I was thinking the other day about a drug discovery project that I used to work on, some years ago. It had some interesting chemical matter, a small chiral heterocyclic core that looked as if it could be elaborated in all sorts of directions. But that’s the key part: it only looked that way, to every chemist who saw it. When you actually went into the lab and tried to realize any of those ideas, well, that’s when the fun started.

Nothing seemed to work, or at least when something did, it was the fourth attempt at the second work-around. Hardly anything straightforward ever succeeded, and this made the whole project a very frustrating one to present to the rest of the department. “Why don’t you…”, “We tried…”, “But can’t you just…”, “No, you can’t.”

I was, for a while, one of those people asking such questions from the audience, until I found myself joining the project myself. I came in sleeves rolled up, full of ideas about how to get this thing moving in the right direction. But inside of a month, I was like all the rest of them, resting my forehead on the glass of my fume hood and wondering where things had gone wrong. While in this thoughtful position, people would come by and asked me why I didn’t just do the so-and-so reaction, because that one couldn’t fail. Those on the project were not as grateful for this kind of advice as the people offering thought we should be.

Chemistry gets into this sort of trouble more often than biology, because, let’s face it, the biologists have more excuses. Organic chemistry has gotten to the point where it’s supposed to work, one way or another. When it doesn’t, when the chemists actually start to talk about not being able to make something at all, it’s news. Usually, what we mean by such talk is that we can’t make it in the time allowed or the budget provided—throw enough time and money into the organic chemistry, and we really can do most anything. But biology has a ways to go to reach that stage. No amount of time and money seems to be enough to fix some of those issues. There are so many variables, especially as you move up from proteins to living cells, that there’s always some reason why things aren’t going so well today. Anyone who’s done assays, or been around the people who do, realizes this. Then extrapolate up to human clinical trials , and it’s a wonder that anything works at all. Mind you, 90% of the things that go into trials don’t.

But what if you don’t know anything about it? Then you look in from the outside and wonder what’s wrong with all these people.
That’s the situation the entire drug discovery effort finds itself in with the public at large. The general public, it’s safe to say, doesn’t have a very good grasp of the state of knowledge in biochemistry or toxicology. Five or ten minutes of viewing Dr. Oz’s program will usually make that clear—and five or ten minutes is all I can recommend in good conscience. People want to believe that this or that herb, berry, or supplement will do various wonderful things for them. Believing that also entails believing that the existing medical research establishment is too dumb, too lazy, or too corrupt to have figured any of this out on its own. The advertising for these things often goes ahead and takes that step for the customers, going on about how this new breakthrough is something “they” don’t want you to know about, and so on.

So people get the idea that there are indeed cures for many things which in fact, we can’t cure yet, and furthermore, that the reason we haven’t had them until now is the incompetence or venality of the drug researchers, the FDA , or just “them” in general. It’s not a good situation, especially since one of our main counterarguments, which is true, by the way, is that we don’t know enough yet to come up with such cures. This looks like an unfortunately thin excuse after say fifty years of intensive research on the causes of cancer or Alzheimer’s, but to be honest, that’s because most people outside of the sciences have never come across any problems that hard.

There’s a famous article by Yuri Lazebnik entitled “Can a Biologist Fix a Radio?”, and it gets across some of these points. He has a fascinatingly uncomfortable graphic showing a schematic diagram of a radio’s circuits compared to a biochemist’s view of its workings: double-headed arrows going between a few three-letter acronyms, with the occasional dashed line. Lazebnik is mostly making a plea for biology to adopt some sort of formal language or notation, which would allow for really useful diagrams to be constructed, and I’m still of two minds on that. Overall, I guess that I wish that biology were at the point where such formalism would be possible, but I don’t think that it is, yet. I completely agree about the near-uselessness of all those pathway diagrams, where this circle points to that square, which has a dotted arrow pointing over to that blob. I think, though, that the relatively straightforward inner workings of electromagnetism lend themselves to formal description, but as long as there’s no equivalent to Maxwell’s equations for biochemistry, we’re not going to get as far as we’d like with that program.

Lazebnik tries to address just the sort of arguments that I and others make about this, but he doesn’t convince me. My take is that biological systems are still just too complex, with too many signaling modes, feedback, and interconnection, to be formalized by anything useful at this point. The word I’m looking for is “inhuman”. Radios and computer chips, etc., are built by people, and are thus comprehensible by people. Cells were not—they’re bizarre piles of improvisation, weirdly tuned Rube Goldberg machines formed by a billion years of work-or-die selection pressure. They’re the nearest thing to a totally alien technology that we’ve ever come across, and I realize how strange that sounds.

But how do you get that point across in a newspaper article—or worse, a newspaper headline? My guess is that you just don’t, because it’s for sure that no one has so far. That leaves us going back to the patients, the investors, and the taxpayers year after year saying, “Well, you know what, that whole business has turned out to be more complicated than we thought.” It’s no wonder that people get impatient, or worse, start to suspect bad faith. And it’s no wonder that they’re ready to be customers of the people who tell them that things are actually a lot more simple. Just chew on this amazing jungle root, and your troubles will be gone. Three easy payments, and if you call within the next thirty minutes, we’ll throw in an extra month’s supply for free.

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Derek B. Lowe
Contributing Editor

Derek B. Lowe has been employed since 1989 in pharmaceutical drug discovery in several therapeutic areas. His blog, In the Pipeline, is located at www.corante.com/pipeline and is an awfully good read. He can be reached at derekb.lowe@gmail.com.