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michaelzlin's profile
Michael Lin, MD PhD 🧬
Michael Lin, MD PhD 🧬
Michael Lin, MD PhD  🧬
@michaelzlin

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Michael Lin, MD PhD  🧬

@michaelzlin

Associate Professor of Neurobiology & Bioengineering @Stanford ☘️🧪🦠🧠🌈🔬📖🇺🇲🌏 Molecular engineering for voltage, viruses, and SARSCoV2. Fan of facts.

Harvard/UCLA/HMS/UCSD/Stanford
linlab.stanford.edu
Joined July 2015

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    1. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      And molnupiravir is different from remdesivir. Remdesivir worked by blocking replication entirely, not by inducing mutations. See this article entitled "Molnupiravir: coding for catastrophe". Given the authors' enthusiasm, the irony appears unintentional. https://www.nature.com/articles/s41594-021-00657-8 …pic.twitter.com/MaNKjoonrN

      2 replies 16 retweets 90 likes
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    2. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      Dr. William Haseltine made the same points earlier than me. See below. I'll just add we now *know* molnupiravir doesn't always kill off SARSCoV2 in people. Heck we know it only prevents hospitalization 30% of the time! Viral mutation is a real concern. https://forbes.com/sites/williamhaseltine/2021/11/01/supercharging-new-viral-variants-the-dangers-of-molnupiravir-part-1/?sh=2a8d10416b15 …pic.twitter.com/vW4JaM8DYH

      4 replies 30 retweets 93 likes
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    3. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      Past arguments aimed at addressing the concern over sublethal mutagenesis were in actuality less than reassuring. As in frightening. Next few posts describe quotes fromhttps://www.advisory.com/daily-briefing/2021/11/09/molnupiravir …

      2 replies 6 retweets 45 likes
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    4. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      Merck's Hazuda said "we don't see any infectious virus" in people who took the 5-day course. We now know that that cannot possibly be true. The virus only prevents hospitalization by 30% (95% CI 1%-50%). That means most people who would get hospitalized still get hospitalized.pic.twitter.com/eTFB9b7EPn

      2 replies 7 retweets 51 likes
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    5. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      What Hazuda said might have been true for an initial set of healthy volunteers but is clearly NOT TRUE for those people who take the drug and become hospitalized anyway. So this statement is NOT accurate and thereby NOT reassuring anymore.

      2 replies 3 retweets 41 likes
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    6. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      Next, a virologist found 162 mutations after 30 rounds of replication in sublethal molnupiravir. That's about 5 mutations per round. When we do directed evolution of proteins, we aim for 4-5 mutations per gene per round. It's routine to find mutants with improved fitness this waypic.twitter.com/bZUS4OFo7C

      1 reply 10 retweets 50 likes
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    7. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      We will often find 1 or 2 mutations out of 4-5 are beneficial and the others neutral. 5 mutations per round is not enough to guarantee loss of function of the entire virus (30,000 nt genome). The observation that "most of the mutations slowed the virus' growth" is NOT reassuring.

      1 reply 5 retweets 38 likes
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    8. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      We need 100% of the mutant viruses to be worse. Even 0.1% of mutant viruses being better is not good enough. That 0.1% will go on to infect the next cell and propagate into unlimited numbers of viruses with higher fitness in the future.

      2 replies 6 retweets 40 likes
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    9. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      Thus we've seen *no* proof that molnupiravir only mutates SARSCoV2 to less fit forms. Given the disaster that mutation to more virulent or evasiave forms would be, the burden must be on Merck to prove that doesn't happen.

      2 replies 13 retweets 70 likes
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    10. Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      And finally, we don't need molnupiravir anyway. It works far worse (~30% vs hospitalization) than drugs that don't cause viral mutagenesis, such as monoclonal antibodies (>70%) or protease inhibitors (89%).

      1 reply 18 retweets 90 likes
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      Michael Lin, MD PhD  🧬‏ @michaelzlin 26 Nov 2021

      In conclusion, it would be highly irresponsible to approve molnupiravir unless the possibility of sublethal accelerated viral mutagenesis is thoroughly addressed and satisfactorily rejected, especially within the target population of patients at risk of hospitalization.

