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Note on the cultish status of organic synthesis: Part 1

When I was in graduate school, a friend and I used to joke that the most egotistical elitists are to be predominantly found in two fields: particle physics and the total synthesis of complex organic molecules. As with most jokes and exaggerations, this one had a shred of truth in it. We had read about the hubris arising from a belief in strict reductionism to be found among particle physicists, and we had heard of similar hubris arising from a sense of mastery over nature found among synthetic organic chemists. What physicist has not heard Paul Dirac's quote that quantum mechanics would explain "all of chemistry", and what organic chemist does not like to gossip about slave-driving synthetic chemists who think they are doing other chemists a favor by contributing to what they have proclaimed to be the highest calling in their field? There is little doubt that more than many other branches of chemistry, organic chemistry and synthesis in particular enjoy (or is it suffer from?) a cultish status.

More recently, a few comments on the "greatest chemists" post at The Skeptical Chymist again struck a chord. The writers of the post wondered whether "organic chemists are just a little insular and think that their bit of the chemistry kingdom is the only one that matters?". Another commenter reaffirmed this sentiment by saying that more than other fields of chemistry, "organic chemists have a culture of legend-making".

I agree with both these statements and I think there are three main reasons why organic synthesis has lent itself to cult-making. A major reason is the personalities, their exquisite language and metaphors, their harnessing of armies of graduate students and postdocs and the stories they loved to weave around their science. The second reason is simply the great practical utility of organic chemistry in improving the quality of life. The last and perhaps the most important reason is the continued perception of organic synthesis as the ultimate chemical science which has lifted the great veil of nature and allowed man to wrest Nature's deepest secrets from her; there is something stupendous in having a mere mortal synthesize chlorophyll from scratch. The three reasons are connected, but each brings a distinct flavor to the argument. In this post I will dwell on the perceived cult of personality in organic synthesis, and will leave the rest of the discussion for another post.

So let's talk about the personalities. At the outset let's make it clear that not all organic chemists revel in showmanship, and such generalizations can be flawed. There are of course dozens of brilliant chemists who are extremely unassuming, letting their colleagues put on the shows in papers and in lectures. Yet as we all know, belief depends as much on perception as on reality, and there is a very distinct feeling in the chemical community that synthetic organic chemists love to perform more than others.

Is this true? Well, more than most other chemists, organic chemists have surrounded themselves with stories reminiscent of tales of great human adventures, exploits, triumphs and follies. Myth-making has contributed somewhat uniquely to organic chemistry. Part of the myth-making and legend-building was engendered by a happy accident of history that inadvertently did some harm to the perception of the field- the name of this happy accident was Robert Burns Woodward. So much has been said about him that it's not worth repeating. But there was no comparable chemist in any field during his time, and as long as he lived, Woodward achieved feats that almost defied belief. It's hard to see how organic synthesis would have turned into a mythical endeavor had it not been for this singular man. Others like Corey, Djerassi, Danishefsky, Nicolaou etc. simply carried on the tradition. Harvard became the mecca of organic synthesis, and Woodward and Corey's laboratories turned into Plato's academies through which every budding intellectual in the field had to pass in order to get a stamp of respect. Even today it's remarkable how many top synthetic organic chemists in the world have trained with one of these masters. The students in turn have carried forward the legend-making and perpetuated the reputation of the field, like Homer's portraits of Hector, Achilles and the great wars they fought in.

A corollary to the legend-making is the language and the metaphors. Look up some of the most famous total synthesis papers and the authors make them sound less like synthesis and more like a combination of Tenzing and Hillary's conquest of Everest and Michelangelo's painting of the Sistine Chapel. For instance, a review on the synthesis of the CP molecules begins with stories and portraits of Thesus's pursuit of the fearsome Minotaur. Organic synthesis is portrayed as the ultimate art and adventure and organic chemists are intrepid explorers venturing into the unknown. There is no doubt that synthesis is an art and that synthetic chemists are explorers, but so are other scientists. In fact, protein crystallography probably lends itself to the mountain-climbing metaphor even more since crystallographers sometimes stake their entire careers on the relentless chase of a single structure. Yet it's organic synthesis and not other branches of chemistry which claims to be the epitome of art, science, adventure and determination. I suspect that is partly because unlike synthesis, crystallography is a more interdisciplinary activity that cannot be easily labeled as chemical.

Again, one has to inevitably partly blame Woodward. For instance, consider this masterpiece from his colchicine synthesis which makes us feel like we are reading not Woodward but Tolkien:

"Our investigation now entered a phase which was tinged with melancholy. Our isothiazole ring had served admirably in every anticipated capacity and some others as well...it had mobilised its special directive and reactive capacities dutifully, and had not once obtruded a willful and diverting reactivity of its own. Now it must discharge but one more responsibility- to permit itself gracefully to be dismantled, not to be used again until someone might see another opportunity to adopt so useful a companion on another synthetic adventure. And perform this final act of grace it did."

A more exquisite paean to a five-membered ring containing carbon, nitrogen and sulfur was never penned. No wonder synthesis acquired the status of a highly-refined art form. One wonders how the field would have been perceived had it not been for the flourishing phrases, the allusions to mountain-climbing and Greek classics and the romantic metaphors. Not everyone does this of course, but it seems to be widely prevalent among top synthetic chemists.

