Field of Science

On chemistry's multiple cultures

As an organic-turned-computational chemist, I once went to a drug discovery conference where conversation during the coffee break turned to our respective backgrounds in chemistry. Computational chemists traditionally fill a niche in drug discovery and hence are not as abundant as traditional organic chemists. When I mentioned I was a modeler, the medicinal chemist I was talking to said in mock disapproval, "Oh, you are one of those chemists!". It reminded me a little of a moment in the 2008 presidential debate when, in reference to an apparently wasteful spending bill, John McCain dismissively referred to Barack Obama as "That one".

While the remark was made in jest, it was not the first time I had encountered such a reaction. The remark is unfair not only because many computational chemists have a sound background in and appreciation for organic, physical or biological chemistry but because computational chemistry as a field is a much newer endeavor than synthesis; virgin territory where the real peaks are yet to be scaled. The general problem of synthesizing an arbitrary complex molecule has been largely solved but the general problem of calculating the free energy of binding for an arbitrary protein-ligand complex is one that we are far from surmounting. Computational chemistry has yet to see its full share of its Woodwards, Coreys, Fischers and Robinsons.

But I digress.

Much has been made of C P Snow's famous "two cultures" signifying a fundamental divide between science and the humanities. It is undoubtedly important that we remedy this rift since humanity as a whole needs both. But what is less discussed is the proliferation of multiple cultures within a field. These cultures can sometimes be as divisive as the overarching cultures of science and the humanities.

This phenomenon is as true in chemistry as it is anywhere else. If we as a community want to pitch the merits of our discipline to the public, we must first make sure that our own house is in order. Sadly I don't find this to be the case, especially within academic chemistry. Computational chemistry is considered flippant by experimentalists, biochemistry is considered too hyped by materials chemists and inorganic chemistry is just plain boring for many biochemists.

This is in spite of the fact that every discipline of chemistry has its own strengths and uses and draws on all others. A biological chemist can gain little insight unless he or she knows the basics of organic chemistry. A synthetic organic chemist must know about metallic oxidation states to get the most out of the power of organometallic chemistry. Many fields of chemistry can be enriched by computational models that can constrain the choice of compounds to be made, pathways to be investigated, enzymes to be crystallized. You cannot study mechanisms in either inorganic, organic or biological chemistry without knowing about thermodynamics and kinetics, and a materials chemist without an understanding of solid-state chemistry and physics may just be limiting his or her chance to gain deep insight into organic electronics. Thus it's obvious that every field of chemistry feeds off every other. Especially in today's age when most important problems are complex and inherently interdisciplinary, one cannot afford to rely only on one's own speciality. A team of experts in different branches of chemistry approaching a complicated problem is piecewise no more competent to judge the whole than is the team of blind men who each approach one part of the famed elephant.

In spite of this obvious utility of every subfield of chemistry and its reliance on every other, chemistry departments are rife with turf wars. Sometimes the rivalry is healthy and the multiple cultures can foster a productive tension between different camps that leads to the rigorous testing and perfection of certain approaches. Often it is not. Sometimes it borders on the comical. I heard of a heterocyclic chemist who in his classes would eschew almost any structure that had more than two chiral centers, relegating the study of such unruly sp3-rich compounds to those lowly polyketide chemists. A total synthetic chemist was quick to condemn an elegant quantum chemical calculation on a particularly complex molecule, no matter that experiment actually supported the calculations. Medicinal chemists often put down the utility of computational models, in spite of the fact that prudent modelers themselves consider their models as more of constraining guidelines than accurate depictions of "reality". Now, in many cases the real problem is not the science but the scientists who have oversold the power of their approach, but that in no way forgives those who would condemn the discipline wholesale instead of rebuking its overenthusiastic practitioners.

If we are to make the most of a complex problem, we need to pick the strengths of each discipline and utilize it as well as we can. This fact is probably recognized more by scientists working in inherently multidisciplinary fields like energy, drug discovery and nanotechnology. These scientists know for a fact that the problems in their field are too complex to be addressed by only one approach, instrument, field or school of thought. Drug discovery scientists for instance recognize (or at least should recognize) the essential utility of synthesists, biologists, formulators, crystallographers and modelers in the discovery of a new drug. Yet you find turf wars even among such interdisciplinary scientists who are often convinced that their latest brainwave is the answer to life, the universe and everything else.

