure what kind of resources one would need to open source their software. SBOL certainly seems interesting, thank you for mentioning it and thank you for your reply.
    - tudorw 9y ago
      Open sourcing is not a zero sum affair for the creator, I expect licensing agreements would need to be legally cleared and signed off, there would be an expectation of documentation to accompany the release and some kind of communications after release which would call on resources.
kristiandupont 9y ago
This is fascinating! As someone who knows nothing about this domain whatsoever, could someone point me to some (easy to digest) introductory material? I signed up now, but the terminology is completely alien to me..
- jfarlow 9y ago
  Proteins are the machines produced to atomic specification by a genetic blueprint encoded in DNA. The are the tools life uses to accomplish most of its tasks. Proteins are formed like 'beads on a string' - a chemical single-dimensional chain, where twenty different chemical 'amino acids' are mix-and-matched. The amino acids are strung from an 'N' terminus to a 'C' terminus in order to produce nearly every machine all biology uses for every task a cell might need to survive - structural, chemical, metabolic, energetic, sensation, etc. Once produced, the chain of amino acids folds in on itself in 3D, and many 'motifs' or 'domains' have particular functions as sets of tens to hundreds of amino acids. The software, Pinecone, allows you to characterize and then mix-and-match those domains to produce protein machines with novel function. It is essentially a 1D CAD program that outputs 3D atomically defined objects, but compiles down to DNA that nearly any organism can read. It's not all that different from a molecular Kerbal Space Program - a hardware store for protein domains - but one where you can press 'print' and get your DNA delivered. - Protein Domains: https://www.youtube.com/results?search_query=protein+domains https://www.youtube.com/results?search_query=protein+domains - How proteins are made: https://www.youtube.com/watch?v=gG7uCskUOrA https://www.youtube.com/watch?v=gG7uCskUOrA - Visualization of protein machines in use: https://www.youtube.com/watch?v=wJyUtbn0O5Y https://www.youtube.com/watch?v=wJyUtbn0O5Y - Economically, socially & therapeutically valuable Proteins: https://serotiny.bio/notes/proteins/ https://serotiny.bio/notes/proteins/ The basic concepts and terminology are a mix of biochemistry and molecular biology and are describing organic machines that are thousands to hundreds of thousands of atoms, and a couple of nanometers in length on a side.

skummetmaelk 9y ago

3...2..1.. Prion disease! Seriously though, how would you prevent such automated designing from having unintended side effects?

jfarlow 9y ago
The software is useful because it allows you to have some idea of the function of each component prior to their assembly. Further, at this point, the software is designed for R&D far far upstream of being put directly used as a therapeutic. Finally, if a design causes some problem, we want to know that - we allow that undesirable property to be discovered in the laboratory, annotated, and communicated so that others know to not use such designs.
- skummetmaelk 9y ago
  Is it actually possible to construct proteins from functional components like we design digital logic and software? Don't the parts interact in highly complex ways that take a lot of compute time to solve?
  - jfarlow 9y ago
    If you're trying to compute from first principles (atom by atom), yes, exactly - that's a very hard problem. And if you're rearranging entire protein domains rather than point mutations - that's an intractable problem. And it is precisely the problem we are trying to solve - how can you have any idea what the function of a novel protein will be when you are swapping around hundreds of amino acids at a time? We've taken a different approach. A 'small data' approach, where we manually, and semi-automatedly ingest hard-earned empirical data about each domain, and make it computationally accessible. We give heuristics and logic to a biologist's intuition about 'this protein never seems to work when it's at the N-terminus', rather than trying to compute why it doesn't work by simulating the movements of 100,000 atoms over 10ns. And though many (generally synergistic) interactions won't be predictable in this manner, many will be. We help get you to those designs likely to work as quickly as possible. And the more empirical data ingested, the faster we think we can get you there. Further, even if it's not 100% effective at predicting the single best design, enriching the search space of a large (and expensive) screen is itself valuable. Life already mixes & matches DNA to create new functional all the time, we're just making that same process explicit and accessible. It turns out the function of any given protein domain is actually reasonably robust to being split up and rearranged. Especially when the goal is 'some function', or 'good enough', and you're not messing with or trying to tune a protein absolutely required for life.
e40 9y ago
3...2..1.. Prion disease! Can you explain that?
- y2kenny 9y ago
  I guess OP was alluding to diseases caused by bad protein: https://en.wikipedia.org/wiki/Prion#Prion_diseases_and_their_transmission_properties https://en.wikipedia.org/wiki/Prion#Prion_diseases_and_their... A well known example is mad cow disease.
- jfarlow 9y ago
  Prions are 'misfolded' proteins [1] that, in their misfolded form actually cause other proteins to also misfold - a physical viral cascade. A really crazy concept not too dissimilar from a kind of biological 'grey goo' - and in real life actually happens to cause diseases like 'mad cow'. The implication is that blindly engineering a protein might create such a physical virus. I would suggest that the likelihood of accidentally creating such a virus is very much like accidentally creating stuxnet. Possible, but extraordinarily unlikely. And further, would such a thing be made, we'd like to know about it while it's still in the lab and can be contained, learned about, and prevented in the future. [1] https://en.wikipedia.org/wiki/Prion https://en.wikipedia.org/wiki/Prion
pishpash 9y ago
Also a totally new class of bio weapons.