The power of personality also extends to power over other human beings, and this has always been a sensitive topic that has contributed to the field's reputation. In the latter half of the twentieth century, the ability to synthesize increasingly complex molecules translated to the need to amass armies of students and postdocs. Woodward's collaboration with Swiss master Albert Eschenmoser on the stunning synthesis of Vitamin-B12 is a telling example; the synthesis involved dozens of graduate students and postdocs in a kind of trans-Atlantic relay that spanned 12 years and almost a hundred steps. Who would not be swayed by such overarching ability to attract personnel, resources, time and funding? Other total synthesis chemists also typically command such a glut of labor. For a long time, organic synthesis was regarded as the ultimate character-building experience. Hard work is of course essential to success in any science, but organic synthesis seemed to require a particularly intense combination of the ability to constantly bounce back from failure and the cheerful stamina of a marathon runner. This is perhaps one of the reasons why total synthesis students in my department appeared darker and more self preoccupied than others, and it could also contribute to the perceived sense of hubris among synthetic chemists. But that is also one of the reasons why total synthesis students are highly sought-after in both academia and industry, not just for their technical abilities but for their doggedness.

Nonetheless, while synthetic activity continues to be regarded as a character-building experience, the reputation of synthetic chemists has suffered in recent years because of their reliance on cheap labor and the unusually harsh working hours that synthesis students have to endure. Synthetic chemists have been held up as slave-drivers who care little about their students' education and simply need them to serve as automatons who plug one step's intermediate into the next. There have even been rumors of students forced to compete against each other for the quickest route to the product, with the "loser" not making it to the authors' list on the paper. New students are being advised not to spend five years working in a high-profile total synthesis group if they want to have a life outside graduate school. Stories of student suicides have done nothing to improve the situation, although one wonders if such stories are also not to be found in other disciplines and are simply being highlighted because of the high-profile nature of the groups. Is this reputation deserved? I don't know, but it certainly seems to contribute to an unfavorable view of total synthesis.

Yet this view has not generally colored the status of the field. Total synthesis still commands the attention of first-rate blogs, synthesis papers still make it to highly-cited lists, and total syntheses are still enthusiastically lauded as the works of art which they undoubtedly are. While the reputation of synthesis may have suffered because of myriad factors, the power of personality and the artistic metaphors have guaranteed it a special place in the minds and souls of chemists. The ghost of Robert Burns Woodward lives on in more than one way.

A few of my favorite (chemical) things...

Chemjobber has started a meme about the top things you like about chemistry. Here are a few of mine. Chime in, here, there and elsewhere.

1. The strange, alluring mix of part rigor part empiricism
2. Sounds, colors, smells and crystals better than celluloid can deliver. Then there's celluloid itself, a chemical
3. That in its everyday depiction of molecular structures, chemistry comes closer to art than any other science.
4. The constant opportunities to spar with physicists about the limitations of reductionism
5. The pleasure of being able to appreciate Roald Hoffmann, Philip Ball, Sam Kean and others
6. The recurring challenge of striving to explain to the public why not all "chemicals" are bad
7. The unceasing, perpetual sense of astonishment that molecules as simple as serotonin, amphetamines and dopamine can cause profound behavioral changes
8. The fact that chemists can fanatically obsess about the 2-norbornyl cation with an intensity that elicits memories of the Montague-Capulet feud
9. The sheer reach of chemistry- from the innards of a superconductor to those of a supernova
10. The sense of satisfaction (often sadistic) from the constant bickering about the Nobel Prize in chemistry that simply reinforces the astonishing diversity of the discipline
11. The fact that all of life lives and thrives within a 3 kcal/mol window and that we still find it enormously challenging to predict energies within 1 kcal/mol
12. The pleasure of pointing out to biologists that knowing the pKa values of organic compounds can be rather useful
13. The fact that the origin of life is a quintessentially chemical problem that will keep chemists busy until the end of time
14. The smug satisfaction that comes from carrying around a bottle of sodium hydroxide bicarbonate in your pocket, just in case there's that freak acid spill
15. Linus Pauling
16. Robert Burns Woodward
17. The bizarre fact that models in chemistry actually WORK!

Who are the greatest chemistry teachers?

In April 2009, Physics Today celebrated the life of physicist John Archibald Wheeler with a special issue. Not only was Wheeler one of the great scientific minds of the twentieth century, but he was also a legendary teacher who influenced an entire generation of physicists. As one of the articles in the issue notes, Wheeler supervised more PhD theses at Princeton University than any professor in the history of the department. His graduate students included Richard Feynman and Kip Thorne. But the real impact of Wheeler's mentorship is obvious from an even more striking fact- he supervised more senior undergraduate theses than anyone else. And even when he became a world-famous physicist, Wheeler still taught the freshman physics course. The article concludes by suspecting that Wheeler's influence as a mentor probably exceeds even his great influence as a scientist.

This got me thinking. Who are the great teachers of chemistry? As in the case of the greatest chemist discussion, the answer seems to be easier to answer in case of physics. A roster of great twentieth-century physicist-teachers immediately brings to mind the names of Arnold Sommerfeld, Niels Bohr, Max Born, Ernest Rutherford, Robert Oppenheimer, Isidor Rabi, Wheeler and many others. What great scientists would populate a similar list of outstanding chemist-teachers?

Fist let's lay out the criteria for being a great teacher. Simply supervising a large number of PhD students may be important but is not enough since PhD students are usually essential for research and are also lamentably often utilized as cheap labor. Undergraduate teaching will definitely count highly on the list since it usually takes a genuine love of teaching to divert precious time toward elementary courses. Then there's the matter of pedagogy, often displayed through first-rate textbooks. Great chemists who made concerted efforts to educate through the writing of timeless textbooks will also count.

