Thread by @EricTopol

1. Structural biology has been a standout in the pandemic, mapping the virus, antibodies and vaccines atom by atom. So I had a conversation with one of its leaders, Andrew Ward @WardLab1, my @scrippsresearch colleague soundcloud.com/prescrippsions…

2. Back in 2016, Andrew and his colleagues were the first to see and publish the coronavirus spike protein, via cryo-electron microscopy (a common cold virus, HKU1) nature.com/articles/natur… @nature
Note the team, which proved to be formidable
@McLellan_Lab @KizzyPhD Barney Graham

3. In the podcast, Andrew reviews how they came together. A next act was the famous 2P (2 proline substitutions) paper that was rejected 5 times before being published @PNASNews
Subthread about that here:

https://twitter.com/erictopol/status/1338210550740762624?lang=en

4. "If I showed you HKUI or #SARSCoV2, you couldn't tell the difference" —Andrew Ward
It was @goodwish916 who nailed the 2P substitution (not an easy feat, Ps are like "staples") that stabilizes the trimeric spike protein, avoiding its spring loaded mechanism from opening up

5. If the 2P hadn't been discovered, the immunogenicity of the vaccines which used this Δ would have been significantly compromised.
With 2P, you get the cells to make > 50X antibody production vs wild-type spike protein

6. We discussed how rejected papers sometimes turn out to be the most important of all (also e.g. #CRISPR). Of course, reviewers didn't know #SARSCoV2 was coming. "Coronaviruses weren't in vogue."

7. You'll get an appreciation for the impact of cryo-EM unraveling structures that were not previously possible and why, in part, @McLellan_Lab moved from Dartmouth to UT-Austin. The sheer excitement of structural biologists solving #3D puzzles

8. Now cryo-EM is a "pedestrian tool"
Here's @WardLab1 @ScienceMagazine paper on cryo-EM of the @Novavax vaccine science.sciencemag.org/content/370/65…

9. We discussed the "new" B.1.1.7 variant with 23 mutations, including N501Y, and the South African N501Y, both associated with high transmission rate. This was my favorite part of the discussion: the perfect "high-five"

10. Here is Andrew showing me the ACE2-tyrosine structure and the impact of the added tyrosine from the N501Y mutation, the "high five" that enhances the lock-and-key. If this isn't a structural biologist at work, nothing is!

11. Andrew thinks this is a/the key mutation (the molecular high-5) that accounts for the heightened transmission. The good news the vaccine should not be affected by this or other mutations, because the vaccine induces so many different antibodies.

12. That's so long as the #SARSCoV2 drift is not too far. The other good news is the relative ease of using predictive tools to tweak next versions of the vaccine to tackle the changes...the booster shots of the future

13. I hope this gives you some appreciation of the incredible contributions of structural biology in the pandemic and how this field of science played a major role in developing our exit strategy and now the impact of the virus's evolutionary changes

14. If you prefer the video version

and a new @PNASNews paper on deep learning applied to cryo-EM including #SARSCoV2 pnas.org/content/118/2/…
"Deep Tracer" @DAIS_research