The problem with molecular modeling is not just molecular modeling

I am attending the Gordon Conference on Computer-Aided Drug Design (CADD) in the verdant mountains of Vermont this week, and while conference rules prohibit me from divulging the details of the talks, even the first day of the meeting reinforces a feeling that I have had for a while about the field of molecular modeling: the problems that plague the field cannot be solved by modelers alone.

This realization is probably apparent to anyone who has been working the field for a while, but its ramifications have become really clear in the last decade or so. It should be obvious by now to many that while modeling has seen some real and solid progress in the last few years, the general gap between promise and deliverables is still quite big. The good news is that modeling has been integrated into the drug discovery process in many small and sundry ways, ranging from getting rid of duplicates and "rogue" molecules in chemical libraries to quick similarity searching of new proposed compounds against existing databases to refinement of x-ray crystal structures. These are all very useful and noteworthy advances, but they don't by themselves promise a game changing impact of modeling on the field of drug discovery and development.

The reasons why this won't happen have thankfully been reiterated several times in several publications over the last fifteen odd years, to the extent that most reasonable people in the field don't get defensive anymore when they are pointed out. There's the almost complete lack of statistics that plagued the literature, leading people to believe that specific algorithms were better than what they actually were and continuing to apply them (this aspect was well emphasized by the last GRC). There's the constant drumbeats about how badly we treat things like water molecules, entropy, protein flexibility and conformational flexibility of ligands. There are the organizational issues concerning the interactions between modelers and other kinds of scientists which in my opinion people don't formally talk about with anywhere near the level of seriousness and the frequency which they deserve (although we are perfectly happy to discuss them in person).

All these are eminently legitimate reasons whose ills must be exorcised if we are to turn modeling into not just a useful but consequential and even paradigm-shifting part of the drug discovery process. And yet there is one other aspect that we should be constantly talking about that really puts a ceiling on top of even the most expert modeler. And this is the crucial reliance on data obtained from other fields. Because this is a ceiling erected by other fields it's not just something that even the best modelers alone can punch through. And breaking this ceiling is really going to need both scientific and organizational changes in the ways that modelers do their daily work, interact with people from other disciplines and even organize conferences.

The problem is simply of not having the right kind of data. It's not a question of 'Big Data' but of data at the right level of relevance to a particular kind of modeling. One illusion that I have felt gradually creeping up the spines of people in modeling-related conferences is that of somehow being awash in data. Too often we are left with the feeling that the problem is not that of enough data, it's only of tools to interpret that sea of information.

The problem of tools is certainly an important one, but the data problem has certainly not been resolved. To understand this, let's divide the kind of data that is crucial for 'lower level' or basic modeling into three categories: structural, thermodynamic and kinetic. It should be obvious to anyone in the field that we have made amazing progress in the form of the PDB as far as structural information is concerned. It did take us some time to realize that PDB structures are not sacrosanct, but what I want to emphasize is that when serious structure-based modeling like docking, homology modeling and molecular dynamics really took off, the structural data was already there, either in the PDB or readily obtained in house. Today the PDB boasts more than a hundred thousand structures. Meticulous tabulation and analysis of these structures has resulted in high-quality datasets like Iridium. In addition there is no dearth of publications pointing out the care which must be exercised in using these structures for actual drug design. Finally, with the recent explosion of crystallographic advances in the field of membrane protein structure, data is now available for virtually every important family of pharmaceutically relevant proteins.

Now consider where the field might have been in a hypothetical universe where the PDB was just getting off of the ground in the year 2015. Docking, homology modeling, protein refinement and molecular dynamics would all have been in the inky backwaters of the modeling landscape. None of these methods could have been validated in the absence of good protein structure and we would have had scant understanding of water molecules, protein flexibility and protein-protein interactions. The Gordon Conference on CADD would likely still be the Gordon Conference on QSAR.

Apply the same kind of thinking to the other two categories of data - thermodynamic and kinetic - and I think we can see some of the crucial problems holding the field back. Unlike the PDB there is simply no comparable database of tens of thousands of reliable thermodynamic data points that would aid the validation of methods like Free Energy Perturbation (FEP). There is some data to be found in repositories like PDBbind, but this is still a pale shadow of the quantity and (curated) quality of structures in the PDB. No wonder that our understanding of energies - relative to structure - is so poor. When it comes to kinetics the situation is much, much worse. In the absence of kinetic data, how can we start to truly model the long residence times in protein-ligand interactions that so many people are talking about these days? The same situation also applies to what we can call 'higher order' data concerning toxicology, network effects on secondary targets in pathways and so on.

The situation is reminiscent of the history of the development of quantum mechanics. When quantum mechanics was formulated in the twenties, it was made possible only by the existence of a large body of spectroscopic data that had been gathered since the late 1870s. If that data had not existed in the 1920s, even wunderkinder like Werner Heisenberg and Paul Dirac would not have been able to revolutionize our understanding of the physical world. Atomic physics in the 1920s was thus data-rich and theory poor. Modeling in 2015 is not exactly theory-rich to begin with, but I would say it's distinctly data-poor. That's a pretty bad situation to be in.

The reality is very simple in my view: unless somebody else - not modelers - generates the thermodynamic, kinetic and higher-order data critical to advancing modeling techniques the field will not advance. This problem is not going to be solved by a bunch of even genius modelers brainstorming for days in a locked room. Just like the current status of modeling would have been impossible to imagine without the contributions of crystallographers, the future status of modeling would be impossible to imagine without the contribution of biophysical chemists and biologists. Modelers alone simply cannot punch through that ceiling.

One of the reasons I note this problem is because even now, I see very few (none?) meetings which serve as common platforms for biophysical chemists, biologists and modelers to come together and talk not just about problems in modeling but how people from these other fields can address the problem. But as long as modelers think of Big Data as some kind of ocean of truth simply waiting to spill out its secrets in the presence of the right tools, the field will not advance. They need to constantly realize the crucial interfacing with other disciplines that is an absolute must for progress in their own field. What would make their own field advance would be its practitioners knocking on the doors of their fellow kineticists, thermodynamicists and network biologists to get them the data that they need.

