IIRC, this is still true if you exclude the spike protein and use a higher similarity threshold.
Why would one do that? Well, two reasons. First, the spike more variable as it is subject to greater evolutionary pressure as the major component of the viral surface. Second, in coronavirus reverse genetics typically the virus is segmented into multiple pieces, most of which compose the non-spike backbone and a subset which compose the spike protein. This is intentional to enable the swapping of spike proteins. So, if SARS-CoV-2 is spike-swap or spike variant assembly, a RaTG13-like virus could be the "backbone" of SARS-CoV-2.
Moreover, a hypothetical SARS-CoV-2 backbone could exist in the viral sequences list the WIV took down in Sept. 2019. They sequenced RaTG13 a few years prior. The lab's raison d'etre is collecting and sequencing coronaviruses poised for spillover. And, with modern DNA synthesis technology, it's not difficult to print out arbitrary backbone contigs for a viral assembly.
This doesn't test the "epigenetic information theory of aging."
First, there is no survival analysis. How is the mouse younger if it doesn't live longer? Similarly, the OSK "rejuvenated" mice display lower lean muscle mass.
Second, the causality is (willfully?) misinterpreted. The endonuclease used to causes DNA double-strand breaks does NOT directly alter the epigenome. Instead, it induces DNA-damage repair stress. One consequence, of many, is epigenetic (chromatin) dysregulation. DNA damage stress is well known to accelerate aging phenotypes. In fact, David published on how p53 stress from repeated DNA damage - using the same endonuclease setup - initiates a DNA damage response in turn promoting cell-cycle exit and cell elimination [0].
Third, cutting "non-coding" DNA in this case involves cutting specific ribosomes (cell translation machinery). Given that this pressure is constitutive, it's likely that these ribosomes evolve resistance to the nuclease by mutating functional sequences. However, the authors never assessed the mutation and function of these ribosomes.
Lastly, the in vivo AAV transduction efficiency isn't measured. This makes the OSK "rejuvenation" result hard to interpret. All cells get DNA damage (germline edit), but only transduced cells (<10% at best in whole organism) get some OSK exposure. Yet, the whole organism is "rejuvenated"? Is there a positive spill-over from OSK expression?
All the core claims about epigenetic information are either incorrect or grossly misleading. The perturbation, site-specific DNA damage, does not cause only loss of whole-cell epigenetic information. Hard to imagine how this got into Cell. I guess a big name and 20+ figures is all you need these days?
I'm surprised the insurance will pay for this. The judgment, and actions by Oberlin's administration, strongly suggest they were acting in bad faith. The college's behavior exceed negligence, the typical threshold in these sort of insurance contracts.
Pretty incredible Oberlin can get out of this considering what other insurers will do to avoid paying for incidents with cause.
Never thought of this distinction before! Thanks for making this distinction.
This seems to hold in other contexts. People tend to tolerate price discrimination at an aggregate level (e.g. senior/student discounts) but loathe individual-level price discrimination (e.g. college tuition). I wonder if it's the unfairness or uncertainty
There a quite a few things missing from this paper that would make it a good a good drug discovery paper.
First, they didn't discover a drug - they found a hit. 30 days from target to hit using conventional high-throughput biochemical screening would take 2-4 months. So, this is 3x faster, but that's not the rate limiting step. Validation and in vivo studies will take >4 mo and 1-12mo respectively.
Second, if we take this as a "we found a hit" paper, I want to know how specific your hit is. This would be one of the major advantages of using AF2 - screen against related proteins with some structural or functional similarity. This is the time intensive and oft overlooked part of good in vitro screening campaigns. Potency is nice (although 9 μM isn't impressive), but ultimately selectivity is paramount when targeting a class of proteins with well conserved binding sites, like kinases. If they found a promiscuous CDK inhibitor that happens to hit CDK20, then I bet there are tons of previously reported promiscuous CDK inhibitors that will hit CDK20 too.
Third, this paper is surprising because it exploits none of the cool new things AF2 could enable. In addition to what you mention above, the authors could have tried to counter screen (much faster in silico!), find an allosteric inhibitor, identify a PPI/complex inhibitor, or take a leap by generating a SAR series in silico and validating a few selected compounds in vitro.
Overall, this paper seems both incremental and misdirected. Saving 2 months in the discovery phase, pre-IP, is worth ~0. Not sure anyone there has much experience developing drugs. Hits are nice, but rarely the hard part. However, a hit on a protein from a structurally divergent class would be a major accomplishment.
NIH likely funds 2/3rds of US biomedical research and ~1/3rd of global biomedical research by dollar value [0]. That link lists other big sources (ERC, MRC, US DoD, HHMI). My sense is that this landscape will change rather quickly with pandemic-inspired biomedical/defense initiatives and more private institutes in the US.
Moreover, NIH funding, due to its central role in supporting biomedical research, is often necessary for getting a tenured PI position. Many high caliber R1 schools require multiple R01 NIH grants for tenure. Often private funding sources are less valuable to universities because they pay lower indirect rates (<10% vs >40%) on sponsored research. As institutions are so dependent on NIH funding, the NIH can exert influence far beyond the research it funds directly.
Why would one do that? Well, two reasons. First, the spike more variable as it is subject to greater evolutionary pressure as the major component of the viral surface. Second, in coronavirus reverse genetics typically the virus is segmented into multiple pieces, most of which compose the non-spike backbone and a subset which compose the spike protein. This is intentional to enable the swapping of spike proteins. So, if SARS-CoV-2 is spike-swap or spike variant assembly, a RaTG13-like virus could be the "backbone" of SARS-CoV-2.
Moreover, a hypothetical SARS-CoV-2 backbone could exist in the viral sequences list the WIV took down in Sept. 2019. They sequenced RaTG13 a few years prior. The lab's raison d'etre is collecting and sequencing coronaviruses poised for spillover. And, with modern DNA synthesis technology, it's not difficult to print out arbitrary backbone contigs for a viral assembly.