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Yuri Deigin

@ydeigin

Apr 22

4 years after my first Medium article on Covid origins, I wrote another one. In it, I make the case that SARS-CoV-2 is precisely the virus WIV was hunting for in 2019.

Below is a thread on the key points:yurideigin.medium.com/sars-cov-2-is-…

2/

In 2018, WIV started looking for SARS-like viruses that were 10–25% different from SARS1 in their spike but could still enter human cells, and escape SARS1-based antibodies. SARS2 fits those criteria like a glove.

3/

Moreover, as I will show below, precisely because SARS2 or its BANAL-like progenitor could evade SARS1-based vaccines and antibodies, such strains would have been prioritized and likely turned into full-genome synthetic backbones.

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Yuri Deigin

@ydeigin

Apr 11

In our debate on Covid origins, Peter @tgof137 kept insisting that the DEFUSE proposal was only interested in viruses that are only within a 95% similarity to (i.e. at most 5% different from) SARS1. I thought I fully explained that Peter was mistaken and the judges have agreed with me (see the clip below) but Peter keeps repeating that claim (e.g. in the Astral Codex writeup).

Now, with the FOIA of the DEFUSE drafts we now have clear evidence that even strains with up to a 25% difference from SARS1 were of interest.

🚨 Moreover, the 2019 EcoHealth grant renewal letter for their joint grant with WIV actually said that they would PRIORITIZE strains that had between 10% and 25% difference from SARS1 in their spike gene.

Details in the thread below.

This is the relevant excerpt from the DEFUSE FOIA:

🚨 But this is an even more important piece of evidence as this is the 2019 EcoHealth NIH grant renewal application for their joint grant with WIV that has been ongoing since 2014. In it we see that by 2019 their interest has shifted to focusing on novel SARS-like strains that are 10-25% different from SARS1 in their spike.

It is also noteworthy that they are talking of anticipating finding another 100-200 novel CoVs by sampling 5000 bats.

ecohealthalliance.org/wp-content/upl…

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Yuri Deigin

@ydeigin

Dec 13, 2023

Skeptics of epigenetic rejuvenation via partial reprogramming often point to low efficiency of full reprogramming in support of their skepticism.

Indeed, under standard conditions in vitro, only a small proportion of cells forced to express Yamanaka factors end up finishing the journey to pluripotency. This has led skeptics to further suggest that the rejuvenation we observe in reprogrammed cells is a manifestation of selection of apriori healthier cells by the reprogramming process rather than bona fide rejuvenation.

However, several observations mentioned in the attached video argue against this. First observation is that essentially 100% of starting cells can be reprogrammed to iPSC by Yamanaka factors if their H3K36 repression is transiently ablated in the early stages of reprogramming. And secondly, the earliest stages of reprogramming actually open up chromatin in all cells, even in the ones that don’t end up transitioning to pluripotency.

I think this has implications for both safety and efficacy of epigenetic rejuvenation by partial reprogramming, as its goal is actually to avoid a change in cell identity while at the same time giving cells a quick epigenetic jolt in the hopes of resuscitating them back to a healthier state. If we now observe that essentially all cells expressing Yamanaka factors get that jolt in the first days of partial reprogramming, that’s quite encouraging.

So the video below has excerpts from interviews with Konrad Hochedlinger and Ken Zaret from this year’s Cold Spring Harbor’s Cell State Conversions Meeting, as well as from Ken Zaret’s excellent CSHL keynote there. I’ll post links to the original videos in tweets below.

Bonus: Juan Carlos Izpisua Belmonte asks two very insightful questions:

(Dr. Belmonte is one of the pioneers of partial reprogramming as he led the group at Salk that published the seminal Ocampo et al. 2016 paper. He is now at Altos Labs)

Source interview 1 (Konrad Hochedlinger):

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Yuri Deigin

@ydeigin

Dec 4, 2023

https://twitter.com/ydeigin/status/1731399158479675632

Here’s another example of virologists trying to downplay the importance of DEFUSE using bad arguments. I’ve already addressed objections built on treating DEFUSE as gospel or dismissing its importance because it wasn’t funded but here I want to address two more arguments: “DEFUSE proposed inserting an FCS only in pseudoviruses” and “DEFUSE only talked about cleavage sites in S2 and the novel SARS2 furin cleavage site separating S1 and S2 doesn’t count”:

https://twitter.com/ydeigin/status/1731399158479675632

In actuality, DEFUSE clearly stated that pseudovirus work was meant as a first, pre-screening step which could then lead to chimeric virus testing and ultimately to testing using the full backbone of the original virus. Here I’ve highlighted the relevant DEFUSE excerpts:

