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was visiting Madras, and was both shocked and fascinated to hear Sommerfeld tell him that quantum theory had rendered outdated much of the physics he had learnt.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

Physics and the search for fundamental laws: Is physics turning into biology?

The Standard Model of particle physics
contains many fundamental values which
may be a result of pure accident

Physics, unlike biology or geology, was not considered to be a historical science until now. Physicists have prided themselves on being able to derive the vast bulk of phenomena in the universe from first principles. Biology - and chemistry, as a matter of fact - are different. Chance and contingency play an important role in the evolution of chemical and biological phenomena, so beyond a point scientists in these disciplines have realized that it's pointless to ask questions about origins and first principles.

The overriding "fundamental law" in biology is that of evolution by natural selection. But while the law is fundamental on a macro scale, its details at a micro level don't lend themselves to real explanation in terms of origins. For instance the bacterial flagellum is a product of accident and time, a key structure involved in locomotion, feeding and flight that resulted from gene sharing, recombination and selective survival of certain species spread over billions of years. While one can speculate, it is impossible to know for certain all the details that led to the evolution of this marvelous molecular motor. Thus biologists have accepted history and accident as integral parts of their fundamental laws.

Physics was different until now. Almost everything in the universe could be explained in terms of fundamental laws like Einstein's theory of general relativity or the laws of quantum mechanics. If you wanted to explain the shape and structure of a galaxy you could seek the explanation in the precise motion of the various particles governed by the laws of gravity. If you wanted to explain why water is H20 and not H30 you could seek the explanation in the principles of quantum mechanics that in turn dictate the laws of chemical bonding.

But beyond this wildly successful level of explanation seems to lie an impasse. The problem arises when you try to explain one of the most profound facts of nature, the fact that the fundamental constants of nature are fine-tuned to a fault, that the universe as we know it would not exist if these constants had even slightly different values. For instance, it is impossible to imagine life existing had the strength of the strong force binding nuclei together been even a few percent smaller or larger. Scientists have struggled for decades to explain why other numbers like the value of Planck's constant or the electron's mass are what they are. In fact this is one of the biggest gaps in the Standard Model of physics, an otherwise spectacularly successful paradigm that nonetheless contains arbitrary constants that defy an origin story. It seems now that physicists are giving up trying to explain conundrums like these, or at least giving up trying to do it the way they always have.

Two books that I read recently drove the point home to me. One was Max Tegmark's "The Mathematical Universe". In the book Tegmark takes us on a dizzying journey through modern physics that ends in the fanciful realm of multiple universes. It's hardly the first book to do so. Multiple universes have been invoked to explain many problems in physics, but their most common use is try to explain (or explain away, as some seem to rightly think) the problem of the fundamental constants. The purported "solution" sounds simple; we can stop wondering why the fundamental constants have the precise values that they do if we assume the existence of a potentially infinite number of universes, each of which has a different set of values for the constants. Our universe just happens to have the right combination that allows sentient life to arise and ask such questions in the first place.

Leaving aside the fact that multiple universes still belong to speculation and science fiction rather than science, what is really striking about them to me is that they have finally transported physics into the realm of biology. What physicists are essentially saying is that there have been several universes in the past and there are likely several universes in the present, and our unique universe with its specific combination of fundamental constants is an accident. The multiple universe argument is very much similar to the argument establishing evolution by natural selection as the centerpiece of biology: there have been several species with several genotypic and phenotypic features, and our own human species is a result of contingency and historical accident. This is not so much an explanation as an admission of incomplete knowledge, but biologists are fine with this since it does not obviate any natural law and is still part of a satisfying overarching theory.

It looks like with the postulation of multiple universes physicists too have stepped over from the land of fundamental explanatory laws into the land of historical accident and contingency. This is a radical shift in the way physics has been done until now and a rather painful blow to the physicist's view of nature. One might also say that biology is having the last laugh. In the sixteenth and seventeenth century when biology was still doing the messy job of cataloging data and trying to make sense of the mess, physics was marching on, discovering precise regularities and generalities in nature's offerings. Since then several sciences including biology and economics have suffered from "physics envy". But now it ironically looks like physics' successful run at predicting everything from first principles might have become a victim of its own success. It may be the case that physicists' spectacular findings themselves have illuminated their own limitations. In his book "The Accidental Universe", physicist and writer Alan Lightman puts it thus:

"Dramatic developments in cosmological findings and thought have led some of the world's premier physicists to propose that our universe is only one of an enormous number of universes, with wildly varying properties, and that some of the most basic features of our particular universe are mere accidents - random throws of the cosmic dice. In which case, there is no hope of ever explaining these features in terms of fundamental causes and principles."

