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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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August 27, 2012

Chemistry's Mute Black Swans

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Posted by Derek

What's a Black Swan Event in chemistry? Longtime industrial chemist Bill Nugent has a very interesting article in Angewandte Chemie with that theme, and it's well worth a look. He details several examples of things that all organic chemists thought they knew that turned out not to be so, and traces the counterexamples back to their first appearances in the literature. For example, the idea that gold (and gold complexes) were uninteresting catalysts:

I completed my graduate studies with Prof. Jay Kochi at Indiana University in 1976. Although research for my thesis focused on organomercury chemistry, there was an active program on organogold chemistry, and our perspective was typical for its time. Gold was regarded as a lethargic and overweight version of catalytically interesting copper. More- over, in the presence of water, gold(I) complexes have a nasty tendency to disproportionate to gold(III) and colloidal gold(0). Gold, it was thought, could provide insight into the workings of copper catalysis but was simply too inert to serve as a useful catalyst itself. Yet, during the decade after I completed my Ph.D. in 1976 there were tantalizing hints in the literature that this was not the case.

One of these was a high-temperature rearrangement reported in 1976, and there was a 1983 report on gold-catalyzed oxidation of sulfides to sulfoxides. Neither of these got much attention, as the Nugent's own chart of the literature on the subject shows. (I don't pay much attention when someone oxidizes a sulfide, myself). Apparently, though, a few people had reason to know that something was going on:

However, analytical chemists in the gold-mining industry have long harnessed the ability of gold to catalyze the oxidation of certain organic dyes as a means of assaying ore samples. At least one of these reports actually predates the (1983) Natile publication. Significantly, it could be shown that other precious metals do not catalyze the same reactions, the assays are specific for gold. It is safe to say that the synthetic community was not familiar with this report.

I'll bet not. It wasn't until 1998 that a paper appeared that really got people interested, and you can see the effect on that chart. Nugent has a number of other similar examples of chemistry that appeared years before its potential was recognized. Pd-catalyzed C-N bond formation, monodentate asymmetric hydrogenation catalysts, the use of olefin metathesis in organic synthesis, non-aqueous enzyme chemistry, and many others.

So where do the black swans come into all this? Those familiar with Nasim Taleb's book
will recognize the reference.

The phrase “Black Swan event” comes from the writings of the statistician and philosopher Nassim Nicholas Taleb. The term derives from a Latin metaphor that for many centuries simply meant something that does not exist. But also implicit in the phrase is the vulnerability of any system of thought to conflicting data. The phrase's underlying logic could be undone by the observation of a single black swan.

In 1697, the Dutch explorer Willem de Vlamingh discovered black swans on the Swan River in Western Australia. Not surprisingly, the phrase underwent a metamorphosis and came to mean a perceived impossibility that might later be disproven. It is in this sense that Taleb employs it. In his view: “What we call here a Black Swan (and capitalize it) is an event with the following three attributes. First, it is an outlier, as it lies outside the realm of regular expectations, because nothing in the past can convincingly point to its possibility. Second, it carries an extreme impact. Third, in spite of its outlier status, human nature makes us concoct an explanation for its occurrence after the fact, making it explainable and predictable.”

Taleb has documented this last point about human nature through historical and psychological evidence. His ideas remain controversial but seem to make a great deal of sense when one attempts to understand the lengthy interludes between the literature antecedents and the disruptive breakthroughs shown. . .At the very least, his ideas represent a heads up as to how we read and mentally process the chemical literature.

I have no doubt that unwarranted assumptions persist in the conventional wisdom of organic synthesis. (Indeed, to believe otherwise would suggest that disruptive break- throughs will no longer occur in the future.) The goal, it would seem, is to recognize such assumptions for what they are and to minimize the time lag between the appearance of Black Swans and the breakthroughs that follow.

One difference between Nugent's examples and Taleb's is the "extreme impact" part. I think that Taleb has in mind events in the financial industry like the real estate collapse of 2007-2008 (recommended reading here
), or the currency events that led to the wipeout of Long-Term Capital Management in 1998. The scientific literature works differently. As this paper shows, big events in organic chemistry don't come on as sudden, unexpected waves that sweep everything before them. Our swans are mute. They slip into the water so quietly that no one notices them for years, and they're often small enough that people mistake them for some other bird entirely. Thus the time lag.

How to shorten that? It'll be hard, because a lot of the dark-colored birds you see in the scientific literature aren't amazing black swans; they're crows and grackles. (And closer inspection shows that some of them are engaged in such unusual swan-like behavior because they're floating inertly on their sides). The sheer size of the literature now is another problem - interesting outliers are carried along in a flood tide of stuff that's not quite so interesting. (This paper mentions that very problem, along with a recommendation to still try to browse the literature - rather than only doing targeted searches - because otherwise you'll never see any oddities at all).