If multiple cultures are sporadic among more applied chemists, they are virtually endemic in academia. How many times have you come across a total synthesis chemist who believes that all of organic chemistry essentially exists to serve the science and art of total synthesis? The materials scientist who believes that organic electronics is the only field worth working in for the next fifty years? And how about that computational chemist who believes that the time when computation is so pitch-perfect that you don't even need to make the molecule is already here? Academic chemists who have dedicated their careers to one single technique, methodology, class of molecule or paradigm are unfortunately among the biggest contributors to the proliferation of multiple cultures. They are quicker to pick favorites and to condemn other modes of thinking, and their very strengths that make them unique experts in their area also constrain them into a local minimum of narrow thought.

This will not do. If we want to hold up the discipline of chemistry as a shining contributor to the welfare of society, we must first make sure that the infighting is kept to a minimum. On a practical level, this would mean giving greater publicity to interdisciplinary chemical fields that automatically feature the participation of a wide variety of chemical scientists. We cannot represent a united front if those from our own ranks remain squabbling and divisive. Ultimately there is one kind of chemistry, the one that applies itself to and solves society's most pressing problems. We need every kind of chemistry to make a contribution to this enormously challenging goal.

If we want to reform the culture of chemistry, we first need to ensure that there is a united culture in the first place.

What lessons did you learn from your graduate school advisor?

For better or worse, very few professional relationships in your working scientific life have as much of an impact on your career and your thinking as those with your graduate school advisor. You learn a lot from him or her, and sometimes if things unfortunately don't go well (as in the case of the recent much discussed fiasco), you learn what not to do.

Your graduate school advisor imparts little tidbits of wisdom every single day. And yet there are a chosen few general lessons which stay with you long after you leave. These are lessons which you may not have imbibed consciously, and yet you find them being an integral core of your everyday scientific thinking. There is no big secret in these lessons, yet the process of internalization has greatly amplified their impact on a personal level. I was lucky to have been educated by two first-rate scientists who were (and are) also great human beings. I learnt a lot from them, but a handful of lessons have stayed put. This is of course a listing of key scientific lessons. Let's not even get started on other kinds of lessons which would fill an entire notebook.

1. Always question the assumptions: This was the single-most important lesson I learnt in graduate school and one that was driven home both subconsciously as well as vociferously. Because if the assumptions are flawed or questionable, then no matter how beautiful or even meticulous the study, ultimately it may be fundamentally wrong. How many times have you come across a piece of work which looks both exhaustive and elegant, and yet you don't buy it simply because you cannot accept the basic premise?

Questioning the assumptions can keep you from being swayed by pretty papers in prestigious journals and turn you into the critical thinker that you crave to be. More importantly, this habit will be a perpetual guide that will help you realistically assess the conclusions of every project that you work on. Ultimately you have to remember that there is always an assumption behind every piece of scientific analysis, and assumptions are like enemies bearing gifts who want to become friends. You want to be suspicious of them until convinced beyond a shade of doubt.

2. Keep in touch with the basics: I mentioned this point in my last post, but it's worth reiterating. I used to be impressed by how my advisors would bring a point from college chemistry to bear on the analysis of a seemingly complicated synthetic scheme, reaction mechanism or NMR spectrum. Discussions of complicated problems often used to revolve around basic ideas of nucleophilicity and basicity (remember the differences in trends?!), hydrogen bonding, ring conformations and oxidation states. Chemical problems often look complex because simple principles like to dress themselves up in fancy forms. These principles reveal themselves only when interrogated by equally simple questions. The great mathematician Paul Erdos once said that a tough problem proves its worth by fighting back. But on the flip side, it can also give way sometimes when subjected to the simplest of inquisitions.

3. Think multifactorially: Most problems in chemistry, no matter what discipline they are from, involve dissecting the myriad factors operating in a system and then putting your finger on the one that tips the balance. Integral to such an analysis is to first list the factors. A useful technique I try to practice is to list all the factors responsible for a particular chemical effect.

