How chemistry exemplifies the Fermi method

In my review of the new biography of Enrico Fermi I alluded to one of Fermi's most notable qualities - his uncanny ability to reach rapid conclusions to tough problems based on order of magnitude, back of the envelope calculations. This method of approximation has since come to be known as the Fermi method, and problems which can especially benefit from applying it are called Fermi problems.

It struck me that chemistry is an especially fertile ground for applying the Fermi method, and in fact many chemists probably use the technique unconsciously in their daily work without explicitly realizing it. For understanding why this so, it's worth taking a look at some of the details of the method and the kinds of problems to which it can be fruitfully applied.

At the heart of the Fermi method is a way to make educated guesses about different factors and quantities that could affect the answer to a problem. Usually when you are looking at complicated problems not just in physics or chemistry but in psychology or economics for that matter, much of complex problem solving involves examining different factors that could influence the magnitude and nature of the solution. For instance, say you were calculating the trajectory of a bomb dropped from an airplane. In that case you would consider parameters like the velocity of the plane, the velocity of the bomb, air resistance, the weight of the bomb, the angle at which it was dropped etc. If you were trying to gauge the impact of a certain economic proposal on the economy, you would consider the market and demographic to which the proposal was applied, the presence or absence of existing elements which could interact positively or negatively with the proposed policy, rates of inflation, potential changes in the prices of certain goods relevant to the policy etc. The first part of the Fermi method simply involves writing down such factors and making sure you have a more or less comprehensive list.

The second part of the Fermi method consists of making educated guesses for each of these factors. The crucial aspect of this part is that you don't need to make highly accurate predictions for each factor to the fourth or fifth decimal place. In fact it was precisely this approach that made Fermi such a novelty in his time; it was because physicists could calculate quantities to four decimal places that they were often tempted to do this. Fermi showed that they didn't have to, and in some sense he weaned them away from this temptation. The fact of the matter is you don't always need a high degree of accuracy to reach actionable, semi-qualitative conclusions; you just need to know some rough numbers and get the answer right to an order of magnitude. That was the key insight from Fermi's technique.

Now, before I proceed and discuss how these two aspects of the Fermi method may apply to chemistry, it's worth noting that there are of course several examples in which an order of magnitude answer is simply not good enough. A famous example concerns the very Manhattan Project of which Fermi was such a valued member. In the early phases of the project when General Leslie Groves was picked as head of the project, he quizzed the scientists in Chicago about how much fissile material they would need. When they said that at that point all they give him was an answer correct to an order of magnitude, he was indignant and pointed out that that would be tantamount to ordering a wedding cake and not knowing whether to order enough cake for ten people or one person or a hundred people.

Notwithstanding such specific cases though, it's clear that there are in fact several example of general problems which can benefit from Fermi's technique. Chemistry in fact is a poster child for both the key aspects of the method illustrated above. Many problems in chemistry involve estimating the various kind of forces - electrostatic, hydrophobic, hydrogen bonds, Van der Waals - influencing the interaction of one molecule with another. For instance when a drug molecule is interacting with a protein, all these factors play an important role. Sometimes they synergize with each other and sometimes they oppose each other. Using the Fermi method then, you would first simply make sure you are listing all of them as comprehensively as possible. The goal is to come up with a total number resulting from all these contributions that would crucially provide you with the strength or free energy of interaction between the drug and the protein; a quantity measured in units of kcal/mol.

This part is where the method is especially useful. When you are trying to come up with numbers for each of these forces, it's valuable simply to know some ranges; you don't need to know the answers to three decimal places. For instance, you know that hydrogen bonds can contribute 2-5 kcal/mol, electrostatic interactions usually add 1-2 kcal/mol, and all the hydrophobic interactions will add a few kcal/mol to the mix. There are some trickier estimates such as those for the entropy of interaction, but there are also approximations for these. Sum up these interactions and you can come up with a reasonable estimate for the free energy of binding. The job becomes easier when what you are interested in are differences and not absolute values. For instance you may be given a list of small molecules and asked to rank these in order of their free energies. In those cases you just have to look at differences: for instance, if one molecule is forming an extra hydrogen bond and the other isn't, you can say that the first one is better by about 2-3 kcal/mol. You can also use your knowledge of experimental measurements for calibrating your estimates, another trait which Fermi supremely exemplified.

This then is the Fermi method of approximate guesses in action. One of the reasons it's far more prevalent in chemistry than physics is because unlike physics, in chemistry it's usually not even possible to calculate numbers to very high accuracy. Therefore unlike some physicists, chemists would not even be tempted to attempt to do this and would have already resigned themselves (if you will) to making do with approximate solutions. Today the Fermi method is incorporated in both the minds of seasoned working chemists as well as in computer programs which try to automate the process. Both the seasoned chemist and the computer program try to first list all the interactions between molecules and then try to estimate the strengths of each interaction based on rough numbers, adding up to a final value. 