But ultimately, nothing counts as much as inspiring students and immersing them in the philosophy of your subject, giving them a sense of the "taste" of the discipline, communicating to them the excitement of doing research and asking questions that will stay with them throughout their careers. A great teacher who may not be ideally suited for classroom teaching will still make the list if he invites his students for long walks and afternoon tea to engage them in informal and intense discussions about science. For instance, Robert Oppenheimer almost never taught an undergraduate class and his lectures were often opaque to everyone but the best students. Yet he managed to create the finest school of modern physics in the United States in the 30s and 40s, largely because of his immense charisma and brilliance and the sense of truly working at the frontier of physics that he communicated to his students. After classes, Oppenheimer would often invite his students out for dinner and spend the evening listening to classical music and discussing physics. As Hans Bethe put it:

Probably the most important ingredient Oppenheimer brought to his teaching was his exquisite taste. He always knew what were the important problems, as shown by his choice of subjects. He truly lived with those problems, struggling for a solution, and he communicated his concern to the group

So who then are the great chemist-teachers? As usual this represents a limited collection of my personal favorites. Incidentally, the greatest chemist of the twentieth century was also one of its greatest teachers. When Linus Pauling was teaching undergraduates at Caltech and could not find a satisfactory textbook, he wrote his own. "General Chemistry" is still in print and still quite readable. With E. Bright Wilson, Pauling also wrote "Introduction to Quantum Mechanics", the first modern quantum chemistry textbook. And then there's of course the momentous "The Nature of the Chemical Bond" which was known not only for its science but for its superb pedagogy. Pauling's lecture demonstrations to undergraduates were also well-known. A student of his described how Pauling would rapidly juggle a lump of sodium in his hands and talk at length about sodium's vigorous reaction with water, all the while warily eyeing a beaker of water on the table. The lump would then "accidentally" fall into the beaker. While everyone including Pauling ducked, nothing would happen, and Pauling would nonchalantly add, "But its reaction with alcohol is much less violent". Another chemist who taught through explosions and colors was Hubert Alyea at Princeton. Sadly, the art of the lecture demonstration seems to be lost to modern chemical education.

Speaking of textbooks, one cannot forget the author as great teacher. Sadly many of them are now forgotten and deserve to be resurrected. For some reason British authors especially stand out as marvelous pedagogical expositors in the classical tradition. A true gem for instance is "Valence" by Oxford theoretical chemist Charles Coulson whose crystal clear treatment of quantum chemistry has stood the test of time. A fair number of students who trained with Coulson later became outstanding theoretical chemists in their own right. I would place him high on the list. Then there's Stuart Warren, coauthor of my favorite organic chemistry textbook who also wrote one of the definitive books on retrosynthetic analysis. And there's the little known and under-appreciated "Guidebook to Mechanism in Organic Chemistry" by Peter Sykes which in my opinion is the most devastatingly concise and clear treatment of the subject ever written. In Sykes's hands, nucleophilic substitution sounds like a well-crafted violin sonata.

Among American authors I would name Morrison and Boyd, not famous scientists but authors of an outstanding organic chemistry text (which unfortunately was not updated). Ernest Eliel's book taught stereochemistry to a generation of organic chemists and I have always had it on my shelf. There's F. Albert Cotton's definitive textbook on inorganic chemistry; Cotton was also known as a prolific trainer of PhDs. And there's biochemistry volumes by Albert Lehninger and Lubert Stryer which are both pillars of authority and clarity in their field.

In the early part of the century the center of scientific excellence was in Europe. The great European chemists Svante Arrhenius and Walther Nernst were both extremely influential as mentors. So were Robert Robinson and Leopold Ruzicka. Harvard chemist Theodore William Richards who won the Nobel Prize for his accurate determination of atomic weights deserves special mention; his students included G N Lewis, Roger Adams and James Bryant Conant. Lewis himself was the most influential chemist of his time and imparted his style of thinking to many outstanding chemists, including Glenn Seaborg.

Let's talk about the latter half of the century. Robert Burns Woodward did not teach undergraduate courses and in fact in his later years was known to be pre-occupied with his own research to the detriment of his students. Yet Woodward's influence was so towering that his students adopted his style merely by being around him. In his earlier years he was known as a great teacher, especially by way of his famous Thursday seminars which used to last into the night. Woodward's students have populated the corridors of organic chemistry and the impact of his way of doing chemistry is undeniable. So is E J Corey's. I don't know if Corey taught undergraduates, but he has trained hundreds of students and postdocs who have carried his science all around the world and the sheer reach of Corey's chemistry and philosophy is probably greater than of any organic chemist in history. A traditional pilgrimage to Corey's lab for a postdoc was like a mandatory pilgrimage to one of the great European centers of physics in the early twentieth century. Corey qualifies as a great guide in spite of some unfortunate stories from his lab.

Caltech chemist Jack Roberts also stands out for two things- training students like George Whitesides, and writing some great books; one of the earliest accounts of MO calculations for American students, a first-rate organic textbook co-authored with Marjorie Caserio and an excellent volume on NMR basics. Another great mentor is Ronald Breslow who has trained three generations of chemists that have filled up the top ranks of academic chemistry; Nobel laureate Robert Grubbs for instance got his PhD with Breslow. Finally I want to note Dudley Herschbach who was also known for teaching introductory chemistry at Harvard and who willingly accepted the responsibility of being the c0-master of a dorm.

We could go on. There are of course many who I have not noted, and I invite others to offer their own examples. Sadly this list is fundamentally unfair since it leaves out outstanding college professors who are not very well-known as scientists. Such a list would be especially valuable.

