Why’d you have to go and make things so complicated?

If your work deals somehow with chemical substances and their effects on living creatures (medicinal chemistry, pharmacology, toxicology etc), the question you most dread is surely ‘Is this compound poisonous or not?’ To a layperson, this sounds like a completely reasonable thing to ask, a perfectly simple question that for some reason sends the degree-holders in lab coats into fits of explanation (‘it’s complicated…’), or sometimes just into fits.

Most of the readers of this column are in that lab-coated category (or not far from it) and will appreciate the problem. Paracelsus was right, for one thing: the dose really does make the poison. And the dosing schedule can make the poison, too, as well as the dosing route, and the type of animal being dosed, as well as several other, less obvious, variables. The example I always use is to ask someone whether selenium is a toxic element or an essential nutrient, and the only valid answer is that it’s both, depending on the dose and the situation. It’s safe to say that these sorts of answers are usually not what people are looking for.

But this is what happens when you ask for a two-valued answer in a world that often refuses to conform to either/or criteria. A major underlying problem is one of definition – in this case, what we mean when we say ‘poisonous’. It’s a mistake to assume that every adjective describes a binary switch. The status of a light bulb (on or off?) comes close, but reality is loaded with dimmer switches and contingencies. With a rheostat, even a light bulb could be in a state best described as ‘uselessly on’, and it’s hard to come up with a distinction in any area that’s truly sharp. Alive or dead, you say? What about a virus or a dormant seed?

Another underlying problem is the domain of applicability. Newton’s laws of motion are perfectly useful until you start moving closer to the speed of light or near a heavy enough object. Back in the med-chem labs, trying to get rid of all the compounds that aggregate in solution and give false positives in binding assays is a futile task, because aggregation behaviour depends on the assay conditions. A compound that’s a total false positive in one assay could be a valuable lead from another. Likewise, an assay that’s perfectly reasonable for one programme could be a useless distraction (or worse) in another.

It’s hard to come up with a distinction that’s truly sharp. Alive or dead, you say? What about a virus or a dormant seed?

And this is the world where we scientists live. We can make no useful distinctions unless we all know what definitions we’re using and how far they extend. Outside the lab, though, this can come across as tremendously annoying. The worst mismatch is probably between scientific issues and political ones. Some MP or Senator wants to know if drug X is harmful or not, and the stream of qualifications and hedges that comes in response ends up sounding less like someone being precise and more like someone trying to avoid answering the question. ‘It’s complicated’ is often just the (simple!) truth, but people get tired of hearing it. That’s true even within R&D-driven organisations, when upper management wants to know why project Y hasn’t progressed and the people working on it start in with their tales of woe.

While the politicians sometimes seem surprised to learn that there are complications at all, the industrial managers know all about them but have heard it all before. ‘Sure, every programme has its issues. But some of them deliver. Why can’t yours?’ If this is your situation, it would be prudent to devote some forethought to how you’ll answer such a question. You’ll want to minimise the hand-waving and special pleading and get right to the issues and uncertainties that are holding things up. This assay is too variable, or these two readouts contradict each other, or no one knows what to make of these confounding results. Are there ways to resolve these questions? If so, lay them out, and if not, lay that out too and make it clear that a decision will have to be made with what’s available. Doing this can clarify your own thinking as well. ‘It’s complicated’ is true, but it’s not enough. Of course it’s complicated. Everything is. It’s a complicated world. The question is what best to do about it.