3 ms·

The top selling check-point inhibitors ie "immunotherapy", Keytruda and Opdivo, were not found by anything remotely resembling 'engineering'. It was a tradition

by dkural 7y ago

The top selling check-point inhibitors ie "immunotherapy", Keytruda and Opdivo, were not found by anything remotely resembling 'engineering'. It was a traditional lab science and drug discovery. If anything those two drugs have expanded their lead commercially, with no other PD1 drug approaching it. None of the top 10 selling Abs are drug-conjugated. CAR-T is struggling mightily in the clinic - it is the opposite of "scalable" due to the personalized nature, and has a terrible side-effect profile. TCRs are far from 'engineered' in any real sense, highly dependent on patient MHC and the specific neo-antigen, with no one able to rationally design from scratch a TCR. Synbio's challenge is not necessarily engineering a genome faster. It's that no one knows what to make, per se. What should we print? We don't know how to design proteins or enzymes. Designing assays to measure a good vs bad design is often the rate-limiting step.

Gatsky 7y ago
I see you have a specific idea about what ‘true bioengineering’ should look like. But you have just made this up, based on your own ideas, which I simply reject. Your first paragraph glosses over all the work that goes into making a useful antibody candidate, a process of iterative modification to meet certain specifications. I don’t see a problem calling this engineering. Your point about market penetration as a judge of ‘engineeringness’ is also silly. There are antibody drug conjugates that serve a specific patient population very well, the fact they aren’t in your ‘top 10’ is irrelevant. So what if CAR-T cells are struggling in the clinic? It is an entirely new treatment modality. There are people walking around who would be dead without it. You deride it because it isn’t an instant global panacea? Your point about Synbio is also wrong. Leaders in the field just wrote a position piece in Science and genome writing was listed as one of the major challenges. You’re trying to tell me that George Church ‘doesn’t know what to build?’ Pure bunk.
- dkural 7y ago
  Dear Gatsky, My point is not that there is no engineering or no biotech in the world - to the contrary. There is antibody engineering, biomedical engineering, and many other types of engineering. I am a computational biologist. I actually worked at the George Church Lab, playing with the Polonator (an early sequencer prototype). I started a computational biology company (Seven Bridges Genomics), and then spun a biotech from it. So I truly believe in engineering. Try to think of my argument as trying to add higher resolution to the debate, instead of being against/for your argument. My main argument is against over-crediting what the software and algorithmic component of this is, precisely because I think it is too important. Another wider argument is are humans rationally designing anything / do we understand the wider design principles. So let's go back to immunotherapy. Neither the target PD1/PDL1, nor the therapies themselves were enabled in particular by "in-silico" methods. Nivolumab and Pembrolizumab were not designed with much algorithmic or software input, but discovered through good old experiments / lab science/engineering. There is no human designer or algorithm in the world where if I give a target, they can rationally design an antibody. What we do is brute force + affinity selection / "directed evolution" to force nature come up with an answer still. We have no clue how to design it like one would design a bridge. I think CAR-T is amazing technology - my point there remains: the therapies so far did not at use in-silico design of the Chimeric Antigen Receptor so far (the CAR part).. The low success in the clinic is precisely due to our inability to actually design these things properly. Similarly, neoantigen selection remains a big challenge due to lack of rational principles. A CAR is not too different from a TCR or Antibody, which we don't know how to rationally design. I believe that genome writing is a major challenge. Again you are widely missing my point: Suppose you had a very cheap, abundant, perfect genome writer. What would we write? George, who was an advisor to my first company and kicked off our Hackathon, would be the first to admit that protein design is a major challenge. Venter wrote an entire organism - and it was mycoplasma verbatim. We are only able to copy nature or cajole it at the moment, because fundamentally we don't know how to design biology. It is because we don't really understand it very well, which makes it such an exciting time to be in the field. None of this means these won't be done, or that teams around the world are not trying to do it this moment. There are amazing labs and companies working on these. What I am saying is more specific: Immunotherapy, CAR-T, or genome writing, in its first generation, as it exists, cannot be recruited as a showcase for computationally led, "in-silico" driven advances in biology. I do believe this will change shortly.

by dkural 7y ago

Gatsky 7y ago

I see you have a specific idea about what ‘true bioengineering’ should look like. But you have just made this up, based on your own ideas, which I simply reject. Your first paragraph glosses over all the work that goes into making a useful antibody candidate, a process of iterative modification to meet certain specifications. I don’t see a problem calling this engineering. Your point about market penetration as a judge of ‘engineeringness’ is also silly. There are antibody drug conjugates that serve a specific patient population very well, the fact they aren’t in your ‘top 10’ is irrelevant. So what if CAR-T cells are struggling in the clinic? It is an entirely new treatment modality. There are people walking around who would be dead without it. You deride it because it isn’t an instant global panacea? Your point about Synbio is also wrong. Leaders in the field just wrote a position piece in Science and genome writing was listed as one of the major challenges. You’re trying to tell me that George Church ‘doesn’t know what to build?’ Pure bunk.

dkural 7y ago
Dear Gatsky, My point is not that there is no engineering or no biotech in the world - to the contrary. There is antibody engineering, biomedical engineering, and many other types of engineering. I am a computational biologist. I actually worked at the George Church Lab, playing with the Polonator (an early sequencer prototype). I started a computational biology company (Seven Bridges Genomics), and then spun a biotech from it. So I truly believe in engineering. Try to think of my argument as trying to add higher resolution to the debate, instead of being against/for your argument. My main argument is against over-crediting what the software and algorithmic component of this is, precisely because I think it is too important. Another wider argument is are humans rationally designing anything / do we understand the wider design principles. So let's go back to immunotherapy. Neither the target PD1/PDL1, nor the therapies themselves were enabled in particular by "in-silico" methods. Nivolumab and Pembrolizumab were not designed with much algorithmic or software input, but discovered through good old experiments / lab science/engineering. There is no human designer or algorithm in the world where if I give a target, they can rationally design an antibody. What we do is brute force + affinity selection / "directed evolution" to force nature come up with an answer still. We have no clue how to design it like one would design a bridge. I think CAR-T is amazing technology - my point there remains: the therapies so far did not at use in-silico design of the Chimeric Antigen Receptor so far (the CAR part).. The low success in the clinic is precisely due to our inability to actually design these things properly. Similarly, neoantigen selection remains a big challenge due to lack of rational principles. A CAR is not too different from a TCR or Antibody, which we don't know how to rationally design. I believe that genome writing is a major challenge. Again you are widely missing my point: Suppose you had a very cheap, abundant, perfect genome writer. What would we write? George, who was an advisor to my first company and kicked off our Hackathon, would be the first to admit that protein design is a major challenge. Venter wrote an entire organism - and it was mycoplasma verbatim. We are only able to copy nature or cajole it at the moment, because fundamentally we don't know how to design biology. It is because we don't really understand it very well, which makes it such an exciting time to be in the field. None of this means these won't be done, or that teams around the world are not trying to do it this moment. There are amazing labs and companies working on these. What I am saying is more specific: Immunotherapy, CAR-T, or genome writing, in its first generation, as it exists, cannot be recruited as a showcase for computationally led, "in-silico" driven advances in biology. I do believe this will change shortly.