In an age where universities are increasingly weighing the value of professors based almost exclusively on their grant-winning capabilities, it's worth reminding our institutions that fifty years ago teaching was taken as seriously as research. And as the above examples demonstrate, there is absolutely no discrepancy between being a world-class scientist and a world-class teacher. Teaching introductory chemistry and being a Nobel laureate are not diametrically opposed concepts. In many ways mentorship goes much further than research ideas. It's a lesson worth remembering.

"The Thexperiment Cafe": Bridging theory and experiment?

Discodermolide and dictyostatin are complex, flexible molecules that bind to the protein tubulin and promote the assembly of microtubules during cell division. This mechanism, similar to that of the bestselling drug Taxol, derails the precise timing of cell division and kills cells by causing apoptosis or cell death. Since cancer is quintessentially a disease of aberrant cell division, both molecules have emerged as potentially promising anticancer agents. Discodermolide and dictyostatin are of special interest not only because of their extraordinary potency, but especially because they seem to retain that potency against cells which have become resistant to taxol.

A year ago I co-authored a J. Med. Chem. paper that proposed a protein-bound conformation for discodermolide using a combination of NMR data and molecular modeling techniques. We followed up with a paper published last week in JACS in which we applied similar techniques to dictyostatin. In a nutshell, the two studies revealed surprising and unexpected dissimilarity in the solution and protein-bound 3D conformations of the molecules; similarity which is belied by their superficial 2D structures. While dictyostatin presents a diverse family of conformations, discodermolide sustains a remarkably constant conformation in very diverse environments (solid-state, solution, and in the protein binding site) that is enforced primarily by steric factors.

I would like to describe the work in the latest paper separately, but for now I am intrigued by another aspect of the problem. In both cases we proposed protein-bound conformations of two medicinally relevant molecules, but in both cases our conformations were not unique. In case of dictyostatin there is at least one alternative proposed conformation while in case of discodermolide there are no less than two. Of course we think that our proposed conformation better satisfies the data (otherwise we wouldn't have published the papers!), but the fact is that we are now presented with a puzzle. Which of the proposed conformations is correct and what technique would best resolve the quandary? The answer is unambiguous: x-ray crystallography on dictyostatin and discodermolide bound to tubulin should tell us what the correct conformation is.

Max Perutz once said that one of the most attractive qualities of science is that there is usually only one right answer, unlike politics where the answer depends on the viewpoint. I think this example illustrates that quality. The question is well-defined. We now have several competing proposals for the protein-bound conformations of two important molecular targets, but we know that there must be only one bound conformation in the solid-state, one right answer. Which conformation among these is it? Or is it a totally different one which has slipped through the cracks? The question is important not only because it would reveal the mode of action of a potentially novel class of anticancer drugs, but also because it could be very useful to organic chemists who could then modify the structures of the drugs based on their bound conformations to improve their potency and other properties.

In case of discodermolide, one molecule, three proposed conformations. But only one true conformation to rule them all. Which is it? In one sense the gauntlet has been thrown in front of crystallographers and the goal should be tantalizing for them, especially because there is a single right answer. The task will undoubtedly be difficult. Until now only the tubulin-binding drug taxol has succumbed to x-ray crystallography while the drug epothilone has lent itself to electron diffraction. Both dictyostatin and discodermolide are flexible molecules that won't yield to protein co-crystallization easily. And yet the solution would almost certainly result in publication in a top journal and new directions for synthetic chemists. Most importantly, it would be the definitive validation of a scientific puzzle that is currently unresolved.

But this train of thought brings to my mind another idea. Wouldn't it be great if we could have an exclusive website where experimentalists post results that theorists have to explain and theorists post results that experimentalists have to validate? The interplay between theory and experiment has of course been the bedrock of science since antiquity. But all too often, the right kind of puzzle is not clearly communicated by one group to another. Sure, if you work in a particular field, you will probably be up to speed on the literature in your field. But the sheer deluge of information ensures occasional omission, and sometimes you may also be interested in potential challenges from other areas which cannot be easily communicated to you. For instance, the dictyostatin/discodermolide puzzle may be interesting to scientists who don't have anything to do with tubulin but who are simply eager to test a new structure determination method that can be applied to such complicated molecules. As we all know, solutions to scientific puzzles can emerge from unexpected corners, and scientists sometimes may find surprises from other fields that pique their curiosity. For example, the spectacular harnessing of physics-based methods in chemistry and biology is well-known.

Yet scientists in one field cannot possibly keep track of all other fields whose developments may be attractive to them. For instance a physicist who may be developing a promising new electron diffraction technique, potentially applicable to tubulin and discodermolide, is usually not going to be aware of literature in this area. In such cases, it would be tremendously useful to have a website whose express purpose is to serve as a bridge between theorists and experimentalists. The website would be divided into the traditional fields of science along with interdisciplinary sections. Every week, a theorist or experimentalist would pose a puzzle from his or her field whose unambiguous solution he or she believes would be amenable to experimental techniques. The puzzle would be tagged with the names of all possible fields to which it could be relevant. People could vote up or down a problem which they find particularly enticing and tractable. Experimentalists from different disciplines can then take a look at the problem. The right answer could come from left field, from quarters which were completely unexpected for the scientist who posed the question. There would still be some querying that would be necessary, but the specific nature of the website would necessitate far less wading through literature from other fields than what's usually required. Similarly, experimentalists could post curious, unexplained results that would tickle theorists' grey cells.

The website could perhaps be called "The Thexperiment Cafe" or something less obnoxious. It would be a place where theorists and experimentalists rendezvous and challenge each other with specific puzzles. It could bypass the usual exhaustive literature searching and serve as a rapid delivery vehicle for problems whose solutions are unambiguous (or even ambiguous!) and which could benefit members from each camp. Experimentalists and theorists could be one big, happy family. And science will always win.