That last problem suddenly catapults the whole challenge to a new level of complexity and urgency, since convincing other kinds of scientists to do the experiments and procure the data that would allow your field to advance is a daunting cultural challenge, not a scientific one. Crystallographers were busy solving pharmaceutically relevant protein structures long before there were modelers, and most of them were doing it based on pure curiosity. But it took them fifty years to generate the kind of data that modelers could realistically use. We don't have the luxury of waiting for fifty years to get the same kind of data from biophysical chemists, so how do we incentivize them to speed up the process?

There are no easy ways to address this challenge, but a start would be to recognize its looming existence. And to invite more scientists from other fields to the next Gordon Conference in CADD. How to get people from other fields to contribute to your own in a mutually beneficial relationship is a research problem in its own right that deserves separate space at a conference like this. And there is every reason to fill that space if we want our field to rapidly progress.

On the impact of social media and Twitter on scientific peer review

I am very pleased to note that an my article on the impact of social media and especially of blogs and Twitter on peer review in chemistry in particular and science in general has just come out in a special issue of the journal 'Accountability in Research'. This project has been in the works for almost a year and I have spent quite a bit of time on it. The whole issue is open access and it was made possible by the dedicated and generous efforts of my colleague and friend, the eminent historian of chemistry Jeff Seeman. I am privileged to have my article appear along with those by Roald Hoffmann, William Schulz, Jeffrey Kovac and Sandra Titus. All their papers are highly readable.

Here in a nutshell is what I say. I have had a very dim view of Twitter recently as a vehicle for cogent science communication and rational debate, but in this article I find myself full of praise for the medium. This sentiment has been inspired by the use of Twitter in recent times for demolishing careless science and questioning shoddy or controversial papers in the scientific literature. In my opinion the most spectacular use of Twitter to this effect was Nature Chemistry editor Stuart Cantrill's stark highlighting of 'self-plagiarism' in a review article published by Ronald Breslow in JACS in 2012 (I hold forth on the concept of self-plagiarism itself in the article). As I say in my piece, to my knowledge this is the first and only instance I know in which Twitter - and Twitter alone - was used to point our errors in a paper published in a major journal. If Cantrill's analysis was not a resounding example of peer review in the age of social media, I don't know what is.

I have had a much more consistent and positive views of blogs as tools for instant and comprehensive peer review, and thanks to the vibrant chemistry blogosphere that I have been lucky to be a part of for almost eleven years, have witnessed the true coming of age of this medium. There is no doubt that peer review on blogs is here to stay, and in my article I address the pitfalls and promises inherent in this development. One of the most important concerns that a naive observer would have regarding the use of blogs or Twitter for peer review is the potential for public shaming and ad hominem attacks - and such an observer would find plenty of recent evidence in the general Twittersphere to support their suspicions. Yet I argue that, at least as far as the limited milieu of chemistry blogs is concerned, the signal to noise ratio has been very high and the debate remarkably forward-thinking and positive; in fact I think that, by and large, chemistry blogs could serve as models of civil and productive debate for blogs on more socially or politically contentious topics like evolution and climate change. I am proud to be part of this (largely) civil community.

What I aim to do in this piece is to view the positive role of Twitter and blogs in effecting rapid and comprehensive peer review through the lens of three major case studies which would be familiar to informed observers: the debacle of 'arsenic life', the fiasco of hexacyclinol and the curious case of self-plagiarism in the Breslow 'space dinosaurs' review. In each case I point out how blogs and Twitter were responsible for pointing out mistakes and issues with the relevant material far faster than official review ever could and how they circumvented problems with traditional peer review, some obvious and some more structural. The latter part of the review raises questions about the problems and possibilities inherent in the effective use of these tools, and I muse a bit about how the process could be made fairer and simpler.

Due to the sheer speed with which blogs and social media can turn our collective microscopes on the scientific literature and the sheer diversity of views which can be instantly brought to bear on a contentious topic, there is no doubt in my mind that this new tier of scientific appraisal is here to stay. In my opinion the future of completely open peer review is bright and beckons. How it can complement existing modalities of 'official' peer review is an open question. While I raise this question and offer some of my own thoughts I claim to provide no definitive answers. Those answers can only be provided by our community.

Which brings me to the crux of the article: although my name is printed on the first page of the piece it really is of, by and for the community. Hope there will be something of interest to everyone in it. I welcome your comments.

The Tim Hunt affair is destroying our community from within. We need to not let that happen.

So much ink has been – and continues to be – spilt over the Tim Hunt affair that I have nothing to add to it. The only thing that’s clear by this point is that the episode is more complicated than what it appeared at first. And it's also clear that both sides could have done things differently. Beyond that you look at the evidence and make up your mind.

I am writing this post for a very different reason. As someone who can call himself at least a semi-veteran of the blogosphere (for about 11 years), I can truthfully say that I have never seen the community so bitterly divided against itself. I reach this conclusion based on observations of arguments on Twitter, Facebook and other sources. Although I have occasionally posted about the episode on these sources I have largely been an observer. And what I observe is definitely disturbing. Many of the people involved in these arguments have been prominent members of the blogging and journalism community, and some of them are my friends and colleagues. And in all the years that I have blogged and seen these leading members of the community in action, I have never seen people who once stood as allies in a common cause fight with each other with the ardor that we historically associate with Protestants and Catholics, or with Sunnis and Shiites. And just like these groups, what is most remarkable and disconcerting is to see these people be at each others’ throats in spite of supposedly having so much in common.

To put it simply: I think that as a community we are destroying ourselves in profoundly anti-intellectual and divisive ways.

To be sure, the signs have been there for a few years. People either in favor of or against a particular argument have often adopted a take-no-prisoners attitude, especially on Twitter which has turned into a veritable Frankensteinian nightmare at times. Whether you call it public shaming or something else, the tendency to band together, rain down on people with indignation, discard them and then move on to the next outrage has turned into a regular Thursday morning occurrence. It’s not even a novelty anymore.

And yet I am seeing something qualitatively new with the Tim Hunt episode. A maelstrom of words that reaches new levels of divisiveness and vitriol. I am seeing fights break out between people who I would never have expected to fight with each other. I am seeing people simply refuse to agree with each other, even if the general agreement might be broad and they might be arguing about interpretations or about subtleties. I am seeing very reasonable people engage in ad hominem attacks in an endless fury of cyclical gyrations.

