- Joined
- May 26, 2019
Not really, but I won't say it is totally impossible, as that would be intellectually dishonest. The problem is that the way the layman understands gene editing (which affects the crazy amount of bureaucratic bullshit I deal with regularly) is a deep lack of undertanding regarding just how hard the actual physical constraints really are.
Even if I understood what every base pair in the human genome did, what happens next is to actually do something about it. I'll briefly outline the 3 biggest issues with the "layman" understanding of the process, and then talk about the killing blow to this technology being developed at least in our lifetime.
The first issue is with the extent of reaction. ("Reaction" herein referring to a hypothetical gene edit.) To complete this reaction with no adverse effects to the patient, the reaction must be completed 100% across the entire body of the patient. Primarily, this is because while the trouble gene may not be expressed significantly across the entire body, it will be expressed enough to leave a cytoskeletal signature. If the cytoskeletal signature is not attuned to what the immune system is programmed by the genome to recognize as native, there will be attack by the immune system. Imagine the immune system attacking nerve cells for a worst case scenario. Furthermore, should the bad gene not be edited where it is significantly expressed, there will be consequences across all biological processes that particular gene is implicated in. This include malignant side reactions, incomplete reactions, etc. Thus, if you edit the genome you must do it across the entire bodies with all possible forces of Chemical Kinetics, Thermodynamics, and fluid mechanics working against you. If not impossible, this is at the minimum unbelievably difficult to overcome.
Secondly, genomic editing as we understand it, especially in CRISPR cas-9 enzymes, is effectively irreversible. You start that process, you better finish it and there is no room for significant error. This means that GIVEN the error that this hypothetical process would have, any corrective action will propagate such error further, possibly with fatal results. In biopharma, if your product kills a patient, You're done. That's it, your firm ceases to exist and your technology is immediately shit-canned. Not having a method to deal with a patient not responding well to your therapy means you basically must achieve perfection, which again, if not impossible, unbelievably difficult.
Finally,there is selectivity. This is the one where we have a fighting chance. The main reason the He Jiankui incident is so bad is that the CRISPR CAS-9 enzymes he used were absolutely nowhere near selective enough to only act on the base pairs he wanted to target. This means the patients experienced gene editing in the wrong places. Couple this with the extent of reaction problem, and the irreversibility of it and most people are sure his patients are dead or severely adversely affected. We still have problems with selectivity when working with gene therapies because Watson-Crick base pairing alone simply is not enough. There are issues with the molecular structure of the genetic material itself, the kinetics of the Watson-Crick binding (which we don't understand very well, given that chemical kinetics is effectively it's own complex, painful, and tedious field of study), and the simple statistical issue of finding a treatment with enough base pairs to be unique, but small enough to be feasibly delivered to be considered. And this is just scratching the surface, I haven't even gotten into the mathematics, the problems with the mathematical models, or the logistical problems of performing the experiments needdd to get the mathematicd and our understanding of the science to the level needed to being working selectively.
Now for the big issue with developing gene EDITING tech: Sense-Antisense technology. (Herein:"S-AS") with this, I can make a small, synthetic strand of DNA, chemically attuned to be delivered to the body systems of the patients where its effect is relevant. S-AS tech uses these DNA strands to bind to the mutated gene during it's expression, when the polymerase has unzipped the helix, and thus silences the mutation because the polymerase will not read the resulting double-strand. With annealing procedures, the phosphothioate backbone can be modified to have a sense strand, which the polymerase would read and express instead. This sense strand thus acts to "repair" the mutation. As the helix is zipped back up, the S-AS oligonucleotide is kicked off of the strand. Thus there are two advantages immediately: the S-AS tech does not leave a significant cytoskeletal signature, and if they patient responds adversely, the solution is to deliver the complimentary oligo to the S-AS strands, the result is then digested and ceases to work, yielding reversibility. All that's left is to play with selectivity and you can achieve close to, if not the exact same affect as the editing technology with far less risk involved, so why fund develolment of the Gene editing tech? Pharmaceutical investors don't give a shit how sci-fi and cool gene editing sounds, and neither does uncle sam.
Secondly, genomic editing as we understand it, especially in CRISPR cas-9 enzymes, is effectively irreversible. You start that process, you better finish it and there is no room for significant error. This means that GIVEN the error that this hypothetical process would have, any corrective action will propagate such error further, possibly with fatal results. In biopharma, if your product kills a patient, You're done. That's it, your firm ceases to exist and your technology is immediately shit-canned. Not having a method to deal with a patient not responding well to your therapy means you basically must achieve perfection, which again, if not impossible, unbelievably difficult.
Finally,there is selectivity. This is the one where we have a fighting chance. The main reason the He Jiankui incident is so bad is that the CRISPR CAS-9 enzymes he used were absolutely nowhere near selective enough to only act on the base pairs he wanted to target. This means the patients experienced gene editing in the wrong places. Couple this with the extent of reaction problem, and the irreversibility of it and most people are sure his patients are dead or severely adversely affected. We still have problems with selectivity when working with gene therapies because Watson-Crick base pairing alone simply is not enough. There are issues with the molecular structure of the genetic material itself, the kinetics of the Watson-Crick binding (which we don't understand very well, given that chemical kinetics is effectively it's own complex, painful, and tedious field of study), and the simple statistical issue of finding a treatment with enough base pairs to be unique, but small enough to be feasibly delivered to be considered. And this is just scratching the surface, I haven't even gotten into the mathematics, the problems with the mathematical models, or the logistical problems of performing the experiments needdd to get the mathematicd and our understanding of the science to the level needed to being working selectively.
Now for the big issue with developing gene EDITING tech: Sense-Antisense technology. (Herein:"S-AS") with this, I can make a small, synthetic strand of DNA, chemically attuned to be delivered to the body systems of the patients where its effect is relevant. S-AS tech uses these DNA strands to bind to the mutated gene during it's expression, when the polymerase has unzipped the helix, and thus silences the mutation because the polymerase will not read the resulting double-strand. With annealing procedures, the phosphothioate backbone can be modified to have a sense strand, which the polymerase would read and express instead. This sense strand thus acts to "repair" the mutation. As the helix is zipped back up, the S-AS oligonucleotide is kicked off of the strand. Thus there are two advantages immediately: the S-AS tech does not leave a significant cytoskeletal signature, and if they patient responds adversely, the solution is to deliver the complimentary oligo to the S-AS strands, the result is then digested and ceases to work, yielding reversibility. All that's left is to play with selectivity and you can achieve close to, if not the exact same affect as the editing technology with far less risk involved, so why fund develolment of the Gene editing tech? Pharmaceutical investors don't give a shit how sci-fi and cool gene editing sounds, and neither does uncle sam.
That's about as layman as I can put it, feel free to DM and talk about this stuff. It's fun
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