deleted 9y ago

[deleted]

snakeanus 9y ago

Is there any plan to open source the software?

jfarlow 9y ago
Not at the moment. We do love open source and have an interest in seeing what we can make open. But currently we simply don't have the resources to do so. There is the Synthetic Biology Open Language (SBOL) that is being developed to make this kind of information interoperable. The standard is young, eager and important work that we appreciate and follow. http://sbolstandard.org/ http://sbolstandard.org/
- snakeanus 9y ago
  > But currently we simply don't have the resources to do so. Such as? I am unsure what kind of resources one would need to open source their software. SBOL certainly seems interesting, thank you for mentioning it and thank you for your reply.
  - tudorw 9y ago
    Open sourcing is not a zero sum affair for the creator, I expect licensing agreements would need to be legally cleared and signed off, there would be an expectation of documentation to accompany the release and some kind of communications after release which would call on resources.

kristiandupont 9y ago

This is fascinating! As someone who knows nothing about this domain whatsoever, could someone point me to some (easy to digest) introductory material? I signed up now, but the terminology is completely alien to me..

jfarlow 9y ago
Proteins are the machines produced to atomic specification by a genetic blueprint encoded in DNA. The are the tools life uses to accomplish most of its tasks. Proteins are formed like 'beads on a string' - a chemical single-dimensional chain, where twenty different chemical 'amino acids' are mix-and-matched. The amino acids are strung from an 'N' terminus to a 'C' terminus in order to produce nearly every machine all biology uses for every task a cell might need to survive - structural, chemical, metabolic, energetic, sensation, etc. Once produced, the chain of amino acids folds in on itself in 3D, and many 'motifs' or 'domains' have particular functions as sets of tens to hundreds of amino acids. The software, Pinecone, allows you to characterize and then mix-and-match those domains to produce protein machines with novel function. It is essentially a 1D CAD program that outputs 3D atomically defined objects, but compiles down to DNA that nearly any organism can read. It's not all that different from a molecular Kerbal Space Program - a hardware store for protein domains - but one where you can press 'print' and get your DNA delivered. - Protein Domains: https://www.youtube.com/results?search_query=protein+domains https://www.youtube.com/results?search_query=protein+domains - How proteins are made: https://www.youtube.com/watch?v=gG7uCskUOrA https://www.youtube.com/watch?v=gG7uCskUOrA - Visualization of protein machines in use: https://www.youtube.com/watch?v=wJyUtbn0O5Y https://www.youtube.com/watch?v=wJyUtbn0O5Y - Economically, socially & therapeutically valuable Proteins: https://serotiny.bio/notes/proteins/ https://serotiny.bio/notes/proteins/ The basic concepts and terminology are a mix of biochemistry and molecular biology and are describing organic machines that are thousands to hundreds of thousands of atoms, and a couple of nanometers in length on a side.