      6:42 PM - 26 Nov 2021
      • 33 Retweets
      • 204 Likes
      • Information for dinner john_r365 Dr. Jesse Coker RGI Helen Gurova Lia Clark 🏳️‍🌈 selen Sealion RogueLemming🇨🇦🍁🦜⌛ #CanadianJuggernaut
      6 replies 33 retweets 204 likes
        1. New conversation
        2. Michael Lin, MD PhD  🧬‏ @michaelzlin 27 Nov 2021

          BTW, no, I'm not getting paid to bash on Merck. I didn't get paid to point out J&J vaccine efficacy was low either. And neither am I anti-drug or anti-vaccine. My lab develops drugs and my kids got vaxxed within a week of their earliest possible dates.

          3 replies 10 retweets 107 likes
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        3. Michael Lin, MD PhD  🧬‏ @michaelzlin 27 Nov 2021

          I'd just like my children (and yours) to grow up in a world where we use vaccines and medicines effectively, and where they don't have to worry about the possibility of hypermutated viruses generated from the irresponsible use of mutagenizing drugs.

          3 replies 22 retweets 170 likes
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        4. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          Have been busy the last few days, but figured I'd add to this thread, as the AMDAC meeting is going on right now, and FDA had uploaded new materials for that meeting that *finally* discuss the viral mutagenesis issue.

          1 reply 4 retweets 36 likes
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        5. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          First we'll rewind a little to what was previously said in public about molnupiravir accelerating VOC evolution. Below, Haseltine explained his concerns while vague generalizations/guesses were presented for the other side (hardly assuring) https://www.science.org/content/article/prominent-virologist-warns-covid-19-pill-could-unleash-dangerous-mutants-others-see-little-cause-alarm …pic.twitter.com/wPxyV6NeTO

          1 reply 4 retweets 39 likes
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        6. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          "I don’t share the alarm in this. If you force an organism to mutate more, it’s more likely to be bad for the virus" is not reassuring at all, for many reasons. One, even if "more likely" is true, it's not good enough. We need 0% chance of viruses surviving molnupiravir.

          1 reply 5 retweets 53 likes
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        7. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          Second, it's *more* likely molnupiravir will end up creating a virus with mutations that help it evade immunity or spread, so the guess is wrong, In fact this is a mathematical certainty. As stated above, we already know that at some concentrations of the drug...

          2 replies 14 retweets 56 likes
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        8. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          coronaviruses will pick up 162 mutations in 30 cycles, compared to their usual rate of 23 after 250 passages without drug, while reaching titers AS HIGH AS untreated virus (Fig 6 below)! If you do the math, that's about a 50-fold increase in rate.https://journals.asm.org/doi/10.1128/JVI.01348-19 …

          3 replies 12 retweets 52 likes
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        9. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          So we already have empirical evidence the drug can create mutated virus without killing it. Eventually some of those non-lethal mutations will create an advantage. This is easy enough to imagine in the case of mutations that break antibody binding sites in the spike protein,

          1 reply 10 retweets 36 likes
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        10. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          as we are seeing now in omicron. Once there is an advantage of course that virus copy will outgrow others in the body, escape immunity, and transmit. It's the same as natural evolution, just sped up by the increased mutagenesis rate.

          3 replies 5 retweets 40 likes
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        11. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          It's a mathematical/physical/chemical certainty that concentrations of molnupiravir that are not lethal to coronaviruses but can mutate them exist at some time or some place in treated patients. First drugs have partial efficacy at certain concentrations, it's never all or none.

          1 reply 3 retweets 37 likes
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        12. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          At lower concentrations you see partial effects, again here expected from lower concentrations causing a few mutations. Here's the actual inhibition curve for molnupiravir (prev called NHC) on coronaviruses MHC and MERSCoVpic.twitter.com/f0Ge4eJ4ra

          2 replies 1 retweet 23 likes
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        13. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          When you dose a drug, obviously it starts from 0 concentration everywhere in the body to some higher concentration, but it passes gradually through all concentrations in between. For oral drugs, usually it takes an hour or two to reach peak. And then it gradually falls.

          2 replies 3 retweets 30 likes
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        14. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          If someone forgets a dose or stops taking the drug, then doses fall down below the targeted concentration. So at ramp-up and ramp-down viruses are passing through mutagenizing concentrations of molnupiravir that are also known not to kill it.

          2 replies 4 retweets 43 likes
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        15. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          There's also the issue that not all tissues achieve the same concentration of drug. We don't take out nasal biopsies to figure out if a drug is reaching target doses in the nose; we just look at blood levels. We completely expect drug concentrations could be lower in some tissues

          1 reply 5 retweets 43 likes
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        16. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          Finally, given the poor clinical results, the targeted dose isn't even at a level that kills virus reliably in high-risk people. So for all the reasons above, we can expect there will be viable mutated virus in patients taking molnupiravir at least some times if not most times.