The method does not work all the time since every interaction is modeled, so it may potentially miss some important real life component. But it works well enough for chemists and computers to employ it in a variety of useful tasks, from narrowing down the set of drug molecules that have to be made to prioritizing molecules for new materials and energy applications. Enrico Fermi's ghost lives on in test tubes, computers, fume hoods and spectrometers, more than even his wide-ranging mind could have imagined.

The man with an inside track to God: A new biography of Enrico Fermi

Scientists come in at least as many flavors as fruit. Some are inspired philosophers, others are get-your-hands-dirty mechanical craftsmen, yet others are like birds which can survey multiple parts of the scientific landscape from a very high altitude. But whatever other classification you may use, there are two distinctions which scientists have always exemplified. They can be either theoreticians or experimentalists, and especially these days, they are all specialists. In an age where it can take a lifetime to understand the complexities of even a narrow part of your science, excelling at every subfield of a scientific discipline, let alone both theory and experiment, would seem like an impossible feat.

Enter Enrico Fermi, the likes of whom we are unlikely to see for a very long time. Bucking almost every neat scientific distinction, Fermi was the only scientist of the twentieth century who was supremely accomplished in both theoretical and experimental physics. Almost any of his discoveries would have been enough to net a Nobel Prize, and yet he made at least half a dozen of them. In addition he was one of the three or four physicists of the century who were universalists, making contributions to and displaying a sound grasp of pretty much every branch of physics, from the microscopic to the cosmic. In my opinion, among his contemporaries only Hans Bethe, John von Neumann, Richard Feynman and Luis Alvarez came close to demonstrating the same breadth, and none of them excelled in both theory and experiment. You could ask Fermi any problem, and as long as he could calculate it he could give you an answer: no wonder that his colleagues called him the "Pope of Physics". It also helped that he lived through a century in which physics made momentous contributions to the human intellect and condition, and he was both fortunate and supremely qualified to be a major part of these contributions. As just one aspect of his extraordinary imprint on physics, no scientist has as many measurements, rules, laws, particles, statistics, units, and energy levels named after him as Fermi. He was also one of America's greatest immigrants.

This is a fine biography of Fermi written by Gino Segre and Bettina Hoerlin - a practicing physicist and a historian of science - who both had connections to Fermi through their families. Hoerlin's father worked on the Manhattan Project. Segre is the nephew of Emilio Segre, Nobel Prize-winning physicist and one of Fermi's closet friends and collaborators. The authors document Fermi's upbringing in Italy at the turn of the century. The Fermis came from a verdant, hilly region of Italy known for its industrious farming community, and throughout his life Fermi maintained his love for manual labor and the mountains, qualities endemic to many people from this region. His father was a railway inspector. Enrico was a child prodigy who combined great intellect with hard self-reliance and perseverance, qualities which were inculcated by his hardworking parents. A life-changing tragedy at age fifteen - the sudden death of his brother with whom he was best friends - turned him toward physics and mathematics. His performance as a seventeen year old in the entrance examination for a well-known university in Pisa displayed knowledge that would have been substantial for a graduate student. From then on his scientific development proceeded smoothly, and before he was 30 he was both Italy's leading physicist as well as one of the world's greatest scientists.

The book lays out many of Fermi's major discoveries. Two in particular bracket his unsurpassed talents as both a theoretician and an experimentalist. In 1933 Fermi came up with a mathematical theory of radioactive decay and the weak nuclear force. And in 1942 he and his team assembled the world's first nuclear reactor. It is almost impossible to imagine any other scientist accomplishing these two very different and very important feats; the famed historian C. P. Snow paid Fermi the ultimate tribute in this regard when he said that, had Fermi been born twenty years before, he could have discovered both Niels Bohr's quantum theory of the atom (theory) and Ernest Rutherford's atomic nucleus (experiment). In the 1930s Fermi and his team became the world expert on neutrons; life in the physics institute on Via Panisperna in Rome was bucolic in spite of being intense. He almost single-handedly discovered the power of slow neutrons which are used to harness nuclear energy in reactors. He and other leading physicists also narrowly missed discovering nuclear fission, mistaking fission products for elements beyond uranium. Rome under his scientific tutelage became a magnet for scientists like Hans Bethe and Edward Teller who learnt the art of problem-solving in physics from the master. Fermi's marriage to a very intelligent and resourceful woman, Laura, cemented his family life. But the pall of fascism was dropping on Italy through the person of Benito Mussolini. Laura was Jewish, and by 1938 Fermi realized that he had to emigrate to another country. Fortunately the receipt of the 1938 Nobel Prize gave him the perfect opportunity to flee to the United States. Along with other brilliant scientists like Bethe, Albert Einstein, Leo Szilard and John von Neumann, Fermi became one of fascism's greatest gifts to this country.

