Field of Science

Modular drug design software?

The latest issue of C&EN has an interesting article (unfortunately subscription only) about how quantum chemists are making code for standard protocols in quantum chemistry calculations available to each other as off-the-shelf modules. The movement has been driven by the realization that whenever someone develops a new quantum chemistry program he or she has to go through the tedious process of rewriting code for standardized algorithms like the Hartree-Fock method for calculation of potential energies of molecules. Why reinvent the wheel when you can simply buy it off the shelf in a centralized local tire shop?

I like this idea and I applaud the quantum chemists for having the generosity in sharing their code. But that left me wondering how soon it would be before something similar could happen in the world of computational drug design, or whether it would even be feasible.

The essence of methods like Hartree-Fock is that their highly iterative and standardized nature made them instantly amenable to computation. Your code for Hartree-Fock may be faster and cleaner than the other fellow's but the basic methodology which can be captured in a well-defined flowchart is not going to change. Contrast this with 'standard' drug design software protocols like docking, similarity searching and molecular dynamics calculations. 

Even though the objective is the same in every case, every practitioner uses his or her own favorite technique for their calculations; for instance docking can be physics-based or knowledge-based or it may depend on genetic algorithms. The sampling algorithms in MD may similarly be different in every case. Docking or MD are thus not as 'standardized' as say the Hartree-Fock method so it may be difficult to offer these protocols as standardized modules.

However I cannot see why it may not be possible to offer even more specialized components that are in fact standard for the wider use of the community. For instance, certain force fields - parameters and equations for calculation of structure and energetics - are pretty standard; the MMFF force field will have a certain set of components and the MM2 will have another. Similarly in a protocol like MD, the precise methods of sampling can be much more standard compared to the overall package. So in principle these methods could be packaged as standardized modules and offered to users.

The ideal situation for computational drug design would be an age where a variety of protocols ranging from quantum chemistry, docking and MD to homology modeling, gene and protein sequence comparison tools and toxicity and PK prediction algorithms would be available for any user to patch together, rearrange and deploy in the solution of his or her particular problem. 

Going even further, we could envisage an age where the tools of systems and computational biology are thoroughly ingrained in the drug discovery process so that one can now add standard systems tools to the toolbox; for instance, in such an age, not only would I be able to snatch standard docking protocols from a website but I would also be able to combine them with some kind of a wiring diagram of the protein which I am trying to target linked to its partners, so that I know exactly which partner hubs I should additionally dock my drug against in order to maximize its efficacy and minimize its toxicity. And who knows, maybe I can even get to a stage where I can download some kind of a minimalist but accurate model of an entire cell and observe how my drug will qualitatively perturb its network of organelles and signaling pathways.

For now this sounds like a pipe dream, although I suspect that the cultural barriers to sharing algorithms with commercial potential may be much harder to overcome than the scientific hurdles to actually incorporating systems biology in drug discovery and making the whole process modular. That's where the siren song of these socialist quantum chemists would be particularly relevant.

The 2014 Fields and Nevanlinna prizes: Celebrating diversity

"And if we cannot end now our differences, at least we can help make the world safe for diversity." - John F. Kennedy
An Iranian woman, a first and a second generation Indian, an Englishman and a Brazilian. Most of them working in the United States - The 2014 Fields and Nevanlinna prizes celebrate diversity like no other.
Quanta Magazine has a wonderful set of profiles of this year's top math prize winners that are worth reading. 
Maryam Mirzakhani is especially notable as the first woman to win the prestigious prize. The profiles are accompanied by short videos. The prizewinners are a varied bunch whose interests and origins are spread across geography and mathematics. From topology to number theory, from geometry to chaos theory, they seem to have it all covered.

Diversity and bridge-building across nations and cultures have always been an important part of science - witness Eddington's confirmation of Einstein's general theory of relativity right after Germany and England had been embroiled in a catastrophic war. But in no field is this more apparent than in pure mathematics where people across the world can be connected purely by way of ideas, unencumbered by political or religious affiliations or commercial applications. Hopefully we can look forward to more such celebrations.

How Robin Williams helped me out in graduate school

Spring 2004. I was a callow first year graduate student, with an insouciance and naiveté befitting a first year graduate student. At that point like most of my fellow grads, I was hungry for knowledge and thought that everything that I needed to know would be found in books and lectures. Lab work was simply a question of putting some of this knowledge into practice and producing a passable PhD thesis.