Woodward on the difference between mathematics and chemistry

When I was studying organic chemistry in college, my uncle who was a pharmacist and who had studied the subject himself used to say that "organic chemistry is just like mathematics, only simpler". There was more than a shred of truth in this statement. The logic inherent in the theorems of math is mirrored in the precise logic of reactivity and structure in organic chemistry. At one point in college my interests deviated toward physics and math.

But I wisely realized the allure of chemistry, not only because I thought my abilities were more suited for this discipline but because chemistry presented some special features; for instance, while logic may apply in both math and chemistry, in chemistry you could find exceptions (as James has nicely documented) and the whole concept of absolute 'truth' was much more provisional. At the same time there were models of great predictive power and elegance, such as the Woodward-Hoffmann rules. This strange mix of rigor and empiricism inherent in chemistry really captivated me. Mathematicians may be drawn to the rock-solid certainty of mathematical truths, but for me, the more complex nature of chemical reality made it seem much more human.

Yesterday I was reading R B Woodward's fabulous Cope Lecture in which he documents his interest and growth in chemistry. Woodward was such an extraordinary intellect that he could have probably had an outstanding career in any discipline. In fact he says that he was tempted by mathematics at one point but then recognized the unique nature of chemistry. He gives two reasons which I think do as fine a job of capturing the essence and allure of chemistry as any other. The first reason would probably be appreciated by all of us who were drawn to the subject. The second reason sums up the nature of science itself, what Richard Feynman called "imagination in a straitjacket". In chemistry, ideas have to answer to reality.

Here's the master speaking (the italics and capitals are his):
"The fact is that I have always been very fond of mathematics- for one short period, I even toyed with the possibility of abandoning chemistry in its favour. I enjoyed immensely both its conceptual and formal beauties, and the precision and elegance of its relationships and transformations. Why then did I not succumb to its charms? For two reasons, I believe:

FIRST, because by and large, mathematics lacks the sensuous elements which play so large a role in my attraction to chemistry. I love crystals, the beauty of their form- and their formation; liquids, dormant, distilling, sloshing!; the fumes; the odors- good and bad; the rainbow of colours; the gleaming vessels, of every size, shape and purpose. Much as I might think about chemistry, it would not exist for me without these physical, visual, tangible, sensuous things.

SECOND, while in mathematics, presumably one's imagination may run riot without limit, in chemistry, one's ideas, however beautiful, logical, elegant, imaginative they may be in their own right, are simply without value unless they are actually applicable to the one physical environment we have- in short, they are only good if they work! I personally very much enjoy the very special challenge which this physical restraint on fantasy presents"
To which we can only say, "Amen!".

Delivering a few Knox

When I was a kid I was inspired by the story of George Washington Carver, the indomitable African-American agricultural scientist who overcame horrific experiences of racism in the late nineteenth century and rose to fame for his science and humanity. I remember especially being impressed by his harnessing of the humble peanut plant and turning peanuts into an astounding variety of other food and textile products. The story of this remarkable man continues to serves as an inspiration.

Unfortunately I did not hear of too many African-American chemists later, with Percy Julian being a noteworthy exception. Thus I am now gratified to read the remarkable story of the Knox brothers- Larry and William- brought to us by Profs. Gortler and Weininger of Brooklyn College (CUNY) and Worcester Polytechnic Institute. Larry and William were grandsons of slaves in North Carolina who had bought their freedom. Both brothers climbed the rungs of a racism-ridden educational ladder, obtained PhD degrees at MIT and Harvard, contributed to the war effort and pursued successful careers in industry. An African-American chemist- let alone two brothers- getting a science PhD in those days was wholly exceptional. The article puts their achievements in perspective by emphasizing the statistics; "That one family should produce almost 7% of all black Ph.D. chemists over a 25-year period is remarkable—especially a family with its roots in the slave-holding South".

Larry obtained his PhD with Harvard chemist Paul Bartlett, perhaps the leading American physical organic chemist of the late twentieth century, and followed up by working with the distinguished chemist William von Doering. William worked on the Manhattan Project with future Nobel laureate Willard Libby who pioneered radiocarbon dating. The Knox brothers' accomplishments were outstanding even as they grappled with the scourge of discrimination; at one point, Doering and Larry had driven up to Chicago for an ACS meeting and had to sleep in the car because no motel would admit a black man, even in the North.

Gortler and Weininger deserve commendation for bringing us the story of these unsung heroes. Incidentally, the ACS is celebrating the chemical contributions of African-American chemists this month. Eleven outstanding chemists are featured in the collage, with the twelfth block left empty. It seems to me that the Knox brothers more than qualify to fill this block, and I am disappointed that the ACS left them out.

Chemistry: The difference between important and useful

Over on the Skeptical Chymist blog there's another discussion about using highly cited chemists to gauge the importance of chemical sub-fields. In the past post I suspected that highly cited chemists lists from the 50s through the 90s would reflect the now seemingly diminished importance of organic synthesis. Partly goaded by this, Michelle Francl of Culture of Chemistry drew up a list of chemist citations from the 80s and 90s. Interestingly, there are no bona fide synthetic organic chemists in there. However, as a commentator on the Chymist's blog noted, a better metric of judging trends might be to count the number of highly cited papers in every sub-field in every decade rather than just looking at highly cited chemists. In my opinion, the latter would do a much better job of indicating the supremacy of organic chemistry from the 50s through the 90s.

