I get asked fairly often about natural products in drug discovery – it’s a topic that appeals to reporters and the general public, since the idea of pulling some sort of cure out of the rain forest or a deep-sea coral is interesting and dramatic. (Of course, some of the natural product cures have come from rotting pieces of fruit from a corner store, which isn’t quite as good a scene in a movie. For every rapamycin, isolated near an Easter Island statue, you have a rosaramicin, isolated from the soil in a Texas golf course.
The question I want to put to people today is: how bad is the diminishing-returns problem in this field? I think that we’ve clearly picked a lot of the proverbial low-hanging fruit. By now we’ve raided the traditional pharmacopeias from cultures all around the world, largely using up the rough-and-ready human activity data that have been accumulated over the last few thousand years. Past that, huge natural product collections have been screened in all sorts of directions, by all sorts of techniques, for decades now. Biological space is huge, and chemical space is huge, but in the intersection of “testing for activities we care about with compounds we can obtain from nature”, I’d say that a fair amount of coverage has occurred.
Now, that coverage is certainly not enough to say that we should give it up, and just not screen natural product collections. That would be foolish; there are still plenty of things to try. But what I’m wondering is how far down the “long tail” of the distribution are we by now? Have we discovered a majority of the really interesting natural products, or perhaps just a majority of the ones that can be fairly readily discovered? I don’t know about the former, but I’m willing to believe that latter.
Over the years, in reaction to beliefs like this, people have turned to less-explored regions and ecosystems, searching for things that have a better chance of not having shown up before. Extreme environments, less-sampled marine organisms, remote jungles – all of these have had (and are having) their days. (I should also mention that we humans create some pretty extreme environments ourselves that are worth sampling!) I would like to see some good drug leads and tool compounds come from Antarctic valleys and deep-sea sampling, but I don’t believe that just moving to odder environments will balance out the amount of searching we’ve done so far. We’re still in the position of doing more and more work, to make larger and large screening collections, to find fewer and fewer hits.
There are several possible ways out of this situation, but none of them are particularly easy. You have to think that there are many interesting compounds that just have never been isolated or tested in sufficient quantities, either because we do’t have enough of them in any collection and/or because they’re just found in such small amounts to begin with. So analytical chemistry’s relentless march could pull some of these back out into the light, but it’ll be work, for sure. There’s also the “cryptic natural product” idea that came up around here again just recently – inducing the formation of rare active substances that only get produced under specific threats or stress conditions. I like that one, and it has the advantage of probably selecting for things that have fairly high biological activities (as opposed to random metabolites), but it’s still a young field, with a lot of work to be done in it. Similarly, there’s the (old) idea of co-culturing microorganisms in order to pit them against each other. That has the advantage of perhaps producing some new active compounds as well as leading to screens against organisms that otherwise can’t be cultured at all – never forget, most bacteria and fungi don’t grow under standard in vitro conditions at all.
Every few years, it seems that you can find articles about the rebirth of natural products research (here are some from the recent crop of them). I wouldn’t mind that at all, if it’s true, but I can’t help but think that I’ve heard it before. So what do you think? Are natural products always poised to make a comeback, or will they really do it?