I was a voracious reader and used to check out as many books on chemistry, physics, drug discovery, molecular modeling and the history of science as I could physically carry out of the library. Because I was cocky and stupid, I used to read these ponderous books and think I understood the world. I threw around jargon from quantum mechanics, biochemistry and the philosophy of science and thought that because I understood the jargon I comprehended how to apply it to real life situations. I lived in blissful ignorance of the fact that all my bookish knowledge was almost useless when measured against the fickle complexities of real life problems. 

Surprisingly, I had not seen "Good Will Hunting" until my first year of graduate school. It turned out that my introduction to the movie was also an awakening and I have to thank a fellow graduate student, more experienced and wiser in the ways of the world, for this. Once, as I was strutting around the lab, tossing out concepts from quantum chemistry and pontificating on how a particular protocol could be better for a certain kind of molecular system - all when I had never actually applied such protocols to real life problems - my fellow graduate student interrupted my chatter to suggest something.

He asked me if I had seen the movie "Good Will Hunting". I said I had heard of it but had not seen it yet. He told me to watch the movie, focus on the main protagonists and tell him what I thought. I checked out the movie from Blockbuster (I know) that very same evening and was blown away when I saw it. That's because I could relate immediately to the protagonist, Will Hunting (Matt Damon). I wasn't even remotely close to being a genius like him, but the similarities nonetheless struck home. Just like me Will was cocky and arrogant, and just like me he thought that his bookish knowledge made him an expert on the world's affairs.

But the scene from the movie that really left me feeling like I had been mowed down with a scythe is the scene in the park with Robin Williams and Matt Damon in which Williams's character (Sean Maguire) launches into what I consider to be one of the most beautiful and profound monologues in movie history.



In a previous scene Will had displayed his customary indifference and arrogance by presuming to know everything about Sean's life through the lens of a particular painting that he had painted.

In the scene Sean shows Will how deeply ignorant and naive he is. The monologue's basic message is simple: You may have read everything there is to know about the world, but that does not mean you have seen the world. Here are the lines that I found most poignant and profoundly true:
So if I asked you about art, you'd probably give me the skinny on every art book ever written. Michelangelo, you know a lot about him. Life's work, political aspirations, him and the pope, sexual orientations, the whole works, right? But I'll bet you can't tell me what it smells like in the Sistine Chapel. You've never actually stood there and looked up at that beautiful ceiling; seen that. If I ask you about women, you'd probably give me a syllabus about your personal favorites. You may have even been laid a few times. But you can't tell me what it feels like to wake up next to a woman and feel truly happy. You're a tough kid. And I'd ask you about war, you'd probably throw Shakespeare at me, right, "once more unto the breach dear friends." But you've never been near one. You've never held your best friend's head in your lap, watch him gasp his last breath looking to you for help. I'd ask you about love, you'd probably quote me a sonnet. But you've never looked at a woman and been totally vulnerable.
I could almost hear Williams speaking to me, translating his words about Shakespeare, war and love into ones about science and knowledge. 
"If I asked you about synthesis, you'd probably give me the skinny on every total synthesis ever done. Woodward, you know a lot about him. Life's work, academic aspirations, him and the MIT chemistry department, his marathon drinking binges, right? But I'll bet you can't tell me what it means to spend two years' worth of your life synthesizing even a moderately complex organic molecule and having your efforts fail in the twenty-fifth step. You've never actually stood there and compared the NMR spectrum of your product with its natural counterpart. If I ask you about drug design, you'd probably give me a long synopsis of the challenges in drug development. You may even have talked to an actual pharmaceutical scientist. But you can't tell me what it feels like to be a part of a multidisciplinary team of scientists, work on a project for five years, guide it through false alleys and a litany of frustrations, and then see it fail in Phase 2 clinical trials. And I'd ask you about the philosophy of science, you'd probably throw Kuhn at me, right, "Normal science often suppresses fundamental novelties because they are necessarily subversive of its basic commitments". But you've never been part of a paradigm shift yourself, seen the world shift beneath your feet the way the creators of quantum mechanics did."
At that point I felt more sober than what I would have had I suddenly stopped drinking after a twenty-year binge. It was as if a wall of wisdom had driven itself between me and some cherished destination that I now realized did not exist. I did not even know half the things that a fictional Williams would have admonished me about, and yet here I was, wallowing in the heady, careless naiveté of premature intellectual jubilation.