Lightman also quotes the doyen of physicists, Steven Weinberg, who recognizes this watershed in the history of his discipline:

"We now find ourselves at a historic fork in the road we travel to understand the laws of nature. If the multiverse idea is correct, the style of fundamental physics will be radically changed."

Although Weinberg does not say this, what's depressing about the multiverse is that its existence might always remain postulated and never proven. This is an ever worse scenario because the only thing that a scientist hates even more than an unpleasant answer to a question is no answer at all. It's not inaccurate to say that many physicists - and especially those like Weinberg who have been part of the spectacular revolution in physics during the 60s and 70s - are distressed by this fact.

The metamorphosis of physics into a historical science means that many of the facts that have troubled the field's foremost practitioners may be a product of chance and fundamentally unexplainable in terms of more basic laws. I must emphasize that this is not some kind of "end of physics" scenario that I am imagining here (unlike my colleague John Horgan); there are still plenty of very challenging questions dealing with the application of the fundamental laws that will keep physicists occupied for decades. Foremost among these may be the conundrum of emergent phenomena which themselves are very fundamental in fields like neuroscience and economics. I am also not implying that physicists should simply give up looking for fundamental laws. But their methodological take on finding these laws may have to change. As far as the deep question of why certain building blocks of the universe seem to exist within very narrow constraints is concerned, physicists might simply have to accept that there is no true causal explanation for the fact.

String theory, which at one point was considered a promising strategy to unify quantum mechanics and gravity and possibly explain such problems, has been severely floundering for the last few years. Bereft of testable predictions, some of its proponents have now resorted to thinking of the theory as a good example of “non-empirical” science. This kind of thinking seems to me to be an alarming cop-out. As the physicist Carlo Rovelli explained in a recent talk, many predictions like antimatter and the bending of starlight of gravity have started out as non-empirical predictions based on pure thought. But they were not regarded as a legitimate part of science until they were experimentally verified. In addition the predictions they made were testable in a very well defined manner. To consider a theoretical framework as perpetually being a legitimate part of science as a non-empirical framework would be contrary to all the science that we know and love.

Are physicists justified in feeling despondent because they seem to be tapping the bottom of the barrel in their search for fundamental laws and because their efforts to explain these laws at a truly basic level have not borne fruit? I don't think so. Biologists have known about contingency and accident ever since Darwin wrote his great book, but not only has this not made them emotionally unstable but it has also not kept them from making spectacular discoveries in their discipline. Just because a system of laws might have a historical origin based on accident does not mean that there are no great truths about the system still waiting to be discovered. But more importantly, perhaps physicists need to embrace contingency to be as much of a fundamental law as any other. Biologists know this; in fact they know that there would be no evolution in the first place without contingency, and they know that it is thanks to historical accident that they get to study the incredibly rich cornucopia of living structures that the earth has presented to them.

The best thing would be for physicists to realize that just because the ultimate laws of their discipline might have a fundamentally accidental origin, it does not mean that the manifestations of those laws are any less important or useful. The most important page they should lift out of the biologists' playbook is very simple; when ideas about a field evolve, it is best for the practitioners of the field to evolve too.

This is a revised and updated version of an older post.

2016 Nobel Prize picks

The nice thing about Nobel Prizes is that it gets easier to predict them every year, simply because most of the people you nominate don't win and automatically become candidates for the next year (note however that I said "easier to predict", not "easier to correctly predict"). That's why every year you can carry over much of the same list of likely candidates as before.

Having said that, there is a Bayesian quality to the predictions since the previous year's prize does compel you to tweak your priors, even if ever so slightly. Recent developments and a better understanding of scientific history also might make you add or subtract from your choices. For instance, last year the chemistry prize was awarded for the discovery of DNA repair systems, so that might make it a bit less likely for a biological discovery to be recognized this year. 

This time as in previous years, I have decided to separate the prizes into lifetime achievement awards and specific discoveries. There have been fewer of the former in Nobel history and I have only three in mind myself, although the ones that do stand out are no lightweights - for instance R B Woodward, E J Corey, Linus Pauling and Martin Karplus were all lifetime achievement awardees. If you had to place a bet though, then statistically speaking you would bet on specific discoveries since there have been many more of these. So here goes:

Lifetime achievement awards

Harry Gray and Steve Lippard: For their pioneering and foundational work in the field of bioinorganic chemistry;work which has illuminated the workings of untold number of enzymatic and biological processes including electron transfer.

