Field of Science

What if the Manhattan Project had been like an Alzheimer's disease drug discovery project

The vast K-25 gaseous diffusion plant at Oak Ridge - an
engineering endeavor (Image: Nuclear Secrecy Blog)
Every once in a while you will find someone comparing a major scientific or technological challenge to the Manhattan Project - among such comparisons would be the Human Genome Project and the Brain Map Initiative. It's also not unheard of for drug discovery being uttered in the same breath as the Manhattan project; for instance administrators and scientists have been calling for new antibiotic discovery to be placed on the same footing as the wartime quest to build the first atomic bomb.

To be honest, most of these comparisons obfuscate more than they instruct. It's not that they are entirely invalid, but their core kernels of truth significantly differ.

To see why, let's compare a typically challenging, novel drug discovery project like finding a cure or mitigating therapy for Alzheimer's disease to designing Fat Man or Little Boy. The mandate for the Manhattan Project was, "produce a practical military weapon that works by harnessing energy from nuclear fission of uranium or plutonium". The mandate for Alzheimer's disease would be "discover and develop a small molecule that mitigates or cures the symptoms of Alzheimer's disease and that is potent, safe, enters and exits the body in a reasonable period of time and causes minimal side effects".

The first thing to notice is the difference between the word "produce" and "discover". Manhattan was not a discovery project, and the word "produce" in fact appeared in the first line of the 'The Los Alamos Primer', the indoctrination lectures given by physicist Robert Serber at the beginning of the adventure. Production is more akin to engineering than science, so that word sets the tone for the entire project. That is not to say that Manhattan did not involve science and scientists - of course it did. But the key thing to realize is that the basic discovery part of the science had been done between 1938 and 1942. This part was symbolized by four milestones: the discovery of fission in December 1938 by Hahn and Strassmann, the first 'proof of principle' calculations by Frisch and Peierls in March 1940 indicating the feasibility of a fission weapon, the working out of the actual mechanism and effects of a bomb in the summer of 1942 by Oppenheimer and his associates at Berkeley and the successful initiation of a nuclear chain reaction by Fermi and his associates in Chicago in December 1942. By the time the project started in March 1943, the atomic constitution of matter was thus firmly mapped and the elementary particles which were required to harness fission were all discovered and their properties charted as either 'known knowns' or the 'known unknowns'.

The major challenges associated with the project were thus not discovery challenges. It was fully known by the beginning of the project that if you suddenly bring a sufficiently large lump of highly purified uranium-235 together you would cause a very big bang. The key words there were 'large', 'purified' and 'suddenly' and these words really signaled the enormous engineering challenges. To produce a large and purified lump of uranium or plutonium would take vast chemical and engineering complexes in Oak Ridge, TN and Hanford, WA which employed hundreds of thousands of workers and whose use of resources like electricity and copper would rival the size of the US automobile industry. That was really mostly engineering, the unimaginably strenuous application of man and machine in separating two isotopes from each other and in creating a novel element.

The 'sudden' part of the challenge was equally important and again heavily steeped in engineering. For the uranium bomb this was not a big issue since a heavy modified gun would do the job. The really novel find - and this would be classified as a discovery, albeit of an applied kind - was the mechanism of a plutonium weapon. In the summer of 1944 it was realized for good that given the spontaneous rate of fission of Pu-240 which was contaminating the samples of Pu-239 produced in the Hanford reactor, a gun-type weapon that would work for uranium would simply cause an equivalent plutonium weapon to pre-detonate. The solution circumventing this problem - implosion using shaped 'lenses' - was probably the most novel discovery/invention to come out of the Manhattan Project. The novelty of this solution was why they tested the plutonium bomb in July 1945 but not the uranium bomb. In fact implosion could be considered to be the one truly novel 'secret' to come out of the project.

But again, putting implosion into practice was almost completely engineering. Brilliant scientists like John von Neumann did contribute in calculating how you would get a perfectly symmetrical, inward-looking shock wave to compress the plutonium core, but the key challenges were designing and fashioning the explosive lenses - layered arrangements of slow and fast-burning plastic charges that would alternately diverge and then precisely converge a shock wave - that would make implosion possible as well as crafting detonators that would fire simultaneously on the surface of the weapon to send the shock waves in. To that end the metallurgists and chemists at Los Alamos were put to work refining these plastic arrangements from hot molds, shaping them and smoothing out even the tiniest air imperfections in the form of bubbles that would cause the shock waves to deviate from perfect symmetry. Similarly experts in electronics were put to work inventing new timing systems for detonators. This work was all chemistry, chemical engineering, electronics and machine shop. It involved not exalted, Nobel Prize-winning minds but the most practical minds, minds which sometimes lacked even a college degree but which could work wonders with their hands (one of these minds happened to be that of David Greenglass, the spy who shuttled secrets to Klaus Fuchs). In fact this part of the project was so important that much of the details are still classified, and rightly so. Master the design of explosive lenses and you command the explosive consequences of plutonium.

