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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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« Controversial Scaffold Is Right | Main | A New Diels-Alder »

October 15, 2012

There Will Be No More Woodwards

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Posted by Derek

Explaining R. B. Woodward to a non-chemist, via jazz. And they were probably right, too. But that brings up an interesting question, one that applies to organic synthesis as well as every other human activity. At what point does a field become incapable of supporting Titans?

Consider organic chemistry. There were many major discoveries that had to be made before we (as a civilization) even understood what was going on. Atomic theory itself, valences, tetrahedral carbons, spectroscopy: without these and similar foundational work, you're not going to get very far. But at some point you've got enough material for the next genius to come along and make the most out of it, and I'd put Woodward in that category. He had just enough tools to make his work barely possible, and he had to invent quite a few more along the way. This gave him plenty of room to demonstrate just how good he was at organic synthesis. Complex molecules that would have been beyond structural determination in years past were now there (in theory) for the taking, but these were still well out of reach for all but the most inspired.

To switch fields of achievement, I recall reading someone's opinion once that Bach wasn't all that good, all things considered. I didn't care for that when I saw it (I like Bach very much), but the argument was that he got there "firstest with the mostest", as they said in the Gold Rush, and did such a thorough job on the musical styles of his day (counterpoint, the fugue form, etc.) that no one could ever stand on his level again. You couldn't, because Bach had already Been There and Composed That. Now, that undermines the author's original point, I think, because only a musical genius could have covered so much ground so well, but his second point stands: once Bach had done it, it was done. Anyone who composes a theme-and-variations in contrapuntal style will be compared to him, and probably unfavorably.

Similar arguments can be made across the arts and sciences. But the sciences have the advantage of not being subject so much to the whims of fashion. Picasso, I've long thought, helped create the art world in which he would be considered a great painter. (It reminds me of the way that successful organisms set up a positive feedback loop with their environment, helping to induce the conditions in which they can thrive). There are catastrophic events in both ecologies, of course, that change the requirements of fitness - Burne-Jones (to pick one example) went so far out of fashion by the 1950s and 60s that people were throwing his paintings away with the trash. But the art world has set itself up with fashion as part of its motor. Styles of painting come and go, because styles of painting have to come and go. But Newton's discoveries stand right where they were when he made them - si monumentum requiris, circumspice. Newtonian mechanics do not go out of fashion.

The only thing that can be done to alter great scientific discoveries of the past is to show how they fit into previously-unrealized larger contexts (as Einstein did with Newton). That, naturally, tends to get harder and harder as time goes on. Once the brush is cleared in science, it tends to stay cleared. That process can uncover new problems, but those are the tougher ones. This line of thought brings on talk of the End Of Science, as John Horgan put it, with which you may contrast Vannevar Bush's "Endless Frontier" (which helped establish the modern funding system for academic science in the US. My own take is that the frontier is endless for practical purposes for the foreseeable future, but not similarly endless in every direction at once.

There will, I'd say, never be another R.B. Woodward. Heraclitus aside, we have stepped into that river already, and crossed it. That's not to say that there are not great challenges in synthetic organic chemistry - there are - but it means that there is much less scope for a sky-filling fireworks display like Woodward's career. Anyone trying to recapitulate it is wasting time and effort that could be better applied.

Update: Wavefunction has thoughts on the issue here.

Comments (32) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Nick K on October 15, 2012 8:56 AM writes...

There will never be another Woodward, mainly because Organic Chemistry has been ploughed over too many times by too many people. We're running out of things to explore.

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2. Electrochemist on October 15, 2012 8:56 AM writes...

Another great piece, Derek, and one that fits together nicely with your thoughts on the recent Chemistry Nobel.

The next Woodward might in fact be a "chemical biologist." Woodward could in some ways be the Newton to the next Einstein.

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3. Jose on October 15, 2012 9:08 AM writes...

Absolutely true, and well put; who can have two Nobels, with a strong claim to a third (ferrocene)?

That said, I think Baran is the only one whose work is most assuredly in the breathtaking category.

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4. Jerry on October 15, 2012 9:18 AM writes...

Constructing large complex molecules (antibodies) in an effective manner that will allow SAR will uncover a whole new frontier that will require a Woodward like figure with a similar feedback loop environment.

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5. Synthetic Biology on October 15, 2012 9:19 AM writes...

Constructing large complex molecules (antibodies) in an effective manner that will allow SAR will uncover a whole new frontier that will require a Woodward like figure with a similar feedback loop environment.

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6. Anonymous on October 15, 2012 9:19 AM writes...

@3

Fred Sanger?

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7. Synthetic Biology on October 15, 2012 9:21 AM writes...

Respectfully Disagree. Constructing large complex molecules (antibodies) in an effective manner that will allow SAR will uncover a whole new frontier that will require a Woodward like figure with a similar feedback loop environment. We have a long way to go before closing the patent office.

