Digital features in the Journal of Medicinal Chemistry

J. Med. Chem. has an editorial describing how the journal plans to make structural information in papers more accessible in a digital format. Most of this would entail having spreadsheets of compounds with SMILES strings supplied along with the paper. I applaud this effort since the ability to view and manipulate structures in 2D and 3D is one which chemists have long coveted but not realized until now.

With this issue, therefore, the Journal of Medicinal Chemistry embarks on an initiative to integrate the chemical information it publishes with digital media and chemical software. The first step in this effort is the linkage of articles with molecular formulas in a format that can be generated by and read into chemical software. The immediate benefit is that readers will be able to transfer compounds from articles into chemical drawing programs, databases, and computational tools. In the near future, this association of articles with computer-readable chemical formulas will provide a foundation for the creation of new journal features that will bring chemistry to life on the Web and in digital readers and tablets. 

Authors are invited to use their existing chemical drawing programs (e.g., ChemDraw, ACD ChemSketch, Marvin Sketch) to generate a computer-readable SMILES formula for each compound presented in their articles. These formulas are then pasted into a simple spreadsheet, along with basic information about each compound. Ideally, this spreadsheet will provide a machine-readable version of the key data presented in the article’s tables. 

Ideally I would like a PDF manuscript to be fully interactive. You should be able to right-click on a protein structure and be able to directly view it in the PDB. Better still would be an ability to rotate and zoom in on the 3D structure inside the PDF format in real time. A similar capability for small molecules would also be immensely useful; being able to look at structural parameters (bond lengths, angles etc.) and conformations extracted from manuscripts in real time would be quite enabling. We aren't there yet but I have little doubt that it's only a matter of time. This is a propitious beginning.

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:

"An implication of this work is that elsewhere in the universe there could exist life forms based on D amino acids and L sugars...Such life forms could even be advanced versions of dinosaurs,  if mammals did not have the good fortune to have the dinosaurs wiped out by an asteroidal collision, as on Earth. We would be better off not meeting them."

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:

"From there, Breslow makes the jump to advanced dinosaurs. But why might extraterrestrial life be in that form? “Because mammals survived and became us only because the dinosaurs were wiped out by an asteroid, so on a planet similar to ours without the asteroid collision it is unlikely that human types would be there, more probably advanced lizards (dinosaurs),” Dr. Breslow told The Huffington Post in an email."

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.

Are chemists much more secretive and obsessive than physicists?

Derek said it on his blog today and I have been saying it for some time. The physics community did itself and others a great service by floating ArXiv, which has become the standard venue for publication of premium physics papers focused on theory and computation. As Derek asks, why isn't there such a free service started by chemists for their community?

I concur, and a related question I have concerns being able to look at citations. The APS website (which hosts the JACS-equivalent physics journal Physical Review among others) allows readers to view the number of citations for all its papers and therefore allows us to sort papers by citations. No such feature exists for ACS or Wiley chemistry journals; as far as I know one has to log in to a paid site like Web of Science to be able to view citations.

This leads me to a question of psychology. Are chemists much more secretive and obsessive about their data and results compared to physicists? Are they much more self-conscious about revealing the impact (or lack thereof) of their publications to the public? Does some vestigial culture of secrecy going back to the alchemists' creed still linger in our minds?

It could not have to do with the status of the field since many branches of physics are as cutting edge as fields of chemistry. The first explanation that comes to my mind has to do with the color green. It's pretty clear that compared to physics, many fields of chemistry such as medicinal chemistry and materials science have money-making written on them. Unlike most physicists, chemists can patent their molecules and make money from them to a much greater extent. If this is the case, then a control group might be that of engineers. Is a reluctance to make publications or citations easily available also prevalent among the engineering community?

Yet such money-making results constitute only one part of the chemical literature. What about the several academic chemistry papers that have no tangible commercial potential? Why not make them available for free and make their citations available? I don't know the right explanation for this habit, but simple inertia and lack of vigorous discussion and initiative seem to clearly play a role. I do hope it's not because of a statistically significant difference between chemists and physicists that causes the former to hoard results.

The way I see it, the chemistry community clearly should borrow a page from the physicists. Firstly, certain kinds of chemistry papers (just like theoretical papers on ArXiv) need to be made available for free. Secondly, we all deserve a look at citation data which should not be so inaccessible and expensive. If science is supposed to be a community enterprise, this seems to be the least we can do.

Who are your favorite technical writers in chemistry?

