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".

The protein folding funnel and its discontents

Speaking of protein folding, here's something interesting. One of the most enduring views of protein folding from the last decade is that of an "energy funnel". The funnel was invented by the UCSD chemist Peter Wolynes in the 90s (the original paper is highly readable) and essentially depicts a plot of the configurational enthalpy (or effective energy) of the protein on the Y axis vs the configurational entropy on the X axis. In real situations this plot is multidimensional.

The funnel suggests a way out of Levinthal's paradox which contrasts the fast folding times for virtually all proteins with the vast amount of conformational space to be searched. According to the funnel viewpoint, the energy of the protein on the Y axis decreases and becomes more favorable even as the entropy on the X axis decreases, leading to fewer conformations to be searched and allowing the protein to rapidly find the native structure. The funnel has become a mainstay of descriptions of protein folding and has made its way into textbooks.

The funnel view of protein folding had always puzzled me a little for the simple reason that we usually think of the enthalpy and entropy of the protein (and in fact of any chemical system) as opposing factors. Entropy would hinder the protein even as it formed more "native" contacts and led to a favorable enthalpy. Yet the funnel seems to suggest a synergy between these two factors. Many papers have said that the funnel "guides" the protein to its correct conformational state. In this week's Nature Chemical Biology, one of the founding fathers of the field, Martin Karplus, sheds some light on this confusion and informs us that the traditional view of the funnel is indeed a little misleading.

To support his argument, Karplus illustrates two examples of protein folding studies using two kinds of systems. One is a lattice model system in which the protein is approximated by beads on a lattice. Native contacts in the protein are indicated by adjacent beads on the lattice. The other folding simulation is a standard molecular dynamics simulation of an alpha helix. In both cases the proteins are small (about 30 residues) but their behavior at low and high temperatures is intriguing.

At low temperatures, the folding landscape is more "rugged" and folding is slower. This is a well-established concept and it simply means that there is less energy for the protein to explore all the available local minima. At high temperature the landscape is "smooth" and the protein has enough energy to explore many conformational states. What is striking is that while the effective energy (enthalpy) at high temperature decreases smoothly all the way to the native state, the free energy (which is what we should really be worrying about) has a significant barrier. Thus this barrier has to come from entropy. The crucial thing to note is that at high temperatures, the free energy is dominated by the increasing unfavorable entropy engendered by the greater number of conformations that the protein has to search.

Ultimately it's easy to forget that the protein folding "funnel" is only a theoretical construct, an intuitive model. Has anyone actually observed a funnel for a real protein? As the article notes, for now the answer is a decided "No". Unfortunately it may be impossible to ever do so since to construct a real funnel one would need knowledge of every single conformational state that a protein visits on its way to folding. In addition since folding is a statistical phenomenon, one would also need knowledge of every starting trajectory. Needless to say, for now this is at best a pipe dream. However the funnel remains a useful construct provided we remember the subtleties and caveats that Karplus has described. Ultimately it's a model, and like other models it need not be real, but it should at least be useful.

Karplus, M. (2011). Behind the folding funnel diagram Nature Chemical Biology, 7 (7), 401-404 DOI: 10.1038/nchembio.565

Lindau 2011: What do scientists do after winning the Nobel Prize?

Most of us know about the prize-winning work of this year's Lindau Nobel Laureates, but how many of us keep track of what they did after winning the coveted honor? Scientists' lives after the Nobel Prize change dramatically. As former Lindau attendee Richard Ernst put it, they are now expected to be oracles on everything from international politics to religion, even when their knowledge of most other things is as limited as that of other people. There is no common thread; after winning the Prize, scientists' lives become as varied as those of all of us and in some cases a little more interesting. Here's a short portrait of life after the Nobel Prize illustrated with a select few examples...

Read the rest of the post on the Lindau blogs site...

The fine-tuning problem in protein folding: Is there a protein multiverse?

One of the deepest questions physicists have struggled with in the last half-decade is the so-called "fine-tuning problem". The fine-tuning problem asks why the values of the fundamental constants (Planck's constant, the speed of light, the mass of the electron etc.) are what they are.