All this is disturbing for several reasons. The most important one is simply that this debate threatens to fragment the community into factions, each one of which refuses to give way and hear the other side of the debate. Meanwhile the moderates, the ones who are afraid to descend into the shouting matches for good reason, will continue to stay on the sidelines and their voices will continue to be largely silent. What you will end up with is a divided community of absolutist and polarized factions. What are the chances then that these factions with their history of bitterness and personal attacks will actually come together when something truly worthy of righteous indignation happens? To me these chances appear slim.

The second serious reason why this couldn’t possibly be good for the community or for anyone else for that matter is because it sends a very wrong message to the world at large, the vast community of ‘third party’ observers who don’t have a dog in the hunt but who simply want to know the truth (shouldn’t we all?). Simply put, this wider community will start ignoring us when something genuinely important or disturbing happens because they will rightly think that we have cried wolf all too often. They will start to think that we are neither good journalists nor good activists and all we are interested in doing is pointing fingers without effecting real progress. It’s worth thinking about this in a very practical way: if we raise hell at every single episode, no matter what its significance or lack thereof in the bigger scheme of things, how will people who want to learn from us be able to distinguish between all these episodes? If we decide to get outraged to the same extent at every single perceived injustice, trip-up, sin and faux pas, then not only are we not optimally allocating our outrage, but we also run the risk of not having enough left for the things that really matter. In addition we only end up equating outrage with actual action. This helps neither us, nor the true victims, nor the broader community. All it does is create smoke without fire and engender suspicion about our goals.

Thirdly and perhaps most importantly, all this simply stops us from learning from each other. Words about surrounding ourselves with echo chambers have become clichés, but they are clichés because they are true. If we decide that we are going to banish – if not from physical sight then at least from our Twitter feeds – everyone who disagrees with even parts of what we believe, if we passionately subscribe to that old chestnut that those who aren’t with us must automatically be against us, if we divide people into black and white categories of friends vs enemies based on some arbitrary ruler of at least 95% agreement, if we stop believing that someone can even vehemently disagree with parts of our worldview and still be aligned with our broader causes, then we will very rapidly get to a stage when the only people we converse with most of the times are largely intellectual clones of ourselves. At the very least our learning process will then become starkly impoverished.

All this and more has already happened, but the Tim Hunt has really taken the gloves off and exposed the cracks in the whole structure in my opinion, and nothing about it says good things about the future existence of a vibrant community where people respectfully disagree with and learn from each other.

How did we get to this stage? Everyone will offer their own views and there are undoubtedly very many responsible factors, but I continue to believe that the single overriding factor is the following: We have made almost every argument one about identity and ideology rather than about ideas. This is a general observation that has been shored up by other people, and Twitter is merely its most virulent manifestation. These days it has become almost impossible to say something without people regarding you not as an independent living and breathing human being with individual ideas but as part of some ideology or background. You cannot simply be John Doe saying something, something whose validity has to be evaluated on its own intrinsic merits; instead you have to be John Doe – feminist, John Doe – sexist, John Doe – libertarian, John Doe – person with white/black/brown/male/female privilege.

Now I understand that our opinions are undoubtedly dictated by our background, our community and yes, our privilege. But they are also dictated as much by our existence as independent thinking entities. To assume in the absence of evidence to the contrary that our identity must be the only thing shaping our opinions is at the very least unscientific (you are simply assuming one causal factor among several) and at worst an attitude that insults our unique existence as independent thinkers. My opinions on any matter are a function of both my background and of the logical chain of thinking that proliferates through my mind. To automatically assume that only my background is responsible for my opinions, or that the logical chain cannot exist without my background, is frankly an insult to the wonderful workings of the human mind and the history of human thought.

This constant, knee-jerk appeal to someone’s background and identity introduces a bias that can very much color your opinion about that person, and this bias is inherent in the simplest cases. It damningly breeds precisely the divisiveness that we claim to be against. For instance when two people are having an argument, the moment you start criticizing one person by stating their skin color in your opening argument becomes the moment when you are inevitably going to analyze their behavior through those particular tinted glasses. Is their skin color relevant to the debate and your disagreement with them? Maybe, and maybe not, but it’s both unscientific as well as profoundly unobjective to assume that it is without further scrutiny or reasonable cause. Assuming this ironically pastes the same label of discrimination on us that we often seek to abolish. Similarly when we assume that someone is saying something because of their ‘privilege’ (which is a very real thing), we shift the focus of the conversation from what’s being said to who’s saying it. It is time that we started evaluating people’s words and ideas on their own merits and not only as necessarily linked to their identity and ideological underpinnings (which may not even exist in their own mind).

What is even more disturbing is that this behavior is increasingly prevalent among those who identify themselves as liberals (although it’s also not absent among conservatives). For instance I have often observed this bizarre bias among people who say they are committed to diversity; what is confounding to me is that these people often appear to be committed to every other kind of diversity (gender, skin color, political affiliation) except diversity of ideas. Ideas have been at the forefront of human civilization for ten thousand years. Since when did they become secondary? What exactly makes them occupy a rung lower on the ladder from identity? It is downright weird for me to see this anti-intellectual behavior especially among liberals, some of whom are scientists or science journalists and who more than most members of the general public cherish the value of ideas.

I could go on with even more details, but they will add little to the general point. This elevation of identity above ideas and the alienation of people with different ideas who might still share a common core is hugely detrimental to the present and future of a community ostensibly engaged in sharing viewpoints and growing by learning from each other. The only result of this divisive attitude will be the fragmentation of people who heartbreakingly are far more similar to each other than what they think. 

I am neither so naïve nor do I consider myself so enlightened as to propose any solution for this disturbing trend. And yet I cannot help but observe that in a sense part of the solution is even now bleedingly simple, and I propose this solution - more a guideline than a solution, really - in the form of a plea. Find middle ground. Constantly seek the places where you agree rather than disagree, and you will find that there are more of those around than you think. Do not banish people even with divergent ideas from sight and mind, because these are really the only ones who can teach you something new; allowing these people to speak their minds is not easy, but the rewards are important. Respect diversity of ideas as much as diversity of identity, and stop automatically pigeonholing people into categories of identity and examining their arguments through these lenses. If you feel offended by something first try to understand it; it's hard, but it's worth the trouble. Finally, just stop equating every perceived and real act of dissension, of contrary opinion and thought as disloyalty to some real or fictitious ‘cause’ or ideology, as a less than perfect fit to a conviction. We are more similar than we think, we are more complex than we think, and we are much more than the sum of our identities. And that realization is really the only one that can bring us together at the end of the day.

