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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: derekb.lowe@gmail.com Twitter: Dereklowe

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June 1, 2010

The Truth Shall Make Ye. . .Unhappy?

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Posted by Derek

Here's an article on a topic that's come up around here before: psychological and cognitive barriers to discovering a new drug. These include confirmation bias, poor risk assessment, an over-reliance on recent experience, etc. The tricky part is that some of these cognitive mistakes might actually be reasonable adaptations to the problems of drug research itself:

The history of science and medicine is full of wrong ideas that prevailed for many years, despite mounting evidence to the contrary: phlogiston, the four humours, spontaneous generation of life and inheritance of acquired traits. These are examples of ‘confirmation bias’, which means that ‘we tend to subconsciously decide what to do before figuring out why we want to do it’ and seek evidence that tends to confirm rather than refute our initial judgment. . . In medicine, such ‘bad science’ can cost many lives; therefore, major institutions and professions have procedures and rules – notably peer review – that seek to protect against the pernicious effects of excessive self-confidence (setting aside, here, the issue of blatant fraud).

In our direct experience, discovery scientists admit that false optimism helps keep them functioning despite the recognized reality that most of their projects fail. This seems an essential trait of scientific heroes of the past yet, paradoxically, might count as a cognitive error in a business setting:

Now there's one that I hadn't considered, although I have thought a lot over the years about the differences between the business side of the industry and the discovery side. I'm not sure that "false optimism" is what keeps me going, though - I try to realize that most projects fail, but I try to make sure that they didn't fail because of something that I did (or didn't do) myself. The authors, though, quote from another study of the same phenomenon, which raises an interesting question:

Given the high cost of mistakes, it might appear obvious that a rational organization should want to base its decisions on unbiased odds, rather than on predictions painted in shades of rose. However. . .optimistic self-delusion is a diagnostic indication of mental health and well-being. . .The benefits of unrealistic optimism in increasing persistence in the face of difficulty have been documented. . . The observation that realism can be pathological and self-defeating raises troubling questions for the management of information and risk in organizations. Surely, no one would want to be governed entirely by wishful fantasies, but is there a point at which truth becomes destructive and doubt self-fulfilling?’

And that brings up a phrase that I use often, that it's easy to sit in the back of a conference room and tell people that their ideas aren't going to work. And you're right well over 90% of the time if you do that, but to what end? I'm going to have to think about this idea of "destructive truth" a bit more, but I wanted to put it out there for comments. I'll return to the whole cognitive bias problem as well, because there's more to it than just this. . .

Comments (28) + TrackBacks (0) | Category: Who Discovers and Why


COMMENTS

1. Chemjobber on June 1, 2010 10:24 AM writes...

"...optimistic self-delusion is a diagnostic indication of mental health and well-being."

That's fantastic.

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2. noname on June 1, 2010 11:07 AM writes...

Here's what I've learned (this is more from small biotech start-up than big pharma): those VPs/research directors who keep a smile plastered on their face no matter how bad the data, the ones who constantly cheerlead for the breakthrough that is right around the corner when every experiment is failing, the ones who float around with an air of triumph when everyone's making sure their CVs are current: those are the most valuable leaders. Keeping the team hard-working is how to get through the rough patches. Optimism is a great motivator. It's not easy to risk looking like a big fake, like a deluded flim flammer, when deep down inside you know this ship could be headed for the iceberg. But to ever let that admission slip into your public persona is to immediately forfeit the entire game. Call it self-delusion if you will, but I think it is actually good and deliberate leadership, based on a knowledge of human nature.

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3. Xtrapairohands on June 1, 2010 11:17 AM writes...

I agree. Often we have little say in what programs we work on anyway. So when members of the team are constantly saying what a bad project this us or how none of the data makes sense or how nothing seems to be working it becomes much more difficult to stay engaged and focused. Particularly when those comments are coming from department heads and in a public venue.

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4. John on June 1, 2010 11:27 AM writes...

I don't know the whole history behind this area of research, but would suggest two caveats:

1) There is a problem of survivior bias. When you go after an "unsolvable" problem and solve it, you become famous. Everybody has heard of Kary Mullis. Does anybody remember the name of any of the tens of thousands of Medieval alchemists who tried to convert lead into gold?

2) Once a decision has been made to pursue a high risk / high reward project, irrational optimism may be a necessary emotional response to keep researchers fully intellectually engaged because of the cognitive dissonance problem. But this is different from concluding that irrational optimism is a good basis on which to choose projects to work on.

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5. Hap on June 1, 2010 12:14 PM writes...