The reason why physicists are so worried about the values of these constants is because presumably if the values were even a little different from what they are, the universe and life as we know them would not exist. For instance, even a slight weakening of the strong nuclear force that holds nucleons together would prevent the formation of atoms and thus of all complex matter. Similarly, a slight change in the electromagnetic force would fundamentally alter the interactions between atoms crucial for the formation of chemical bonds between the molecules of life.

There thus seems to be some factor during the evolution of the universe responsible for fine-tuning the values of the constants to their present values within an incredible window of accuracy. The fine-tuning problem is a real problem not least because some religious believers point to the unchangeable and precise values of the constants to be the work of some kind of intelligent designer.

In the last few decades there have been a few attempts to resolve the fine-tuning problem. Probably the most exotic and yet in some ways the most reasonable solution has been to assume the existence of multiple parallel universes. Multiple universes (or multiverses) were first proposed by Hugh Everett, a brilliant and troubled physicist who worked on nuclear weapons targeting, as a way around the so-called "measurement problem" in quantum mechanics. The measurement problem is fundamentally embedded in the quantum description of our world. The unsettling thing (and one that troubled Einstein) about quantum mechanics is that it assigns probabilities to certain events, but provides no answer as to why only one of those events materializes when we make a measurement. Everett worked around this conundrum by assuming that in fact all possible events actually do take place, but only one of them is part of our universe; the rest of the events also occur, but in parallel universes. Everett's interpretation which was regarded to be a fringe explanation for years (thus making it successfully into science fiction books) is now taken seriously by many physicists.

Being a problem associated with the most fundamental constants of nature, the fine-tuning problem makes its way into all "higher-level" sciences including chemistry and biology. In chemistry the fine-tuning problem takes on a fascinating form and entails asking why certain molecules have become fundamental to living systems while other more or less equivalent alternatives have been discarded during evolution. For instance, why alpha amino acids (and why not beta or gamma amino acids)? Why left-handed amino acids and right handed-sugars? Why phosphates and not sulfates or silicates? In retrospect one can think of answers to these questions based on factors like stability, versatility and ease of synthesis, but ultimately we may never know. However, the fine-tuning problem also manifests itself in one of the most fundamental processes in the workings of life; protein folding.

The protein folding problem is well-known; given an amino acid sequence, how can a protein fold into a single three-dimensional structure and reject the countless number of other possible structures it can fold into? What is even more remarkable about this problem is that several thousand of those other structures are almost equienergetic with the preferred folded structure and yet they do not form. In fact it is this energetic equivalency between several structures that plagues all modern computational protein folding algorithms; the problem is not so much to generate the one correct structure as it is to distinguish it from other structures that are very close to it in energy. The fundamental assumption in all these algorithms is that the correctly folded structure is the lowest-energy structure. But that does not mean it differs in energy from the other solutions disproportionately. Therein lies the rub.

Ever since I heard about the protein folding problem this issue has bothered me as I am sure it has others. Consider that the free energy difference between two different protein structures may be only 5 kcal/mol or so, about the energy of a single hydrogen bond. Yet a protein when it folds unerringly picks only one among the two structures. How can nature manage to pick the right solution every one of millions of times when it folds proteins inside our body each second? To put it another way, here's the "fine-tuning problem" in protein folding: why does a protein always adopt one and only one correct structure even when many other structures, very similar in energy and presumably in function, are available to it?

From a retrospective evolutionary standpoint the answer to this conundrum is perhaps not too surprising. Imagine what would happen if every time a newly synthesized copy of a given protein folded, it formed a slightly different structure. This heterogeneity and lack of quality control would play havoc with the intricate signaling networks in our body. Evolution simply cannot afford to have different three-dimensional structures for the same protein, no matter how slightly different they are. No wonder that quality control in protein folding is extreme. Of course nature does make occasional mistakes, but wrongly folded proteins are quickly degraded and destroyed.

Nonetheless, the original dilemma persists and metamorphoses into a further interesting question: isn't it possible for a protein structure that is slightly different from the one true structure to be functional? There are two possible answers here. Perhaps the alternative structure was functional during evolution at one point, but competition from the slightly better structure weeded out the former from the gene pool. If this is the case, could there be a chance that there is some unknown form of life in which this other slightly different yet perfectly reasonable structure still exists, happily doing its job with no evolutionary pressure around to discard it? The best way to answer this question is to compare proteins from different species, something that has been extensively done for years. But such a comparison usually reveals protein homology, in which the sequences themselves are slightly different and yet perform similar functions.

