Stuff that might be true

I'll add to the below list as thoughts pop into my brain....

*"Celebrity" genes are over-rated. Last I looked there are something like 10,000 papers primarily devoted to tp53. Every now and then I stumble across a knockout that has not, to my knowledge, been performed before. One might think that such knockouts would be less likely to generating a long list of significantly perturbed transcripts than, say, a tp53 knockout. I just entered a study involving a CHSY3 knockout into the database. That's the first instance of a CHSY3 perturbation in the database, and the knockout had a major effect on transcript abundances in the underlying study. This sort of thing happens again and again...it's not as if the list of genes whose knockout strongly alters cell activity was exhausted a decade ago.

*Our understanding of biology is strongly biased according to the order of discovery. As an example, it seems that folks have a fairly fixed idea of what micro-RNAs do, if they do anything at all. When perusing micro-RNA overexpression and inhibition studies, the studies in which large numbers of transcripts are significantly altered (versus few or none) usually seem to involve the symbol "mir" followed by a small number, not a large number (e.g. mir1 vs mir1234). This may seem odd until you consider that, in the early days of miRNA research, new mirnas would simply be given the first integer that had not already been taken. In other words, the early mirnas, which were discovered because they actually did something in cells, may have created the illusion that there may be thousands of interesting mirnas, all of which act according to the principles associated with the earliest mirnas.

*Also, regarding miRNAs: it's possible that, at "ground truth" level, the typical miRNA only targets one or a few transcripts (1). This is based on an observation I haven't quantified: that miRNA overexpression and inhibition studies, in contrast to these experiments conducted on ordinary transcripts, often seem to strongly alter the expression of one or a handful of transcripts, followed by a clear drop-off in significance and/or fold-change.

*Some genes may reach celebrity status because they are exceptions to a rule: that one type of study (e.g. knockouts) usually overlaps weakly, if at all, with other types (e.g. chip-seq). P53, for example, breaks the rule: the genes altered in P53 knockouts often do overlap with P53 chip-seq results. Of course, P53 also has the property that it is often mutated in cancer, so another possible "truth" is that genes that break the rule are precisely the ones that get targeted by viruses or cancers.

*Modern biology is hugely skewed by the results of experiments in which cells are essentially blasted with extreme conditions that are rarely, if ever, experienced in normal living creatures...complete knockouts, targeted alterations of single genes, micro-RNA levels 100X greater than anything ever experienced in nature, etc. These conditions are very often measured over extremely short time scales, largely due to the limitations of cell culture approaches. It is possible that these approaches have skewed biology in massive fashion. Again, consider Alzheimer's, a disease whose seeds may be planted decades before symptoms become obvious...I've yet to see any sort of experiment, either with mice or cell culture, that parallels the set of genes that are typically upregulated in Alzheimer's. Perhaps this is simply because of the near-impossibility of conducting experiments over the course of decades.

1. Just as an example, a study in which mir138 was inhibited (GSE173982) results in very significant downregulated of a single transcript, NDUFA9. Another one...mir-222-3p treatment results in the very significant downregulation of a single transcript (Gm10925) in GSE167753.

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