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8. Helical_Investor on October 15, 2012 9:23 AM writes...

I'd tend to agree. Sure, there will be great chemists, as there are current great trumpet players, but there is always a time and place for an art form and/or a scientific discipline to have a convergence where the learnings of the past combine with newer tools (spectroscopy & publishing or radio & albums) and result in a period of exponential achievement. We are still seeing 'greats' in Biology, though here too the pace may be slowing. If you want to see where the next 'greats' will emerge, perhaps this cartoon will help.

http://xkcd.com/435/

The greats in math predate the greats of physics and the greats of chemistry & biology. We are seeing now the 'fields of lower purity' build on the works in the others to begin their own renaissance periods.

Aside: For the scientists here, please listen to this chopped short (4 min)TED talk as well. Effective communication is of course the way to spread greatness.
http://www.ted.com/talks/melissa_marshall_talk_nerdy_to_me.html

Zz

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9. Curious Wavefunction on October 15, 2012 9:38 AM writes...

Well said Derek. The question to ask is whether the general problem has been solved. And the answer for organic synthesis is yes. Your post provoked some thoughts on my own blog.

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10. Brett on October 15, 2012 10:14 AM writes...

My own take is that the frontier is endless for practical purposes for the foreseeable future, but not similarly endless in every direction at once.

Agreed. You can be grateful that you don't have a bar as high as the one that experimental particle physicists have to jump - yet (although you do need expensive trials).

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11. See Arr Oh on October 15, 2012 10:34 AM writes...

Wow, jazz influences on organic synthesis must have been the theme of the weekend!

My own humble contribution:
http://justlikecooking.blogspot.com/2012/10/the-chemical-real-book.html

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12. Brandon on October 15, 2012 10:35 AM writes...

I agree that titans can only really stand at the forefront of a new field, since that's where the bulk of great research can be performed. But you're kinda closing things off if you think that means there can never be another Woodward. Like Einstein, the next titan will just have to pivot the field, directing things in a new, unexplored path.

Presentism makes all of yesterday's problems seem easy and tomorrow's beyond our abilities. The key is to realize that Woodward's greatest achievements weren't static, 'built this molecule' victories. His success was expanding a small field into a large one.

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13. MTK on October 15, 2012 11:06 AM writes...

@2,

"The next Woodward might in fact be a 'chemical biologist.'"

Except that Woodward was a chemical biologist too, as I recall, or at least a biochemist.

I don't know or recall all the details, but I remember a biochemistry class within the biology dept. where we were going over the shikimic acid pathway. The prof mentioned how the one part of the pathway had been the object of much scientific study over the years and no one had come up with a suitable solution. When one of the leading researchers in the area came and gave a seminar at Harvard Woodward attended it and during the Q and A proposed the mechanism and pathway which later turned out to be correct.

It was unclear to me whether RBW just happened to think of it on the spot or whether he had worked it out in advance and "just happened" to attend the seminar. Regardless the general tone of the professor was that they were all astounded by his genius such that he could step into such a studied area tangential to his field of expertise and so quickly solve the problem.

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14. newnickname on October 15, 2012 12:00 PM writes...

@12: "When one of the leading researchers in the area came and gave a seminar at Harvard Woodward attended it and during the Q and A proposed the mechanism and pathway which later turned out to be correct."

Another story, I believe told by Konrad Bloch himself, is that when he visited Harvard (from Chicago) to discuss his steroid biosynthesis work, he met with RBW in his office. RBW proceeded with something like, "THIS must be the biosynthetic steroid pathway and here are the experiments we need to do to prove it." Block moved to Harvard, RBW's insights were mostly correct, Bloch won a Nobel (no share for RBW?) and the rest is history. (In an early paper ("The Staling of Coffee"), RBW commented on a C30 hydrocarbon [not identified; could it be squalene?] that decreases over time as the steroid components increase.)

As told to me by those who were there, RBW was strongly geared towards "modern" chemical bio in his final years and would done more along those lines ... except that he died in 1979.

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15. luysii on October 15, 2012 12:39 PM writes...

There's certainly room for another Woodward in protein chemistry (and protein biophysics). Protein functional groups certainly aren't fancy to an organic chemist, although some of the cofactors certainly are (particularly FeMo in nitrogenase which contains a hexacoordinated carbon { Science vol. 337 pp. 1672 - 1675 '12 } ). Why the side chains don't react with each other isn't entirely clear. There is a salt bridge in the 7 transmembrane G protein coupled receptors (GPCRs) between an acid and amine -- why not an ester?

Consider that tool of cell biologists -- green fluorescent protein -- the fluorophore is formed by reactions among the side chains -- see http://luysii.wordpress.com/2009/09/25/are-biochemists-looking-under-the-lamppost/. Why doesn't this happen all the time?