That's not what we are looking for. What we are looking for is "two" proteins with absolutely identical amino acid sequences which in two different creatures adopt slightly different three-dimensional structures and perform similar functions. Or they could even perform different functions, thus validating evolution as a force that puts slight differences to optimal use. Let us call these proteins with identical sequences but different functional folds "fold mutants". To my knowledge such fold mutants have not yet been found.

A second albeit more exotic solution to the fine-tuning problem appeals to a possible "protein multiverse". The argument here is that the kind of protein structures which we observe are indeed not the only feasible or functional ones. There are in fact other structures which are not only well-folded but also functional. For some reason, evolution, during its intricate dance of maintaining order, structure and function, chose to discard these structures in favor of ones that were more functionally relevant in this universe. However there is no reason why they could not have been picked in a different universe, where the laws were slightly different. There is another way to think of a protein multiverse; as a set of valleys and peaks where the valleys correspond to different folded structures. Such a metaphor has also been used by physicists to argue that our universe with its own set of fundamental constants corresponds to one local minimum in this "multiverse landscape", with other universes populating the other dips. Similarly we could imagine a protein multiverse landscape in which different protein folds occupy different valleys; we favor a particular fold only because it inhabits our own valley, but that does not stop other folds from corresponding to the others.

In a different universe, hemoglobin could have folded into a marginally different structure in which it bound not oxygen but some other small ligand like ammonia more efficiently. Such a fold mutant of hemoglobin would be useful to creatures which survive in an ammonia-rich environment (ammonia in fact has a greater temperature range as a liquid compared to water). Or one could imagine a fold mutant of carbonic anhydrase, which catalyzes the conversion of carbon dioxide to bicarbonate at a different pH or a different temperature. Fold mutants of known proteins could have every conceivable property different from their original "correctly" folded counterparts, including shape, size, polarizability and stability. The fold mutants could be exquisitely adopted to living conditions in their parents universe. Their special folds could be stabilized by environments differing from those found on earth in ionic strengths, hydrogen bonding capabilities and hydrophobicities. For a given protein, this alternative fold could in fact be the lowest in energy and its companion fold found in our universe could be slightly higher in energy.

This kind of speculation immediately suggests two explorations. One is to look for fold mutants in other parts of the universe. This search would be part of the search for extraterrestrial life that has been going on for years. But the point is that if we happen to find fold mutants of existing proteins on other planets or in other inhospitable environments, these mutants would provide powerful support for the solution of the fine-tuning problem. They would tell us that the fine-tuning problem exists only in our narrow-minded anthropocentric imagination, that there could indeed be many folds of the same protein that are robust and functional and that we just happen to inhabit a part of the universe that stabilizes our favorite fold.

The other more readily testable experiment asks if we can produce different functional folds from the same amino acid sequence by varying the experimental conditions. It's of course well-known to crystallographers and protein chemists that slight changes in physicochemical conditions can play havoc with the structure and function of their proteins. But most of the times these slight changes in conditions produce misfolded protein junk. Is there an example of someone slightly (or even radically) varying conditions in a test-tube and producing two different folds of the same protein that are both stable and functional? If there is one I would be very eager to know about it.

On the other hand, if it turns out that it's impossible to find two different functional folds for a single protein, such an observation might well lend credence to the physicists' multiverse with differing fundamental constants. It might well be that under the present values of fundamental constants, it is impossible to stabilize a slightly different protein fold and make it functional. Perhaps only a slight albeit conceptually radical restructuring of the fundamental constants could result in a universe that is friendly to fold mutants. Such a universe would still enable the creation of complex matter through the appropriate combination of the constants, but it would indeed result in life very different from what we know.

The protein multiverse could thus help resolve the fine-tuning problem in protein folding and make biochemists and physicists part of the same multiverse fraternity. More importantly, it could once again reinforce the diversity of creation. One could have different universes with the same fundamental constants but different protein folds or different universe with entirely different combinations of the constants themselves. Take your pick.

If uncovered, such diversity would only echo J B S Haldane's quote that the "universe is not only queerer than we suppose, but it is queerer than we can suppose".

