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Two whole-genome CRISPR screens for SARS-CoV-2 resistance are on bioRxiv.

**Among the top 100 hits in each screen, 99 are non-overlapping.**

Could cell type-specific differences could explain this discrepancy? And if so, what’s the “right” way to study SARS-CoV-2 in culture?
A few thoughts: Wei recovered ACE2 as their #1 hit, which is strong evidence in favor of the biological validity of their screen.

(Heaton didn't recover ACE2, which they suggest is because their cells transgenically express ACE2 cDNA, though I don't get why that should matter.)
Wei also validated a large number of their top hits in individual CRISPR assays.

Heaton validated their top hit, the kinase SRPK1, by treating cells with an "SRPK1 kinase inhibitor", given at 50uM! No way on earth that that's specifically inhibiting a single kinase.
On the other hand, the Wei screen was done in Vero cells, which don't fully recapitulate the "normal", TMPRSS-dependent coronavirus-uptake pathway.

The Heaton screen was done in human A549 lung cancer cells.

wired.com/story/scientis…
Interestingly, the only hit in common between both screens is the kinase SIK1.

SIK1 is generally non-essential in human cells and the knockout mice are viable and healthy. Seems like an exciting hit to study!

ncbi.nlm.nih.gov/pmc/articles/P…
Here are the links to the CRISPR screening papers. I'm interested in what people think... what's the best way to study SARS-CoV-2 in culture?

biorxiv.org/content/10.110…
biorxiv.org/content/10.110…
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Jason Sheltzer
@JSheltzer
Here are the publication records and research topic areas of 63 faculty candidates in the life sciences who interviewed at R1 institutions in 2019-2020.

70% have a first-author paper in Cell, Nature, or Science, 22% have a K99, and 30% have unpublished work on bioRxiv.
Methods: faculty candidate seminars were found on public departmental websites. Pub records were acquired from Google Scholar or Pubmed, and K99's were found on NIH Reporter. I did my best to summarize research topics by reading the abstracts of a candidate's recent papers.
The candidates were interviewed at a variety of public and private R1 institutions. I focused on departments studying genetics, cell biology, cancer biology, biochemistry, and related fields in the life sciences.
Read 23 tweets
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Jason Sheltzer
@JSheltzer
Our new preprint on #COVID19 with Stefan Pöhlmann, Markus Hoffman, and @joans is up. We show that proteases other than TMPRSS2 are capable of promoting SARS-CoV-2 uptake, but camostat (and its active metabolite) can still inhibit their activity.

biorxiv.org/content/10.110…
TMPRSS2 is commonly described as “necessary” for SARS-CoV-2 activation. Many papers look at the expression patterns of ACE2+/TMPRSS2+ double-positive cells, ostensibly to shed light on which cell types are vulnerable to coronavirus infections. But it isn’t that simple!
ACE2 is necessary for viral uptake. TMPRSS2 expression in an ACE2+ cell is sufficient for uptake. But that DOES NOT mean that TMPRSS2 is also necessary! Hoffman et al. show that other TMPRSS-family proteases - particularly TMPRSS13 - are fully capable of activating SARS-CoV-2:
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Jason Sheltzer
@JSheltzer
New from my lab in @NatureRevGenet - we take a deep dive into the tools and platforms that can be used to discover and characterize cancer drug targets. nature.com/articles/s4157…
Work from my lab and from several others has demonstrated that many genes previously reported to be cancer-essential are in fact dispensable for cancer growth.
In many cases, these incorrect results were due to experiments done with off-target RNAi reagents and/or promiscuous small molecules.
Read 14 tweets

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