Then there's the way that we deal with such things even when we do encounter them. Nugent's recommendation is to think hard about whether you really know as much as you think you do when you try to rationalize away some odd report. (And rationalizing them away is the usual reponse). The conventional wisdom may not be as solid as it appears; you can probably put your foot through it in numerous places with a well-aimed kick. As the paper puts it: "Ultimately, the fact that something has never been done is the flimsiest of evidence that it cannot be done."

That's worth thinking about in terms of medicinal chemistry, as well as organic synthesis. Look, for example, at Rule-Of-Five type criteria. We've had a lot of discussions about these around here (those links are just some of the more recent ones), and I'll freely admit that I've been more in the camp that says "Time and money are fleeting, bias your work towards friendly chemical space". But it's for sure that there are compounds that break all kinds of rules and still work. Maybe more time and money should go into figuring out what it is about those drugs, and whether there are any general lessons we can learn about how to break the rules wisely. It's not that work in this area hasn't been done, but we still have a poor understanding of what's going on.

Comments (16) + TrackBacks (0) | Category: Chemical News | Drug Industry History | The Scientific Literature | Who Discovers and Why


1. CMCguy on August 27, 2012 10:32 AM writes...

On of your most excellent posts Derek, Thanks

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2. luysii on August 27, 2012 11:21 AM writes...

Paradigms shift more quickly in molecular biology. For instance, a whole new mechanism of protein evolution has been found recently [ Cell vol. 150 pp. 671 - 672, 831 - 841 '12 ]. It works by by expanding the part of the genome coding for a given protein, and letting natural selection work its magic on the multiple copies of the gene, rather than just one.

The work was done in the vaccinia virus, which expands its DNA coding for one particular protein (called K3L) when it is under assault by the cellular protein PKR. Initially this helps survival by just making more K3L, but then a mutation in one of the K3L genes occurs which makes it more resistant to PKR. This is n-fold more likely to happen with n copies of the gene than with just one. Remember poxviruses have very large genomes for viruses.

The truly intriguing thing about the process, is that once the mutation occurs producing increased resistance, the expansion collapses (like an accordion), leaving no trace (which is why no one had a clue to its existence till now).

Just how often this happens in evolution is, of course, unknown at this time (because no one has looked). But it's definitely a paradigm shifter.

For more on this please see It even contains an accordion joke

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3. milkshake on August 27, 2012 12:00 PM writes...

regarding rule of 5: It is instructive to look where it is not applicable - beta lactam and macrolide antibiotics (they do not need to be human cell permeable) and the instances where is more than applicable - in CNS drugs, its rather like rule of 3

In chemistry it is rarely a single "black swan" event, rather more like gradual accumulation of odd pieces until somebody smart enough to pay attention and following the(unpopular)sub-field will produce a breakthrough result

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4. justin on August 27, 2012 12:48 PM writes...

It may be that a hole in the literature is due to poor or no results or inherent unrepeatability (since that means the work is unpublishable) rather than lack of exploration or experimentation. Unless there is some way of reporting "tried this and it didn't work" it is going to be difficult to tell "never been done" from "plenty of wasted effort and nothing to publish"

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5. g0pr on August 27, 2012 12:58 PM writes...

Great post, Derek. And thanks for pointing at an excellent article by William Nugent. Thoroughly enjoyed that article. Articles such as this energize me, who's been otherwise depressed and even resentful (career-wise). A phenomenon not too uncommon these days among many un(der) employed (med)chemists!

Anyhow, synthetic chemists have been very traditional and sort of slow for paradigm shifts. While Nugent's article focussed on chemical reactions, there are paradigm shifts in the tools we use have helped us in advancing our research tremendously. One example, I can think of is flash column chromatography. In those days, gravity columns used to be the rule and that slow dripping was thought to be important for better purification. And that elegant short paper by Mitra and Still changed everything - one of the most cited papers in chemical literature.. Of course, it is even better these days with automated purification systems such as CombiFlash, etc... Thanks again.

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6. Good Day on August 27, 2012 1:33 PM writes...

Interesting you mentioned Medicinal Chemistry, Derek, as Pharma increasingly seems to be doing all it can to actively preclude Black Swan events.
De Vlamingh had to journey to the very edge of the known world to discover his. In contrast, the past decade has seen medicinal chemists methodically labelling larger and larger regions of physicochemical space with "here there be dragons".
Is there a word for the reverse of exploration?

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7. Clinicalpharmacologist on August 27, 2012 5:24 PM writes...

Exploration is still the correct word. The problem is that the pharma biz has abandoned exploration and settled for the unadventurous building of unproductive cities on the plains.

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8. Process researcher on August 27, 2012 9:11 PM writes...