Or consider hemoglobin, which has been studied out the gazoo for half a century with the most sophisticated weapons in our arsenal. If we really understood it, we'd have a small molecule inhibitor to prevent hemoglobin S from sickling -- but we don't. See http://luysii.wordpress.com/2009/11/09/some-humility-is-in-order/

Then there's the whole issue of why proteins appear to adopt only a few of the myriad conformations available to them. This is swept under the rug by the 'concepts' of the energy funnel/landscape, which (to me) seems to explain the phenomenon by describing it in other words.

The list goes on

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16. Rhodium on October 15, 2012 1:02 PM writes...

I think there are two aspects of RBW that combined to make him dominate. One was his showmanship. Every appearance was an event and his life story was operatic. If you want to compare him to musicians, a reasonable comparison would be to Mozart, also a child prodigy. He told the story that he came up with the Diels-Alder reaction independently, as a teenager, by considering the resonance forms of benzene without the sigma framework. Perhaps what is really remarkable is that those who knew him believed that story. Even his cologne drew attention to himself. You could tell he had walked down the hall 10 minutes before due to the quantity he used.

He did have remarkable high standards for himself, and that may have gotten to him in the end. The only time I talked to him (except for the first year graduate student: what project do you want? talk) was at a department dinner welcoming back alumni where Kistiakowsky (I think) gave an after dinner talk "Better Living Without Chemistry?" RBW, quite drunk, heckled the speaker, acting as if the thesis of the title were being defended. Eventually a few of the faculty wives got him to shut up. Later a postdoc and I found him and partially propped him up while we rambled on, speaking words of hero worship. At one point he said, "Well, sometimes I do not have a very good opinion of myself" and that has always stuck with me. I wonder if he really met the goals he had for himself.

The other aspect of RBW (besides his intelligence) was his command of the basics of the field. It seems he understood the interplay of nucleophilicity, sterics, kinetics, orbitals, etc. better and earlier than anyone else. He also knew what the field needed in terms of technology and he made sure that everyone ended up using spectroscopy and HPLC (essentially nobody knew about HPLC until RBW's Boston IUPAC talk on separating B12 intermediates). I think his prejudice against using enzymes in synthesis was based upon not trusting things he could not understand at the molecular level.
Personally I do not want to bet against human cleverness. If a field has enough supporting experimental results and background physics, someone really good at pattern recognition and synthesis (in the philosophical sense) could be another RBW. Perhaps in nano science, perhaps in drug development (although I think we don't have enough supporting cell biology there) perhaps even in organic synthesis since not all his syntheses were optimal (look at his PG work for example or his efforts at high temperature superconductors).

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17. Curious Wavefunction on October 15, 2012 1:06 PM writes...

@14: there's also evidence that RBW was working on organic superconductors and electronics during his last years.
http://www.roaldhoffmann.com/sites/all/files/1-s2.0-S0040402011006582-main.pdf

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18. Curious Wavefunction on October 15, 2012 2:52 PM writes...

luysii 15: There's certainly a lot of things we still have to understand about protein chemistry. But the answers to those questions are going to come as much from new experimental techniques and instrumentation as from conceptual advances. It seems very hard to imagine how one person could supply all that knowledge. Protein folding is a good example of a field where understanding has come from multiple quarters, from several groups, and from both theory and experiment. I see a greater Woodwardian role for someone in neuroscience where it would be great to have a real theory of the brain that encompasses the different levels of hierarchy.

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19. Synthetic Biology on October 15, 2012 3:08 PM writes...

Respectfully Disagree. Constructing large complex molecules (eg antibodies) in an effective manner that will allow SAR will uncover a whole new frontier that will require a Woodward like figure with a similar feedback loop environment. We have a long way to go before closing the patent office.

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20. Hap on October 15, 2012 3:52 PM writes...

I think it's probably arrogant to assume that no one can come along to do better - considering the amount of things that it is difficult or impossible to make, much less make on useful scale, plenty of others that require lots of guessing to do well, and still others that aren't reproducible, there's plenty of room for someone to change how we do things. Peptide synthesis, the paragon of automated synthesis, still seems to require eight million methods (protecting groups/coupling reagents/deprotection methods) to work, and still fails for lots of peptides. I don't know if there's room for a foundational insight to change synthetic methods, but it seems like there's too much we don't know and can't do to rule one out.

I think the problem we have (and it's not just true of synthesis, but of lots of research) is that it takes a lot of mediocre work to get that one diamond, and we seem unwilling to pay that price. We keep hoping that someone else will do the grunt work, and that we can magically pick the diamond from the pile, despite that not having been the intellectual history of...well, anything. We keep hoping that we can make every at bat end in a home run so that it doesn't take so long (or so much money) to win - unfortunately, most players that do that (and the teams that pay them) end up doing poorly.