Stuart Schreiber and Peter Schultz: For their founding of the field of modern chemical genetics and their impact on the various ramifications of this field in chemistry, biology and medicine. Schreiber has already received the Wolf Prize this year so that improves his chances for the Nobel. The only glitch with this kind of recognition is that a lot of people contributed to the founding of chemical biology in the 1980s and 90s, so it might be a bit controversial to single out Schreiber and Schultz. The Thomson-Reuters website has a Schreiber prediction, but for rapamycin and mTOR; in my opinion that contribution, while noteworthy, would be too narrow and probably not sufficient for a prize.

Robert Langer for his extensive contributions to drug delivery: Much of what Langer does is actually chemistry, but his practical impact has been on medicine so a prize for him would lie more squarely in medicine. It's clear though that he deserves some kind of lifetime recognition.

Specific awards

John Goodenough and Stanley Whittingham for lithium-ion batteries: This has been on my list for a very long time. Very few science-based innovations have revolutionized our basic standard of living the way lithium-ion batteries have. Generally speaking, recognition for the invention of specific devices have been rather rare, with the charged-coupled device (CCD) and the integrated circuit being exceptions. More importantly, a device prize was given out just two years ago in physics (for blue light-emitting diodes) so based on the Bayesian argument stated above, it might make it a bit unlikely for another device-based invention to win this year. Nonetheless, a prize for lithium ion batteries more than most other inventions would conform to the line in Alfred Nobel's will about the discovery that has "conferred the greatest benefits on mankind."

Franz-Ulrich Hartl and Arthur Harwich for their discovery of chaperones: This is clearly a discovery which has had a huge impact on our understanding of both basic biological processes as well as their therapeutic relevance. However, as often happens with the chemistry prize, this one could also go to medicine.

Krzysztof Matyjaszewski for atom-transfer radical polymerization, Barry Sharpless for click chemistry, Chi-Huey Wong for oligosaccharide synthesis and Marvin Caruthers for DNA synthesis: It's highly unlikely that these three gentlemen will receive any prize together, but I am grouping them under the general title of "organic and polymer synthesis" for convenience.

Matyjaszewski's name has been tossed around for a while, and while I am no expert in the field it seems that his ATRP method has had enough of a practical and commonplace impact to be a serious contender; plus an award for polymer chemistry has been long due. Click chemistry has also been extensively applied, although I am less certain of its industrial use compared to say, the undoubted applications of palladium-catalyzed chemical reactions.

In the world of biopolymers, oligosaccharide synthesis has always been an important field which in my opinion has received the short end of the stick (compared to the glamorous world of proteins and nucleic acids, lipids and carbohydrates have always been the black sheep) so recognizing Wong might be a kind of redemption. On the other hand, recognizing Caruthers for DNA synthesis (perhaps along with Leroy Hood who automated the process) seems to be an obvious honor in the Age of Genomics. Hood has also been highlighted in the public eye recently through a new biography.

The medicine prize

As is traditionally the case, several of the above discoveries and inventions can be contenders for the medicine prize. However we have left out what is potentially the biggest contender of all until now.

Jennifer Doudna, Emmanuelle Charpentier and Feng Zhang for CRISP-Cas9: I don't think there is a reasonable soul who thinks CRISPR-Cas9 does not deserve a Nobel Prize. In terms of revolutionary impact and ubiquitous use it almost certainly belongs in the same shelf that houses PCR and Sanger sequencing. 

There are two sets of questions I have about it though: Firstly, whether an award for it would still be rather premature. While there is no doubt as to the broad applicability of CRISPR, it also seems to me that it's rather hard right now to apply it with complete confidence to a wide variety of systems. I haven't seen numbers describing the percentage of times that CRISPR works reliably, and one would think that kind of statistics would be important for anyone wanting to reach an informed decision on the matter (I would be happy to have someone point me to such numbers). While that infamous Chinese embryo study that made the headlines last year was quite flawed, it also exposed the problems with efficacy and specificity that still bedevil CRISPR (these are problems similar to the two major problems for drugs). My personal take on it is that we might have to wait for just a few more years before the technique becomes robust and reliable enough to thoroughly enter the realm of reality from one of possibility.