There is a surprisingly common belief among scientists that the public speaking skills of most scientists are inversely correlated to their achievements in science. This is certainly true of many chemists I have seen, including some Nobel Laureates who would put a fly on the wall to sleep. I have attended three ACS meeting and I can probably count two or three speakers whose speaking skills matched the high level of their research accomplishments (Dennis Dougherty, Eric Jacobsen and Ron Breslow all come to mind; Dougherty was a hoot).

Surprisingly, this is a phenomenon also seen in technical scientific articles. Some of the best chemists in the world are also masters of long-winded explanations. So it is always refreshing to see someone who has achieved a lot in science and is also able to explain his or her science to the community in concise and creative words. I am not talking about popular chemistry writers here (although that is another rare breed); the papers I am thinking of are strictly technical in nature.

So what makes a technical chemistry paper readable? Simplicity, certainly; the material that you present should be easily understandable to someone skilled in the trade. Ideally it should also be comprehensible to fellow chemists in other fields and perhaps even to related scientists in different fields. Secondly, the material should drive home the creative impact of the work. If it's a synthesis you are describing, the language should make clear the elegance, economy and practical utility of your synthesis. If the paper is structural, it should drive home the uniqueness, interactions and functional relevance of your chemical or biochemical structure. If computational, the paper should highlight the advantage of your computational method over other approaches, emphasize the connection to experiment and clearly enlighten experimentalists about the strengths and limitations of the approach.

Ultimately, your paper should make clear the unique vantage point that your particular field of chemistry enjoys. If it's a review, it should stand as the defining review in the field by virtue of the scope and explanatory power of your writing. Most importantly, it should be a paper which you keep coming back to under diverse circumstances. During the course of my brief chemical career I have come across a handful of chemists and their papers that satisfy these criteria. In some cases there's a single memorable paper while in others there's a whole slew Here are a few from that collection:

1. Jack Dunitz: Dunitz, now in his nineties and still doing research at the ETH, is not only one of the leading crystallographers of the twentieth century but also one of the best technical writers in chemistry I have encountered. Three of his papers have especially stood out for me for their brevity and creativity. One is his papers is titled "Organic Fluorine Hardly Ever Accepts Hydrogen Bonds" which should be required reading for every structural and medicinal chemist. Another is "The Entropic Cost of Bound Water Molecules" (Science, 1994, 264, 670) which puts an upper limit on the free energy that you can get from displacing water molecules in protein binding sites. A third paper is "Win Some, Lose Some: Enthalpy-Entropy Compensation in Organic and Biological Systems" (Chem. & Biol. 1995, 2, 709) which advances an elegant and very simple argument for the relative unimportance of hydrogen bonds in molecular recognition; basically entropy and enthalpy almost perfectly cancel each other out for a hydrogen bond . All three papers are devastatingly brief and drive home some very important points.

2. Ken Dill: Ken Dill at UCSF is one of the world's leading experts on protein folding and structure. In 1990 he wrote a review titled "Dominant Forces in Protein Folding" (free PDF) which still stands as an authoritative review on the topic. This review is one of the most highly cited papers in Biochemistry since the journal's publication. What is remarkable about the article is the sheer amount of territory Dill covers, from the hydrophobic event and molecular dynamics to experimental studies of protein folding. Much has been learnt since 1990 but the basic ideas in the paper are still valid and it remains a commanding overview of the field.

3. R B Woodward: Enough has been said about the man on this blog, but his papers often constituted poetry in (electronic) motion. Woodward's language had that special tinge that comes from having a personal relationship with every single compound that he encountered, from the simple nitric acid to vitamin B12. Almost any of his papers is breathtaking in both language and content, but I will especially recommend his famous works on strychnine (Tetrahedron, 1963, 19, 247) and reserpine (Tetrahedron, 1958, 2, 1) as masterpieces of scientific writing- and of literature.

4. K C Nicolaou: Say whatever you want about the man, but his review articles have an unmistakable feel of heroic achievement. Yes, maybe he exaggerates a little and yes, maybe the rash of pictures from Greek mythology is a little too much, but the man has written some of the best reviews of organic syntheses. And like Woodward, Nicolaou does an admirable job in his reviews of bringing out the excitement, beauty and achievement of the field. My favorites? Brevetoxin B and the CP molecules.

5. Anthony Nicholls: More recently, I have found computational chemist Anthony Nicholls of OpenEye to be an unusual clear and incisive technical writer. What is notable about his papers is the careful dissection of all factors involved in a particular system as well as an honest admission of limitations of current methods. His papers present a balanced perspective of theoretical and computational methods and clearly point out gaps and opportunities for improvement. I would especially recommend his co-authored review on metrics for evaluating and presenting computational methods in drug design and a critical and enlightening study of solvation of organic molecules that points to the challenges in calculating properties of complex systems.