Nobelist Roger Kornberg: "If there is any one subject an educated person should know, that is chemistry"

Roger Kornberg received the 2006 Nobel Prize in Chemistry for figuring out the atomic-level details of the process of transcription, that foundational aspect of life that frees up the message in DNA and allows it to work its magic through messenger RNA. 

Following the announcement of the prize, Kornberg had a remarkable exchange with an interviewer in Stockholm when the interviewer asked him whether the work he was doing could rightly be classified as 'structural biology' or something else. In the process he offered a supreme paean to chemistry as the central science.

“The fact remains as I said that the boundaries have blurred, but what is more is that the work that we do in the structural biology department is in some places done in departments of chemistry and in other places done in departments of biology.  

Beyond that I might add that in my personal view chemistry is really the queen of the sciences; chemistry is the common ground for all scientific investigations. So our best hope of applying physical principles for the world around us is at the level of chemistry. Our best hope of understanding the biological organism and ultimately the form and function of the human body is at the level of chemistry. I have said before and I would repeat that if there is any one subject that an educated person should know in the world that is chemistry.”

As if this glowing praise was not enough, Kornberg further elaborated on his view of the necessity of chemistry when the interviewer asked him about what kind of preparation he expects potential students and postdocs in his lab to have.

"I have a very straightforward answer to your question. The one thing I look for is chemistry. People come to my lab from a background in biology, they come from a background in physics, and the question I always ask is about their training in chemistry; if they have studied chemistry then what chemistry did they study and how well did they do it. 

If someone comes along who has studied physical and organic chemistry and have been good at it, then I know they will fit in well, that they will succeed in what we do…absent that I’m doubtful…if they’re a biologist they must have done chemistry, if they’re a physicist then they must at least show an aptitude for chemistry."

Kornberg's superlative leanings toward chemistry may seem excessive but he makes an excellent point. His statement that our best hope of applying physical principles for the world around us is at the level of chemistry succinctly captures the emergent nature of chemical science that frees it from its underpinnings in physics. DNA is composed of quarks, but you cannot understand its principal properties like base pairing and hydrogen bonding at the level of quarks. You can only understand them - both philosophically and practically - only at the molecular level, only at the level of molecular orbitals and electronegativity.

The central science of chemistry reigns over biology, over applied physics, over astronomy, over engineering, but it often works its subtle but powerful influence through the shadows. Like the spacetime of general relativity it simply is everywhere.

Oliver Sacks's "mad and impudent" idea for winning first prize in an important exam: five pints of hard cider

Oliver Sacks's wonderful, bracingly honest memoir "On the Move" is a must read. If you see Sacks interviewed he would strike you as a shy and diffident if intensely curious man, but one of the things that shines through the book is his occasional tendency to display "violent enthusiasms, and extreme immoderation" in all matters, whether they concerned alcohol, drugs, relationships, bodybuilding or binge eating. Fortunately for Sacks these risky experiences were instructive rather than ruinous, and they contributed to the further enrichment of what was already an immensely interesting life.

One such early experience was his frenzied, alcohol-laden, impulsive attempt to win the first prize in an important college anatomy exam.

"My mother, a surgeon and anatomist, while accepting that I was too clumsy to follow in her footsteps as a surgeon, expected me to at least excel in anatomy at Oxford. We dissected bodies and attended lectures and, a couple of years later, had to sit for a final anatomy exam. When the results were posted, I saw that I was ranked one from bottom in the class. I dreaded my mother’s reaction and decided that, in the circumstances, a few drinks were called for. I made my way to a favorite pub, the White Horse in Broad Street, where I drank four or five pints of hard cider – stronger than most beer and cheaper too. 

Rolling out of the White Horse, liquored up, I was seized by a mad and impudent idea. I would try to compensate for my abysmal performance in the anatomy finals by having a go at a very prestigious university prize – the Theodore Williams Scholarship in Human Anatomy. The exam had already started, but I lurched in, drunkenly bold, sat down at a vacant desk, and looked at the exam paper. 

There were seven questions to be answered; I pounced on one (“Does structural differentiation imply functional differentiation?”) and wrote nonstop for two hours on the subject, bringing in whatever zoological and botanical knowledge I could muster to flesh out the discussion. Then I left, an hour before the exam ended, ignoring the other six questions. 

