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Hidden Constraints in Coronavirus Genes

1:38:13 recording · AUTO · 2 speakers

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Brief overview

A gene the virus no longer uses sticks around anyway, and NIH called that work dangerous.

  1. A broken gene can still be load-bearingThe mutated ORF2 was never deleted over 15 passages, breaking the less-is-more expectation for RNA viruses.
  2. Coronavirus genomes fold across their gene bodiesUnpublished structure assays show secondary structure throughout ORF2, not just in the 5' and 3' UTRs.
  3. The flag fell on BSL-2 mouse-virus passagingThe experiments NIH objected to were MHV, a virus that has never infected a human in 75 years, passaged in a macrophage cell line.
Executive Summary AI
  • Recording TWEVO 117 on August 20, 2025, Nels tells Vincent he received a letter from the National Institutes of Health flagging the virus-evolution work in his R35 renewal as, in his words, dangerous gain-of-function research, part of a wave in which 40 projects were suspended and another 170 flagged.6:02
  • The paper at the centre of it is Hidden Evolutionary Constraints Dictate the Retention of Coronavirus Accessory Genes, driven by former postdoc Stephen Goldstein, published last December, with contributions from Zoe Hilbert, Diane Downauer, Nima Morshiri and virus and cell reagents from Susan Weiss and Sunny Shin at Penn.14:52
  • The experiment took mouse hepatitis virus with the NS2 phosphodiesterase knocked out in ORF2 and the host gene ACAP7 inserted at ORF4, then passaged it in mouse macrophages and in L2 fibroblasts: ACAP7 was lost in the fibroblasts where OAS/RNase L pressure is relaxed, but the dead ORF2 sequence survived 10 and then 15 passages in both cell backgrounds, like a rock.47:32
  • Nima Morshiri then checked the pattern against millions of SARS-CoV-2 sequences in GISAID and found the same thing for ORF8, which persists despite disabling stop codons such as position 27 in B.1.1.7 and position 8 in XBB.1.X, pointing to hidden non-coding constraints like RNA secondary structure across the gene body.56:14
  • Nels closes on the politics, reading David Relman of Stanford on self-censorship and intimidation of PIs and Mark Lipsitch of Harvard predicting the suspensions will damage health security, while Vincent picks Jake Scott's Stat News piece on Kennedy's terminated half billion dollars of mRNA vaccine funding and its 181-page bibliography.1:06:52
Key Quote
“So it violated this notion of less is more evolution.”
— Nels44:58
Key Quote
“So to think that we could engineer a virus is ridiculous, and it shows a lack of understanding of the field.”
— Vincent1:02:53
Key Quote
“They've shifted that onto the researchers.”
— Nels1:11:07