The second question I have about it is the whole patent controversy, which if anything seems to have become even more acrimonious since last year, reaching worthy-of-optioning-movie-rights level of acrimonious in fact. Generally speaking Nobel Prizes try to stay clear of controversy, and one would think that the Nobel committee would be especially averse to sullying their hands with a commercial one. The lack of clear assignment of priority that is being played out in the courts right now not only tarnishes the intellectual purity of the discovery, but on a more practical level it also makes the decision to award the prize to all three major contenders (Doudna, Charpentier and Zhang) difficult. Hopefully, as would be fitting for a good novel, the allure of a Nobel Prize would make the three protagonists reach an agreement to settle their differences over a few beers. But that could still take some time. A different way to look at the whole issue however is to say that the Nobel committee could actually heal the divisions by awarding the prize to the trio. Either way, a recognition of CRISPR is likely going to be one of the most publicly debated prizes of recent times.

It's also interesting to note that the folks at Thomson Reuters have cited only George Church and Feng Zhang in their picks. A prize only for the duo that leaves out the Berkeley scientists would likely ignite a bitter controversy that might make the controversy over the MRI prize pale in comparison. I don't think any kind of CRISPR recognition that cites only Church and Zhang would be good for the reputation of either the Nobel Prize or for science as a whole.

The bottom line in my mind: CRISPR definitely deserves a prize, and its past results and tremendous future potential may very well tip the balance this year, but it could also happen that the lack of robust, public vindication of the method and the patent controversy could make the recognition seem premature and delay the actual award.

Craig Venter, Francis Collins, Eric Lander, Leroy Hood and others for genomics and sequencing: The split here may be pretty hard here and they might have to rope in a few consortiums, but as incomplete and even misleading as the sequencing of the human genome might have been, there is little doubt that it was a signal scientific achievement deserving of a Nobel Prize.

Alec Jeffreys for DNA fingerprinting and assorted applications: Alec Jeffreys is another perpetual favorite on the list and one whose invention has had a huge societal impact. I have never really understood why he has never been recognized.

Karl Deisseroth, Ed Boyden and others for optogenetics: Optogenetics is another invention that will almost certainly get a prize; its methodology is fascinating and its potential applications for neuroscience are amazing. But its validation seems even more incomplete to me than CRISPR's so it would be rather stunning if they get the prize this year. (On a side note: I am probably among the minority who think that awarding the prize for RNA interference in the 1990s was also too early and quite premature).

Ronald Evans for nuclear receptors: It would be odd if a major class of proteins and therapeutic drug targets went unrecognized.

Bert Vogelstein, Robert Weinberg and others for cancer genes: This again seems like a no-brainer to me. Several medicine prizes have been awarded to cancer genetics so this certainly wouldn't be a novel idea, and it's also clear that Vogelstein and Weinberg have done more than almost anyone else in identifying rogue cancer genes and their key roles in health and disease.

The Thomson-Reuters team has cancer immunotherapy on their shortlist which I think is another good choice.

The physics prize: There is no doubt in my mind that this year's Nobel Prize in physics will be awarded to Kip Thorne, Rainer Weiss and Ron Drever for their decades-long dogged leadership and work that culminated in this year's breakthrough discovery of gravitational waves by the LIGO observatory. It's a dead ringer. Drever sadly suffers from dementia, but that certainly should not preclude the Nobel committee from honoring him. For those wanting to know more about the kind of dedication and personality clashes these three men brought to the project, Janna Levin's book which came out earlier this year is a great source.

There is another recognition that I have always thought has been due: a recognition of the ATLAS-CMS collaboration at the LHC which discovered the Higgs boson. A prize for them would emphasize several things: it would put experiment at the center of this important scientific discovery (there would have been no 2013 Nobel Prize without the LHC) and it would herald a new and necessary tradition of awarding the prize to teams rather than individuals, reflecting the reality of contemporary science.

The Thomas-Reuters team predicts a chaos theory prize for the inventors of the OGY method. However it seems to me that a Nobel Prize for chaos theory and the study of dynamical systems - a field that surprisingly has not been recognized yet - should include any number of pioneers featured for instance in James Gleick's amazing book "Chaos", most notably Mitchell Feigenbaum.

So that's it from my side. Let the bloodbath games commence!

Other predictions: Thomson-Reuters, artkqtarks, Everyday Scientist, In the Pipeline