The results were in The Times that weekend; I, Oliver Wolf Sacks, had won the prize. Everyone was dumbfounded – how could someone who had come one but last in the anatomy finals walk off with the Theodore Williams prize?"

Needless to say, it may not be the best idea to assume a causal relationship between cider and success and try this in an exam venue.

Lessons on scientific leadership: From Medawar, Perutz, Oppenheimer and others

In an age in which companies and academic institutions are struggling to seek good leadership in the face of flagging funding, short-term thinking and a confusing incentive system, it may be helpful to get some insights from three of the twentieth century's most talented scientists, thinkers and writers.

Peter Medawar who won a Nobel Prize for his discoveries regarding the immune system and organ transplantation also wrote eloquent books on science, its methodology and its human side. 

His "Advice to a Young Scientist" is especially worth reading, but so are his words on what makes good scientific leaders:

"I construe my function as director of research as mainly to create the kind of environment which is conducive to the advancement of learning. That sounds pompous, but this is all a director can do. You cannot direct people to have ideas, and no one can have a big enough grasp of the whole of biological science to be able to say which lines of research are certainly going to be fruitful and which are are certainly going to be a waste of time. So what one has to do is simply create an environment and an atmosphere in which science flourishes."

In those few lines Medawar has hit upon the essential nature of the kind of independent-minded, open-ended, egalitarian research establishment which produces the best kind of science. It requires a measure of humility and foresight to understand that one cannot grasp the totality of any research endeavor which they are directing, and the best strategy therefore is to gather good people and then let them think and collaborate in their own ways. Today's CEOs, managers and thought leaders should take note.

Over the years this message was not lost on a select few scientific institutions which became torchbearers of the high art of science. Bell Labs was certainly among them, but one of the very best was the Medical Research Council's Laboratory of Molecular Biology in Cambridge, established after the structure of DNA was discovered, and founded by pioneers of molecular biology like Francis Crick, Max Perutz, Sydney Brenner and others. Over the last sixty years the LMB has produced no less than thirteen Nobel Prize winners (along with others who have been affiliated with the institute), an unprecedented achievement which it has bequeathed from its Cambridge predecessor - Maxwell and Rutherford's Cavendish laboratory which was another powerhouse of Nobel-caliber work. The mission of the LMB was, and is, to bring in the best scientists, not care too much about their prior publications but instead look at the novelty of their ideas, and then give them almost complete freedom to pursue those ideas.

Of all the directors of the LMB, the one who exemplified its tradition best was Max Perutz. Perutz who shared the Nobel Prize for his pioneering work on the structure of proteins was known to be a very hands off director who at the same time naturally inhabited a role as an active, unassuming member of the hoi polloi.

Some of the Nobel Laureates at the MRC;
household names in molecular biology

Perutz was a scientist's scientist - his last manuscript was submitted a few days before he passed away and appeared after his death - but he was also a warm individual who never thought of himself as a director. The LMB was always fiercely egalitarian, but never more so under Perutz. He had lunch and tea with the postdocs at the institute, shared his ideas with them, asked seemingly naive questions and never told anyone what to do.

And then there was Robert Oppenheimer. When Oppenheimer was put in charge of the Manhattan Project almost no one could believe it - he hadn't even been in charge of a university department until then (as one scientist put it, he wouldn't have expected Oppenheimer to run a hot dog stand). And yet Oppenheimer brought all his great talent for thinking and organizing to bear on the project, and in the process became not just the best director that any of the Manhattan Project scientists - including his nemesis Edward Teller - had ever seen but a model for other organizations. What made him tick? Here's Victor Weisskopf who worked with him and later became the chairman of the physics department at MIT:

"He did not direct from the head office. He was intellectually and physically present at each decisive step. He was present in the laboratory or in the seminar rooms, when a new effect was measured, when a new idea was conceived. It was not that he contributed so many ideas or suggestions; he did so sometimes, but his main influence came from something else. It was his continuous and intense presence, which produced a sense of direct participation in all of us; it created that unique atmosphere of enthusiasm and challenge that pervaded the place throughout its time."