For instance, if I were analyzing the binding of a ligand to a protein, I list all the possible hydrogen bonds, stacked aromatic interactions, hydrophobic contacts and other kinds of forces that could possibly operate between the different parts of the molecule and the protein. If it were to try to predict the stereochemistry of a reaction, I would think of dominant conformations, steric factors in the reagent and substrate, electrostatic interactions between the two. More sophisticated analysis can then follow, but this simple action puts things in perspective and sets you up favorably for getting a feel for the system.

These lessons are certainly not panaceas and it takes a lot of practice and experience for them to become second nature (although ideally they eventually should). As time goes by you also find yourself adding your own functionality to them. But I will be grateful to my graduate school advisors for imparting them. And not through mere words, but through purposeful action.

What scientific lessons did you learn in graduate school?

What is chemical intuition?

Recently I read a comment by a leading chemist in which he said that in chemistry, intuition is much more important than in physics. This is a curious comment since intuition is one of those things which is hard to define but which most people who play the game appreciate when they see it. It is undoubtedly important in any scientific discipline and certainly so in physics; Einstein for instance was regarded as the outstanding intuitionist of his age, a man whose grasp of physical reality unaided by mathematical analysis was unmatched. Yet I agree that "chemical intuition" is a phrase which you hear much more than "physical intuition". When it comes to intuition, chemists seem to be more in the league of traders, geopolitical experts and psychologists than physicists.

Why is this the case? The simple reason is that in chemistry, unlike physics, armchair mathematical manipulation and theorizing can take you only so far. While armchair speculation and order-of-magnitude calculations can certainly be very valuable, no chemist can design a zeolite, predict the ultimate product of a complex natural product synthesis or list the biological properties that a potential drug can have by simply working through the math. As R B Woodward once said of his decision to pursue chemistry rather than math, in chemistry, ideas have to answer to reality. Chemistry much more than physics is an experimental science built on a foundation of rigorous and empirical models, and as the statistican George Box once memorably quipped, all models are wrong, but some are useful. It is chemical intuition that can separate the good models from the bad ones.

How then, to acquire chemical intuition? All chemists crave intuition, few have it. It's hard to define it, but I think a good definition would be that of a quality that lets one skip a lot of the details and get to the essential result, often one that is counter intuitive. It is the art of asking the simple, decisive question that goes to the heart of the matter. As in a novel mathematical proof, a moment of chemical intuition commands an element of surprise. And as with a truly ingenious mathematical derivation, it should ideally lead us to smack our foreheads and ask why we could not think of something so simple before.

Ultimately when it comes to harnessing intuition, there can be no substitute for experience. Yet the masters of the art in the last fifty years have imparted valuable lessons on how to acquire it. Here are three I have noticed:

1. Don't ignore the obvious: One of the most striking features of chemistry as a science is that very palpable properties like color, smell, taste and elemental state are directly connected to molecular structure. There is an unforgettably direct connection between the smell of cis-3-hexenol and that of freshly cut grass. Once you smell both independently it is virtually impossible to forget the connection. Chemists who are known for their intuition never lose sight of these simple molecular properties, and they use them as disarming filters that can cut through the complex calculations and the multimillion dollar chemical analysis.

I remember an anecdote about the chemist Harry Gray (an expert among other things on colored coordination complexes) who once deflated the predictions of some sophisticated quantum chemical calculation by simply asking what the color of the proposed compound was; apparently there was no way the calculations could have been right if the compound had a particular color. As you immerse yourself in laborious compound characterization, computational modeling and statistical significance, don't forget what you can taste, touch, smell and see. As Pink Floyd said, this is all that your world will ever be.