Bethe's Dictum: "Always work on problems for which you possess an unfair advantage"

Hans Bethe in his young days

Hans Bethe has long been a big hero of mine, not only because he was one of the greatest scientists of the twentieth century but also because he was one of its most conscientious. The sheer body of work he produced beggars belief, but so does his rocklike, steadfast determination on which others could rely in the most trying of times – and there was no dearth of such times during Bethe’s lifetime (1906-2005).

Bethe’s diversity of contributions to virtually every branch of physics was probably rivaled only by Enrico Fermi in the 20^th century. The seminal body of work that he produced encompasses every decade of his unusually long life, beginning with his twenties as a student of Arnold Sommerfeld in Munich and ending only a few months before his death at age 99. It ranges across almost every imaginable field of theoretical and applied physics: quantum mechanics, nuclear physics, quantum electrodynamics, astrophysics, solid state physics, nuclear weapons and nuclear reactor design, missile engineering. In addition there is the vast trove of documents featuring his key contributions to government policy over six decades. The sum total of this oeuvre is so large that it led one of Bethe's distinguished colleagues to joke that it must have been the result of a conspiracy crafted by many people who all decided to publish under the name "Hans Bethe".

What made Bethe so successful? Intelligence, certainly, but the twentieth century had no dearth of off-scale intelligent scientists, especially in physics. Coupled with very high intelligence were some other qualities that his fellow scientists noted: supreme powers of concentration and an indefatigable stamina (he could churn out hundreds of pages filled with equations sitting at one place from dawn to dusk with almost no mistakes), a facility with almost every mathematical tool and trick used in physics, and a remarkable versatility of talent that could combine mathematical rigor (which he learnt from Sommerfeld) with simplicity and physical intuition (which he learnt from a postdoctoral stint with Enrico Fermi).

To some extent many of these qualities are intrinsic and cannot be acquired, but others definitely can. Among the latter is a quality that’s best encapsulated in my favorite Bethe quote: “Always work on problems for which you possess an unfair advantage”. Since so many of modern physics’ ansatzs, rules and equations are named after Bethe, I will call this piece of advice ‘Bethe’s Dictum’.

I believe that Bethe’s Dictum was largely what allowed Bethe to achieve everything that he did, and I think it’s a profoundly useful dictum for the rest of us. How did Bethe himself apply this dictum? Here’s what I wrote in a review of Bethe’s recent biography written by his longtime friend and biographer Silvan Schweber:

It is not possible for us to mirror the extraordinary mental faculties of minds like Bethe and Einstein. But we can very much try to emulate their personal qualities which are more accessible if we persevere. In case of Bethe, one of his most important traits was an uncanny ability to sense his own strengths and limitations, to work on problems for which he "possessed an unfair advantage". Bethe knew he was not a genius like Dirac or Heisenberg. He could not sit in a chair and divine the deep secrets of the universe by pure thought. Rather, his particular strength was in applying a dazzling array of mathematical techniques and physical insight to concrete problems for which results could be compared with hard numbers from experiment. He could write down the problem and then go straight for the solution; this earned him the nickname "the battleship". 

Another important thing to learn from Bethe was that just like Fermi, he was willing to do whatever it took to get the solution. If it meant tedious calculations filling reams of paper, he would do it. If it meant borrowing mathematical tricks from another field he would do it. Of course, all this was possible because of his great intellect, formidable memory and extraordinary powers of concentration, but there is certainly much to learn from this attitude toward problem solving. The same approach helped him in other aspects of his life. He became extremely successful as a government consultant and scientific statesman partly because he knew when to compromise and when to push ahead.

The ability to pick problems for which you possess an unfair advantage, to selectively apply your strengths and minimize your weaknesses, is important in all walks of life. And yet it is easy to overlook this match between abilities and problems because too often we choose to study what’s fashionable, what’s “cool” or the "in thing", or what seems to attract the most funding rather than what our intellect and personality is best suited for. I got a minor taste of Bethe’s Dictum myself when I was in college. I was intensely interested in physics then and had almost made up my mind to major in it. And yet my father who clearly knew Bethe’s Dictum without knowing anything about Bethe wisely counseled me to seriously consider chemistry, since he thought that my abilities would be more suited to that field. In retrospect I think he was absolutely right. I am sure I would have enjoyed studying physics and might have even become a passable physicist, but I have little doubt that my tendency to think more broadly than deeply is better suited to chemistry and biology, where one cannot derive most facts from first principles and where memory and connections between various sub-fields can play a more important role than raw mathematical ability and intelligence. I suspect many fields of experimental physics are similar.

Bethe’s Dictum is especially important in a world which suffers from an extravaganza of choices for professional and interdisciplinary study. The dictum is also important when deciding whether to learn something new or maximize the use of something old; it hints at achieving a balance of these activities. And it’s especially important advice for young people who are just starting out in your career. It’s perfectly fine to try to study something which you are passionate about, but passion can only take you so far. The hard fact is that talents and interests may not always overlap, and down the road on which lies interest without talent also lies frustration. In the long term it might be far better to study something which may not be your absolute top interest but for which you possess an unfair advantage in terms of your temperament and skill set. It’s probably the most important lesson we can learn from Hans Bethe’s extraordinary, long and satisfyingly lived life. 

Image source

Book review: Leonard Mlodinow's "The Upright Thinkers:The Human Journey from Living in Trees to Understanding the Cosmos"

Occasionally it is a wise idea to step back and look at all of humanity's intellectual achievements and marvel at what we as a species have achieved and what all we take for granted. What is truly amazing is not that we created this multifaceted world around us but that we developed a systematic intellectual recipe - the scientific method - to do so in the first place. The evolution and products of that recipe are what Caltech physics professor Leonard Mlodinow dwells on in this wonderful and witty book that charts the products of human curiosity, and in the process we get a grand and elevating tour of humanity's ideas, from the beginnings of agriculture to the theory of relativity. It's one of those stories that makes us consider our intellectual and social faculties in awe; no wonder that I felt great reading it.