Or would it? To get a better idea of the whole issue I did something which I thought was obvious, and was surprised by the results.
The exercise really got me thinking about the very nature of judging achievement and importance in chemistry.

I simply logged on to the ACS website and looked at the list of
highest-cited JACS articles of all time. Although extrapolating to chemical significance from this exercise is as fraught with limitations as extrapolating from ISI/Thomson Reuters lists, most of us would agree that JACS has mirrored important chemical developments in the last fifty years. So is the list of heavy hitters unsurprisingly dominated by Woodward, Smalley, Corey, Djerassi, Sharpless or Grubbs? Surely the top spot would be taken by the greatest chemist of all time?

Hardly. Of the top ten articles, four including the top two belong to computational chemistry, a field that has often been regarded as relatively unfashionable compared to organic synthesis, chemical biology, materials science and polymer science. Ask scientists to name the most important chemists of the last fifty years and very few will state the names of John Pople or Michael Dewar, let alone Peter Kollman, Clark Still or Warren Hehre. Yet computational chemistry dominates the list of the top 20 highest cited papers in JACS. Where is the chemical God Woodward in the list? Or his successor Corey? In fact no one who looks at the JACS list would even suspect that organic chemistry ever dominated the chemical landscape.

Does this mean that organic synthesis was hyped for fifty years and we were convinced
of the towering implications of the field by a conspiracy of chemical raconteurs led by R B Woodward? Certainly not. To me the list only signifies the signature character of chemistry: on a practical basis, in chemistry 'importance' is judged by utility rather than by any other single metric. If you look at the computational chemistry papers in the JACS list, you will realize that each one of those papers contributed techniques which became universally adopted by all kinds of chemists doing calculations on all kinds of molecules. Woodward's papers on synthesis may seem like great works of art compared to these pragmatic prescriptions, but chemists going about their daily business may have scant use for them. Considering this emphasis on utility, I was actually surprised not to see some of Corey's papers- such as the one describing the oxidation of secondary alcohols- on the list. I was also surprised not to see the work done by the palladium crowd, not to mention the Sharpless epoxidation and dihydroxylation accounts.

But the examples which are included make the context clear. Consider the solvation models developed by Clark Still which are a mainstay of molecular simulation. Consider the force fields developed by Peter Kollman and Bill Jorgensen, again incorporated in leading computer programs and used by thousands around the world. And of course, the pioneering Nobel Prize winning quantum chemical programs developed by John Pople brought high-flying theory to the bench. In fact a very few people cited by ISI/Thomson Reuters feature in the list. Whitesides does, but again, for his very practical and important work on generating monolayer films on surfaces. Ralph Pearson is similarly cited for his very helpful development of the hard/soft acid base concept. Robert Grubbs actually makes it, but again for his decidedly practical innovation of olefin metathesis.

Interestingly, when the general history of chemistry is written, the pioneering articles which make the list will almost certainly not be these highly cited ones. They will instead be the synthesis of chlorophyll or fullerene, or those detailing the reactions of CFCs with the ozone layer. The cracking of hydrocarbons will probably be mentioned. And of course there will be all those papers on the nature of the chemical bond, featuring Linus Pauling and others. In the long-term, what would stand out from the chemical canon would be the papers which laid the foundation of the field, not the ones which allowed chemists to calculate a dipole moment with better accuracy. And yet it's the latter and not the former which make the JACS list.

These observations based on a most limited data set should not be taken too seriously. But I think that they drive home an important point. In chemistry, what's regarded as important by history and what's regarded as important by chemists going about their daily work might be very different. We may wax eloquent about how Pauling's paper on hybridization lit up the great darkness, or how Woodward's synthesis of Vitamin B12 reminds one of Chartres Cathedral, but at the end of the day, all a chemist wants is to grow some thiol monolayers on gold and calculate their interactions from first principles.

Is the age of traditional organic synthesis over?

The Skeptical Chymist pointed me to a list of top 10 chemists from 2000-2010 produced by ISI /Thomson Reuters. I am copying the list from the Chymist's post:

"The data given is all from ISI/Web of Science: papers published, citations and 'impact' (citations per paper). I'll give you the top ten here:
Charles M. LIEBER; Harvard University (74 papers, 17,776 citations, 240.22 c/p)
Omar M. YAGHI; University of California Los Angeles (90, 19,870, 220.78)
Michael O’KEEFFE; Arizona State University (73, 12,910, 176.85)
K. Barry SHARPLESS; Scripps Research Institute (60, 9,754, 162.57)
A. Paul ALIVISATOS; University of California Berkeley (93, 14,589, 156.87)
Richard E. SMALLEY†; Formerly Rice University (60, 9,217, 153.62)
Hongjie DAI; Stanford University (88, 12,768, 145.09)
Xiaogang PENG; University of Arkansas (59, 8,548, 144.88)
Valery V. FOKIN; Scripps Research Institute (54, 6,853, 126.91)
Peidong YANG; University of California Berkeley (95, 11,167, 117.55)"

The most striking thing about this list for me is the lack of hard-core organic chemists in there. There are two bona fide synthetic chemists (Sharpless and Fokin) and no total synthesis people. Almost any such list from the 50s through the 90s would have been dominated by organic chemists engaged in methodology and total synthesis. Of course, as an enabling discipline synthesis is still key for all the research carried out by these heavy hitters. Organic synthesis will still be ubiquitously embedded in key chemical innovations. Organic chemists will still make important contributions and their syntheses will continue to be works of art imbued with elegance and economy. But organic chemistry as seen and practiced for forty exciting years by the old guard seems to be distinctly on the wane. I can almost sense a sigh and the wistful note of nostalgia.