2. Get a feel for energetics: The essence of chemistry can be boiled down to a fight unto death of countless factors that rally either for or against the free energy of a system. When you are designing molecules as anticancer agents, for hydrogen storage or solar energy conversion or as enzyme mimics, ultimately what decides whether they will work or not is energetics, how well they can stabilize and be stabilized and ultimately lower the free energy of the system. Intimate familiarity with numbers can help in these cases. Get a feel for the rough contributions made by hydrogen bonds, electrostatics, steric interactions and solvent influences. This is especially important for chemists working at the interface of chemistry and biology; remember, life is a game played within a 3 kcal/mol window and any insight that allows you to nail down numbers within this window can only help. The same goes for some other parameters like Van der Waals radii and bond lengths. Linus Pauling was lying in bed with a cold when he managed to build accurate models of the protein alpha helix, largely based on his unmatched feel for such numbers.

A striking case of insights acquired through thinking about energetics is illustrated by a story that Roald Hoffmann narrates in a recent issue of "American Scientist". Hoffmann was theoretically investigating the conversion of graphene to graphane, which is the saturated counterpart of graphene, under high pressure. After having done some high-level calculations, his student came into his office and communicated a very counter-intuitive result; apparently graphane was more stable per CH group than the equivalent number of benzenes. What happened to all that discussion of unsaturation in aromatic rings contributing to unusual stability that we learnt in college? Hoffmann could not believe the result and his first reaction was to suspect that something must be wrong with the calculation.

Then, as he himself recalls, he leaned back in his chair, closed his eyes and brought half a century's store of chemical intuition to bear on the problem. Ultimately after all the book-keeping had been done, it turned out that the result was a simple consequence of energetics; the energy gained in the formation of strong carbon-carbon bonds more than offset that incurred due to the loss of aromaticity. The fact that it took a Nobel Laureate some time to work out the result is not in any way a criticism but a resounding validation of thinking in terms of simple energetics. Chemistry is full of surprises- even for Roald Hoffmann- and that's what makes it endlessly exciting.

Another example that comes to my mind is an old paper by my PhD advisor which refuted an observation indicating that a group in cyclohexane was purportedly axial. In this case unlike the one above, the intuitive and commonly held principle- that substituents in cyclohexanes are equatorial- turned out to be the right one, again based on some relatively simple NMR-assisted computational energetic analysis. On the other hand, the same kind of thinking also led to the discovery that the C-F groups in substituted difluoro-piperidines are axial! Sometimes intuition leads to counter intuition, and sometimes it asserts itself.

3. Stay in touch with the basics, and learn from other fields: This is a lesson that is often iterated but seldom practiced. An old professor of mine used to recommend flipping open an elementary chemistry textbook every day to a random page and reading ten pages from it. Sometimes our research becomes so specialized and we become so enamored of our little corner of the chemical world that we forget the big picture. Part of the lessons cited above simply involve not missing the forest for the trees and always thinking of basic principles of structure and reactivity in the bigger sense.

This also often involves keeping in touch with other fields of chemistry since an organic chemist never knows when a basic fact from his college inorganic textbook will come in handy. Most great chemists who were masters of chemical intuition could seamlessly transition their thoughts between different subfields of their science. This lesson is especially important when specialization has become so intense that it can sometimes lead to condescension toward fields other than your own. Part of the lesson also involves collaboration; what you don't have you can at least partially borrow.

Ultimately if we want to develop chemical intuition, it is worth remembering that all our favorite molecules, whether metals, macrocyles or metalloproteases, are all part of the same chemical universe, obeying the same rules even if in varied contexts. Ultimately, no matter what kind of molecule we are interrogating, Wir sind alle chemikers, every single one of us.

Lindau 2011: What do you want me to translate now?

In 1969, one of the more memorable incidents in the public advocacy of science took place. The American physicist Robert Wilson was asked to testify before Congress in support of the construction of the Fermi National Accelerator Laboratory, known as Fermilab. For Wilson, building this huge machine had been a labor of love and nobody had a better background for it. He had worked on the Manhattan Project where he was the youngest group leader in the experimental division, and after the war he had become a professor at Cornell University.