In the United States Fermi was already known as the leading nuclear physicist of his generation. When nuclear fission was discovered in Germany at the end of 1938, there were legitimate fears that the Nazis would harness it to build an atomic bomb. Efforts to investigate fission in the US kicked into high gear, especially after Pearl Harbor. It was not surprising that the scientific community turned toward Fermi to assemble the world's first nuclear reactor. The book's account of this tremendous feat involving black graphite bricks and faces, the squash stand at the university and the sometimes amusing consequences of secrecy is worth reading. First at Columbia and then memorably at Chicago, Fermi and his team achieved the first self-sustaining nuclear reaction on December 6, 1942: a coded telegram went out to the leaders of the Manhattan Project saying that the "Italian navigator had landed in the New World". Even if he had accomplished nothing else this would have been sufficient to enshrine Fermi's name in history. But he kept on making major contributions, first at Chicago and then at Los Alamos. At Los Alamos Fermi's universal expertise was so valued that Oppenheimer created an entire division named after him (the F division). He became a kind of all-round troubleshooter who could solve any problem in theoretical or applied physics, or in engineering for that matter. He had an uncanny feel for numbers, and became known for posing and solving 'Fermi problems' which benefited from quick, back of the envelope, order-of-magnitude estimates. The iconic realization of the Fermi method was during the world's first atomic test in New Mexico on July 16, 1945, when, as the shockwave reached him, Fermi threw pieces of paper into the air and calculated the yield of the test based on the distance at which they fell. This calculation compared favorably with more sophisticated measurements that took several days to acquire.

After the war Fermi became a professor at Chicago where he again served as a magnet for the new generation of physicists exploring the frontiers of particle physics and cosmology. He was an incredibly clear and succinct teacher, and gave his students a true feel for the entire landscape of physics. Teaching was not just limited to classrooms but spilled over into the lunch cafeteria and on hikes. Physicists like Freeman Dyson and Richard Feynman made pilgrimages to see him from around the country, and six of his students received Nobel Prizes. Even after winning enough accolades for a lifetime, he worked harder and more diligently than anyone else. His colleagues joked that he was the man with an inside track to God, so all-encompassing were his scientific and computing abilities. His notes on thermodynamics, quantum mechanics and nuclear physics are still available and they attest to his clarity. At Chicago he not only made important contributions to experimental particle physics but he also made the first forays into computing. The so-called Monte-Carlo method which allows one to explore features of a system by making random jumps bears his imprint.

While not a very sentimental man, Fermi's friendliness, integrity, modesty and impartial, non-emotional attitude endeared him to almost everyone he came in contact with. He was friendly and had an impish sense of humor, but while not cold was also not a warm person who engaged intimately with those around him; this quality led to a family life which while not unhappy was also not particularly joyous, and his relative lack of affection was reflected in the brisk relationship that Fermi had with his daughter and son. He despised politics but still served on important government committees because of his feelings of duty toward his adopted country. Remarkably, his neutrality through some very politically fraught times was not detested, and he was one of the very few scientists who was admired by people who were each other's sworn enemies. While he opposed the hydrogen bomb on moral terms and testified on behalf of Oppenheimer during the latter's infamous hearing, he also served as a consultant to Los Alamos once he realized that the Russians might also get the bomb; characteristically enough, he correctly predicted how long it would take them to build their first thermonuclear weapon. People looked to him for impartial guidance in almost every matter which could benefit from rational introspection.

Art and music baffled Fermi, but his rational analysis of these things only endeared him more to his friends and colleagues. At an art exhibit on the immigrant experience for instance, he calculated the ratio of the lengths of legs and heights of the immigrants in the photos and concluded that his own dimensions fit the statistical distribution. At Los Alamos he quickly memorized the rules of square dancing and danced with unerring accuracy but almost zero passion. His modesty and tendency to shun the limelight was also a great draw. He could as easily chat with janitors as with other Nobel Laureates. No task was beneath him, and his great ability to perform routine work without complaints or fatigue was instrumental in his success: whatever it took to solve a problem, Fermi would do it. When flabbergasted scientists asked him how he did it, Fermi would often reply with a smile, "C.i.f, con intuito formidable" ("with formidable intuition"). Often his distinguishing quality was pure stamina; whether it was a tennis match or a physics problem, he would beat the problem (and his opponents) into submission by sheer perseverance and doggedness. His manner of playing sports mirrored his manner of doing science: shun the style and elegance, and go straight and relentlessly for the solution using every technique at your disposal. The method of approximate guesses which came to be named after him has been used to estimate a wide variety of disparate numbers, from the number of extraterrestrial civilizations in the galaxy to the number of piano tuners in Chicago (his favorite example).