Since I first saw that scene it has probably become my favorite scene of all time, and the movie itself is now my all time favorite. I have memorized dozens of lines from it and I find myself watching it at least once every month. But the central message of the movie which has stayed with me is very simple: knowledge, no matter how extensively you acquire it, does not automatically translate to wisdom, let alone real world experience. It's of course important to get as much knowledge as you can and share it, but it's also imperative to be always mindful of what it takes to turn that knowledge into understanding and expertise. That extra something is experience, it's team work, it's character-building. Knowledge is important, necessary in fact, but not sufficient. No amount of reading about classical architecture is a substitute for smelling the air in the Sistine Chapel.

For the last ten years, many times when I was getting ahead of myself, many times when I thought I actually understood how to apply a scientific concept I have watched that scene. And so today, when I feel myself stunned and deeply saddened by Robin Williams's premature passing, I realize the debt I owe to him and that magnificent monologue. He may be no more, but I am hoping his words will keep my head sober and my feet on the ground. Every time I think I know, I will hear Robin's voice saying, as patiently and clearly as he says to Will, "You don't have the faintest idea what you're talking about."

In small and big ways Robin Williams touched the lives of countless people. Among them was a chemistry graduate student. Thank you for that, Robin.

Celebrating the 1939 Leo Szilard letter to FDR and setting the record straight

Leo Szilard was the principal architect of the famous
letter to FDR. But even today Einstein's name is the one
most associated with the event. This needs to change
(Image: NNSA).
Today marks the 74th anniversary of the famous letter that physicist Leo Szilard wrote to President Franklin Roosevelt. In the letter Szilard alerted the president to the startling recent discovery of nuclear fission and more ominously, warned him that Germany had likely started working on the implications of this discovery for waging war. When FDR saw the letter, he famously called his aide "Pa" Watson and handed the letter to him saying, "Pa, this requires action".

Thus began the momentous road leading down to the Manhattan Project. But Szilard had seen this road six years before, at a traffic light in London when, stepping off the curb he saw the essence of energy from the atom before anyone else.

The above account may sound strange and raise eyebrows since I seem to have omitted the name of the one famous person who is most associated with the FDR letter - Albert Einstein. But the point that I want to make is that a story about the letter focusing exclusively on Szilard will still be more accurate than a story focusing exclusively on Einstein. Both accounts would be inaccurate, but in Isaac Asimov's words the second would be "wronger", and yet it's the one that has stuck in the minds of most people.

Leo Szilard remains one of the most brilliant, wide-ranging and underappreciated scientists in history. Bill Lanouette has performed an invaluable social service in writing a brilliant and definitive biography of the man which is a must read. In case of the so-called "Szilard-Einstein letter", Szilard's role cannot be overemphasized. First of all, he was the one who, based on his unique traffic light insight six years back, instantly grasped the terrifying implications of nuclear fission for war. This was based not just on his scientific insight but on his incredible political insight, a trait that had constantly marked him apart from his fellow scientists. More than almost any of them Szilard saw political events before they overtook the world, and this time was no different.

But Szilard was not just a man of thought, he was also one of determined and preemptive action. He immediately recruited the efforts of his fellow Hungarian scientists Eugene Wigner and Edward Teller in communicating the importance of the momentous discovery to the highest powers. At first Szilard's overriding concern was regarding the existence of uranium ore in the Belgian Congo which Germany could hoard. He wanted to alert the Belgian royal family, and he realized that the one person in his circle who knew them was Einstein. Szilard and Einstein were old friends and colleagues, having filed a patent for a refrigerator during their carefree time in heady Berlin in the 1920s. 

But Szilard also realized that any action on fission would need government support on a massive scale. And he again realized that nobody else in his circle carried the weight that Einstein did. So he recruited Wigner in driving him to Einstein's summer cottage on Long Island. The first meeting was on July 12: When Szilard told Einstein about the discovery of fission and its implications Einstein was completely surprised, saying "Daran habe ich gar nicht gedacht" ("I had not thought about that"); his surprise indicates Szilard's overarching role in initiating the set of events. Szilard not only approached Einstein but also drafted two letters, one addressed to the Belgian ambassador and another to FDR. The emissary for delivering the second letter was going to be Alexander Sachs, an economist who knew Szilard and who had the ear of the president.