The book opens with one of the best first pages that I have ever come across, and while I won't give away the punch line it features a story about Mlodinow's father in the Nazi concentration camp Buchenwald that drives home the powerful and innate nature of curiosity. Suffice it to say here that Mlodinow's father decided that he would rather go hungry than be in ignorance of the solution of a mathematical puzzle posed to him by an inmate. In fact Mlodinow's father who is a classic example of the American success story (émigré European tailor with little education, concentration camp survivor whose son becomes a well-known physicist and writer) makes an appearance frequently and movingly in the book.

Mlodinow leads us through most of the early defining events in the history of civilization; the settlement of cities, the development of agriculture, writing, mathematics and astronomy by the Sumerians, Mesopotamians, Mesoamericans and the Egyptians and the first stirrings of science in the great Greek cities. He dwells on the curious case of Aristotle who in spite of being a brilliant thinker failed to understand the key function of both experiments and mathematics (as emphasized by his forebear Pythagoras). Moving on from the Greeks, we meet the Romans who displayed another paradoxical mix of supreme ability for the practical application of mathematics and engineering without any interest in the theoretical foundations of these disciplines. In addition, Aristotle in particular and the Greeks in general saw everything in terms of purpose and therefore were loath to simply explain things in terms of their structure and composition. Sage thinkers like Democritus and Lucretius of course speculated tantalizingly on entities like atoms and laws of motion but these concepts never strayed away from being anything more than idle speculation.

It is only when we get to the Indians, the Chinese and the Arabs that we start to see the stirrings of a genuine appreciation for theoretical constructs like proofs, theorems and universal properties of geometric figures. The Arabs especially elevated both science and medicine and translated the texts of Aristotle while Europe was plunged into the darkness of ignorance and religious wars for four hundred years. But for some reason they then went into a downward spiral from which they still haven’t recovered. It was through the fortuitous passage of a few European men of learning that the Arabs’ writings got transported to Europe. But the Europeans still had to throw off the yoke of Aristotle. Even though Copernicus made a stellar start in initiating the revolution and made the first dent in usurping humans from their previously exalted place in the cosmos, the defining moment never really came until Galileo strode on the stage with his telescopes and heresies. Mlodinow tells us how Galileo really was the first modern scientist who valued both mathematics and the primacy of experiment in explaining the world. He also served as the first widely example of the clash between science and religion. From there it is but a short journey to the genius of Newton who truly elevated science to the level of a systematic investigation of nature that could often be unraveled using mathematics. Mlodinow communicates Newton’s brilliance as well as his flaws as a petty human being and a tireless student of occult claptrap.

The rest of Mlodinow’s book follows territory that would be well known to history of science aficionados. As a chemist I was especially delighted that he devotes two separate chapters to the rise of chemistry from the ashes of alchemy. Lavoisier, Priestley, Dalton and Mendeleev make honored appearances. The later parts of the book deal with the other great idea of human civilization – Darwin’s evolution by natural selection. The last parts of the book take us through the lives and work of the physics pioneers Einstein, Bohr and Heisenberg. Mlodinow halts his grand tour of ideas roughly before World War 2, but not before making a passionate case for the foundational role that sheer curiosity has played in marking our species as something different from all other life on the planet.

Generally speaking Mlodinow does a great job leading us through the signal events of human intellectual history, and while it’s not realistic to expect him to cover every single discipline, individual and theory, I was disappointed by what I thought were some major omissions. For instance, how can one write a book on the history of science without mentioning Francis Bacon whose emphasis on observation was really paramount to the beginnings of modern science and still serves to guide its central tenets? And on the other end, how can one omit Rene Descartes whose emphasis on reason and pure thought has been almost equally important? There is also no discussion of neuroscience or the early achievements of medical science, both of which showcased curiosity in its finest hours. Mlodinow also curiously omits Faraday while mentioning Maxwell, and mentions Mendel in passing while dwelling on Darwin. Finally, it seems a bit of a parlor trick to write an entire book on scientific and technological betterment without saying anything about the evils to which the same humans have put their science.

No matter. An incomplete tour of everything that humanity has achieved through the agency of its unique curiosity is still better than no tour at all, and Mlodinow is a witty and sensitive guide on this journey. The next time you feel that the world is descending into chaos, unreason and malaise, pick up Mlodinow’s book and mull over what we as a species have achieved, both in terms of our ideas and the immensely gifted creatures that we have occasionally produced. You might just feel a bit better about yourself.

John Keats's "Chapman's Homer" (chemistry and drug discovery version)

Inspired by the title of this post.

Original version ("On First Looking into Chapman's Homer")

Much have I travell'd in the realms of gold,
And many goodly states and kingdoms seen;
Round many western islands have I been
Which bards in fealty to Apollo hold.
Oft of one wide expanse had I been told
That deep-browed Homer ruled as his demesne;
Yet did I never breathe its pure serene
Till I heard Chapman speak out loud and bold:
Then felt I like some watcher of the skies
When a new planet swims into his ken;
Or like stout Cortez when with eagle eyes
He star'd at the Pacific — and all his men
Look'd at each other with a wild surmise —
Silent, upon a peak in Darien.

Chemistry and drug discovery version 
*Clears throat*

"Much have I travell'd in the realms of drugs,

And many goodly folds and targets seen;
Round many lipid bilayers have I been
Which bends in fealty to van der Waals's hold.
Oft of one wide expanse had I been told
That the deep-pocketed ion channel ruled as its demesne;
Yet did I never solvate its pure ligand
Till I heard Pauling speak out loud and bold:
Then felt I like some watcher of the cytoplasm
When a new target swims into his ken;
Or like stout Woodward when with eagle eyes
He star'd at the polyketide — and all his postdocs
Look'd at each other with a wild surmise —
Silent, upon a peak in Cambridge, MA."

The fundamental philosophical dilemma of chemistry

The classic potential energy curve of chemistry
hides a fundamental truth: bonds mean short distances,
but short distances don't mean bonds

Every field has its set of great philosophical dilemmas. For physics it may be the origin of the fundamental constants of nature, for biology it might be the generation of complexity by random processes. Just like physics and biology chemistry operates on both grand and local scales, but the scope of its fundamental philosophical dilemmas sometimes manifests itself in the simplest of observations.

For me the greatest philosophical dilemma in chemistry is the following: It is the near impossibility of doing controlled experiments on the molecular level. Other fields also suffer from this problem, but I am constantly struck by how directly one encounters it in chemistry.