This giant of science was struck down by cancer in 1954 when he was still in his prime. The book talks about visits made by various famous scientists and friends to the hospital where he was installed after exploratory surgery indicated no hope. They could not believe that the indefatigable Enrico would soon be no more. All came away shaken, not because they saw an emotionally fraught man in pain but because they saw a perfectly calm and rational man who had reconciled himself with reality. He knew exactly what was happening to him and was making plans for publishing his last set of notes. Characteristically, he was measuring the rate of saline intake and calculating how many calories he was getting from it. When he came home and his wife rented a hospital bed for him, he predicted that he would only need it until the end of the month. True to his amazing calculating prowess, he passed away two days before the predicted date, on November 28, 1954.

This book in general lays out a warm and engrossing picture of Enrico Fermi. As I see it, it is up against two challenges. Firstly, it's relatively sparse on the science and does not always provide adequate background. In this context it is a light read and comes across unfavorably compared to Richard Rhodes' seminal book "The Making of the Atomic Bomb" which goes into great depth regarding Fermi's work, especially on the Chicago nuclear reactor. Rhodes' volume is also better on giving us a detailed picture of Fermi's contemporaries. Secondly, it cannot resist comparison with two old Fermi biographies. His wife Laura's endearing biography of him named "Atoms in the Family", published only a few months before his death, provides as intimate a picture of the personally reticent Fermi as we can expect. This book's view understandably is not as intimate. The same goes for "Enrico Fermi: Physicist", a biography of Fermi written by his friend, fellow Nobel laureate and uncle of one of the present book's authors, Emilio Segre. Segre was a top-notch physicist who worked with Fermi from the beginning and who does much recreating the early days of Fermi's childhood and his experiments in Rome. That description provides another personal touch which is again not as vivid in this volume.

Notwithstanding these comparisons, I am glad that Segre and Hoerlin wrote this book to introduce one of history's greatest and most unique scientists to a new generation. No scientist has contributed more practically and in a more versatile manner to modern physics. And few scientists have combined extraordinary and universal scientific talents with the kind of personal humility and decency that Fermi exemplified. For all this his life story needs to be known anew.

Subrahmanyan Chandrasekhar: A study in fortitude and rigor

It's Subrahmanyan Chandrasekhar's birthday today. "Chandra", as he was fondly known to friends and colleagues, was one of the twentieth century's most important astrophysicists. In addition he was probably its most rigorous and mathematical, applying hard and baroque mathematics to problems ranging from hydrodynamics to collapsing stars. His Nobel Prize came in 1983, and it should have come earlier. Chandra's life provides a good example of quiet rebellion against a traditional scientific establishment, and it's for this reason that it deserves wide study.

By all accounts Chandra was marked to be a great scientist from his birth. Born in the city of Lahore (now in Pakistan) to a respected civil servant, he quickly outpaced his fellow students in his study of advanced mathematics and physics. In the 1920s when he was attending college in the progressive city of Madras (now Chennai) he met the renowned physicist Arnold Sommerfeld when Sommerfeld was visiting Madras, and was both shocked and fascinated to hear Sommerfeld tell him that quantum theory had rendered outdated much of the physics he had learnt. That however was a deficiency that Chandra could remedy. As the famous story goes, at the mere age of nineteen, on a long voyage from India to England to attend graduate school at the University of Cambridge, he did the calculation that was to enshrine his name in history. That analysis which used tools from relativity and quantum theory that were far beyond the grasp of any other nineteen year old physics student, finally led to the establishment of the so-called 'Chandrasekhar limit', a limit for the mass a white dwarf can sustain before it collapses under the weight of its own gravity. 

A few years later Chandra had a famous showdown with Arthur Eddington, the doyen of English astronomers and one of the most famous scientists in the world. It was Eddington who had confirmed Einstein's famous prediction of starlight bending in 1919, and by 1935 when he went up against Chandrasekhar, he was renowned for both his physical theories and his popular writing. The showdown came in a seminar when Chandra put forward his carefully calculated contention that white dwarfs cannot be stable beyond a certain mass. What happened beyond that mass even Chandra did not know, but like his brilliant contemporary and friend Paul Dirac, he was brave enough to trust the mathematics. Eddington however saw Chandra's theorizing leading to a pathological physical reality. He could not conceive of a star keeping on collapsing, and he simply stated without proof that there must be some law of nature that prevented this. It was the classic case of the bastion of conservatism going up against the brash new kid on the block, although Chandra was no brash Richard Feynman cheekily rocking the establishment: he was simply courageous enough to quietly follow the numbers wherever they led.

