Eric Topol Profile picture
23 Dec, 14 tweets, 9 min read
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:
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

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More from @EricTopol

24 Dec
We've now doubled the peak hospitalizations from the previous 2 US case surges.
And it's no wonder the death toll again today is nearly 3,500.
@COVID19Tracking
Sure the virus is hard to contain, but that's especially the case when so little is being done Image
The @HHSGov declared covid as a public health emergency on Jan 31st
And @WhiteHouse a national emergency March 13th whitehouse.gov/presidential-a…
If that was emergency, then what is this?
The actions we could take beyond financial support that still has not been approved......
1. Distribute high quality (surgical or K/N95) masks to all households [@USPS planned 650 million distribution in April, blocked by @WhiteHouse]
2. Make mask mandates a national policy with enforcement
3. Provide free rapid home covid tests to all households for daily use
Read 5 tweets
21 Dec
The B.1.1.7 variant has 23 mutations
I spoke to Andrew Ward (@WardLab1) @ScrippsResearch today (podcast coming) about its structural biology. He thinks the N501Y (in common w/ South Africa variant) is the driver for increased transmission; he's not concerned re: vaccine efficacy
On @CNN @wolfblitzer, @NYGovCuomo just said the new variant transmits 70-fold the D614G and that it accounted for Europe’s 2nd wave. Both are wrong!
While the B.1.1.7 variant is thought to have been derived from accelerated evolution in an immunocompromised patient with covid (see examples in these 2 @NEJM reports), if the functional culprit is indeed N501Y, that might turn out to be a red herring
Read 4 tweets
18 Dec
1. There are limited data about the vaccines for people who have had covid. But we can learn from the @Pfizer @BioNTech and @moderna trials which had 3% and 2.2% participants respectively confirmed at baseline (via FDA briefing docs)
2. In the Pfizer trial there were 9 reinfections among 670 participants (1.3%) who received placebo which was the same rate as those without prior infection (259 of 19,818 participants, 1.3%).
Only 1 reinfection in the vaccine group (after ≥ 7 days) for those w/ prior infection
3. We need to learn more about this with so many people with prior infections getting vaccinated. But this finding suggests vaccine-induced immune response may add protection to the natural response and adds another layer to the superhuman concept 👇
Read 4 tweets
18 Dec
How do you get to over 240,000 covid cases in one day?
Ask the USA.
An unabated virus.
A rudderless country.
Today @COVID19Tracking
With more than 114,000 Americans hospitalized
Our status in San Diego and LA.
Hope yours is better
Read 4 tweets
17 Dec
You have one guess for what is @ScienceMagazine's Breakthrough of the Year, 2020 😉
The new issue is full of insightful, useful content on the pandemic
This "Year like No Other" timeline is the best I've seen so far
@ScienceVisuals
science.sciencemag.org/content/370/65…
science.sciencemag.org/content/370/65…
Vaccines. The hope. @sciencecohen reviews the vaccine landscape, the 95% efficacy in context, and gets personal about his mother
Read 5 tweets
14 Dec
1 down, 200+ million to go
Why 200+ million (not 300), and how we could get there faster
The functionality of the health system CEO in this photo is striking 😉
Read 4 tweets

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