Oppenheimer had remarkable powers of persuasion and was seemingly and effortlessly attuned to the wishes of everyone among the thousands of people and their families working at Los Alamos. In spite of his persuasive personality however, he always made sure that everyone's ideas were heard. For instance he supported the idea of implosion that was proposed by physicist Seth Neddermeyer, taking him into a corner and asking him to keep thinking about it even when the idea met with opposition from leading scientists like Hans Bethe and Enrico Fermi. Once he encountered a pregnant woman on the street and lectured her on how to take care of her health. The woman who was at first indignant shortly admitted that Oppenheimer was right.

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Oppenheimer brought the same esprit de corps to his leadership of the Institute for Advanced Study in Princeton. He started the tradition of afternoon tea: "Tea", he said, "is where we explain to each other what we don't understand". As director he also made persistent efforts to bring together leading thinkers from the humanities and the sciences, so that the same institute that housed logician Kurt Gödel and physicist Albert Einstein also housed diplomat George Kennan and archeologist Homer Thompson. Whether it was addressing human concerns or scientific and intellectual ones, whether in the engineering milieu of Los Alamos or the rarefied milieu of the IAS, Oppenheimer supremely excelled at one of the most important tasks of any scientific leader - building bridges.

Perhaps the biggest lesson that Medawar, Oppenheimer and Perutz understood is one of humility in the face of ignorance. Giving people free rein to pursue their ideas is not just so that you can avoid conflict and smoothen public relations, but because it is an essential requirement in an organization whose job is to explore the depths of the unknown. No thought leader or self-professed prophet can ever prioritize different lines of thinking in terms of their relative importance. This is simply because nobody knows what the "right" line of thinking is; there are no real prophets in science. Oppenheimer understood this well when he said:

"There must be no barriers to freedom of inquiry … There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors.Our political life is also predicated on openness. We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress."

R B Woodward. Vitamin B12. 3.5 hours. Enough said.

Dylan Stiles (of pioneering "Tenderbutton" fame - username tender, password button in case you want a trip down memory lane) has uploaded a rare and valuable 3.5 hour lecture of the demigod of organic synthesis, R B Woodward, giving a talk on his joint total synthesis of vitamin B12 with ETH Zurich's Albert Eschenmoser.

The talk starts with a charming and funny introduction by Canadian biochemist David Dolphin who dwells on Woodward's background and achievements. Before the talk begins an assistant makes daiquiris. Yes, daiquiris. After that the master takes the reins.

This is a demonstration of intellectual prowess from another day and age, when synthesis was king and R B Woodward was Zeus with lightning bolts. There are four important observations to note here: first, that it's about vitamin B12 which at that time was the most complex organic molecule ever synthesized, second, that it starts with a neat lineup of cigarettes on the table, all of which have been smoked by the end, third, that there are daiquiris on the table and in Woodward's hand, and fourth, that the talk is a short and breezy three and a half hours long. All four of these facts attest to the force of nature that called itself Robert Burns Woodward.

The B12 synthesis involved a truly remarkable trans-Atlantic relay comprising almost a hundred postdocs and graduate students and the synthesis itself is almost a hundred steps. At the end of the talk Woodward places a series of flags on the table, each representing the country of origin of the postdocs and students who worked on the project (99 from 19 countries to be exact). Since then no one has attempted the construction, probably because of lack of interest but also likely because of lack of stamina.

As for the length, Woodward's talks were legendary, and he was known to fill entire blackboards with beautifully drawn structures - using multiple colors of chalk. He would start at the top left hand corner and finish at the bottom right hand corner. As attested to by this marathon lecture, the length of the talk was whatever Woodward wanted it to be. His colleagues started measuring lecture time in units of milli-Woodwards, with his longest talk pegged as 1 Woodward.

A former postdoc of his once said that they generated three anecdotes about Woodward: 1. He never gets drunk (as evidenced by his heavy drinking of scotch), 2. He never gets tired (as evidenced by his ability to work eighteen hours a day and make do with only 3-4 hours of sleep every night) and 3. He never perspires.

