Field of Science
























Would Ron Breslow's dinosaurs be typing this post?

Much has been written about a recent perspective in JACS written by Ronald Breslow on the origin of homochirality during the origin of life. There's excellent commentary on the topic from See Arr Oh and Paul@Chembark. Briefly, Breslow's paper describes some pretty interesting research from his and other groups establishing a possible mechanism for the transfer of chirality from alpha-methyl amino acids to standard amino acids, followed by the amplification of that small chirality excess through a variety of plausible mechanisms involving the concentration of the dominant enantiomer.

The paper would have remained an interesting chemistry curiosity about the origin of life. It could have even served to remind the public that the origin of life is chemistry's Big Question, had it not been for two lines at the end of the piece:


What was interesting was that when I first came across the paper, I spent about two seconds on this line and moved on. The line is an amusing attempt at humor. You usually don't see humor in a technical paper, but in fact I am all for it; I think we need to spice up our otherwise dry scientific literature with the occasional joke. The content of the paper obviously had nothing to do with dinosaurs; it was about a specific technical chemical puzzle in the origins of life. And nothing would have come out of it had not the ACS PR office created a sensationalized news piece wrongly centered around these two lines. Scant attention was paid to the scientific substance of the paper, and it didn't help when other popular venues like The Huffington Post also questioned Breslow about it and received the following answer:


This set of events led to some unfortunate consequences. For one thing, the undue emphasis on dinosaurs at the expense of homochirality was another nail in the coffin of the public communication of chemistry. Here was a chance to explain to the public why the origin of life is chemically fascinating, but instead the chemical substance got overwhelmed by the precipitate of publicity surrounding dinosaurs. If the ACS is wondering why chemistry is having such a PR problem, now would be the time to look in the mirror.

The situation was exacerbated by more serious matters. Following a tip from some commentators, Stu Cantrill of Nature Chemistry looked up two old Breslow papers on the same topic and found out an extreme case of self-plagiarism; most of the paper seems to have been copied verbatim from the other sources. Breslow should not be blamed for inserting that little joke at the end - it was the media which sensationalized it - but he cannot be excused for the gratuitous self-plagiarism.

That's about what I want to say about this unfortunate episode since others have extensively covered it, but I do want to focus on Breslow's reply to The Huffington Post. Some have chided him for it, but the statement is actually not as absurd as it sounds since Breslow is asking a famous, age-old question in evolutionary theory: If the tape of evolution were re-run, would it again produce dinosaurs, Breslow and ACS editors? Or in other words, how predetermined is evolution, and how dependent is it on accidents? This question is a profound one , since if the answer is even an affirmative "yes", it has serious implications for not just science but for theology and philosophy and the whole puzzle of human existence. 

Stephen Jay Gould was a powerful advocate of contingency in evolution, and his argument is not surprising to see. Evolution has been shaped by so many quirks of environment and the fate of individual organisms and species, that it would be naive to think that chance did not play a role in it. A single piece of wood accidentally drifting apart and carrying a few species on it to an isolated island can sculpt the evolution of that species. And we know for a fact that more massive events like volcanoes and earthquakes certainly did this. In fact it was geologist Charles Lyell's descriptions of such seismic events that started Darwin down the path to evolution and natural selection. It seems thus that if one could hypothetically run "what if" scenarios, it's very unlikely that anything approximating modern humans and dinosaurs could ever arise.

But this answer is not as obvious as it sounds. The biologist Simon Conway Morris has put forth a competing scenario in which certain universal features of evolution guarantee the presence of common adaptations during the evolution of species. This argument is based on what's called "convergent evolution" which essentially refers to the existence of common solutions to diverse evolutionary problems. A typical example would be all kinds of mammals, fish, amphibians and reptiles whose bodies are adapted to swimming. In most of these creatures you see similarly shaped, streamlined bodies, muscles and bones which are suited for swimming. Another principle concerns homologous structures (and not convergent evolution, as a commentator reminded me) like the digits of the hand, whose basic plan seems to be conserved across species. Indeed, homologous evolution provide some of the strongest pieces of evidence for common evolutionary origins. Thus Morris's argument is that even if the evolutionary tape were to run again, something similar to humans, dinosaurs, frogs and eagles (although the details would certainly differ) would be seen if the process were allowed to keep to itself for a few billion years. This interpretation acquires even greater significance when applied to humans; would such an intelligent, successful and self-centered species as Homo sapiens have evolved in an alternative evolutionary universe?