Characteristically, Chandra did not contradict Eddington any further. He realized that he was the underdog and wisely conceded defeat...for the moment. He then waited a full five decades before a host of other brilliant theoreticians and experimentalists validated his seminal insight. It was Chandra's discovery of limiting masses for stars that finally led Robert Oppenheimer in 1939 to postulate the existence of black holes. In twentieth century physics, Oppenheimer and Chandra's papers on gravitational collapse bracket two very different personalities. Chandra waited quietly after his confrontation with Eddington, while Oppenheimer curiously simply forgot about his own groundbreaking contribution and remained indifferent to it for the rest of his life. After the war, John Wheeler, Dennis Sciama and Yakov Zeldovich put the theory of black holes on a firm footing. Their students Stephen Hawking, Roger Penrose, Kip Thorne and others blazed new pathways that continue to spawn deep insights. But it all started with Chandra.

Chandra who had spent the 1930s in England finally emigrated to the United States in the 1940s, accepting an invitation at the Yerkes Observatory of the University of Chicago. He made this country his own, and like his fellow immigrants Hans Bethe and Enrico Fermi, did much to raise its standing in the world of science. His father who expected him to return to India was deeply pained, but Chandra was convinced that he could have a better life in America, one unfettered by hero worship and the trappings of fame and enriched by friends and freedom to pursue his ideas and opinions. At the same time, although he settled in the US, he retained his love for India and visited often. 

Chandra's invaluable knowledge of hydrodynamics could have been important on the Manhattan Project at Los Alamos. Oppenheimer did invite him, but the delay in his security clearance which probably resulted from a mix of bureaucracy and naive racism kept him from making what would undoubtedly have been key contributions to the complex problems of implosion. Instead of Los Alamos, Chandra spent the war years at the Aberdeen Proving Ground working on ballistics and trajectories. However, he did contribute a bit to the bomb project by analyzing the operation of the calutrons at Oak Ridge, Tennessee.

At Yerkes and Chicago Chandra became famous for being a formidable teacher and top-notch researcher. He became friends with most of the leading physicists of the time, and wrote papers with his fellow Chicago physicist Enrico Fermi. Carl Sagan said that he learnt what mathematical elegance was from Chandra when he was a student there. The future Nobel Laureates C D Yang and T D Lee were taught by Chandra; he considered them so promising that he thought nothing of driving two hours to teach a class of two. In addition Chandra took the previously neglected 'Astrophysical Journal' to new heights. By all accounts he was a strict and fair editor; there are stories of him rejecting phone calls if they came a minute after the official working hours of the journal.

Chandra's mastery of astrophysics was total and incredibly diverse, and the sheer range of his understanding combined with his command of the mathematical tools was probably unmatched by any other scientist from the field. His style was unique. Every decade he used to research an important topic. After spending ten fruitful years exploring it and making important contributions, he would then write an exhaustive treatise that would serve as the standard reference on the subject. He would then move on and conquer another realm for another decade. In this way Chandra mastered and explained stellar structure, radiative transfer, hydrodynamic and hydromagnetic stability, gravitational waves and black holes. Each one of these topics would have been enough to keep a physicist busy for his or her entire career, but Chandra powerfully crisscrossed the entire landscape.

His last great technical treatise was titled "The Mathematical Theory of Black Holes". The volume is so densely mathematical that according to Chandra's own admission, he had to literally invent new symbols when he ran out of the common mathematical, Greek and Roman ones. After putting the finishing touches on this formidable tome, Chandra perhaps wisely decided to spend the rest of his years on more popular topics. Even when exploring these his characteristic rigor and exhaustive approach were apparent. His last book was a detailed and yet accessible analysis of all of Newton's theorems in his great "Principia". After examining his own modern and Newton's supposedly archaic approaches, Chandra concluded that Newton's were still better.

As rigorous and hard an astrophysicist as he was, Chandra was also remarkably well read and cultured. His remarkable wife Lalitha kept him grounded and optimistic. His knowledge of music, art and literature was extensive and this immersion contributed to the memorable clarity of his lectures. He compiled his views on an integrated approach to science, art and the humanities in a set of lectures titled "Truth and Beauty: Aesthetics and Motivations in Science" which is well worth reading. It would not be an exaggeration to say that Chandra embodied both qualities in his more than six decades of amazing contributions to science. As just one example of tributes to him, NASA's flagship x-ray observatory which is allowing us to probe hidden features of the cosmos is named Chandra.