Moreover, the quote from DEFUSE about creating novel “human-specific” cleavage sites in SARS-like viruses is found in the “Testing Synthetic Modifications” section that clearly means work with chimeric viruses:

“We will synthesize [SARS-like quasispecies] with novel combinations of mutations to determine the effects of specific genetic traits and the jump potential of future and unknown recombinants.
…
We will analyze all SARSr-CoV S gene sequences for appropriately conserved proteolytic cleavage sites in S2 and for the presence of potential furin cleavage sites. SARSr-CoV [spikes] with mismatches in proteolytic cleavage sites can be activated by exogenous trypsin or cathepsin L. Where clear mismatches occur, we will introduce appropriate human-specific cleavage sites and evaluate growth potential in Vero cells and [human epithelial airway] cultures.”

The mention of pseudoviruses in the sentence that follows refers to something different — ablating existing rather than creating novel cleavage sites:

“In SARS-CoV, we will ablate several of these sites based on pseudotyped particle studies and evaluate the impact of select SARSr-CoV S changes on virus replication and pathogenesis.”

To be honest, I’m not even sure what that sentence refers to, as it seems to be talking about SARS1 rather than novel SARS-like (SARSr-CoV, i.e. SARS-related) CoVs. Moreover, SARS1 doesn’t have even a single FCS to ablate, let alone several, which makes that sentence even more puzzling. I actually think it might have gotten misplaced from the N-linked glycans section which follows right after and talks about civet SARS1 strains having some ablated glycans that were present in human SARS1, and in that context ablating “several of these sites” in SARS1 actually makes sense.

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Yuri Deigin

@ydeigin

Sep 28, 2023

I was quite shocked to discover that Yaroslav Hunka — the Nazi veteran invited to the House of Commons — was actually previously honored (along with several dozen other Waffen SS veterans) by the Ukrainian Canadian Congress in 2007. Notably, the Ukrainian ambassador to Canada was a special guest at the ceremony and gave a celebratory speech:

Previously, in 2003, Yaroslav Hunka represented the very same Ukrainian Canadian Congress at the 8th Ukrainian World Congress in Kiev. Since 1989 he frequently visited Ukraine and even ran for Verkhovna Rada (Parliament) in 1994.

In 2004 he was made an honorary citizen of Berezhany; war criminals Stepan Bandera and Roman Shukhevych were given the same honor in 2011:

Given Christia Freeland’s close ties with the Ukrainian Canadian Congress, I can’t help but wonder whether she knew Yaroslav Hunka personally and/or was well aware of his invitation to the House.

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Yuri Deigin

@ydeigin

Aug 27, 2023

1/ A key weakness of the Huanan market zoonosis hypothesis is that all 16 earliest Wuhan patients with link to the market had lineage B of SARS2 which is phylogenetically placed later in the ancestry tree than lineage A.

2/ Lineage A initially represented 33% of the Wuhan early cases but quickly went extinct as lineage B seemed to have a fitness/growth advantage as evidenced by early epidemiological data.

3/ So lineage A is two mutations closer to ancestral bat viruses than lineage B and most likely lineage B evolved from it before eventually outcompeting it into oblivion. However, lineage A itself is not at the root of the SARS2 ancestry tree because several phylogenetically earlier genomes are known, i.e. ones that have even fewer mutations than lineage A when compared to bat viruses like RaTG13 or BANAL-52.

One such mutation is C18060T (i.e. bat viruses have a T nucleotide in their genomes [actually, a U as they are RNA viruses but let’s speak DNA here] in position 18060, while the reference human SARS2 genome, Wuhan-Hu-1, has a C nucleotide), and several investigators of SARS2 phylogeny (e.g. @jbloom_lab or Kumar et al. 2021) think that it is likely that the earliest ancestor of all human SARS2 viruses had that mutation.

Such an ancestor is sometimes called proCoV2, and it is basically lineage A with the C18060T mutation (so, in total, it is 3 mutations away from Huanan market’s lineage B: C8782T, C18060T, and T28144C).

Here is the Kumar et al. paper:

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