On August 2 Szilard again had himself driven by Teller to Einstein's cottage. This time Einstein modified the letter and dictated the revised version in German. Szilard came back to Columbia University where he was then installed and asked a stenographer - who thought she must be dealing with a nutcase - to transcribe it in English. The letter clearly laid out the possibility of atomic bombs based on Enrico Fermi's work and also warned about Germany's access to both brilliant physicists and the uranium ore in the Congo.

Szilard had the letters signed by his famous friend and gave both of them to Sachs. The rest is history. But the set of events that transpired make Szilard's absolutely essential role in the "Einstein letter" obvious. In fact it's not too much to say that without Szilard the letter would not have been written. Szilard not only instantly grasped the implications of fission but he alerted Einstein, he explained what the problem was and he drafted the letter. Einstein's main role was in listening, approving and signing. These were all important roles, but surely not as important as Szilard's role in willing the letters into existence in the first place.

So let's make no mistake about it every time we talk about the famous letter to FDR. Einstein played an important role in being the messenger, but Szilard was both the medium and the message. Without Szilard there would have been no letter. And without Szilard this chapter from Einstein's life would have been erased. As he did in 1939, it's a pity that even today Szilard remains the genius in the shadows. He deserves to always have his memory kept alive.

P.S. The Wikipedia entry on the topic is actually a pretty good and accurate account.

The complex truth about "smart" drugs

In 'Limitless', a cognitive enhancement pill
enables Bradley Cooper's character to finish
his novel in four days, learn to play the piano
in three and make millions on the stock market
in two weeks.







There is a comprehensive and very thought-provoking article on "smart" cognitive "enhancer" drugs like Ritalin and modafinil in Mosaic Magazine that's well worth your time. The very fact that I am putting "smart" and "enhancer" in quotes tells you where the article's coming from. The problem with these pills is that their lure is seductive, so more often than not we would all like to overstate their promise. It's thus particularly important to take a realistic view of what they can and cannot do.

For those besieged with multitasking today here's a summary of the main points. Alternatively, of course, you could take a smart drug to help you zip through the article...

1. Nobody really knows how smart drugs work, except for a very limited understanding of substances like caffeine and a few brain pathways like those dealing with nicotinic acetylcholine receptors (in fact, nicotine and nicotine-like substances may well be the only true cognitive enhancers). This fact would be consistent with our general lack of understanding regarding neurological drugs.

2. Most important take-home message: These drugs don't really seem to "enhance" function; rather, they simply optimize existing function. An immediate corollary of this fact is that the drugs would show the greatest effect only in cognitively impoverished brains. Thus, the effect may be marginal to zero in normal people. Studies seem to support this contention.

3. There is an ongoing controversy about whether intense focus brought about by these drugs can stifle creativity. Opinion among neuroscientists seems to be divided, although I find myself leaning toward the pessimistic side. 

4. As the article notes, studies seem to support this pessimistic view for now. Smart drugs don't really cause enhancement across the board; rather, they seem to modify performance on very narrowly defined tasks, especially related to attention and memory.

5. Another important take-home message: It's possible that smart drugs actually don't enhance cognitive function all. Instead what they might simply be doing is lowering other barriers necessary for normal cognitive function. Thus, instead of actually enhancing your ability to learn something for instance, they  might simply be getting rid of the lethargy, procrastination and boredom that often keeps us from learning or picking up a book in the first place. 

This to me sounds logical. A good control experiment to run in this case would be a side-by-side comparison of a purported smart drug with another one that's known to only improve peripheral qualities such as alertness or mood.

6. There is legitimate concern that even if these drugs enhance certain functions, they may be affecting other functions in negative ways. More generally, there is legitimate concern that we simply don't know enough about the brain to understand what the side effects of these drugs on other parts of brain function might be.

7. Big Pharma is shying away from smart drug research partly because we don't understand how they work. Of course, the cynic in me says that we can still get away with marketing the hell out of marginally effective supplements like 5-Hour-Energy, but that's a topic for a different post.

8. The societal implications of smart drugs are fascinating and important. If their significant impact is only on cognitively deprived members of society, then we should legitimately ask whether they should be prescribed more to say, poor or homeless people whose "attention reserves" have been unfortunately spent on more pressing basic issues like health or housing. These are the folks who in theory might benefit the most from such medication. Of course, we would then also have to deal with the potential ethical implications of testing these drugs on such people.