There is a lot of interesting discussion to be had about this topic. It's equally fascinating when applied to chemistry and leads to similar questions. For instance, what are the chances that the foundational compounds of life - DNA, RNA, amino acids, sugars, ATP - would have formed had evolution been left to run again with different tweaks and quirks of fate? Personally I find the questions somewhat easier to answer in case of chemistry since the formation of many of these compounds is governed by relatively simple energetic arguments. ATP's express purpose is to make otherwise unfavorable reactions possible by driving them downhill through high-energy bonds, and if not ATP it's hard to see how some other chemical compounds performing the same function could not have evolved. A great example of an attempt to answer these questions is seen in Frank Westheimer's classic paper "Why Nature Chose Phosphates?" in which he points to the unique properties of phosphate that make it such a dominant source in life's workings, both in metabolism and heredity.

Breslow's question is therefore quite sensible and its implications are fascinating to ponder. How would 2012 have looked like had the dinosaurs not been wiped out by an asteroid? Would they still have been alive and would humans have had the unfortunate fate of co-existing with them? Would they be as smart as humans? Naturally such scenarios would have profoundly affected the evolution and character of our civilization. Or would the dinosaurs have precluded the rise of Homo sapiens, perhaps by nipping our scarce population in the bud and making us extinct? Or would they have become extinct themselves through some other cause, perhaps extreme climate change? How indeed would planet earth have looked like had it still been ruled by dinosaurs?

Naturally we don't know the answers to these questions. But Breslow's little joke at the end, while sounding silly, inadvertently asks a very important and thought-provoking question. Too bad it was all obscured by the charges of self-plagiarism.

Modeling magic methyls

Shamans have their magic mushrooms, we medicinal chemists have our magic methyls. The 'magic methyl effect' refers to the sometimes large and unexpected change in drug potency resulting from the addition of a single methyl group to a molecule (for laymen, a methyl group is a single carbon with three hydrogens, and you don't expect spectacular effects from the addition of such a small modification to a drug). This is part of a broader paradigm in chemistry in which small changes in molecular structure can bring about large changes in properties, especially biological activity.

In this study, researchers from Bill Jorgensen's group at Yale ask what exactly it is that a methyl group can do to a biologically active molecule. They look at more than 2000 cases of purported activity changes induced by methyl groups from two leading medicinal chemistry journals, and their work highlights some unexpected effects of methyls. The techniques used are free-energy perturbation, Monte-Carlo and molecular dynamics simulations to compare methylated and non-methylated versions of published inhibitors in an effort to gain insight into the factors dictating potency.

Firstly, they find that for all their reputation, methyls mostly confer a modest increase in potency. The greatest increase is about 3 kcal/mol in free energy, which considering the exponential relationship between free energy and binding constant, is actually quite substantial. But this happens in a negligible minority of cases; as they find, a 10 fold boost in potency with a methyl is seen in only 8% of the cases, while a 100 fold difference is seen in only 0.4%.

So what does a methyl do? For starters, a methyl is simply a nice, small, lipophilic group so you would expect it to give you some advantage simply by snugly fitting in in an otherwise unoccupied binding pocket. But the real advantage of a methyl is thought to come from kicking out 'unhappy' water molecules; often a small protein pocket is occupied by a highly constrained water molecule that is desperate to join its free brethren in the bulk. A methyl group is usually only too happy to oblige and kick the water out. Now, as the crystallographer Jack Dunitz demonstrated more than a decade back, the maximum free energy gain you could estimate from displacing a water molecule is about 2 kcal/mol. Considered in this light, you would expect a gain of at least that much from a hydrogen to methyl change, but the very rare 3 kcal/mol cases seen seem to call this belief into question. Clearly the common wisdom about methyls displacing waters is not telling us the entire story.

