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 20th 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. 

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."