9. Bottom line: There will be a market for certain smart drugs in the future. But these drugs will very likely be highly targeted, optimizing only limited functions like short attention spans or rote memorization. Enhancing memory or attention in a consistent manner might be an achievable goal in the short-term future, but enhancing creativity or general IQ might well be impossible. The prospect of a pill that enhances cognitive capabilities across the board might likely remain the stuff of movies like 'Limitless' (which is quite an entertaining movie, by the way).

The clearest essay on physics I have read: The beauty and clarity of Paul Dirac's prose

Paul Dirac was sort of the Ernest Hemingway of physics, only better. Both his equations and his prose were as tight, spare and to the point as Hemingway. But unlike the delightfully rough-hewn storytelling of Hemingway Dirac's creations were, in Freeman Dyson's words, "like perfect mathematical sculptures falling from the sky". While his elegant mathematics captivated other scientists and inspired awe, his translation of mathematical precision to his English could frustrate and baffle. Dirac often answered in monosyllables, often did not understand metaphor and spoke only when he felt like. There was a logic behind this behavior that was hard to dispute though; as he pithily put it, "There are always more people willing to talk than to listen."

But while everyday conversation with him could be difficult, the application of his principles of language to his "Principles of Quantum Mechanics" was a spectacular success. Even today the book stands as the simplest and clearest account of quantum theory written by one of its master founders. Like Mozart, the text contains no fewer and no more words than are necessary for a proper exposition and even non-scientists should read the first chapter. Einstein himself cherished his copy, and whenever he needed to look up a technical point would mumble, "Where's my Dirac?" In fact Dirac regarded the book as his last word on quantum theory, so much so that he used to literally read from it in class.

The power of Dirac's language to strip away the inessentials and cut through the fog like a diamond is illustrated in a delightful little book that I recently came across. Titled "From a Life in Physics", it is a collection of talks given at the International School of Theoretical Physics at Trieste in Italy in 1968. The collection features talks by some of the true heavyweights of 20th century physics - Hans Bethe, Dirac, Werner Heisenberg, Eugene Wigner, Oskar Klein and Evgeny Lifshitz.

All the essays are highly readable but not surprisingly, the clearest and most elegant one is by Dirac. In it he essentially tells us how a theoretical physicist thinks and works: "I shall attempt to give you an idea of how a theoretical physicist works - how he sets about trying to get a better understanding of the laws of nature".

Dirac immediately cuts to the chase. He tells us that there are two main procedures by which a theoretical physicist operates. "One is to work from the experimental basis, and for this you must keep closely in touch with the experimentalists. The other is to work from the mathematical basis". How do you work from the mathematical basis, exactly? 
"One examines and criticizes the existing theory. One tries to pinpoint the faults in it and then tries to remove them. The difficulty here is to remove the faults without destroying the great successes of the existing theory."
Immediately here Dirac has hit on the essential formula followed by most successful theoretical scientists. The examples are well-known by now: Einstein invented relativity while preserving the success of Newtonian mechanics. Dirac himself was part of a revolution that invented quantum mechanics while preserving classical mechanics. The resolution of discrepancies led to scientific revolutions. The first procedure is also well known; for instance spectroscopists built a theory of atomic spectra based on a huge amount of experimental data.

Since we are faced with two potential methods for tackling a problem, which one do we follow? Dirac's prescription is clear: 
"Which procedure one follows depends largely on the subject of study. For a subject about which very little is known, where one is breaking new ground, one is pretty well forced to follow the procedure based on experiment. In the beginning, for a new subject, one merely collects experimental evidence and classifies it". 
As an example Dirac accurately notes the development of the periodic table; at first we could only build up a collection of facts based on existing data, but then it became possible for a brilliant scientist like Mendeleev to actually make predictions based on these facts.

On the other hand, when the experimental evidence is well-established, then the theoretician can proceed to organize it in an overarching theoretical framework. Here a striking new criterion enters the game, and no other physicist used it as fruitfully. It is beauty.
"With increasing knowledge of a subject, when one has a great deal of support to work from, one can go over more and more towards the mathematical procedure. One then has as one's underlying motivation the striving for mathematical beauty. Theoretical physicists accept the need for mathematical beauty as an act of faith. There is no compelling reason for it, but it has proved a very profitable objective in the past. For example, the main reason why the theory of relativity is so universally accepted is its mathematical beauty."
I would actually disagree with that last statement: The main reason why the theory of relativity had been so well accepted by 1968 was because of its unerring agreement with experiment. But in Dirac's words you can clearly see the tortuous path that a theoretical physicist exploring a new field treads; he is unsure of the exact direction, and since beauty can often be subjective, he always runs the risk of losing his way and falling into a deep abyss. Only a mind as confident and accomplished as Dirac's can navigate this labyrinthine maze.