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Lindau 2011: From designing airplanes to designing proteins

An inspiration from the birth of aviation

A few weeks ago I visited the small coastal town of Kitty Hawk in North Carolina. Kitty Hawk is where the Wright brothers made their epoch-making first powered flight. Big stones mark the start and end points of the flight. There is a huge monument on top of a hill where they took off and then there are three stones at varying distances at ground level. The three stones indicate the distances covered on every flight; the brothers clearly got better at flying on every attempt.

The Wright brothers' story is inspiring not only because of the watershed in human history which they orchestrated but also because it shows the evolution of a technology at its best. The projects which the brothers undertook cost a few hundred dollars and should serve as a beacon of inspiration in this era of "big science" involving hundreds of millions of dollars. The brothers had a bicycle workshop in which they fashioned many of the components of their infant gliders. They drew inspiration from Otto Lillienthal who had been the first aviation pioneer to make successful glided flights; tragically, Lillienthal was killed on one of his flights, but not before saying "Kleine Opfer müssen gebracht werden!" ("Small sacrifices must be made!").

One of the most important lessons that the Wrights learnt from Lillienthal's adventures was the great value of building 'toy' models. Toy models start from the simplest possible systems which retain the essential features of a phenomenon and then work their way towards greater complexity. This philosophy has been used by many other pioneers of technology, including the scientists and engineers who made the moon landings possible...

Read the rest of the entry at the Lindau blogs website...

Putting the filosophy back into fysiks

How the Hippies Saved Physics: Science, Counterculture, and the Quantum Revival- David Kaiser

Does philosophy have a place in serious science? Many of the founders of modern physics certainly thought so. Einstein, Bohr, Heisenberg and Schrodinger were not just great scientists but they were equally enthusiastic and adept at pondering the philosophical implications of quantum theory. To some extent they were forced to confront such philosophical questions because the world that they were discovering was just so bizarre and otherworldly; particles could be waves and vice versa, cats (at least in principle) could be alive and dead, particles that were separated even by light years appeared to be able to communicate instantaneously with each other, and our knowledge of the subatomic world turned out to be fundamentally probabilistic.

However, as quantum theory matured into a powerful tool for calculation and concrete application, the new generation of physicists in general and American physicists in particular started worrying less about "what it means" and much more about "how to use it". American physicists had always been more pragmatic than their European counterparts and after World War 2, as the center of physics moved from Europe to the United States and as the Cold War necessitated a great application of science to defense, physicists turned completely from the philosophizing type to what was called the "shut up and calculate" kind; as long as quantum mechanics agrees spectacularly with experiment, why worry about what it means? Just learn how to use it. Yet this only swept epistemological questions under the rug.

Curiously, there emerged in the 1970s a quirky and small group of physicists in the Bay Area who tried to resurrect the age of philosopher-scientists. In "How the Hippies Saved Physics", David Kaiser wonderfully tells the very engaging story of this "Fundamental Fysiks" group and how it kept alive some of the deep philosophical questions that had haunted the founding fathers. The "Fysicists" came from a variety of backgrounds, but all of them had been dissatisfied; both by the dismal job market for physicists after the Cold War craze and more importantly by the purely practical approach toward physics which they learnt in graduate school. Interestingly they combined their deep questions about physics with the emerging hippie counterculture of the 60s and 70s and it's pretty clear from the book that they had great fun doing this; after all this was an age when non-conformity was encouraged. Discussions of physics concepts blended seamlessly with Eastern mysticism, forays into LSD-induced mind experiments, New Age workshops at the Esalen Institute in California and meanderings into telepathy, consciousness and parapsychology. Books like Fritjof Capra's "The Tao of Physics" which explored parallels between modern physics and Eastern religions only helped the movement. The small group of physicists was also fortunate to get funding from some unlikely sources, including self-help guru Werner Erhard and even the CIA who was interested in possible connections between ESP and physics. Not surprisingly, mainstream physicists often ignored and sometimes actively condemned such activities