Let me provide some background here. Much of chemistry is about understanding the fundamental forces that operate within and between molecules. These forces come in different flavors: strong covalent bonds (dictated by the sharing of electrons), hydrogen bonds (dictated by weak electrostatic interactions), strong charge-charge interactions (dictated by attraction between unlike charges), hydrophobic effects (dictated by the interaction between 'water-loving' and 'water-hating' parts of molecules) etc. The net interaction or repulsion between two molecules results from the sum total of these forces, some of which may be attractive and others might be repulsive. Harness these forces and you can control the structure, function and properties of molecules ranging from those used for solar capture to those used as breakthrough anticancer drugs.

Here’s how the fundamental dilemma manifests itself in the control of all these interactions: it is next to impossible to perform controlled experiments that would allow one to methodically vary one of the interactions and see its effect on the overall behavior of the molecule. In a nutshell, the interactions are all correlated, sometimes intimately so, and it can be impossible to change one without changing the other.

The fundamental dilemma is evident in many simple applications of chemistry. For instance, my day job involves looking at the crystal structures of proteins involved in disease and then designing small organic molecules which bind to and block such proteins. For binding to their target protein, these small molecules exploit many different interactions including hydrogen bonds, charge-charge interactions and hydrophobic effects to bring about a net lowering of their interaction energy with the protein. The lower this interaction or "free energy" the better the interaction. Unfortunately, while one can visualize the geometry of the various interactions by simply looking at the crystal structure, it is very difficult to say anything about their energies, for to do so would entail varying an interaction individually and looking at its effects on the net energy. Crystal structures thus can be very misleading when it comes to making a statement about how tightly a small molecule binds to a protein.

Let’s say I am interested in knowing how important a particular hydrogen bond in the small molecule is. What I could do would be to replace the atoms comprising the hydrogen bond with non hydrogen-bonding atoms and then look at the change in the affinity of the resulting molecule for the protein, either computationally or experimentally. Unfortunately this change also impacts other properties of the molecules; its molecular weight, its hydrophobicity, its steric or spatial interactions with other molecules. Thus, changing a hydrogen bonding interaction also changes other interactions, so how can we then be sure that any change in the binding affinity came only from the loss of the hydrogen bond? The matter gets worse when we realize that we can’t even do this experimentally; in my colleague Peter Kenny’s words, an individual interaction between molecules such as a hydrogen bond is not really an experimental observable. What you see in an experiment is only the sum total, not the dissection into individual parts.

There have of course been studies on ‘model systems’ where the number of working parts is far less than those in protein-bound small molecules, and from these model systems we have gotten a good sense of the energies of typical hydrogen bonds, but how reliably can we extend the results of these systems to the particular complex system that we are studying? Some of that extrapolation has to be a matter of faith. Also, model systems usually provide a ranges of energies rather than a single value and we know that even a tiny change in the energy of binding can correspond to a substantial loss of effective blocking of a protein, so the margin of error entrusted to us is slim indeed.

It is therefore very hard, if not impossible, to pin down a change in binding affinity resulting from a single kind of interaction with any certainty, because changing a single interaction potentially changes all interactions; it is impossible to perform the truly controlled experiment, a concept which has been at the heart of the scientific method. Sometimes these changes in other interactions can be tiny and we may get lucky, but the tragedy is that we can’t even calculate with the kind of accuracy we would like, what these tiny increments or reductions might be. The total perturbation of a molecule’s various interactions remains a known unknown.

The roots of the problem run even deeper. At the most elemental level, all interactions between molecules are simply a function of one of the four fundamental forces known in nature - the electromagnetic force. Of the four basic forces, gravity is too weak to play a role, while the strong and weak nuclear forces don't usually apply to molecular interactions since such interactions only involve the sharing of electrons. It is the electromagnetic force that is thus ascendant in mediating every single molecular interaction in the universe. When we divide this force up into hydrogen bonds, electrostatic interactions, hydrophobic interactions etc. what we are doing is imposing an artificial division on an indivisible fundamental force, purely for our convenience. It's a bit like the parable of the blind men and the elephant - there is only one electromagnetic force, just like there is only one elephant, but each of us describing that force divides it up into multiple flavors. No wonder then that we are led astray when we think we are doing a controlled experiment, since whenever we think we are varying one flavor or another we are actually varying the same basic parameter and not its independent components. That is because there are no independent components in the true sense of the term.

This inability to perform the truly controlled experiment is thus what I call the great philosophical dilemma of chemistry. The dilemma not only makes the practical estimation of individual interactions very hard but it leads to something even more damning: the ability to even call an interaction an 'interaction' or 'bond' in the first place. This point was recently driven home to me through an essay penned by one of the grand old men of chemistry and crystallography – Jack Dunitz. Dunitz’s point in the essay is that we are often misled by ‘short’ distances between atoms observed in crystal structures. We ascribe these distances to ‘attractive interactions’ and even ‘bonds’ when there is little evidence that these distances are actually attractive.

Let’s backtrack a bit to fundamentals. The idea of ascribing a short distance to an attractive interaction comes from the classic van der Waals potential energy curve (figure above) that is familiar to anyone who has taken a college chemistry class. The minimum of this curve corresponds to both the shortest distance (called the van der Waals distance) between two molecules and the lowest energy, typically taken to signify a bond. However this leads to a false equivalence that seems to flow both ways: van der Waals distances correspond to bonds and bonds correspond to van der Waals distances.

In reality the connection only flows one way. Bonds do correspond to short distances but short distances do not necessarily correspond to bonds. So then why do we observe short distances in molecules in the first place? Again, Dunitz said it very succinctly in a previous review: simply because ‘Atoms have to go somewhere’. The fact is that a crystal structure is the net result of a complex symphony of attractive and repulsive interactions, a game of energetic musical chairs if you will. At the end, when the dust has settled everyone has to find a chair, even if it means that two people might end up uncomfortably seated on the same chair. Thus, when you see a short distance between two atoms in a crystal, it does not mean at all that the interaction between them is attractive. It could simply mean that other interactions between other atoms are attractive and that those two atoms have simply then settled where they find a place, even if the interaction between them may be repulsive. 