Chandrasekhar remains a study in rigor and fortitude. In these troubled times, it's also worth noting that he was one of those select immigrants who made the United States great. When he and his wife Lalitha became American citizens in 1953 - much to the chagrin of his father and family in India who still expected them to return - Lalitha responded to his father with a sobering letter in which she extolled the democratic tradition in the US and Chandra's and her growing fondness for what made the country unique. In a paragraph that is perhaps relevant to this year's election, Lalitha said that she did not think it was right to sit by idly doing nothing while the pall of McCarthyism descended on the country; she felt that she and Chandra had to participate in the country's democratic process, and they could only do this by becoming citizens. 

One can only hope that this country absorbs more intellects like Chandra and his wife and proudly proclaims them as its own.

Psychiatry and neuroscience: Don't sacrifice proven emergence at the altar of unproven reductionism

John Markowitz who is a clinical psychiatrist at the NIH has a cogent column in the New York Times in which he argues that an excessive focus on neuroscience translational research is stifling useful and proven research in psychiatry. His main point is that the neuroscience research is unproven and long term, and while it may promise attractive dividends, there are many patients who need good psychiatric treatment now, patients who cannot work along the timelines promised by cutting edge neuroscience work.

I think in general he's right. Neuroscience seeks to find out the basic mechanisms governing neural health and disease by way of genes, receptors and small molecule drugs. Psychiatry and especially psychotherapy takes a more empirical and holistic approach, trying various combinations of talk therapy and drugs to treat mental illness. Even psychiatry itself has suffered from the kind of crisis that the author talks about. For instance, it is now increasingly clear that talk therapy (especially CBT) works at least as well as psychiatric drugs like antidepressants.

To me, at least part of the debate seems to be about a topic that I have often explored on this blog: emergence vs reductionism. Generally speaking, the goals of neuroscience are reductionist, seeking to modulate mental processes in health and disease by understanding and engineering interactions between genes, proteins and drugs at the molecular and network levels. The goals of psychiatry are emergent and empirical. Psychiatry does not care about the underlying molecular mechanisms of mental health; instead its goal is to work at a higher and more holistic level, empirically trying out different approaches until a particular combination of methods seems to show efficacy. It is not surprising that drugs like antidepressants which aim to interact with specific protein receptors in the brain are often found wanting because they target only part of a much larger system.

This philosophical difference between neuroscience and psychotherapy also strikes me as being a bit similar to the philosophical difference between chemistry and physics which I have often talked about here. Physics may want to find out how the world works by tracing the interactions between elementary particles like quarks, but chemists have little use for this information, benefiting tremendously instead by understanding semi-empirical concepts like hydrogen bonds and hydrophobic effects. The time discrepancy that the author points out regarding the fruits of neuroscience research and psychiatry also applies to physics and chemistry; if chemists waited long enough to be able to use physics and understand every complex molecular system from first principles, we would still be living in the age of alchemy.

The NYT article ends by appealing to the NIH to not sacrifice proven empirical psychiatry research at the altar of long-term translational research in neuroscience, and this underscores yet another one of the more general problems with translational research that I and others have pointed out. It is why the much celebrated and publicized Brain Initiative troubles me; I fear that it will detract from more mundane but effective psychiatric research. Far flung reductionist research may well promise and eventually bring great insights, but it should not be pursued at the cost of immediately workable emergent research whose very lack of precision makes it so useful.

Black clouds and silver linings: 2016 chemistry Nobel Laureate Fraser Stoddart's moving tribute to his wife

Sir Fraser Stoddart shared this year's Nobel Prize in chemistry for constructing tiny molecular machines based on the remarkable phenomenon of self-assembly, a process by which forces between atoms automatically pull diverse molecules together into precise geometric configurations without having to explicitly position them this way. These machines represent much promise for the field of nanotechnology, especially when we figure how to harness the mechanical forces in these molecules to perform specific functions like making copies of themselves, killing cancer cells or building other molecular materials. The Nobel Prize that Stoddart shared with fellow chemists Ben Feringa and Jean-Pierre Savage comes at the pinnacle of entire careers spent patiently exploring the structure and function of these molecular architectures.

One of the many interesting objects Stoddart created in the laboratory was a Borromean ring, a structure which had been mathematically conceived for some time but not physically realized until 2004 when Stoddart and his group chemically synthesized it. From a mathematical standpoint a Borromean ring is a good example of an object from the field of knot theory. It is a complex knot consisting of several interlocking rings. The special property of these rings is that you cannot cut any of them without having the entire structure break apart. From a chemical standpoint the Borromean ring is a tantalizing example of self-assembly, a process in which the individual molecules making up the ring simply 'find' each other and assemble; the chemist has to merely make the individual building blocks and find the right chemical conditions (solvent, temperature etc.) under which they can self-assemble.