The culmination of all this engineering and science is well known, but the tone for that was set in 1943. No wonder Richard Feynman, when describing the Manhattan Project in his memoirs, called it "not science, mostly engineering". He was right.

Now what if the Manhattan Project had been like a novel drug discovery project for Alzheimer's disease? The physicists working on it would still be in the dark ages. The equivalent of fission in Alzheimer's would be the mechanism(s) that causes it, both on the molecular level and on a more global level. We don't know that yet. The Alzheimer's equivalent of protons, neutron and electrons would be the molecular or epidemiological components that cause the disease. There are scattered clues about them, but we really don't know those yet either. Consider the rogue, misfolded protein Aß (amyloid beta) for instance: ten years ago it was regarded as possibly the major culprit in the disease; now it is regarded simply as something associated with the disease in a major way, but nobody knows exactly how. Every major clinical trial that promises to target interesting mechanisms and components in Alzheimer's has failed miserably over the last few years, which is probably not too surprising if we were in ignorance of the real molecular components and were targeting the wrong mechanisms to begin with. 

And even if we knew the mechanisms and the components, the ensuing development of an Alzheimer's drug is no mere engineering challenge. That's because even the most basic processes of drug discovery - things like getting drugs across cell membranes or even getting them to dissolve in an aqueous solution - are too poorly understood to be able to be predicted accurately. Thus, the engineering part of drug discovery is far more tied to a woefully deficient understanding of the science than the engineering part for the Manhattan Project was. The implication of this is that because prediction is largely futile, we have to test tens of thousands of candidates in drug discovery to see what works: What if the Manhattan project needed to build thousands of bomb prototypes to find the one that finally worked? The difference between bomb design and drug design is thus not one of manpower, resources or engineering; it is one of a basic lack of information and deep, dark patches of ignorance. And it arises from the fundamental complexity of biological systems compared to engineering systems.

Thus, if the Manhattan Project were truly an Alzheimer's disease drug discovery project, the physicists working on it would have started not knowing about nuclear fission and not even knowing about protons, neutrons and electrons, let alone about cross sections or plutonium. Here's what their mandate would have looked like then: "Discover what stuff is made up of. Find if any of it can be manipulated to release large amounts of energy. And if you find this, then try to figure out if you can get enough of this special material to make a practical military weapon." In other words, there probably would not have been a mandate to build an atomic bomb in the first place.

However I am ready to take bets on whether this mandate - given to all those brilliant minds in 1942 - would have led to Little Boy or Fat Man by 1945.

Afterthought: So if the Manhattan Project was in fact mostly engineering, it's worthwhile asking why it's associated with science and scientists - and especially physics as opposed to chemistry which was equally important - in the public imagination. I believe the answer in one word is 'myth-making'. Men like Feynman and Oppenheimer are considered so brilliant and fascinating that they have inevitably come to stand in for the whole project.

Other posts on the complexities of biology and the futility of comparing drug discovery with engineering challenges or physics:

1. Why chemistry (and biology) is not physics.
2. Why drug design is like airplane design. And why it isn't.
3. Derek Lowe on what he calls the 'Andy Grove Fallacy': 12.
4. Why it's hard to explain drug discovery to physicists.

Happy Birthday to the man who found life slipping away from his fingers

“In my quest for the secret of life I started my research in histology. Unsatisfied by the information that cellular morphology could give me about life, I turned to physiology. Finding physiology too complex, I took up pharmacology. Still finding the situation too complicated, I turned to bacteriology. But bacteria were even too complex, so I descended to the molecular level, studying chemistry and physical chemistry. After twenty years' work, I was led to conclude that to understand life we have to descend to the electronic level and to the world of wave mechanics. But electrons are just electrons and have no life at all. Evidently on the way I lost life; it had run out between my fingers.”
This quote comes from Albert Szent-Gyorgyi - born 121 years ago today. Gyorgyi was a Hungarian biochemist and Nobel Laureate who discovered vitamin C and worked out many of the components of what we now call the Krebs cycle. 

