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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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October 14, 2004

Circular Mistakes

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Posted by Derek

This is a somewhat reworked version of an early post from my old site, Lagniappe, which I doubt if many of my current readers have ever seen:

I came across a quote from V. S. Naipul which set me to thinking. It's from Among the Believers, his famous (infamous, for some) book on the Islamic world. About the slow post-independence rot of Pakistan, he wrote:

"The state withered. But faith didn't. Failure only led back to the faith. . .If the state failed, it wasn't because the dream was flawed, or the faith flawed; it could only be because men had failed the faith. A purer and purer faith began to be called for."

This seems to me to not only be true, but to be true about many more things than Islamic politics. What it reminded me of was from a David Foster Wallace essay in A Supposedly Fun Thing I'll Never Do Again, where he defines a harmful addiction as something that presents itself as the cure for the very problems it causes. This applies immediately to physical dependencies like alcoholism ("If you had my problems, you'd drink too",) but Wallace goes on to show how it fits the habit of, say, watching five hours of TV a night.

I'm not making Islam = addiction connections here (or TV watching = religion ones, either!) No, what occurred to me is the general problem of systems whose only remedy for failure is to cycle back around again. And if that doesn't work, the only remedy is to do it again, preferably longer, louder, and harder the next time.

A blind spot is built into these systems which allows them to get to the harmful stage. No failure can be the fault of using the system itself - if that were possible, then other courses of action would be possible, too. And that can't be right, can it? But without that choice, you're on a circular highway without any exit ramps.

Look around, and you'll see plenty of these. At your workplace, is there some policy that does nothing but worsen the problem it addresses? And is there any mechanism at all for the policy itself to ever be at fault? Everyone's encountered folks who are so convinced of their own correctness that they just get crazier and crazier. Lots of terrible managers work the same way.

One of the things that has made science, as a system, work so well for so long is that it doesn't rule explanations out very readily. The possibility that a whole system might be at fault is always there; what's more, there are usually some eager researchers ready to try to tear it down. Individuals will make the circular-problem mistake, holding on to untenable theories by making them more and more complicated rather than abandoning them. But it's harder for a whole field of research to get bogged down in this way, and we're the better for it.

The connection between this line of thinking and the pharmaceutical slump of recent years has not escaped me. Is the answer to make even bigger screening libraries, that are then run through even faster? To dig around even more thoroughly in the genome? Or do we need something completely new - in other words, have we failed our ideas, or have they failed us? The fact that we can even ask the questions is the first step in being able to answer them.

Comments (3) + TrackBacks (0) | Category: Drug Industry History


1. Nicholas Weininger on October 14, 2004 10:40 AM writes...

Jeez, you could make a whole book, _March of Folly_ style, about the impact of this way of thinking on history. The first thing that comes to my mind, actually, is the Byzantine Empire's response to the initial rise of Islam: if those desert folk are winning so many battles it *can't* be because we're a vast, lumbering, sclerotic, behind-the-times remnant empire that needs a political/economic/diplomatic shakeup-- no, no, it must be we haven't smashed enough icons!

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2. William Knight on October 14, 2004 1:38 PM writes...

...Or do we need something completely new - in other words, have we failed our ideas, or have they failed us? The fact that we can even ask the questions is the first step in being able to answer them.

This IS the way out of the pharmaceutical slump, to acknowledge its existence and what to do about it. So, how to do it? It's the inherent complexity of the problem that is the cause. Trying to grasp the nature of individual biomolecules is bad enough, but it is the whirling myriad menagerie of them inside and between cells that really makes things impossible.

We need more emphasis on basic research. Current drug development is like a few brave and lucky vikings trying to sail wooden ships to settle the new world. Instead, what was needed was to first build the infrastructure of navigation, manufacturing, communication and finance.

We need to do more than just automate screening libraries and the genome. We should try to automate the whole process of model building at the phenotype level. Create thousands of rich, detailed simulations of molecular interactions of cellular subsystems and pathways. Promote modelling projects on the Internet, each one dedicated to a currently-identified type of cancer. Provide mechanisms to engage people from outside of the field to get excited and participate.

Those are a few ideas for getting out of the slump. Sorry for straying from the equally interesting question about Islam and politics, but this is a pharma blog.

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3. steve on October 18, 2004 6:03 PM writes...

There is no general rule for when persisitence is a virture and when it is folly. Many a battle has been lost because the side that was on the cusp of victory lost heart, granting the enemy a miraculous reprieve. The Sidewinder air-to-air missile, by far the leading weapon in its class for decades, failed over and over again in tests (and was a bootleg project in the first place). The people who figured out how to cure rabies had to slaughter so many dogs before they got a solution that outsiders considered them madmen. I bring up these examples only to compensate for the tilt in the posting.

It seems to me that you need some indicator OTHER than the success rate achieved to date to tell whether giving up or persisting is the greater error. For instance, a plausible theory about why a particular approach is not going to work could be a big help in choosing to abandon it.

Also, fresh tweaks on abandoned old ideas sometimes pay off. Nintendo made a fortune in video games a few years after everyone had decided that the Atari/Mattell/Coleco collapse of the 1980s had proved that the business wasn't viable. Google figured out how to make money in search after Yahoo and Alta-Vista and the rest had given up. String theory applied to unify the fundamental forces got hot years after it was abandoned at the hadron level.

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