There are other pithy gems in the essay. In one of them Dirac describes how Schrodinger tried to apply wave mechanics to the hydrogen atom and failed because he did not take spin - a purely quantum mechanical variable yet to be discovered - into account. Schrodinger's failure leads to another Dirac aphorism:
"The moral of this story is that one should not try to accomplish too much in one stage. One should separate the difficulties in physics one from another as far as possible, and then dispose of them one by one".
Wise words, not just for physicists but for everyone.

Another aphorism arises when Dirac talks about the recalcitrance of many physicists to switch from tensors to spinors in dealing with relativistic quantum mechanics. Being mathematically oriented Dirac did, and was successful. More Zen-like wisdom follows:
"One should always guard against getting too attached to one particular line of thought".
The rest of the essay concerns the theory of quantum electrodynamics. Dirac was never happy with QED since its artificial cutoffs and the procedure of renormalization did not fit with his notion of beauty and elegance. As he characteristically put it: "In mathematics one rejects a quantity because it is very small, not because it is too large and one does not want it". As far as I know, QED and other related theories are still based on the same principles, and Dirac probably wouldn't have been any happier with them today than what he was then.

But here in this essay Dirac demonstrates why he was such a master of clarity and elegant expression; I think at least the first part of the essay should be required reading for beginning students in science. In conveying the essentials of physical theory in such clear prose, Dirac is following some equally wise words from another famous physicist to a fault: 
"Everything should be made as simple as possible, but no simpler."

Genius and Einstein: From 'Great Man' to 'Every Man'?

Einstein is the poster child for
genius because he was a genius
The American organic chemist Robert Burns Woodward was a genius; the craft at which he excelled better than anyone else was making molecules, some of which were so complex that nobody before him thought they could be made. While little known to the general public, the perception of Woodward as an authentic genius was widely shared by his students and colleagues, several among whom counted themselves among the leading chemists of their time. There were others who shared some of his abilities but there was little doubt that only he brought these abilities together at the very highest level and inspired awe with what others considered to be almost preternatural instincts for the behavior of molecules. As a now famous student of his quipped, Woodward "totally, completely overshadowed everyone else. If he walked into the lab and said 'Cut off your arm' you would ask, 'Which one?' ".

The same goes for mathematician Srinivas Ramanujan. Nobody would say that Ramanujan's genius was a result of his culture, upbringing or education. In fact he had little of either of these. What made him special was an unsurpassed inborn ability to literally divine theorems from thin air, a rewiring of neurons that has been seen perhaps two or three other times in history. As his mentor G. H. Hardy acknowledged, Ramanujan was the only true genius he met in his life.

The fact that there is little doubt about Woodward or Ramanujan being unique geniuses was on my mind as I read an article by science writer Matthew Francis debating Einstein's status as the poster boy for genius. It's an odd article and I am not sure what to make of it. On one hand it does recognize Einstein's revolutionary contributions to physics, but on the other hand it also seems to ask if the particular times that Einstein lived in, combined with his eccentricity and public persona, might have dominantly contributed to his image as the archetypal genius. And it wonders if Einstein really stood out in a sea of other highly accomplished individuals.

At the heart of the article seems to be an attempt to critique the so-called 'Great Man' theory of history that imputes extraordinary achievements to a combination of individual intelligence and plain old luck, that is, being in the right place at the right time. I sympathize with this viewpoint; for instance I think it's our obsession with the Great Man theory that often leads us to ignore important contributors to work recognized by the Nobel Prize. But in disillusioning us of this theory, it seems to me that the writer is erring on the other extreme, casting Einstein as one of many geniuses whose labeling as the True Genius was as much the result of social factors as anything else. I think that view ignores the rare, truly great human masterpieces that nature has crafted and deprives us of appreciating what the human race is capable of. This is not about hero worship, it's about recognizing bonafide outliers. There is little doubt of the almost mundane fact that everyone stands on the shoulders of everyone else, but as much as he relied on the support of his fellow men and women, Moses still stood alone at the top of the mountain. The opposite of Great Man is not Every Man.

