Hedgehogs and foxes in chemistry

Isaiah Berlin's parable about hedgehogs and foxes has long since served as a thought-provoking lens for looking at science and scientists. Berlin quoted the Greek poet Archilochus who said that "the fox knows many things, but the hedgehog knows one big thing". Scientists who spend most or all of their careers drilling down deep into one field, problem or idea are hedgehogs. Scientists who instead spend their careers sniffing out and solving interesting problems from several areas are foxes. How does the dichotomy apply to chemists?

At the outset, one thing seems clear: chemistry is much more of a fox's game than a hedgehog's. This is in contrast to theoretical physics or mathematics which have sported many spectacular hedgehogs. It's not that deep thinking hedgehogs are not valuable in chemistry. It's just that diversity in chemistry is too important to be left to hedgehogs alone. In chemistry more than in physics or math, differences and details matter. Unlike mathematics, where a hedgehog like Andrew Wiles spends almost his entire lifetime wrestling with Fermat's Last Theorem, chemistry affords few opportunities for solving single, narrowly defined problems through one approach, technique or idea. Chemists intrinsically revel in exploring a diverse and sometimes treacherous hodgepodge of rigorous mathematical analysis, empirical fact-stitching, back of the envelope calculations and heuristic modeling. These are activities ideally suited to foxes' temperament. One can say something similar about biologists.

The dominance of foxes in chemistry is demonstrated through its long history. Robert Boyle, the first modern chemist who is widely credited for separating chemistry from alchemy, is of course universally known for Boyle's Law but also made contributions to understanding combustion, respiration, color and electricity. The father of modern chemistry, Antoine Lavoisier, discovered the all-pervasive law of conservation of mass, preceded Mendeleev in putting together a tentative classification of elements and pioneered chemical book-keeping (stoichiometry). Similarly, the great chemists of the nineteenth century- Davy, Wöhler, Liebig, Kekule, Mendeleev- were all foxes who, while known for one or two important discoveries, worked in diverse facets of their chosen discipline. Chemical foxes also proliferated in the twentieth century, with Lewis, Langmuir, Curie, Fischer and Sanger being typical examples. Linus Pauling was the ultimate fox, but more on that below.

This does not mean that chemistry has no use for hedgehogs. Far from it. If there's one field of applied chemistry which has reaped riches from hedgehogs' talents, it's crystallography and especially protein crystallography. Crystallography also belongs to physics and biology, but it has enough of a crucial chemical component for crystallographers to call themselves chemists. Among crystallographers, Max Perutz was a hedgehog par excellence. Perutz spent his entire career shining his intellect like a laser beam on the structure of hemoglobin. It was largely his efforts that turned hemoglobin into one of the best studied proteins that we know and it was because of his extensive studies on it that we gained insights into some of the most general and important concepts in protein science, including cooperative effects and allostery. The chemists who won the Nobel Prize two years ago for their solution of the ribosome structure were also supremely focused hedgehogs. Special mention must be made among this trio of Ada Yonath, the "mother" hedgehog who made the ribosome her life's mission and stuck with it longer than anyone else. There are also hedgehogs in some other subfields of chemistry. For instance, Rudolf Marcus who spent his lifetime developing a comprehensive theory of electron transfer processes comes close to being a hedgehog. Similarly, Peter Mitchell is known for one big thing- the development of the fundamental theory of chemiosmosis which is of paramount importance in understanding biological energy transfer.

In every science there are also a few unique individuals who seem to be able to magically morph into both hedgehogs and foxes. The greatest chemist of the century belonged to this class. During his life, Pauling was known especially for the astounding diversity of his contributions and this puts him squarely into the fox camp. But remarkably, the hedgehogs could also claim him as one of their own since the depth of his contributions easily rivals the breadth of his interests. If Pauling had made no other contribution except his theories of chemical bonding, he would have still been hailed as one of the century's great chemical hedgehogs. That Pauling managed to be a fox and still made hedgehog-like contributions to at least three key fields (quantum chemistry, protein structure and molecular medicine) attests to the stature of his accomplishments. Among twentieth century scientists, Enrico Fermi is the only individual in my opinion who commanded both depth and breadth of this magnitude.

It is much harder to locate hedgehogs among organic chemists. The greatest of organic chemists, R B Woodward, was undoubtedly a fox, albeit one of the highest caliber. Other leading figures in the field like Corey, Stork, Djerassi, Westheimer, Breslow and Danishefsky have also been first-rate foxes. Interestingly, there are hedgehogs among synthetic chemists but they are not as well-known. One that comes to mind is the chemist John Sheehan who spent fifteen years of his life trying to synthesize penicillin. Even the great Woodward had stayed away from this molecule's perilous, highly strained beta lactam ring. Sheehan recounted his single-minded obsession in a highly readable book with a fitting title- "The Enchanted Ring". Another organic hedgehog was H C Brown who devoted his career to perfecting the chemistry of boron. Yet another example is George Olah who has had a fifty-year love affair with the chemistry of carbocations. Also, as Derek Lowe hints, organometallic chemistry may yet be a field full of hedgehog riches. The chemists who developed palladium-catalyzed reactions and olefin metathesis were very hedgehog-like.

Many leading contemporary chemists on the other hand are exceptionally gifted foxes. Harry Gray, Stephen Lippard, Stuart Schreiber, George Whitesides, David Baker, Jean-Marie Lehn, Ad Bax, Alan Fersht, Jacqueline Barton, Martin Karplus, Roald Hoffmann, Paul Schleyer, Christopher Dobson, C N R Rao, Donna Blackmond, Chad Mirkin, Eiichi Nakamura, Fraser Stoddart, Ken Houk and Dieter Seebach are but a few examples of individuals who have made first rate contributions to diverse areas of chemistry. In fact, there can be no better tribute to their identity as foxes than the fact that many of them could also be easily classified as physicists or biologists.