The message here is clear: it is folly to describe an interaction as ‘attractive’ simply because the distance is short. This applies especially to weaker interactions like those between aromatic (benzene) rings. I am always wary when I see a benzene ring from a small molecule nicely sandwiched between another benzene ring in a protein and hear the short distance between the two described as a ‘stacking interaction’. Does that mean there is actually an attractive stacking interaction between the two? Perhaps, but maybe it means simply that there was no other place for the benzene ring to be. How could I test my hypothesis? Well, I know that varying the substituents or groups of atoms attached to benzene rings is known to vary their energies of interaction with other benzene rings. So I ask the chemist to make some substituted versions of that benzene ring. But hold on! Based on the previous discussion, I just remembered that varying the substituents is not going to just change the stacking energy; it’s also going to change other qualities of the ring that mess up the other interactions in the system. It’s that problem with performing controlled experiments all over again - welcome to the fundamental dilemma of chemistry.

The fundamental dilemma is why it is so hard to understand individual interactions in chemical systems, let alone exploit them for scientific or commercial gain. We see it in a myriad of chemical experiments, from investigating the effects of structural changes on the rates of simple chemical reactions to investigating the effects of structural changes on the metabolism of a drug. We can’t change one component without changing every other. There may be cases where these other changes might be minuscule, but in reality the belief that they may be minuscule in a particular case will always remain a matter of faith than of fact.

The fundamental dilemma then is why drug design, materials designs and every other kind of molecular design in chemistry is so tricky. It is why so much of complicated chemistry is still trial and error, why observations on one system cannot be easily extrapolated to another, and why even supercomputers are not yet able to nail down the precise balance of forces that dictate the structure and function of specific molecules. In a nutshell, the fundamental dilemma is why chemists are always ignorant and why chemistry will therefore always be endlessly fascinating.

Want to bind small molecules? Get a backbone

Here’s a paper from the Shoichet lab at UCSF that illustrates one of the major problems that drug designers encounter – predicting conformational changes (“entropy” to a physicist). What the study does is to plug a series of eight very simple congeneric ligands – benzene, methyl, ethyl and propyl benzene all the way to hexyl benzene - into a model protein cavity, in this case a lysozyme mutant, and observe the corresponding changes in protein conformation by solving the crystal structures. And the results aren’t exactly heartwarming for early phase drug discovery scientists.

Synthesizing congeneric series of ligands is a standard process in lead optimization and the elephant in the room which is often banished out of sight by drug designers is the possibility of large conformational changes in the protein caused by small changes in ligand structure (the other assumption is constancy in ligand binding orientation, and even that doesn’t always hold). The assumption is that any minor change in structure in the ligand would be accommodated by equivalent, small amino acid side chain movements in the protein.

This study shows that at best that assumption is a faith-based assumption which should always be considered provisional. What the authors observe is that instead of a smooth transition of amino acid side chain movements, you see a discrete and far more significant change in protein backbone movement, resulting in a subtle population of different states which bind the ligands. The difference in binding energy going from benzene to hexyl benzene is not too large – about 1.5 kcal/mol – but you are already seeing backbone movements. What is perhaps a bit more reassuring than this observation is that some of the discrete states are mirrored in lysozyme structures found in the PDB - but the authors looked at 121 structures to substantiate the result. Not the kind of numbers you would expect to find in the PDB for your typical novel drug discovery target.

The conclusions of the paper are a bit discomforting for at least two reasons. Firstly as mentioned above, drug designers often assume constancy or smooth and minor side chain changes in protein conformation when testing congeneric ligands in lead optimization. It’s quite clear that this is always a bit of a gamble: if something as simple as a change in molecular weight could lead to such divergent changes, what would small but important changes or reversals in polarity do? And then one also starts wondering how much weird or divergent SAR could potentially be explained by such unexpected backbone conformational changes.

Secondly, these kinds of changes pose a real problem for molecular modelers. As the paper says, you would need to go to pretty long MD (molecular dynamics) simulations or more radical protein modeling to look at backbone changes; even today, modeling backbone changes by either physics-based methods (like MD) or knowledge-based techniques (like Rosetta) is both less validated and more computationally expensive.

Lastly though, this study is another example of why drug discovery is hard even at a basic scientific level. Countless factors thwart the best intentions of drug designers at every stage, and uncertainty in predicting protein backbone conformational changes must rank pretty high on that list.

We are all Hamiltonians. We are all Newtonians.

Michael Lind is an economic historian who has recently written an excellent history of the United States. Lind divides the thread of American history as flowing in two parallel but competing directions. One thread belongs to the Jeffersonians who oppose central authority and value small government and individual economic initiative. The other belongs to Hamiltonians who favor a strong central government with broad governing powers.

Who wins in this battle? Lind's answer is clear - the Hamiltonians. After doing a careful study of all the institutions and policies that emerged in the United States since its founding, Lind concludes that one can see the sure hand of the Hamiltonians everywhere. He quite certainly does not discount the role of the Jeffersonians in creating private capital, entrepreneurship and innovation, but even these achievements could not have been carried out without an enabling framework set up by the Hamiltonians.

Lind's conclusions reminds us that although Jeffersonians Steve Jobs and Bill Gates and Thomas Edison and John D Rockefeller have made this country the technological powerhouse that it is, we live and breathe the air of Hamiltonians like Franklin Roosevelt, Vannevar Bush, Louis Agassiz and Alfred Newton Richards. At the end of the day we are all Hamiltonians. Even when Jeffersonians play their great game of competition and innovation, it is on a Hamiltonian stage with its well-defined boundaries that they must perform.

A similar thought went through my mind as I was reading Caltech physicist Leonard Mlodinow's first-rate romp through the major ideas and intellectual events of human civilization titled "The Upright Thinkers". Mlodinow takes us through a sweeping trek through the last ten thousand years of science and technology, covering such major milestones as agriculture, mathematics, Greek, Arabian and Renaissance science, Galileo and the birth of modern science, Newton, the evolution of chemistry from alchemy into a bonafide science, all the way to Maxwell, Einstein and the quantum pioneers.

One of the paragraphs that really stood out for me however was one in which Mlodinow communicates the sheer ubiquity of Newton's way of thinking. There is a reason that even with people like Maxwell, Darwin and Einstein following him, Newton can still legitimately lay claim to being the greatest scientist in history. That's because, as Mlodinow says, Newtonian thought has not just pervaded all of science and life but it has become a metaphor for almost everything we do and feel.