However, as Kaiser describes in this fascinating volume, this ragtag group of countercultural philosopher-scientists achieved at least one crucial goal; they kept questions about the philosophical implications of quantum theory alive at a time when most physicists eschewed and disdained such questions. Gradually, they managed to get a handful of mainstream physicists interested in their philosophizing. Much of the connection of this philosophy to real physics centered about a remarkable result called Bell's theorem which essentially reinforced the spooky properties of quantum systems by showing that information in quantum systems can flow instantaneously between particles. Remarkably, this seemingly otherworldly idea of "quantum entanglement" (which gave some of the founding fathers heartburn) now lies at the foundation of some of the most cutting-edge areas of modern physics, including quantum computation and the new discipline of quantum information science. What was considered far-flung by mainstream physicists and kept alive by the Fundamental Fysiks group is now serious physics for many. In fact, at least a few physicists who put Bell's theorem to experimental test are regarded as candidates for a Nobel Prize (these especially include John Clauser, Alain Aspect and Anton Zeilinger who shared the prestigious Wolf Prize- often a forerunner to the Nobel Prize- in 2010).

In the end Kaiser wants to make the case that by keeping such once-disparaged philosophical concepts alive, the Fundamental Fysicists "saved physics". I am a little skeptical of this claim. They certainly managed to nurture and publicize the concepts, but it was the harnessing of these concepts by "real" physicists who were involved with the nuts and bolts of calculation and experiment that actually saved the concepts and kept them from turning into a purely philosophical mishmash. In addition, a lot of concepts that the New Age physicists bandied about belonged squarely in the realm of pseudoscience and the trend continues; people like Deepak Chopra commit gross violations of quantum mechanics on a daily basis. Unfortunately the line between science and non-science can be thin and one of the most intriguing discussions in Kaiser's book is this so-called "demarcation problem". How does one know if today's philosophy is tomorrow's cutting edge science or just noisy mumbo-jumbo? It's not always easy to say.

Nonetheless, I think Kaiser and the Fysicists make a really great general case for why philosophical questions in science have their own place and should not be rejected. For one thing, they are always fascinating in themselves and demonstrate the endless human quest for meaning and reality; as recent discussions indicate, the philosophical conundrums in physics have been far from answered and continue to be explored through even more bizarre ideas like parallel universes and multiple dimensions. And as this wonderful book shows, at least in some cases these discussions may lead to key advances by influencing mainstream physicists who validate them by subjecting them to the ultimate arbiter of truth in science- hard experiment.

Lindau 2011: The beginning

This year I am privileged to be invited again to write for and attend the 61st Meeting of Nobel Laureates in Lindau, Germany. This year's meeting is dedicated to Physiology or Medicine and the list of attendees provides a glimpse of the diversity and impact of biomedical research. These men and women have made enormous contributions to our understanding of biological systems, from elucidating structures and pathways to providing tools of inestimable value. My first post just went up and I will be linking to others as I write more. Here's the first one.

From messy to magical: Preparing for the future of medicine

In the early 1940s, as war raged over the continent, the British mathematician Freeman Dyson and the Indian physicist Harish Chandra were taking a walk in Cambridge. Harish Chandra was studying theoretical physics under the legendary Paul Dirac while Dyson was getting ready to spend a depressing time calculating bombing statistics at Bomber Command.

“I have decided to leave physics for mathematics”, quipped Harish Chandra. “I find physics messy, unrigorous, elusive”. “That’s interesting”, replied Dyson. “I am planning to leave mathematics for physics for exactly the same reason.” Leave their respective disciplines the two did, and both of them had highly distinguished careers in their new fields at the Institute for Advanced Study in Princeton.

I narrate this story because I can imagine almost exactly the same conversation taking place today between a biomedical researcher and any other kind of natural scientist. In fact it’s interesting to compare the status of medicine today with the status of physics when Dyson and Harish Chandra had their conversation. By 1940 physics had underwent a great revolution in the form of quantum mechanics and relativity. Yet there was much to be done and the “second revolution” was in the making. In retrospect it’s clear that very little was known about the strong and weak nuclear forces and nothing was known about the particle “zoo” that would be uncovered in the next few years. It took the efforts of many brilliant individuals to unify crucial concepts and make the whole structure look more consistent and complete.

Medicine in the year 2011 is like physics in the year 1940. Just like physics it has had a recent revolutionary past in the advent of molecular biology. Just like physics there is much of it that is “messy, unrigorous, elusive”. And it’s exactly these qualities that make it a field ripe for another revolution. The future beckons for medicine and biology today as it did for physics in 1940.

Read more at the Lindau blogs website...