As the authors demonstrate, the common wisdom may indeed point to uncommon cases. They look at five cases where methyls give the greatest potency boost, and in no case do they find evidence for displacement of a water molecule. So where's the potency gain coming from? It turns out that it may be coming from a common but often underappreciated factor; conformational reorganization. When a ligand binds to a protein, it exists in several - often hundreds - of conformations in solution. How tightly the protein can bind the ligand depends on how much energy the protein can expend to twist and turn these conformations into the single bound conformation. You would expect that the more similar a molecule's unbound conformation in solution is to its protein-bound conformation, the easier it would be for the protein to latch on to it.

And indeed, that's what they find. Most of the cases they look at concern potency gains coming from putting methyls at the ortho position of a biaryl ring. Organic chemists are quite familiar with the steric, planarity-disrupting effects of ortho substituents on biaryl rings; in fact it's a tried and tested strategy to improve solubility by disrupting crystal packing effects. It turns out that the bound structures of the molecules present a twisted, non-planar conformation. In the absence of methyls, the rings would prefer to stay almost coplanar (or at least less non-planar) in the unbound conformation. But putting methyl groups on twists the rings in the unbound conformation into a form that's similar to the bound one; basically there's more overlap between the solution and bound conformations in case of the methylated versions compared to the non-methylated ones. Consequently, the protein has to expend less energy to turn an already similar conformation into its bound counterpart. This becomes clear simply by comparing the single dihedral angle bridging the two rings in the bound and unbound conformations of one particular molecule (as shown in the figure above).

The study seems to impart what is part of an important general lesson; when designing ligands or drugs to bind a protein, it is as important to take the solution conformations into account. It's not just how the protein interacts with the drug, but it's what the drug is doing before it meets the protein that's equally important.

A citation against citations

In the latest issue of Angewandte Chemie, Stanford chemistry professor Richard Zare has some cogent words of advice for assessing young faculty members when they are up for tenure. Zare has written the article partly as a response to what he sees as an excessive use and abuse of citation indices throughout the world in judging tenure-worthy achievements.

As Zare notes, the h-index which has been adopted in part because it seems to measure both quality and quantity is particularly ill-equipped to measure early success in research. This is mostly because (and this is one of the biggest arguments against any citation metric) the significance of most research does not become obvious until much later. Zare cites the example of physicist Steven Weinberg's paper unifying the electroweak force; while it was cited only a few times in the first few years, it is now one of the most highly cited papers in the history of physics. Another obvious example is Watson and Crick's DNA paper which gathered very few citations in its fledgling years. Thus citations, if they make sense at all, make much more sense in one's later career.

Yet there is a disturbing trend of universities worldwide adopting citation statistics to drive tenure decisions. In some countries like China, researchers are even awarded cash prizes for trying to publish large numbers of papers in both leading and minor science journals. As a recent article bemoaned, this has led to journals like Nature and Science being flooded by papers of dubious quality from certain countries. Not only can such practices create bias against papers from these countries, but they harm the global enterprise of science as a whole by emphasizing publication at the expense of genuinely interesting work.

Far better is to try to objectively judge the promise of young investigators by evaluating their impact on specific subfields. To this end Zare describes the system adopted by the Stanford chemistry department which puts the highest emphasis on 10 to 15 letters of recommendation from around the world. The letter writers are essentially asked to answer the simple question, "Has the investigators' work in his/her chosen area led to new understanding and directions in the field?". Everything else comes second, including the number and authorship rank of papers along with various indices. As Zare says,


I find it very surprising - and encouraging - that the amount of money brought in does not play a major role in determining tenure. If true, this seems to go against disturbing current trends that are geared toward evaluating professors similar to sales managers at Macy's or hedge fund managers on Wall Street.

There is one caveat to what seems to be an otherwise cogent and role model-worthy tenure policy adopted by the Stanford chemistry department. Just as the true impact of research does not become clear until years later, the true value of ideas also does not become clear by asking 10, 15 or even 100 referees. Although this helps, it can mask the fact that most original scientific contributions at least partly challenge conventional wisdom, and keepers of the faith are almost always reluctant in endorsing such contributions. What should really matter is not whether a young scientist's work has led to new truths, but whether it has been interesting enough to spark a flurry of research activity that in turn may lead to minor or major truths. In science, being interesting is more important than being right, and tenure committees should take this fact into account.