"Today we all reason like Newtonians. We speak of the force of a person's character and the acceleration of the spread of a disease. We talk of physical and even mental inertia, and the momentum of a sports team. To think in such terms would have been unheard of before Newton; not to think in such terms is unheard of today. Even those who know nothing of Newton's laws have had their psyches steeped in his ideas. And so to study the work of Newton is to study our own roots."

This a point that should not be lost on us. Even though the tiny details of our life may be infused with quantum events like cooking, metabolism and reproduction, we are truly Newtonian creatures. Quantum mechanics underlies everything we do, but it's layered on a Newtonian stage of events, metaphors and emotions. These days nobody writes books on Newton's laws and everyone writes books on quantum mechanics and relativity, but the fact is that the weird reality described by these theories matters very little for the mundane things in our life. One of them applies to the very fast and the other applies to the very small, and most of our lives deal with objects in between.

Even today after Einstein and Heisenberg and Bohr, 99% of the things that matter to us unfold on a Newtonian stage. Every time we get up from the bed, brush our teeth, drive down the highway, type on our keyboards or fly in an airplane we are obeying the dictates of Newton. Even if our atoms obey the laws of quantum mechanics and dictate the biochemistry of our actions and thoughts, the emergent laws that arise from them and that bear a far more direct connection to our actions are all Newtonian. The fact that we are Newton's children is not just a tribute to the unbelievable sweep of his theories but also a resounding tribute to the limitations of strict reductionism.

Just like even an arch Republican like Nixon had to admit that "We're all Keynesians", even people who (improbably) might be rejecting Newton in 2015 cannot escape the reality that they're all Newtonians. The ubiquity of his thoughts holds us in its sweeping embrace as firmly as gravity holds us to the earth.

Dynamic monopolies and the laws of thermodynamics: An interesting correspondence

In his new book on startups Peter Thiel makes a provocative argument about the necessity of monopolies. He points out that in an environment of perfect competition, everyone is so busy competing just to stay even that they would end up with neither the time nor the resources to innovate. Perfect competition is a dead end as far as truly novel ideas go.

There’s plenty of evidence of history to back up Thiel’s argument, and in no other case is the monopoly-innovation relationship evident as in the case of Bell Labs. Everyone talks about Bell Labs as the greatest cradle of industrial innovation in history but few talk about what birthed and sustained the cradle: the enormous monopoly and profits that AT&T enjoyed for fifty years. AT&T enjoyed this monopoly not just because they made superior products but also because they cut deals with the government that allowed them to always stay a step ahead of their competitors. It was this virtually unchallenged monopoly that allowed the telephone company to funnel its profits into the hallowed Nobel Prize producing milieu of Bell Labs. A similar example exists today with Google which has a monopoly on search. This monopoly brings them enough revenue so that they can entertain ten-year research visions and highly risky but potentially lucrative projects like self-driving cars and research into aging.

What the libertarian Thiel conveniently fails to mention however is that monopolies can use their surplus profits and resources for both good and evil. AT&T might have largely used their profits for fundamental research but Rockefeller and Vanderbilt used it to lobby the government and exploit workers. Similarly today oil companies spend an enormous amount of time and money in erecting massive lobbies in Washington. Of course, Rockefeller and Vanderbilt also used their enormous wealth for philanthropic purposes but the fact that they also sparked movements against low wages and worker exploitation and that Teddy Roosevelt was forced to break up the monopolies in 1907 speaks to how far out of hand the situation had gotten by then.

Thiel does not mention all this; nevertheless he understands that the value of a monopoly is often measured by the time it exists and the reach of its power. That is why in his ideal world monopolies would be what he calls “creative monopolies” and what I will call “dynamic monopolies”. Dynamic monopolies are monopolies which are constantly challenged, not by perfect but by imperfect but still serious competition. Thus they have to constantly keep innovating rather than exploiting their power for political purposes in order to stay on top. Monopolies generally can be harmful, but dynamic monopolies can often be a very good thing.

The value of dynamic monopolies however raises a more general question that is both far more provocative and more disturbing. It is almost a foregone conclusion that in the long view of human history many technological advances have been built on the backs and dead bodies of human beings. In his landmark new book “Empire of Cotton” for instance, historian Sven Beckert talks about the enormous evil of slave labor that allowed capitalism to become a bedrock of Western and eventually all of civilization. The Romans developed superior engineering and the Egyptians built the pyramids backed by thousands of slaves and peasants. Look at every major technological advance in history and you would be hard pressed to find one that did not involve the exploitation of at least some class or group of people. That is why we rightly have government laws which protect the exploited and the disadvantaged. That is why we rightly have human rights organization and the Red Cross.

Nevertheless, the principle that innovation and novelty can only arise from some kind of asymmetry of wealth, distribution or work seems to be a mainstay of history. I realized however that there is a remarkable correspondence between this principle and a most fundamental aspect of science and nature – the laws of thermodynamics. One of the essential truths about life on earth (and presumably everywhere) is that it presents a condition that exists far from equilibrium. In technical terms, the free energy change of living systems is not zero; a value of zero for the free energy only holds for systems at equilibrium. Now existing at equilibrium is a very bad thing for a living creature. In fact as the old saying goes, the only living system at equilibrium is a dead system. Death is the condition of true equilibrium; it is only by driving a system away from equilibrium that living beings can be born, move around, think, prove theorems and write sonnets. All the richness of life comes about because it's trying to be as far from equilibrium as possible.

Just as perfect equilibrium can lead to death, so it seems that perfect competition can lead to stagnation of innovation. Just as we need asymmetry in the thermodynamics of life in order to thrive and even exist in the first place, so it seems that we need asymmetry in the evolution of markets in order to sustain technological progress. That fact leads to an argument in favor of monopolies. 

But what’s even more essential to keep in mind is the ever-changing nature of life. Life can maintain its essential asymmetry only if old life makes way for new. If old life refuses to die it will lead to another condition of equilibrium which will be static instead of dynamic. Similarly technological innovation can maintain its edge only if old monopolies turn over on a reasonably rapid basis  - perhaps over periods of ten to twenty years - and make way for new ones.

Hence the need for dynamic monopolies. And hence the need for government laws that enable such entities. Even the fundamental laws of thermodynamics make a case for them.

Image source