The first molecular Borromean ring: 18 individual
molecules automatically self-assembly under the right conditions

Stoddart described the discovery of these Borromean rings in a talk given six years ago at the Institute for Human and Machine Cognition in Florida. The choice of the venue would be unusual were it not for the futuristic promise of molecular machines in improving human life, a goal also shared by the field of artificial intelligence. The entire talk is worth watching, but one part of the story which really stood out for me was a moving tribute by Stoddart to his wife Norma Stoddart who passed away from breast cancer in 2004. The tribute was not just moving but it also illustrated the classic yin and yang quality of life, with black clouds and silver linings. As Stoddart recounts, the breakthrough in designing the first Borromean ring was very much a sorely needed silver lining, not just because it came after a year of failures in deciphering the structure of these elusive molecules, but because it came at the end of receiving a tragic piece of news:

"It’s all part of life’s rich fashion. It’s not all a bowl of cherries. She was a brilliant scientist, much more able than I. She succumbed to breast cancer, and she fought that disease like no one’s business for 12 years.  She became known, ironically, as the little iron Englishwoman of Santa Monica. So that was Black Tuesday, it was the day that her oncologist said to me that the fight was over because the cancer had metastasized to her brain, and she always said that if that happened the fight would be over. So I came back to the lab from the clinic feeling quite low, and there was the structure of the Borromean Rings. So as they say, every black cloud has a silver lining."

Stoddart clearly enjoyed a very close relationship with his wife, and anyone who has lost a close spouse must know how incredibly hard and unique the pain is. Here's something that struck me: compared to the tragedy of losing a loved one, a specific scientific discovery might seem to provide negligible succor. And yet science has always been an amazing source of strength and certainty in tumultuous times, and this is one of its supremely important and reassuring qualities. Whether one is talking about European physicists finding refuge in the field of quantum mechanics during the politically fraught 1930s or, on a very personal level, a scientist finding refuge in the glow of scientific discovery in the shadow of a personal tragedy, this kind of novelty and joy in discovering new facts of nature is one of the things that makes science so much worthwhile. By recounting this moving story, Stoddart demonstrates not just the joy of science but its quintessential quality as a human endeavor. It is a triumph of the spirit over both scientific and personal hurdles. Thank you, Fraser Stoddart.

Note: Stuart Cantrill who got his PhD with Stoddart tells me that the first Borromean rings based on DNA were made by Nadrian Seeman of NYU. Stoddart and his team's, however, were the first rings based on small organic molecules. Here's a review on these fascinating objects which Stu pointed me to.

Iconic images of science, #1: Rosalind Franklin's DNA photograph

It occurred to me that a reasonable history of modern science could potentially be depicted by some of the iconic images that charted and drove its progress. Whether it was Robert Hooke's pioneering drawings in "Micrographia" or Copernicus's heliocentric model as depicted in "De Revolutionibus orbium coelestium", drawings, photographs and graphs have captured some of the key moments in the march of science. I thought it would be interesting to occasionally post an image from one of these moments along with a brief, entirely personal and selective commentary.

Photo 51: Rosalind Franklin's astoundingly clear x-ray diffraction photograph of DNA taken in 1952 which showed the telltale double-helical signature of DNA. The photo received perhaps the ultimate pop cultural accolade when it became the basis for "Photograph 51", a star power-driven play with Nicole Kidman playing Franklin.

This photo is fascinating in many ways, perhaps most controversially because Franklin's supervisor Maurice Wilkins (who she saw not as a supervisor but as an equal) showed it to James Watson without his knowledge: in Watson's account, when he saw it his "jaw dropped and pulse raced". The pieces swirling around in his and Francis Crick's mind fell in place and the rest was history.

The image is also very intriguing because it points to one of the great what-ifs of scientific history. Franklin was undoubtedly the best DNA crystallographer in the world and there was nothing anywhere else that came close to the clarity of this work, so the tantalizing question is: how soon would she have hit on the idea of a double helix herself? My guess is, not too soon. As wronged as Franklin was by the male establishment and history, she was stubborn and defensive and not very open to other fields, especially chemistry and model-building, the two fields which mattered the most for nailing down the solution to the puzzle. Feeling besieged by the men around her, she was loath to collaborate. Much more than any raw brilliance, Watson and Crick's biggest quality was their willingness to do whatever it takes and beg, borrow, ask - and steal - from any field necessary to crack the structure. In the parlance of Isaiah Berlin's parable, Franklin was a hedgehog, Watson and Crick were foxes.

If she had lived Franklin *should* most definitely have shared in the Nobel Prize for the discovery of the helix: whether she *would* have is another of the what-ifs of history, although given the male domination of the prizes it seems unlikely. Sadly history silenced the question: Franklin died in her 30s of cancer, an iconic figure to generations of future scientists and female scientists in particular.

Big Trouble in Little Synthetic Organic Chemistry?