Wilson was a first-rate amateur architect who saw accelerators as works of art. He lovingly designed Fermilab with his own hands and, in order to add to the aesthetic appeal of the place, turned the surrounding acres into a wilderness housing bison and geese. His efforts paid off; Fermilab would become the largest accelerator in the United States and CERN's primary competitor. In 1969 Wilson was asked to justify the expenditure for the multi-million dollar laboratory in front of Congress. The Cold War was raging, most research and especially physics research was being viewed in the context of national security, and Wilson was specifically asked what contribution the new laboratory would make to national defense. He replied in words that should be etched on the foundation stone of every center of basic research. The research, he said, had no direct bearing on national defense. Instead,

It has only to do with the respect with which we regard one another, the dignity of men, our love of culture. It has to do with: Are we good painters, good sculptors, great poets? I mean all the things we really venerate in our country and are patriotic about. It has nothing to do directly with defending our country except to make it worth defending.

It has nothing to do directly with defending our country except to make it worth defending. In saying these words, Wilson was appealing to the heart of what makes any country great. It is not the fancy cars, the shiny malls, the great financial houses and the cornucopia of industrial food that truly contribute to a country's progress. At one point or another in history, Athens, Florence, Takshashila, Baghdad, Oxford, Gottingen, Copenhagen and Philadelphia were primarily known not for their wealth and the splendor of their monuments but for the unmatched wealth of ideas about science, art, economics, politics, freedom and human dignity that their citizens generated. These ideas are now the bedrock of much of modern civilization. Many of these ideas were solutions to practical problems, but most only sought to explore and push the boundaries of human creativity, curiosity, passion and tolerance. The creators and dreamers of these ideas were less concerned about their practical application and more concerned about their ability to answer questions about human origins and nature, our place in the cosmos and our relationship to other human beings.

Why am I retelling the story of Robert Wilson? Because I believe it strikes at the heart of what these days is fashionably called "translational research". Just like physics research was being viewed through the lens of national defense in the 60s, basic biomedical studies run the risk of being viewed through the lens of translational research in the 2010s. The approach is clearly not popular among leading researchers. In 2009, Nobel Laureate Martin Chalfie gave a talk at Lindau in which he described the great satisfaction he had had from doing non-translational research (in fact Chalifie was going to give a talk about this very topic this year at Lindau but unfortunately could not attend). Chalfie is not alone; as just another example, a few months ago I attended a lecture by another Nobel Laureate, Thomas Steitz, also at Lindau this year. Steitz who won the prize for his exploration of the structure and function of the ribosome proudly announced at the beginning of the talk that "the only kind of translation I have worked on is that orchestrated by the ribosome".

So what is translational research? Many definitions seem to abound and Wikipedia seems to be as good a guide as any: "Translational research is a way of thinking about and conducting scientific research to make the results of research applicable to the population under study and is practised in the natural and biological, behavioural, and social sciences". The goal of translational research especially in medicine seems to transform basic biomedical research discoveries from "bench to bedside".

In the last few years this kind of thinking has has swamped the public discourse on science. New centers are being founded and funded whose mandate is to translate basic research into products directly benefiting humanity. The NIH, the largest biomedical research agency in the world, has also embraced a new National Center for Advancing Translational Research. The director of the NIH, Francis Collins, has not tired of pointing out the exciting advances in discovering new drugs which would be made possible by harnessing data from the human genome project. Not surprisingly, the press has eagerly jumped on the bandwagon, with reports pitching translational research and personalized medicine regularly appearing in the nation's leading papers. Echoing leading scientists, the press seems to be telling us that we should all look forward to supporting translational research in its various guises.

All this makes the idea of translational research sound promising. And yet there must be a good reason why distinguished Nobel Prize winners like Chalfie and Steitz bristle at the mention of translational research. The reason is actually not too hard to discern. The problem is not with applied research per se. Nobody can doubt that applied research especially done by the pharmaceutical and biotechnology industries has saved innumerable lives in the last one hundred years. As Pasteur said, "there is science and the applications of science", and he saw them lying on a continuum. No, there is nothing wrong with trying to turn basic ideas into applied products.

What is wrong is that translational research is being seen as a panacea that will address the flagging rate of new biomedical advances. The thinking seems to declare that if only more people were given more money and deliberately focused on direct application, we would suddenly see a windfall of new therapies against disease. This thinking suffers from two major problems.