Instead, what obviously dominates the list is nanotechnology and materials science. The materials range from pure inorganic materials to organic-inorganic hybrids to biomaterials. Materials science has clearly reigned during the past decade and will probably dominate the chemical landscape even more in the future. I suspect that other lists using different indices will come up with a similar smattering, perhaps with some more core biological chemists thrown in.

Perhaps the old guard of organic synthesis can seek respite in Tennyson's immortal lines:

"Though much is taken, much abides; and though
We are not now that strength which in old days
Moved earth and heaven; that which we are, we are;
One equal temper of heroic hearts,
Made weak by time and fate, but strong in will
To strive, to seek, to find, and not to yield.

It's been a fantastic run, but it's time we moved on.

The road not taken: Do you have the courage to let go?

Science writer Kathy Weston has a sobering and instructive assessment of her life as an academic scientist and as a woman in science on the Science website. Weston quit academic research after twenty years of a promising career. Why?

Her pedigree was outstanding. She got her PhD. at the Medical Research Council in the UK which has been a Nobel laureate-generating factory. She then post-docked with Michael Bishop at UCSF just as Bishop was finishing his Nobel Prize-winning work on oncogenes. After her postdoc Weston got a nice tenure-track position in a leading British university and immersed herself in exciting research. She even got tenure and life looked rosy. But as she says, at some point she started losing motivation after realizing that perhaps she did not have what it takes to get on the path to Stockholm.
"However, I was always hampered by self-doubt. My initial conviction -- essential for anyone who wants to make it as a scientist -- that I could really make a difference, maybe even win a few prizes and get famous, eroded when I realized that my brain was simply not wired like those of the phalanx of Nobelists I met over the years; I was never going to be original enough to be a star. This early realization, combined with a deep-seated lack of self-confidence, meant that I was useless at self-promotion and networking. I would go to conferences and hide in corners, never daring to talk to the speakers and the big shots. I never managed, as an infinitely more successful friend put it, "to piss in all the right places."
Plus as she says, academic life is not as tempting as it sounds since the freedom to work "whenever you want" usually translates to working "all the time". Being a woman made it even harder for her to sustain her interest and drive even as she raised two children in her thirties. At one point she realized that this was not the best way to live her life, and she quit.

Weston's frank and sobering memoir raises a lot of questions. Some of the reasons she failed as an academic scientist can be traced to her own admission that she lacked drive. But one cannot blame her completely. I am pretty sure most of us have the same experience. When we are eager kids interested in science, the horizon glows with possibilities. But as we progress in our scientific careers, the self-doubt that Weston mentions inevitably creeps in. At some point we downgrade our expectations from winning a Nobel to simply doing good research. Further down the line we realize that even getting a top position may be too ambitious and settle for a permanent position in some university. In the extreme case, we may quit science altogether and settle for another profession.

There are two thoughts I have about this. The first thought is that settling for another profession is not a bad thing. One of the fundamental hypotheses I have about life and careers is that many of us don't actually end up professionally doing what we have the greatest aptitude for. Most of us realize much later in life that we are not really cut out for what we have been doing for the past twenty years. The real tragedy is that at that point, pride, financial and personal issues, an unwillingness to let go of our childhood dreams and simple inertia keep us from severing the knot and moving on to a different career. We remain entrenched in our mundane existence and at the age of eighty wistfully wish that life had been different. I have at least a couple of friends who are working 9-5 jobs which do not excite them and whose real passions include writing, music and art. Yet they don't have the heart to let go. Weston must be congratulated for having the courage to admit her shortcomings, taking that very important and drastic step of switching careers and moving on to become a science writer. As she mentions, she sometimes still misses life in the lab, but it's clear that the rational part of her mind assures her that she made the right decision.

The other thought concerns the importance of cultivating people skills which Weston admits she failed to appreciate. Love it or hate it, networking and people skills have become as essential a part of scientific research as the research itself. As Weston says, you need to have the initiative to speak up and interact with people, whether your work is Nobel-caliber or entirely pedestrian. Having an inferiority complex does not help (maybe that's why many academic scientists overcompensate and develop egos as big as planets...). You need to acquire a traveling salesman's skills to pitch guano as if it were gold. As Weston says, it is also very important to find a mentor who will not only inspire and encourage you but serve as a practical conduit to positions, recommendations and funding. Again, these kinds of mentors can only be cultivated through constant networking. The other problem is of course being a woman and balancing a family life with research. That continues to be a real challenge for women in academia, and only a deep overhaul of the system can address this problem.

But it's not just young scientists. As Weston indicates, the system doesn't do too much to encourage people like her to stay on board.
"And what of the system? It failed too, I think. Scientists are judged almost entirely on research output, measured by papers published in the most prominent journals, and grants are not awarded unless your work is competitive at the highest level. Trying to run a lab full time with small children at home is very likely to result in a drop in research productivity or quality, and yet little allowance is made for those of us, mostly women, who find ourselves in this situation"
She is absolutely right. Academic research in the last few decades has gradually become more and more restrictive in many ways, rewarding only those who kowtow to its narrowly defined set of values and constraints. The latest salvo in the struggle has been the dubious decision by certain universities to assess professors' worth primarily based on the amount of money that they bring in, rather than by focusing on other valuable activities like teaching. Nor has it become any easier to bring home the bacon. In several cases the NIH has ended up setting unrealistic standards for awarding funds: on one hand your research needs to be novel enough to be distinguished from everyone else's and on the other hand it needs to rest on tried and tested recipes to stand a chance of becoming successful. In addition the noose has been constantly tightened by an increasingly smaller piece of the pie. This kind of system may reward people at the highest level but it weeds out so many at a slightly lower one whose work is collectively as or more important.