His quote is the best encapsulation I know of the limitations of reductionism, and of the non-reduction of biology to physics in particular. Szent-Gyorgyi zeroes in on the essential problem; as we drill down from unquestionably living cells to molecules to unquestionably non-living individual electrons, life somehow slips away sometime during the transition from between our microscopes, pipettes and petri dishes.

At what point it exactly does this and how is a quest that will continue to occupy us for as long as there is a human mind capable of scientific reflection.

Happy Birthday to the man with five brains

Today is Murray Gell-Mann's birthday. John Brockman calls him "the man with five brains, each one of which is smarter than yours". We are thankful he is still with us and holding forth on a variety of important problems. Gell-Mann of course is famous as the man who, inspired by a line from a book which he predictably would be the right person to have read, invented quarks. Nobody has observed an isolated quark yet, but there have been plenty of Nobel Prize-winning experiments confirming their evidence through other incontrovertible means.

In the 1960s there was a famous running rivalry between Gell-Mann and Richard Feynman for the title of Smartest Man on the Planet (there was another lesser known rivalry between Gell-Mann and Einstein biographer Abraham Pais, who Gell-Mann once bitterly called "that little dwarf"). In terms of raw I.Q. the two New Yorkers certainly were equal to each other. It was the joint presence of these wunderkinder that made Caltech perhaps the most exciting place for theoretical physics in the 60s and 70s. Now most of the public believes Feynman won the contest, but that's probably because, as Gell-Mann put it, Feynman was inordinately fond of generating anecdotes about himself and making himself appear larger than life. The two worked together for a while and admired each other for the rest of their lives, but according to Gell-Mann he eventually got tired of what he thought was Feynman's preoccupation with self-promotion.

In some sense Gell-Mann was the perfect foil to Feynman's anecdote generator, just as Feynman was often the perfect foil to Gell-Mann's predilection for tossing out trivia. I would wager that Gell-Mann's quarks were at least as important as Feynman's quantum electrodynamics, laying the foundation for all the particle physics that followed, including the culmination of the efforts of many people in the Standard Model. Gell-Mann also made other important contributions to physics, including to current algebra and quantum chromodynamics. Ironically, famous rival as he was, it was Feynman who paid Gell-Mann the ultimate compliment: "Our knowledge of fundamental physics contains not one fruitful idea that does not carry the name of Murray Gell-Mann".

Gell-Mann would easily be Feynman's contender for the world's smartest man not only because he has racked up a tremendous amount of achievement in physics but because he also, in the words of his biographer George Johnson, seems to know everything about everything. Simply conquering physics was not enough for Gell-Mann, he wanted to conquer the depths of all human knowledge. His christening of quarks based on a remark from James Joyce's dense "Finnegan's Wake" was not a coincidence. The range of his intellectual facilities equaled that of Oppenheimer, and he can tell you as much about linguistics or classical history as he can about physics; it was his propensity to generously offer trivia about these topics that in part used to drive Feynman crazy. He is fluent in half a dozen languages and known for correcting native speakers' pronunciations of words from their own language. With such a prodigious command of the world's knowledge at his disposal, it's not surprising that he does not suffer fools gladly; he is known to walk out of meetings (like his august predecessor Wolfgang Pauli) if he thinks less of the speaker. I was not afraid of knocking on Freeman Dyson's door, but I would have to fortify my nerves with a few shots of gin before contemplating an encounter with Gell-Mann.

Regarding literature on or by Gell-Mann, you can do no better than George Johnson's "Strange Beauty" which along with James Gleick's "Genius" is the best physics biography I have ever read. Gell-Mann himself has found it notoriously painful to put pen to paper all his life and therefore it is no surprise to find that he almost disowned his own book - part scientific meditation, part memoir- after it was written. And yet I will recommend it warmly: "In "The Quark and the Jaguar" Gell-Mann ruminates across a vast range of time and length scales of the cosmos, from quarks to humans to the entire universe. It has sparkling and remarkably clear discussions of topics like algorithmic complexity and quantum electrodynamics and reading it feels akin to getting an intellectual workout in a swanky gym. With Gell-Mann holding forth on science and the universe, life is at least not dull.

And therefore the best tribute to the man with five brains would be a vodka martini, shaken with a generous helping of nature's fundamental forces and stirred with the ingredients of the cosmos, and held up with a full-throated cry of "Three quarks for Muster Mark!".

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.