The first problem is that history is not really on the side of translational research. Most inventions and practical applications of science and technology which we take for granted have come not from people sitting in a room trying to invent new things but as fortuitous offshoots of curiosity-driven research- the kind that Chalfie and Steitz have dedicated their lives to. Penicillin was discovered through serendipity by a most alert Alexander Fleming who was trying to plate bacterial cultures, not one trying to actually discover the next breakthrough antibiotic. Nuclear Magnetic Resonance was discovered by physicists who were tinkering with atoms in magnetic fields, not ones who were trying to find a method for determining the structures of organic and biological molecules. The discovery of most drugs built upon basic discoveries about human physiology and anatomy made by physicians and researchers who were simply trying to find more about how the body works. The new class of drugs inhibiting protein kinases for instance ultimately owe their development to the discovery of phosphorylation, a fundamental discovery by this year's Lindau attendee Edmond Fischer that was a result of purely basic scientific thinking about how chemical signals are communicated by cells. Similarly, Steitz's ribosome and Chalfie's green fluorescent protein are lending themselves to drug discovery and medical advances in ways which they never planned.

If the history of science teaches us anything, it is that curiosity-driven basic research has paid the highest dividends in terms of practical inventions and advances. Tinkering, somewhat aimless but enthusiastic exploration of biological and physical systems and following one's nose have been the ingredients for some of the key inventions that have transformed our lives. Radar, computers, drugs, detergents, plastics and microwave ovens were all made possible not because someone sat down and tried to discover them but because they arose as fortuitous consequences of elemental, pure research. The hype of translational research not only deflects attention from curiosity-driven basic research but also creates the illusion that asking people to discover new things is the best way to generate new ideas. In fact, trying to discover new things by forcing people to discover them will only siphon off funds from those who have the actual capability of discovering these things.

The second more practical but equally important problem with translational research is that it puts the cart before the horse. First come the ideas, then come the applications. There is nothing fundamentally wrong with trying to build a focused institute to discover a drug, say, for schizophrenia. But doing this when most of the basic neuropharmacology, biochemistry and genetics of schizophrenia is unknown is a great diversion of focus and funds. Before we can apply basic knowledge, let's first make sure that the knowledge exists. Efforts based on incomplete knowledge would only result in a great squandering of manpower, intellectual and financial resources. Such misapplication of resources seems to be the major problem for instance with a new center for drug discovery that the NIH plans to establish. The NIH seeks to channel the new-found data on the human genome to discover new drugs for personalized medicine. This is a laudable goal, but the problem is that we still have miles to go before we truly understand the basic implications of genomic data. It is only recently that we have started to become aware of the "post-genomic" universe of epigenetics and signal transduction. We have barely started to scratch the surface of the myriad ways in which genomic sequences are massaged and manipulated to produce the complex set of physiological events involved in disease and health.

And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.

Chalfie, Steitz and others like them are also right to criticize the frenzy that translational research generates in the popular press. We live in an age when buzzwords are eagerly generated and lapped up by the media. These buzzwords usually run roughshod over subtleties and ambiguities and the press seldom has a taste for indulging these in the first place. Needless to say, committing national resources and public attention to translational research when most of the basics are still to be understood is an endeavor fraught with great risk and uncertainty. It would be far wiser to bolster basic research that can bring us to the brink of real application. There are places where such research is conducted. They are called universities.

Ultimately, the importance of basic research goes back to what Robert Wilson said to Congress. It has to do with the same reasons that we created the Mona Lisa, painted the Sistine Chapel, built Chartres Cathedral, wrote The Love Song of J. Alfred Prufrock and composed the Goldberg Variations. Da Vinci, Michelangelo, T. S. Eliot and Bach were all trying to find the essence of man's soul and his relationship with the universe and with his fellow men. So were Einstein, Newton, Faraday and Darwin. They were not trying to invent a better mousetrap, but the world did beat a path to their door. Similarly, once our basic understanding of biological systems is firmly in place, translation will willingly follow.

The next researcher, when asked to comment on the relevance of his or her basic studies in cell biology to translational research, should echo Wilson: "
It has nothing to do directly with translational research, except to enable it".