In lots of fields, there's enough known that if someone proposes to turn lead into gold, you can guess that their irrational exuberance is either irrational or a con. In drug discovery, it's hard to tell that, because there's lots that no one knows, so when someone is irrationally exuberant, it's hard to tell insanity/evil from persistence in the face of adversity (because the presence of data would be the major way to distinguish those positions, or personal knowledge of the leader, though "you have to be trusted by the people you lie to", as Pink Floyd said.)

This sounds like a dream which can only be survived by staying asleep - if you awaken, you become confused and lost, and then dead, but if you stay asleep, you might get through it. Of course, we're supposed to stay awake, because most likely, the dream won't end well, and we want to live if it doesn't.

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6. Anonymous on June 1, 2010 12:27 PM writes...

I once read a very interesting (and scientifically grounded) book about the relative merits of optimisim and pessimism. It's called Learned Optimism by Martin Seligman. Here's a link:

http://www.amazon.com/Learned-Optimism-Change-Your-Mind/dp/0671019112


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7. John on June 1, 2010 12:53 PM writes...

The problem is that we don't yet have the tools to do the measurements to build the models to gain the insight to understand the problem.

Inheritance of acquired traits is a particularly good example, having gone from Lamarckian nonsense to proven epigenetics within two centuries.

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8. Formerlawyer on June 1, 2010 1:03 PM writes...

How does this play with "Impostor Syndrome"?

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9. processchemist on June 1, 2010 1:46 PM writes...

Speaking about pure science, optimism IMHO is not about denying truth, but about not running out of new models (possible solutions).
But in industrial research nobody has infinite time (and money) to try infinite solutions (and, in my line of work, the only thing really helping in dodging dead ends is experience).

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10. RandDChemist on June 1, 2010 1:59 PM writes...

Who's Kary Mullis?

http://en.wikipedia.org/wiki/Kary_Mullis

Interesting, and a nice debate initiator.

Drug discovery and development is a messy business. An infinite amount of resources and/or time will not guarantee success.

A mentor of mine once stated that it was easy to talk yourself out of an experiment. Very true.

Irrational optimism is important, but it must not ignore facts either.

How does one avoid being unreasonably bound by convention? Chasing an exception can be a fool's errand, but on occasion the fool is right.

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11. Brent Royal-Gordon on June 1, 2010 2:04 PM writes...

Perhaps "irrational optimism" is needed because the magnitude of the benefits is difficult to wrap your mind around otherwise. Scientists are, presumably, much better than most people at scaling their mental perceptions to very large or very small quantities, but it's possible that they still can't quite comprehend the billions of dollars, and the many lives saved or improved, a successful drug might be worth. In the context of that sort of potential gain, continuing through the odds a drug development project faces is a perfectly rational decision--but if they cannot conceive of the scale of the payoff, they must instead delude themselves about the chances of getting it in order to arrive at a correct risk-benefit ratio, and thus make a rational decision.

Hmm, this sounds like something for behavioral economists, actually...

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12. HelicalZz on June 1, 2010 3:05 PM writes...

If you have not read some of the psychological research around optimism, it is very interesting stuff. Some is good, it can be learned (but not as easily as helplessness), but blind optimism is in all cases bad. So yeah .. balance .. which is never easy.

Martin Seligman's 'Learned Optimism' is a great read. His later works are a bit too self-helpish, but 'Learned Optimism' opens with the background research behind the theories (this being a 'show me the data, crowd', that should be appreciated).

Zz

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13. Idlehands on June 1, 2010 3:25 PM writes...

Re no.4
"1) There is a problem of survivior bias. When you go after an "unsolvable" problem and solve it, you become famous. Everybody has heard of Kary Mullis. Does anybody remember the name of any of the tens of thousands of Medieval alchemists who tried to convert lead into gold?"

Isaac Newton (although he wasn't medieval he was certainly an alchemist)

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14. Idlehands on June 1, 2010 3:26 PM writes...

Re no.4
"1) There is a problem of survivior bias. When you go after an "unsolvable" problem and solve it, you become famous. Everybody has heard of Kary Mullis. Does anybody remember the name of any of the tens of thousands of Medieval alchemists who tried to convert lead into gold?"

Isaac Newton (although he wasn't medieval he was certainly an alchemist)

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15. John on June 1, 2010 3:41 PM writes...

Ok, nice piece of trivia and badly phrased on my part. But if all he had tried to do was turn lead into gold, you wouldn't have heard of him.

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16. ex-Pfizerite on June 1, 2010 3:44 PM writes...

Now you see why the FDA requires statistical proof of safety and effectiveness rather than relying on anecdotal accounts of efficacy.

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17. thomas on June 1, 2010 4:19 PM writes...

"The truth shall make ye fret", surely.

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18. pete on June 1, 2010 4:57 PM writes...

"90% of this game is half-mental" - Y. Berra (paraphrased)

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19. cb on June 1, 2010 5:16 PM writes...

I think there are two mechanisms working.