On Freeman Dyson, cadmium estimation and the joy of chemistry

Freeman Dyson who is a hero of mine is someone who has done lots of interesting things during a long and fruitful life. If you look at his writings or talks it is easy to mistake him as a philosopher of science. But as he himself said to me during a long, one-on-one, intellectually sparkling lunch discussion two years ago, a lot of people think that talking about the big picture automatically makes one a philosopher. Dyson has indeed written about a lot of big picture topics, from the origins of life to the colonization of space. But he also maintains that he has always been first and foremost a problem solver, someone who is much more interested in details than in grand theorizing. Whatever philosophy he manages to weave is built on a foundation of solving specific technical problems. This is partly evidenced by his work on highly technical engineering projects ranging from nuclear spaceships to nuclear reactors.

This quality would make Dyson quite comfortable in the company of chemists, since chemistry by its very nature is more a problem-solving discipline rather than a philosophical pursuit like cosmology. I was curious to know Dyson's views on chemistry since he has not really written anything of note on the subject except a review in Physics Today of Roald Hoffmann's fine book "The Same and Not the Same". Unfortunately I did not find time to ask him anything about this during our meeting.

Then I remembered a great collection of interviews with Dyson that I found a few years ago on a website called Web of Stories. This website is a must-see for history of science enthusiasts. It features interviews with scores of famous scientists, humanists and artists from diverse disciplines. The best thing about these interviews is that they are long and detailed instead of two minute sound bytes; each interview lasts in total for a few hours and covers most significant events in the interviewees's life, so you really get a close look at the thought processes of leading thinkers. In one of Dyson's interviews I was delighted to find this:

"I was going to say about chemistry that Roald Hoffmann whom I got to know quite recently, who is a chemist who writes poetry and is a great character, he has the same attitude toward chemistry that I do. I mean it is the beauty of the details rather than any over-arching theory. In that way it's very different from physics, and I had a taste for it. My taste is always more for the details than for the big picture...

...I learned chemistry from Christopher Longuet-Higgins who was already much more of an expert and more excited about chemistry than Eric James. And I remember Christopher bringing to Winchester some crystals of stannic iodide which he had made, which is the most marvelous stuff. It is a brilliant scarlet colour and it makes these beautiful scarlet crystals, and they're also extremely heavy. If you have a little bottle full of it, it feels like lead. So that kind of chemistry I found delightful, just the sort of details of the actual stuff, rather than the theory that lay behind it.

I remember the joy when, here in Princeton, Willard Libby came on a visit once and brought along another little bottle of chemicals, which also was very heavy, and that was barium xenate, which was barium xenon oxide, which of course was an absolute revelation because nobody imagined that xenon could have compounds, being an inert gas. And it was sometime in the 1950s these compounds were discovered, and barium xenate is just such an ordinary stuff. It's a sort of heavy white crystals which are completely stable, they don't show any signs of anything strange and there it is. If you heat them up of course the xenon comes bubbling off..."

So there, I think Dyson would have felt right at home as a chemist. And the point he makes is an obvious and important one that is often lost among the cliched caricatures of chemists bubbling frothy liquids and crystallizing colorful solids that one often sees in literature and cinema. But it's precisely these bubbling liquids and colorful solids that provide chemistry with a palpable reality that's often missing from more theoretical sciences.


Every chemist among us is familiar with this feeling of discovering something unknown, no matter how trivial or important, that actually exists; all the better if it has a brilliant scarlet or full-throated yellow color, as is often the case in chemistry. Dyson is right that there is something unmistakably reassuring, in-your-face - real - about holding a vial of something that was previously considered impossible.

Physicists often like to tell the story of how Einstein felt that "something had snapped inside" him when he saw the predictions of general relativity confirmed by observations of the perihelion of mercury. He surely must have felt the rare, once-in-a-lifetime satisfaction of a great theoretical construct being validated by a real observation that could be boiled down to a single number. We tend to think of Einstein as the great scientist-philosopher, but there he was, being ecstatic about a technical detail that was a crucial part of his magnum opus. Observing barium xenate or cadmium is not quite as momentous as confirming the theory of relativity, but I can readily imagine feeling a shiver down my spine if I had been presented with that sort of chemical evidence. Evidence that seemed to defy the impossible but which I could nonetheless hold in my hand and keep in my closet. That's the joy of chemistry.

A molecular modeler's view of molecular beauty









On physics envy and drug discovery