          2 replies 5 retweets 45 likes
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        17. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          When Katzourakis said, “If you force an organism to mutate more, it’s more likely to be bad for the virus", he's likely thinking in broad evolutionary terms. Coronaviruses' proofreading replicases may keep their 30,000-letter genome from mutating away to dysfunction over time.

          1 reply 5 retweets 37 likes
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        18. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          But molnupiravir's not going to be taken by every person on earth continuously. It's just given for 5 days, and we know it only makes a 30% difference in hospitalization! So a lot of the time (maybe most) virus replicates fine with it. And once the 5 days end, or even earlier,

          2 replies 3 retweets 36 likes
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        19. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          mutated viruses can jump to people *not* taking molnupiravir, so those viruses are now carrying a set of nonlethal mutations and ongoing mutagenesis stops.

          2 replies 4 retweets 36 likes
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        20. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          With due respect, Katzourakis is not a biochemist, has never cultured a virus, has never studied drug concentrations in the body over time after a dose. It's inappropriate to generalize from broad principles of viral evolution to guess that "more likely" things will be fine...

          1 reply 5 retweets 44 likes
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        21. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          if you perform short pulses of nonlethal mutagenesis on SARSCoV2 in people with immune systems, within a population of people not taking the drug, the exact environment for accelerating evolution of immunoevasion.

          5 replies 6 retweets 43 likes
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        22. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          I'd also point out that Merck's claims on viral mutations in patients have changed over time. In the article at https://www.science.org/content/article/prominent-virologist-warns-covid-19-pill-could-unleash-dangerous-mutants-others-see-little-cause-alarm …, they said in people taking the drug for 5 days: "we don’t see any infectious virus".pic.twitter.com/Fq4TgsglTX

          1 reply 2 retweets 32 likes
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        23. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          But later in CNN at https://www.cnn.com/2021/11/23/health/merck-covid-pill-molnupiravir/index.html …, they said viruses did pick up mutations, but these were similar to known ones. If Merck didn't look hard enough the first time, are they looking hard enough now?pic.twitter.com/Q0dlgjiErH

          1 reply 4 retweets 43 likes
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        24. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          And now to today: FDA did post new documents for AMDAC. It's a mixed bag. The discussion questions still don't talk about viral mutagenesis (concentrating on the patient taking molnupiravir, not those who might get infected by newly mutated virus)pic.twitter.com/n1qbUuUXCJ

          1 reply 2 retweets 35 likes
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        25. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          There is one slide in the FDA briefing document raising the issue, but it's half-hearted and lacks the detailed mechanistic explanation I laid out above.pic.twitter.com/ScU4fNWPk1

          1 reply 3 retweets 33 likes
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        26. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          And finally the Merck presentation. They present real data, and then proceed to draw all the wrong interpretations. It's very worrisome.

          2 replies 3 retweets 42 likes
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        27. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          First, they show the inhibition curves. So as before with other coronaviruses, molnupiravir doesn't kill all SARSCoV2 through a wide concentration range. But it shows some activity, so clearly plenty of mutagenesis is going on at those concentrations.pic.twitter.com/duTJGY31wY

          2 replies 7 retweets 36 likes
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        28. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          The wrong conclusion is in the green box: "high barrier to the development of resistance": They mean you can always dose >1uM and kill the virus. That's not the point at all. The point is how to prevent viruses from escaping before enough mutations accumulate to kill them.

          2 replies 4 retweets 40 likes
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        29. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          They then show molnupiravir suppresses viral levels in animals by 100x. They're hoping the gullible think this is great. It's not remotely acceptable when you have mutations accumulating. You need zero surviving virus, whereas 1% of billions of viruses is still millions too manypic.twitter.com/owo2eS7LfN

          2 replies 7 retweets 59 likes
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        30. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          Finally they show mutations occur randomly, so obviously you are going to get new variants with altered protein functions. Yet they say because all mutations in spike were previously seen before they're not worried. This is irresponsibility of the highest order.pic.twitter.com/NuuS63OKzE

          1 reply 11 retweets 63 likes
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        31. Michael Lin, MD PhD  🧬‏ @michaelzlin 30 Nov 2021

          They even tried to unpin molnupiravir from spike mutagenesis by saying "most mutations" were not consistent with the MOA of inducing transitions (e.g. G to A or C to U). Well it was 7 non-transitions to 5. Again, "most" isn't very reassuring.pic.twitter.com/Y15YusH6f3

          1 reply 5 retweets 38 likes
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