Ultimately we can defend all of this by saying that you should pursue a career in scientific research only if you are deeply interested in the process of science itself; any other expectation and you are in the wrong field. There is more than a shred of truth in this. If it is the ultimate search for truth that drives you, then you would indeed be less enamored of awards and publications or even novel discoveries and would be propelled onwards by the sheer joy of discovery rather than its fruits. It shouldn't be Stockholm as much as Satisfaction that should be your goal. Sadly, we and especially others do not live in this perfect world. Scientists crave results and benefits as much as anyone else, and the world beats a path to your door only if you are loudest in convincing it of the importance of your work. We are only human, and maybe that is our flaw. Perhaps Weston's wisdom was in realizing this early enough.

The difference between chemistry and physics: Part 2

In a past post I talked about the lack of 'downward causation' when trying to explain chemistry on the basis of physics and quoted Nobel laureate Roald Hoffmann's complaint about physicists often taking a reductionist approach toward chemistry and failing to understand its essence. From the same indefatigable Hoffmann's wonderful book "The Same and Not the Same" comes another pithy summary of the problem with reductionism in chemistry:

"For a chemist, concepts like aromaticity, acid-base behavior, functional groups and substituent effects wilt at the edges when they are defined too closely. They cannot be mathematicized, they cannot be defined unambiguously, yet they are of fantastic utility to our science".

'Wilt at the edges'- it's a lovely turn of phrase. What does it mean? It does not mean that there is no direct link between these concepts and their underlying explanation in terms of the physics of nuclei and electrons. There very much is. Instead to me it means something analogous to what another Nobel laureate, Steven Weinberg (quite a reductionist himself), said of the universe- "The more the universe seems comprehensible, the more it seems pointless". In case of chemistry it indicates that the closer we approach to purely physics-based explanations of chemical phenomena, the less useful and sensible those explanations seem to us as chemists. It's as if chemical understanding deserts us precisely when it seems to become satisfying for a physicist. That is probably part of what Hoffmann means when he refers to the fraying of chemical concepts at their edges.

To me the real problem with reductionism has not really been philosophical as much as practical. In some cases there is almost no tangible link between a phenomenon and its very deep underlying components. For instance, no one can reasonably draw a causative link between two people falling in or out of love or two countries going to war and the strong force between protons and neutrons. This is what we might term "strong reductionism" where the limitations of reductionist philosophy are stark and obvious. Philosophers love to discuss this kind. But I think that the type of reductionism that is far more relevant to the daily work of most scientists is what may be called "weak reductionism". This type applies to phenomena which can actually be connected to other basic phenomena in a reasonable sense, but it's just that explaining them in terms of these basic paradigms is utterly unhelpful at the level of the phenomena themselves.

Let me state an extreme example which would make this case clear. To a first approximation a physicist might say that there is no difference between a banana, a human being and a suspension bridge since all of them are made out of protons, neutrons and electrons. The only difference is really in their numbers. Almost everyone (including physicists) would realize that non-explanation as absurd. While it does seem like the ultimate unifying elucidation, it says absolutely nothing about the very different functions performed by a human, a banana and a bridge. All three of these respectable entities would resent their reduction to varying numbers of subatomic particles.

An example more familiar to chemists which is stated by Hoffmann also vividly illustrates the problem with reducing chemistry to physics. Consider the carbonyl functional group, a workhorse of chemistry. The most important reaction that this group undergoes is nucleophilic addition. How does physics explain this process? By essentially pitching electrostatics. Physics will tell us that the carbonyl carbon has a partial positive charge and the oxygen has a partial negative one, thus attracting nucleophiles to the carbon. But a chemist would find this simple explanation deeply unsatisfying. There is much complexity associated with addition to carbonyls which goes beyond merely electrostatic attraction. There's the angle of attack of the nucleophile- the well-known Burgi-Dunitz trajectory- which maximizes orbital overlap. There's coordination of positively charged counterions with the oxygen which can dictate the stereochemistry. There's also the size of groups on the attacking nucleophile which can sharply tip the distribution of products through steric effects. Then there's the gradation of reactivity of various nucleophiles based on their size and charge. And finally, there's the all-pervasive solvent which can drastically change product ratios and stereochemistry through solvation effects.

Now note that the truly fundamental underlying basis for all these factors (and indeed, virtually everything in daily life) is the electromagnetic force, and so yes, physics can purport to actually 'explain' all these factors by saying that they are all mediated through electromagnetism. Even steric effects are essentially electromagnetic in nature. Yet this would be akin to saying that wars happen because people get really angry at each other. The physics-based explanation is useless to the chemist since each one of the ingredients responsible for nucleophilic addition constitutes a unique chemical feature and conundrum which the chemist has to understand and predict. A unifying framework for these based on the physicist's conception of electromagnetism does nothing to delineate the special role that each factor plays in controlling the reaction. To a carbonyl-enamored chemist, these determinants are as fundamental in their own right as protons and neutrons are to a physicist.

Thus in such cases, reductionism fails not because there is no palpable connection between the chemical phenomenon and its physical underpinnings, but because the physics-based explanations tend to be useless at the level of chemistry. One of the simple tests for interrogating the utility of reductionism then consists of asking whether a reductionist approach can help truly explain a certain phenomenon at the same level that the phenomenon is embedded in its parent discipline. Sometimes it helps, more often than not it doesn't. The underpinnings of the American Civil War and World War 2 are different. Chemistry is not physics.