Excellent discussion, Derek. Hope to see many more such topics from you. Thanks for bringing it up.

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9. Shane Telfer on August 27, 2012 9:41 PM writes...

Superb post Derek. There is much fertile territory to be explored by those who recognise Black Swans early on. The work of Daniel Kahnmen is relevant here, especially the concept of theory-induced blindness. To quote from his brilliant book Thinking, Fast and Slow,

"Once you have accepted a theory and used it as a tool in your thinking, it is extraordinarily difficult to notice its flaws. If you come upon an observation that does not seem to fit the model, you assume that there must be a perfectly good explanation that you are somehow missing. You give the theory the benefit of the doubt, trusting the community of experts who have accepted it."
So perhaps there's a lead for chemists (that many intuitively follow anyway): solid, reproducible observations that go against the grain of established thinking may be the most fruitful. In my field of inorganic chemistry, I have a treasured quote from Richard Robson who said that the expected outcome from his early experiments was "miserable, ill-defined, amorphous precipitates, difficult or impossible to characterise." In fact, he produced beautiful crystalline coordination polymers, which are the forerunners to metal-organic frameworks.

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10. drug_hunter on August 27, 2012 10:02 PM writes...

I may be off the reservation on this, but I think that until we can model phenomena at the atomic level we will only be able to achieve a limited degree of understanding of properties. Statistical ("QSASR") methods will only get us so far. "Rule-breaker" compounds (cyclosporin is the poster child but look at HCV NS5A inhibitors!) must be successfully avoiding whatever pitfalls derail most big ugly compounds. It has to be because of some very precise atom-level details. So we may be waiting a long time before such things are completely clear.

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11. luysii on August 28, 2012 10:01 AM writes...

I dunno. Back in grad school, we focused on things that didn't fit with current models, as that was where future fame and fortune lay. That's why I found going through Anslyn and Dougherty so depressing. All the stuff we were speculating about back in '60 - '62 seems pretty well worked out and understood. I don't see why a young chemist would go into physical organic. The field seems to have been plowed to a fairtheewell.

That's not to say that the understanding physOrg has given us is to be dismissed, or not used, because it's incredibly clever and very useful in figuring out mechanisms.

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12. Curious Wavefunction on August 28, 2012 4:33 PM writes...

drug_hunter 10: I concur. We have made some headway into understanding the behavior of non-Ro5 compounds. One of the most common strategies for compounds like cyclosporin is to hide their hydrogen bonding groups through intramolecular hydrogen bonds to allow them to get through greasy membranes. And then there's all the myriad transporter and efflux proteins which dictate drug entry; as you rightly indicate, we are barely starting to make a dent in understand the atomic-level details of these.

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13. Jon on August 28, 2012 9:38 PM writes...

Dr. Isaac Asimov wrote that "The most common word or phrase preceding a great scientific discovery is not 'Eureka!' but rather 'That's strange.'" (paraphrased)

If necessary, I could dig up chapter and verse.

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14. Jon on August 28, 2012 9:39 PM writes...

Dr. Isaac Asimov wrote that "The most common word or phrase preceding a great scientific discovery is not 'Eureka!' but rather 'That's strange.'" (paraphrased)

If necessary, I could dig up chapter and verse.

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15. Dan Eustace on August 31, 2012 9:23 AM writes...

Hi Derek,

While your story is interesting in its telling a story of discovery, isn't the world more complex and less simple cause and effect as 'milkshake' (3 above describes)?

Please let me pose another considerations-
by Partnoy in his book "Wait" who wrote:
'quoting Sternberg: “ the essence of intelligence would seem to be in knowing when to think and act quickly, and knowing when to think and act slowly.”
The most insightful writing about decision making has addressed delay indirectly by focusing on how humans deal with uncertainty about the future….
“there is a tendency in our planning to confuse the unfamiliar with the improbable. The contingency we have not considered seriously looks strange; what looks strange is thought impossible; what is improbable need not be considered seriously.
These unconsidered contingencies are
unknown unknowns Rumsfeld
Unquantifable uncertainty Frank Knight
Black swans Nassim Taleb'

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16. molecularsimpleton on September 3, 2012 5:10 AM writes...

Dan's post on this is a very important reminder of the difference between unfamiliar and improbable. By all means explore the unfamiliar as a truly unknown known but do not ignore what knowledge there is which might be pointing to some insights of relevance - this is the improbability access. If you ignore this then it becomes an unknown known (an option which Rumsfeld ignored in his infamous saying). Unknown knowns are those things that are known but have been forgotten or ignored. So if you do decide to go off piste in physchem space be warned - there really are dragons out there!! And off course there are plenty of them in the sweet spot too, but the knowledge that has been gained - at considerable expense to the pharma industry (and patients) - indicates strongly that there are more dragons per journey outside than inside!

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