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Eric Topol Profile picture
@EricTopol
Dec 13, 2020 • 8 tweets • 10 min read • Read on X
Scrolly
Why 2 proline (P) substitutions will go down in history.
Introducing 2P's at the beginning of the central helix (CH) stabilized the spike protein's confirmation upon entering cells.
From the Jan 10 #SARSCoV2 sequence, this 2P Δ was incorporated into the mRNA vaccine designs /1 Image
This was a result of elegant #3D structural biology work @NIH (Barney Graham), @scrippsresearch (Andrew Ward) and collaborators from a @PNASNews paper that was rejected 5 times! pnas.org/content/114/35… /2 ImageImage
Without the 2P design, the mRNA vaccines would have failed.
The remarkable story is told well by @Carolynyjohnson
washingtonpost.com/health/2020/12… /3 ImageImage
The @PBS video explanation is outstanding, by @DrJoeHanson with @McLellan_Lab @UTAustin key driver in this structural biology breakthrough /4 ImageImage
More on the spike protein's confirmation dynamics in this perspective on a new paper @cellhostmicrobe cell.com/cell-host-micr…
Original report cell.com/cell-host-micr… ImageImage
Knowing how the spike protein changed confirmation upon cell membrane fusion was key (and how to Δ it), and the details were furthered by this recent work.
Extraordinary video of the spike protein in motion
w/great cover @oooitsplasma @ScienceMagazine /6 ImageImage
There are 4 #SARSCoV2 vaccines that incorporate the 2P design. Besides @moderna_tx @BioNTech_Group/Pfizer, @Novavax and @JNJNews. And thanks @goodwish916 @WardLab1 @KizzyPhD who I did not acknowledge earlier or didn't have their twitter handle
For an enthralling account of the 2P substitution and its big impact, you can listen or read the transcript thisamericanlife.org Starts at 40 min, with @goodwish916 @McLellan_Lab @KizzyPhD and Barney Graham @ThisAmerLife w/ @dkestenbaum

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More from @EricTopol

Eric Topol Profile picture
Dec 9
We're learning how to control the immune response, like a rheostat, even in the brain. Implications for understanding the basis and potential treatment of autoimmune conditions like multiple sclerosis, #LongCovid, #MECFS, and brain cancer.
A brief review of 6 recent, important reports
in the new Ground Truths, open-accessImage
Such as Programming T cells with brain-specific proteins and payloads
@ScienceMagazine science.org/doi/10.1126/sc…
Or peptide fragments of myelin basic protein that suppress the immune response @Nature nature.com/articles/s4158…Image
Read 4 tweets
Eric Topol Profile picture
Nov 13
New @NEJM
A whopping (~90%) reduction of progression to Type 2 diabetes with tirzepatide (GLP-1 drug, dual receptor) vs placebo in a randomized trial of >2,500 participants with obesity, absolute reduction of 10/100 treated

by @AniaJastreboff and collaboratorsnejm.org/doi/full/10.10…Image
In other GLP-1 new publications today
—Country-wide Sweden reduced hospitalizations for alcohol or substance abuse with these drugs
jamanetwork.com/journals/jamap… @JAMAPsych
—Concerns about discontinuation
jamanetwork.com/journals/jama/… @JAMA_current Image
Other new anti-obesity drugs in the pipeline, one that also increases energy expenditure
@NatureNV nature.com/articles/d4158…Image
Read 4 tweets
Eric Topol Profile picture
Nov 13
A dedicated issue of @ScienceTM on #LongCovid
—Sex-specific differences, with perspective by @VirusesImmunity and @SilvaJ_C
—Insights for therapies @AndreaCoxMDPhD
—Deconvoluting "Osler's Web" @MichaelPelusoMD @DeeksSteven @DrMaureenHanson @SaydahSharon
—+RECOVER Trial, Lyme diseaseImage
Image
Image
science.org/toc/stm/16/773
Where we have failed to date: finding an effective therapy. That has to change
science.org/doi/epdf/10.11…Image
Read 4 tweets
Eric Topol Profile picture
Oct 19
An elegant @Nature study by @AkassoglouLab has illuminated our understanding of the role of fibrin (component of blood clots), #SARSCoV2, and brain inflammation in Covid and #LongCovid.
This discovery and more in the new Ground Truths podcast, with transcript, key figures (such as as the one below) and citations. Open-access. Link in my profile.Image
Image
A clip from our conversation. Unknowingly, @AkassoglouLab was gearing up for understanding this complex pathophysiology for many years before Covid hit
For treatment, it's not just as simple as preventing fibrin clots. It's isolating the pro-inflammatory action of fibrin, targeted by the antibody
Read 4 tweets
Eric Topol Profile picture
Oct 9
Covid and increased risk of major adverse cardiovascular events (MACE) 3-years out

2-fold increased for any severity of Covid
~4-fold increase for Covid requiring hospitalization
"a coronary artery disease equivalent"
interaction with non-O blood types
@uk_biobankahajournals.org/doi/10.1161/AT…Image
"A major finding from our analyses was that the risk
of MACE among the subset of hospitalized COVID-
19 cases without known CVD (ie, primary prevention
patients) was comparable to (or even slightly higher than) the risk in patients with CVD, PAD, or diabetes but without COVID-19."
"one of the first examples of a gene-pathogen exposure interaction for thrombotic events"
I think it's the first one documented, likely others to be unraveled
Read 4 tweets
Eric Topol Profile picture
Aug 2
New US Covid genomic surveillance
The KP.3.1.1 variant is on the move to become dominant, more of a challenge to our immune response than KP.3 and prior variants (especially without new KP.2 booster when we need it for high-risk individuals) Image
It's the deletion 31/31 that makes the KP.3.1.1 spike different, but otherwise 2 mutations away from KP.2 (R346T and Q493E) Image
Buckle up; this wave isn't over yet d/t KP.3.1.1's emergence
Read 4 tweets

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