About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 17, 2011

Block That Metaphor!

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Posted by Derek

Phillip Ball had an interesting piece recently over at Nature News, which touches on a subject that I've also thought about: when does metaphorical thinking help, and when does it hurt? (I've got a whole category on the blog on this topic, although I haven't filled it up with as many posts as I've meant to).

As he mentions, there's no some empirical evidence that metaphors can influence the way we think about a situation, and not in ways that we're consciously aware of. I think that we're particularly vulnerable to this effect in scientific research, because so many of our concerns are outside day-to-day experience. I don't see any way around this: we can't see a G-protein-coupled receptor in action, so we come up with a mental picture to help. We can't visualize the complexities of a biochemical pathway in toto, so we reduce it to a useful simplification. Well, we hope it's useful, anyway.

I have a number of these mental constructs - for example, when I'm picturing a protein surface or a binding pocket, I have a tactile image of something like firm gelatin with a hard surface underneath (ball bearings or pool balls, depending on the scale I'm picturing). Thinking about it, I know where that image comes from - it's from standard molecular graphics representations of van der Waals surfaces around atoms. The charge distributions on the surface come across to me mentally as warm and cold areas, or perhaps sour and sweet. The first of those is probably because many graphics programs represent charges as red and blue; the taste metaphor seems to be my own brain's contribution - characteristically vivid, but of uncertain utility.

In case you're wondering, I do audio, too. Protein-protein surfaces seem, in my mind's eye, to be mildly sticky, which is probably my impression of an overall hydrophobic effect. The charged surfaces, when they come apart, do so in my head with a tactile peeling effect and a faint sound of Velcro.

Now, does my forebrain's special effects budget make me a better medicinal chemist? Who knows? If I've got the wrong impressions, and if I act on them too strongly, they might make me a worse one. The same with other metaphors, both the internal ones and the ones we produce for others. A bad metaphor can do more harm to the people you're trying to teach than good.

This also goes for the metaphors that people bring with them when they think about what we do in drug discovery. I think, for example, that people who design and build complex human-produced systems are prone (naturally enough) to believing that biochemistry and drug design must be similar processes, and thus subject to the same engineering approaches. Those of us wrestling with these problems are stuck trying to explain that not only are living systems more complex, they're complex in a different way as well - you're looking at differences of both degree and kind. But if you're used to circuit diagrams, programming flow charts, or chip design, then you're naturally going to see those when you look at diagrams of biochemical pathways.

The best "harmful metaphor" example I can think of at the moment is the importation of agonist/antagonist nomenclature into the nuclear receptor field. I'd like to find whoever did that and whack them on the head with a board. That misled me when I first started working in the area, and I've seen it mislead countless others since then. "They're pretty much like GPCRs" is the impression given to the unwary, but that's a tall glass containing 5% refreshment and 95% toxic sludge. You have to spend a lot of energy getting it out of your head if you want to have a chance to understand what's going on with those targets, inasmuch as anyone does.

But there may be a larger example: the whole reductionist approach of target-driven drug discovery. That'll be the subject of another post. . .

Comments (28) + TrackBacks (0) | Category: Metaphors, Good and Bad

April 22, 2007

Melting Keys and Squishy Locks

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Posted by Derek

Pretty much the only thing that an interested lay person has heard about ligand binding is the "lock and key" metaphor. I'm not saying that you could walk down the sidewalk getting nods of recognition with it, but if someone's heard anything about how enzymes or receptors work (well, anything correct), that's probably what they've heard.

And there's a lot to it. Many proteins are really, really good at picking out their ligands from crowds of similar compounds. (If they were perfect at it, on the other hand, we drug company types would be out of business). But the lock-and-key metaphor makes the listener believe that both the ligand and the protein are rigid objects, which they most definitely are not. There's no everyday analog to the way that two conformationally mobile objects fit to each other - well, OK, maybe there is, but it's not one that you can safely use for illustrative purposes. Ahem.

The other big breakdown of the lock and key is that it doesn't deal well with the numerous proteins that can recognize more than one ligand for their binding sites. Particularly impressive are the nuclear receptors and the CYP metabolizing enzymes. Both those classes bind a bewildering number of not-very-similar compounds, and they can do it impressively well. They manage the trick by having binding pockets that can drastically change their shapes and charge distributions, as parts of the proteins themselves slide, twist, and flip around. I can't come up with even a vulgar metaphor for that process.

I'm thinking of doing several posts on the limits of metaphor and simplification in science, and if I do, this will be the first. It's a constant struggle not to mistake the picture for the real thing, particularly if the simplification is a pretty useful one. But eventually, no matter how good, the metaphor will thin out on you, and you'll be in the position of a Greek bird pecking at some painted fruit and wondering why it's still hungry.

Comments (29) + TrackBacks (0) | Category: In Silico | Metaphors, Good and Bad