We mentioned the quintessential nature of chemistry as a field of dreams more attractive to foxes rather than hedgehogs. Why is this so? In chemistry unlike physics, overarching general principles are not as important as specific instances and diverse manifestations of these principles. Key unifying principles of course exist and are taught to every budding college chemist, but they are often not as deep compared with general laws in physics or theorems in mathematics. For instance, the theory of acids and bases or that of hybridization is undoubtedly a unifying theory, but it's more a set of rules derived through a mix of theoretical analysis and empirical facts. Few would equate acid-base theory with Maxwell's laws of electromagnetism, the laws of thermodynamics or the theory of Lie groups in terms of depth, fundamental importance and universal applicability. In addition, unifying concepts in chemistry (free energy, crystal field theory, conformational analysis, oxidative phosphorylation, solubility laws) are usually fathered by several individuals and not just one. The ideal of the lone thinker shunning himself or herself from society and heroically wresting nature's secrets from her grasp through single-minded pursuit is an ideal that is alien to chemistry's nature and practice. Finally, many key chemical contributions consist of methods or instrumental advances (NMR, crystallography, gene sequencing, chromatography, PCR) that are necessarily the work of many people.

Does the future of chemistry belong to hedgehogs or foxes? I see no reason for the trends of the past five hundred years to change. Chemistry will essentially remain a game for foxes. This will be even more true in the future than it was in the past because the hottest fields in chemistry like energy, nanotechnology, chemical genetics and drug discovery are especially fox-friendly. However, occasional hedgehogs of the kind described above will also remain an integral part of its development. Foxes will be needed to explore the uncharted territory of chemical discovery, hedgehogs will be needed to probe its corners and reveal hidden jewels. The jewels will further reflect light that will illuminate additional playgrounds for the foxes to frolic in. Together the two creatures will make a difference.

The cult of organic synthesis

In 1828, Friedrich Wöhler synthesized urea - a substance hitherto thought to be produced only by living organisms - from simple inorganic substances. The discovery was a watershed in the history of science. In one fell swoop it shattered the widespread doctrine of vitalism which held that there is something fundamentally different between the animate and inanimate worlds. Wöhler was the triumphant messenger, heralding great expectations for the new adventurers while shattering the dreams of keepers of the faith.

Only ten years before in 1818, a different kind of vitalism was being conceived. That was the year when Mary Shelley published "Frankenstein; or, The Modern Prometheus"."Frankenstein" did for the science fiction genre what Wöhlerdid for chemistry. It infused the vivid imaginations of generations of writers, thinkers and movie-makers with notions of reanimating dead matter.

Now fast-forward to 1960. Woodward synthesizes chlorophyll. Chlorophyll. The substance which more than any other fuels life on this planet. There are telling similarities betweenWöhler's synthesis of urea, Shelley's creation of "Frankenstein" and Woodward's synthesis of chlorophyll. All three speak to man's mastery over Nature. All three embody a conscious or unconscious sense of hubris. And all of them tell us that the allure of vitalism is still alive, albeit in a very different sense. The chemists of Wöhler's generation strove to annihilate the distinction between living and non-living. But the synthetic chemists of Woodward's generation want to do one better and are closer to the brilliant, troubled protagonist of Shelley's novel; they want to not only starkly state the difference between life and death but they want to become the creators of both.

Wöhler's urea and Woodward's chlorophyll demonstrate the second reason for the cultish status of organic synthesis. The first was the cult of personality, but the second is the cult of psychology. There is a truly seductive feeling of power in being able to synthesize a substance like chlorophyll whose constitution seemed for years to be among Nature's most closely guarded secrets. A creature who could unravel the workings of this most fundamental of nature's engines would announce himself to be a true master of creation. What better way to make this announcement than to not only tease apart the strands of this secret but to create it from scratch? In fact it's worth noting the other landmark Nobel Prize winning discovery related to photosynthesis: the unraveling of the structure of the photosynthetic reaction center protein by Harmut Michel, Johann Diesenhofer and Robert Huber. As important as it was, the psychological impact of even this discovery cannot compare to the creation of chlorophyll through human ingenuity.

That is why, among all the chemical sciences, organic synthesis still enjoys a unique status. It harkens back to one of man's most primitive desires, to remake the world in his image; to first closely study, then mimic, and finally improve over nature. There can be no higher accolade for a species than to be congratulated for being able to trump it's very creator. This accolade is manifest in the Nobel committee's tribute to Woodward as well as to organic synthesis when itnoted that "It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here Nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second." In addition organic synthesis not only creates the molecules of life but it saves life, and the production of novel drugs further drives the image of synthesis as an instrument of human triumph.

The new science of synthetic biology promises to satisfy the same craving. The deliberate synthesis and rearrangement of genes to create new organisms from scratch promises the same kind of psychological benefits that the total synthesis of complex substances afforded to both organic chemists and lay audiences. No wonder that discoveries by Craig Venter and others are heralded in the press as the dawn of a new age, and they undoubtedly are. But in terms of their goals, these spectacular advances simply constitute the extensions of an age that began in 1828. And the psychological need goes back even further, when man was living in caves and creating innovative tools, agricultural implements and clothing from animal hides.

It's just vitalism and Frankenstein writ large all over again.