You can certainly validate the second and third anecdotes by watching this video. And let me know if you survive through to the end.

Darwin's "endless forms most beautiful" quote...applied to chemistry

“Thus, from the ashes of alchemy, from war and peace, the most exalted object which we are capable of conceiving, namely, the production of new molecules that never existed before, directly follows. 

There is grandeur in this view of matter, with its several properties, having been originally breathed into a few elements or into one; and that, whilst this planet has gone cycling on according to the fixed laws of thermodynamics, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, synthesized.”

Original quote.

Hit picking parties, eviscerating weaknesses and other vistas from the world of molecular docking

Here’s a good review of the pitfalls and promises of molecular docking by John Irwin and Brian Shoichet (UCSF) which is worth your time, especially if you are a non-specialist who wants a summary of what’s happening in the field. As the review notes, there are many first principles-based reasons why docking should not work – poor calculation of ligand conformations, poor treatment of protein and ligand electrostatics and desolvation, non-existent consideration of protein movement, wishful treatment of water molecules, sloppy representation of x-ray structures...the list just goes on. When docking 10⁷ or so ligands involving 10¹³ total configurations, any one of these “maddening details” can doom your study.

And yet as the authors note both through general considerations and a few case studies, incremental but steady improvements in docking methodology have now made the technique respectable in most structure-based drug design campaigns (which interestingly have provided more drug candidates than HTS). Several reasons have contributed to this respectability. The first is the sheer throughput; no experimental technique can possibly screen 10 million ligands in a few days or weeks, so even with its flaws docking rises up at least as a potential complement to experiment. As the review notes, even a 10% success rate in finding new binders to a good target would be an improvement, and with well-defined binding sites the success rate can surpass high throughput screening (thus, the correct question to ask is not whether your method gives you false positives and negatives but whether this error rate is enough to overwhelm the experimental discovery rate for true positives). The second factor is the existence of massive databases like ZINC and ChEMBL containing millions of annotated ligands which could serve as starting points for ligand discovery.

Thirdly, while the holy grail of docking would be to correctly predict the absolute affinities of your ligands or at least to rank them, the more modest goal is to try to separate binders from non-binders and to discover novel chemotypes. Docking has been reasonably successful in meeting this goal, and the review presents several case studies that discovered interesting ligands which were dissimilar to known ones. In turn however, what really makes the discovery of novel chemotypes interesting is that it could lead to novel biology. It is this ability to potentially “break out of medicinal chemistry boxes” that makes docking attractive. For instance you could potentially find agonists by docking when you only found antagonists before, or – in what is one of the more interesting examples illustrated in the article – you could ‘deorphanize’ an enzyme by docking potential substrates to it and predicting its reaction profile. I still find this evidence anecdotal, but it's at least a good starting point for trying out things.

The rest of the review is also useful, not in the least because - given that it's from the Shoichet lab - there's also an instructive checklist of caveats to keep in mind while experimentally screening (PAINS, aggregators etc.) ligands. There is also a discussion of using homology models for docking. Using homology models is tricky even for lead optimization, so I would be wary in applying them too widely for high-throughput docking. While the review does illustrate an interesting case involving a GPCR, I want to note that I did blog about this case when it was published and described how – new ligands notwithstanding – the calculation seemed to use enough computing power and models to light up a startup, along with copious expert input.

It’s this last point in the review which is really the crux of the matter. When the servers have cooled down and the electrons have stopped flowing, the most important equipment that one can bring to bear on a docking study is a good pair of eyes connected to an experienced brain. Even with small error rates "the scum can rise to the top" ("The scum is out there" could be a good tagline for a X-Files episode about HTS). There is little substitute for careful inspection of top docked hits and looking at things like strain, abnormal charged interactions and wrong tautomeric states; otherwise staring down a computer screen would present the same risks as staring down a gun barrel.

The Shoichet lab has occasional "hit-picking parties" where teams of medicinal and computational chemists examine docked structures, and I suspect these parties are more common in other places than you think (although probably not as common as they should be). It’s only when the high throughput-low accuracy domain of docking meets the low throughput-high accuracy domain of the human mind that docking will continue to be successful. Given what we have seen so far I think there are grounds for hope.