1) There is always a high bar for overturning an existing hypothesis. It is not enough to knock the idea down, it must be replaced with a better model. Take the phylogiston hypothesis, it was an inaccurate model but it sort of kind of worked to explain things. It wasn't knocked down until the atomic theory and chemical changes that occur were fully understood.

2) In science the optimism is more a function of favorably interpreting weak statistics and large error bars. In many cases the outcome cant be reliably predicted until a sizable population or repeated trials are tested. In the drug industry this might not occur until phase III or beyond.

I agree with processchemist, from my vantage point the optimism is completely dependent upon being able to continually develop new hypotheses for explaining and testing the data.
When the new ideas run out pessimism enters.

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20. shazz on June 1, 2010 5:58 PM writes...

Surely a big factor in all this is the personal/professional consequences for failed experiments. Back in the golden age of science when most researchers were self funded members of the wealthy elite the consequences of a failed experiment were very low- just a missed chance to impress your buddies. Then when science was a secure profession with stable jobs, the consequence was just a missed chance to get some fame and maybe a step up the ladder.

Now academic research is a tightrope walk with no net, and a short run of failed projects spells the end of your publishing and funding pipeline. Industry research is also under enormous pressure to get profitable results no matter what.

The result is that science shrinks back into tepid incrementalism. No one is in a position any more to take enormous risks and take on truly innovative approaches.

Why do that and risk everything when you can just crystallise another kinase and churn out a mid level paper?

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21. UKRAIN on June 1, 2010 10:58 PM writes...

For self delusion see:

http://www.ukrin.com/

Even better - read the prep in the patent!

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22. Cartesian on June 2, 2010 4:14 AM writes...

This is true that some persons do not want to accept to be wrong or to not be as good as they think; and this is a great problem for somebody like me who has some good theories which have not been refuted after several years of existence, but which are not going with the ambitions of some persons (this especially in France because I am known their for a longer time).

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23. Anonymous on June 2, 2010 6:13 AM writes...

"And that brings up a phrase that I use often, that it's easy to sit in the back of a conference room and tell people that their ideas aren't going to work. And you're right well over 90% of the time if you do that, but to what end?"

If letting everyone run their half-baked crazy ideas had no price tag attached then this would be fine. But I'm afraid it all does cost money.

And while productivity is the industry's biggest bugbear, I can't help feeling that it isn't down to a lack of ideas, rather a surplus of really stupid ones. Every manager I've ever worked with has felt compelled to embrace new technologies, invent new paradigms and (god help us) six sigma our processes tp new levels of turnover. And in the interim the sheer number of reports and networking sessions I have to attend to get approval for my plans has mushroomed out of control. So why is it that in the old days when my team made a compound it was usually tested in the target assay within 24 hours, often on the same day. Now I'd be lucky for it to make it through the centralised compound collection and collective screening service in a week. It may be more efficient but it's a lot less productive.

Along the way we seem to have lost the understanding that hard graft, carefully designed compounds and a good biological rationale usually win out.

So I think I will continue to dispense some hard-earned truth as long as I can continue !

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24. Free Radical on June 2, 2010 6:53 AM writes...

Hmmm... I agree with shazz, that negative consequences result in a drive toward incrementalism, but certainly Anon 22 is also correct that resources will be forever limited.

Its interesting to me that amongst all the optimism/pessimism debate no one tries to take a 3rd option that more dispassionate. After being pretty depressed in grad school (incompleted naty P synthesis), I really tried to tell myself that a result was just a result, not a reflection on me, or my character, and not something to get depressed, OR excited about. It kind of helped, but it is hard to do that all the time.

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26. Sili on June 4, 2010 5:59 AM writes...

Everybody has heard of Kary Mullis.
::googles "Kary Mullis"::

Ah. I see there's a reason I've happily forgotten that name. I wonder if there's something in the water in Oslo to make chemists who win the Nobel nuts.

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27. Morten G on June 8, 2010 10:17 PM writes...

"I wonder if there's something in the water in Oslo to make chemists who win the Nobel nuts."

He got the peace prize too?

Looking at his Wikipedia page he is probably more likely to have put something in the water. He reminds me a bit of Marvel/DC supervillains actually.

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28. Morten G on June 8, 2010 10:27 PM writes...

Back on subject: If you are optimistic and the project fails you say "Okay, but what's the good news" while if you are a pessimist you go "Told you so".

So when Isaac Newton went into his imaginary boss' office Isaac went "I failed completely to turn lead into gold. Even though they are both heavy and metal and it should have been a sure thing". And then his optimistic imaginary boss went "Well, it seems to me that you've developed differential equations and a working theory of how gravity works that explains the motion of the Sun and the Earth and the Moon. Let's see if we can't get a semi-good publication out of that".

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