Michael Rafferty who teaches in the Department of Medicinal Chemistry at the University of Kansas has a thought-provoking article in the Journal of Medicinal Chemistry in which he questions whether it's time to reinvent the model for training academic scientists in graduate programs to better equip them for the complexity and rigors of modern drug discovery. His target is the cadre of synthetic organic chemists who for decades have functioned as the indispensable backbone of the pharmaceutical industry. The title of the article - "No Denying It: Medicinal Chemistry Training Is In Big Trouble" - should be self-explanatory, in case anyone is wondering where exactly the author's sentiments lie on the topic.

Even today when you say that someone is a "medicinal chemist" it usually means someone who is trained as a synthetic organic chemist, who either goes into the lab and makes molecules himself or herself or who directs other people to do the same. Rafferty is asking whether the decades-old standard of recruitment into medicinal chemistry groups in the pharmaceutical industry - sound training in synthetic organic chemistry - might have to be revised.

Rafferty's basic point is that the kind of wisdom needed to find hits, advance them into lead compounds and finally into drug candidates does not really benefit from having a background in pure synthetic organic chemistry: it's much more about SAR analysis and understanding pharmacological properties. As he points out, the pharmaceutical industry has of course realized and maintained that all that wisdom can be learnt on the job. But Rafferty is not sure, and part of his skepticism comes from two revealing studies that basically showed two things: first, that even experienced medicinal chemists do not agree when picking good leads, and second, that most medicinal chemists even now don't really take optimum properties into account when designing compounds. The problem with lead picking is thus not synthesis, it's an ability to parse a complex landscape of multiple properties. Multiparameter optimization is still a beast whose footprints are rarely found among the thinking of medicinal chemists.

I think in general he's right. Advances in pharmacology, toxicology, computational chemistry and other fields over the past few decades have made it possible to both calculate as well as use property-based information in early stages of drug discovery. The article focuses on lipophilicity as one parameter which really should be considered on a regular basis but which isn't a lot of time. The problem is that a lot of synthesis has turned into a machine for cranking out molecules, so drug discovery scientists end up making molecules because they can be easily made. It's a theme that I and others have written about previously: making molecules is no longer the rate determining step in drug discovery: design is the important paradigm. One of the reasons is that CROs in China and India can now often make molecules as easily as in-house synthetic chemists. In one sense what the article is saying is because these CROs can now pick up the slack, chemists can use the time to more productively think about property-based optimization.

Now while I think it's cogent to include as much property information as possible in early drug discovery, it's worth noting that some of this information is dubious and some is valuable; the problem is that often it's hard to say which information would be dubious and which would be valuable. One of the reasons medicinal chemists disagree on compound selection is because gut instincts and experience can sometimes overrule what may seem like cogent limits on properties like lipophilicity. Nonetheless, having medicinal chemists who are tuned by default to thinking about properties would be a good idea. 

The second caveat I would apply to approaches like this is to not discount the value of a classical synthetic organic chemistry education. As has been amply demonstrated, making a complex molecule over a long period of time is more about handling setbacks, persisting with grit and developing the kind of character that can handle repeated failures than about making the molecule per se. And god knows we need all these qualities in drug discovery, a field which is literally a glutton for attrition and failure. In addition, even today there are molecules which often stump the best efforts of standard synthetic routes. Thus, it's always a good idea to have a core group of accomplished synthetic chemists in any program. In one sense the argument is really about degree, it's about what the size of this core should be, and the article argues that maybe it should be smaller than what has been traditionally thought.

Rafferty's main prescription is that graduate programs training chemists for drug discovery should now focus less on synthesis and more on multiparameter optimization and on other disciplines which can be used to think about properties upfront. The industry should do likewise in deemphasizing training of synthetic organic chemistry and emphasizing broader training in medicinal chemistry during recruitment. When I was in graduate school I was fortunate to study under a world-class medicinal chemist. Not only did his group teach students to think about properties at a relatively early stage, but more in line with what this article says, he also created a very good drug discovery course which gave students a solid flavor of the process and emphasized the contributions of other disciplines like pharmacology, formulation, metabolic studies and molecular modeling. Rafferty is encouraging more graduate programs to include such courses, and I definitely agree with him on this. The second prescription he has is to create more industry-academic partnerships in which industry contributes personnel, scholarships and funding to expose students to actual drug discovery and not just synthesis. A scheme like this has been in place in Europe for some time now.

Wikipedia seems to have caught up with the times when it defines medicinal chemistry as a discipline which 

"In its most common practice —focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology, enzymology and structural biology, together aiming at the discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities (biological activities and properties), i.e., understanding their structure-activity relationships (SAR)."

Perhaps academia and industry can embrace this definition more fully.

Image: Amriglobal