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21. luysii on October 15, 2012 4:03 PM writes...

The advance in understanding proteins will simply have to be conceptual. That's what we call genius anyway. We just can't make that many proteins to see what happens in all cases, even though we can pretty much make any one we wish.

The number of proteins we could make one molecule of is remarkably low considering how many possibilities there are. See -- http://luysii.wordpress.com/2009/12/20/how-many-proteins-can-be-made-using-the-entire-earth-mass-to-do-so/

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22. SMP on October 15, 2012 9:22 PM writes...

When will the Woodward of medicinal chemistry come? Or has one arrived already? The challenge of making any molecule seems to he met but what about making a drug.

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23. SMP on October 15, 2012 9:23 PM writes...

When will the Woodward of medicinal chemistry come? Or has one arrived already? The challenge of making any molecule seems to he met but what about making a drug.

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24. Matt on October 15, 2012 9:41 PM writes...

"If my efforts have led to greater success than usual, this is due, I believe, to the fact that during my wanderings in the field of medicine, I have strayed onto paths where the gold was still lying by the wayside. It takes a little luck to be able to distinguish gold from dross, but that is all."

-- Robert Koch (1908)


Much harder to put together, and less memorable, but hilarious and still strangely applicable is this quote (on the discovery/proof of the connection between microbes and a disease):

"It is safe to say that the little pamphlet which was left to find its way through the slow mails to the English scientist outweighed in importance and interest for the human race all the press dispatches which have been flashed under the channel since the delivery of the address—March 24. The rapid growth of the Continental capitals, the movements of princely noodles and fat, vulgar Duchesses, the debates in the Servian Skupschina, and the progress or receding of sundry royal gouts are given to the wings of lightning; a lumbering mail-coach is swift enough for the news of one of the great scientific discoveries of the age. Similarly, the gifted gentlemen who daily sift out for the American public the pith and kernel of the Old World's news; leave Dr. KOCH and his bacilli to chance it in the ocean mails, while they challenge the admiration of every gambler and jockey in this Republic by the fullness and accuracy of their cable reports of horse-races."

-- Robert Koch (quoted in the 3 May 1882 NYT)


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25. RB Woodweird on October 15, 2012 10:10 PM writes...

The Armstrong anecdote reminds me of the old one about Faulkner in Hollywood:

While hunting one day with director Howard Hawks and William Faulkner, the acclaimed actor Clark Gable asked Faulkner to enumerate the five best authors of the day. “Ernest Hemingway, Willa Cather, Thomas Mann, John Dos Passos,” Faulkner replied, “and myself”. “Oh”, Gable maliciously replied, “do you write for a living?” “Yes”, Faulkner retorted, “and what do you do?”

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26. Sisyphus on October 15, 2012 11:06 PM writes...

The next RBW will be someone who makes some sense out of the "system engineering" that is blueprinted by the human genome; He will not be a chemist, but will probably be a mathematician or engineer; 10 years on and we still cannot make much sense of it. Another area is the biochemical connection between chemical reactions that occur in the brain and sentience.

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27. Anonymous on October 16, 2012 6:39 AM writes...

I am of the belief that much of RBW's early success was due to crystals. In his early papers (quinine; strychnine; etc.) the vast majority of compounds were purified by crystallization (before chromatography was widely adopted or useful), often as salts, sometimes as more than one derivative. While others tried to compete with RBW in synthesis by converting one pile of goo into another (garbage in, garbage out), RBW's students were encouraged to "keep scratching". ("Keep scratching" quote, as told to me by an RBW alum.)

RBW even named his daughter Crystal.

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28. Curious Wavefunction on October 16, 2012 8:42 AM writes...

@21: I think it's a disservice to all those outstanding experimentalists to think that genius can only be conceptual. In fact Freeman Dyson has a longstanding thesis that the major scientific revolutions are really driven by new experimental techniques rather than new ideas. Chemistry with its NMR and x-ray diffraction is a resounding case in point.

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29. skatesailor on October 16, 2012 11:01 AM writes...

@ 16, Rhodium:

On many occasions during 3 1/2 years, and for hours at a time, I sat with RBW and other chemists at his 6-foot-in-diameter conference table. I never knew him to wear any noticeable amount of cologne.

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30. Trulla on October 16, 2012 2:44 PM writes...

"... there is much less scope for a sky-filling fireworks display like Woodward's career. Anyone trying to recapitulate it is wasting time and effort that could be better applied".

What a terrible indictment of modern synthetic chemistry. It feels like we have no ambition left.

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31. Anonymous on October 16, 2012 2:49 PM writes...

Chemistry is dead.......long live Chemistry!!

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32. Mark Fortner on October 31, 2012 11:03 PM writes...

I believe your "firstest with the mostest" quotation actually belongs to Confederate general Nathan Bedford Forrest.

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