The writer first tells us that Einstein was a flawed human being who by today's standards could be called sexist and who harbored intense and sometimes biased political passions. But none of this is new and unknown, nor is it related to his scientific achievements, so I am not sure how a discussion of that aspect of his personality is really relevant to his scientific stature. A man does not get called a scientific genius because he was kind to his wife or donated large amounts to charity. Nor does he get called a dullard because he was corrupt or practiced child labor.

Later on in the piece the author seems to catch hold of the right thread, focusing on Einstein's scientific achievements which mark him apart. Here he makes the rather obvious statement that someone would have made Einstein's discoveries if he had not. Now the "what ifs" of history will always be unknowable, but again, this take doesn't really provide much insight because it would then suggest that nobody should ever be credited with anything, because someone else would have eventually discovered the things that they did. Even the author wisely does not seem to subscribe to this viewpoint. As for the image of Einstein as a product of his culture, I think the writer is confusing 'celebrity' with 'genius'. Genius is often accentuated by celebrity which is indeed a product of culture and media, but in terms of raw scientific contributions it exists independent of these very human attributes. R. B. Woodward was not a celebrity except among fellow scientists, but he was undoubtedly a genius.

The surest way to grasp Einstein's achievements is of course to take a look at the scientific creations he crafted. Not only did he invent special and general relativity but he figured out Brownian motion, the photoelectric effect, Bose-Einstein statistics, simulated emission, the equivalence between mass and energy and a specific theory of heat - and much of this in the single year of 1905. There were undoubtedly many other brilliant scientists working during his time, some of whom the writer notes, but really, nobody else comes close to contributing so many important things in such a short period of time. However even if he had contributed only half of what he did, the general theory of relativity alone would have marked out Einstein as a genius.

On this there is consensus even among the most distinguished of Einstein's fellow scientists. Einstein achieved nothing than a reworking of the fundamental laws of the universe, a view of gravity as the curving of spacetime that at once wedded geometry to physics and opened up previously undreamed vistas of exploration, from black holes to the entire cosmos itself. It's worth noting that the mathematician David Hilbert came close to discovering the so-called field equations that lay at the foundation of general relativity, and French mathematician Henri Poincare seems to have seen glimmers of the philosophical structure encompassing the equations, but there is scarcely any doubt that only Einstein had both the unmatched mathematical and the physical insight necessary to see the big picture and bring it all together. His achievement is not just a hop from Hilbert and Poincare but a leap measured in light years.

No less a luminary than Paul Dirac - a man famous for understatement rather than high praise, once said that someone would have quickly arrived at the special theory if Einstein had not, but no single person would have likely developed the general theory in its complete form if Einstein had not come along. His fellow physicists Enrico Fermi and Lev Landau - again, no slouches themselves - agreed; they made lists of scientists ranked by achievement in which only Einstein placed in the topmost slot, mainly for the invention of general relativity. And in his wonderful popular treatment of the subject, world-renowned relativist Kip Thorne confidently proclaimed that without Einstein, "the general relativistic foundation of gravity would probably have been discovered decades later". And we might also add, probably through the work of many people, akin to the development of quantum theory.

The Aeon article also asks us to take into consideration some of the other extraordinary scientists working alongside Einstein before we single him out - people like Bohr, Planck, Debye, Schrodinger, Heisenberg and Dirac. But as we saw, none of them comes close to combining both the breadth and depth of the contributions that he made. A sillier comparison is with Marie Curie; the author claims that Curie was no less a genius, and he seems to think that sexism and the fact that she was an experimentalist stacked the deck against her. But as a commenter notes, in this case the author seems to contradict himself - if Curie had truly faced sexism then it seems unlikely that she would have been awarded two Nobel Prizes. And again, the comparison really misses the nature of Einstein's contributions since the sexism and the experimentalist angle, while true, are red herrings: Madame Curie was without a doubt a great scientist and an even greater human being, but (as Lloyd Bentsen would have said) she was no Albert Einstein.

If the purpose of this article is to admonish people against applying the 'genius' label lightly then I am on board (although I am not then sure why the author would say "Einstein's genius was different from Curie's"). The moniker has undoubtedly been overused, and its overuse feeds into a general highlighting of the 'Great Man' theory of history that misses the work of many people. But in my opinion articles like this unfortunately end up swerving closer to the other side, pitching the 'Every Man' theory which seems to me to be equally flawed. Projecting Einstein's genius as more a matter of perception, of culture or his times does a disservice not only to his authentic genius but to the ability of the human race and the evolutionary lottery that occasionally produce such extraordinary gems.