In case you don’t know, there’s officially an effort to try to develop chemical probes for basically every protein in the human proteome. The “Target 2035” initiative has been looking through the literature and finding what you’d expect: power-law distributions that have most people working on proteins that other people have worked on. And that’s natural enough, since many of those have evidence of their importance (in human disease, most of the time), and these are the areas mostly likely to lead to real-world applications, not to mention real-world funding.
But it would be a good thing if research were able to branch out more and explore proteins that we don’t know so much about, given the general level of our ignorance. And the belief is that a good way to jump-start that is to provide some pharmacological tools that people can use, which seems like a reasonable assumption to me. As the authors note, “For almost every protein for which a cell-active pharmacological modulator has been made available, the paper describing the modulator is among the top-cited papers on that protein in the entire literature. . .” That said, asking people to go work on proteins of unknown or unclear function is hard enough, and telling them that they will have to develop their own tools if they even want to get started makes the barrier to entry even harder. That’s what we do in the drug industry a lot of the time, and it is no stroll through the petunia patch. Again, the paper:
Regrettably, pharmacological modulators of the required potency and selectivity to support interpretable and reproducible science are both challenging and expensive to invent, and also require skills commonly found in industry.
So I applaud the idea behind this effort. It’s not going to involve strolling past many petunias itself, though, particularly if we’re seriously trying to come up with those probes before 2035. But the Structural Genomics Consortium has had some success developing new probes (and in persuading drug companies to make some of theirs available), so they’re going for it. It’s recognized as an aspirational goal, and also that the only way to realize it will be to take advantage of further advances in technology – if you tried to generate thousands of new reagents the way we’ve been coming up with them to date, the project is simply not realistic at all. The first phase (out to about 2025) is enough of a tall order as it stands:
(i) collecting, characterizing, and distributing existing pharmacological modulators for key representatives from all protein families in the current druggable genome and generation of chemical probes for additional family members; (ii) developing the crucial and centralized infrastructure to facilitate data collection, curation, dissemination, and mining that will empower the scientific community worldwide; and (iii) creating centralized facilities to provide quantitative genome-scale biochemical and cell-based profiling assays to the federated community.
It’s important to note that this effort will be targeting both chemical and biological probes – antibodies or nanobodies that can affect protein function are part of the picture, too, as are protein degraders, allosteric modulators, whatever works and can provide insights. The plan is to try to get the existing let’s-make-better-probes efforts to consolidate under this umbrella and be ready to jump on new ideas and techniques as they become available. And the good news is that this isn’t one of those efforts that has to make it to the end to be really valuable (as pointed out in this Nature writeup on the effort). Right now, the coverage of the proteome with really useful probes is way down in the single per cent range at best, so there’s a vast amount of room for improvement. And similarly, there’s plenty of room for improvement in how we find, assay, and characterize such reagents, and such techniques will have very broad applicability.
So while I think the goal is aspirational indeed, I still think that trying for it is a good idea, and I’ll be watching with interest over the next few years to see what progress is being made. And I have my own suggestion, if funding can be found along the way. Let’s take all the existing physical supplies of the worst chemical probes available, the ones that are still being sold in the catalogs even though they don’t do anything like the label says, the ones that are still appearing in the literature and cluttering up science with unreliable results. . .and put them deep within the most inaccessible locations we can possibly find. Maybe a nuclear waste repository. Maybe if we just round up the world supply of rottlerin and the like, people will finally stop using them.