Field of Science

Macrocycles, flexibility and biological activity: A tortuous pairing

Here's an interesting paper from the Jacobson, Wells and Walsh labs at UCSF and Stanford that seeks to demonstrate how restricting the flexibility of macrocycles may lead to better inhibition of their targets from an entropic perspective. The authors are looking at a non-ribosomal peptide called thiocillin which inhibits the growth of Gram positive bacteria, especially MRSA.

What they wanted to determine was the effect of point mutations in the peptide on the inhibition. They performed saturation mutagenesis between positions 2 and 9 of the peptide and generated 152 mutants whose activities they tested in a minimum inhibitory concentration (MIC) assay. They found that 8 point mutants especially resulted in more potent analogs.

Now there can be several reasons why the potency went up, but one potential reason is entropy. Macrocycles, while often more rigid than their corresponding linear analogs, are still quite flexible. In fact, my own work with the macrocycle dictyostatin in graduate school showed how flexible even a supposedly constrained molecule can be. What this paper finds out is that in cases where the mutant lost activity, there was a corresponding increase in flexibility and entropy as measured by the number and distinctive nature of conformations from a conformational search technique which they have developed. Particularly striking changes in potency occurred when a single residue was modified from having a planar sp2 carbon to a non-planar sp3 carbon: in that case the saturated analog had many more conformations than the unsaturated one.

As someone who has always been partial to the impact of entropy and conformational flexibility on molecular activity, I like this kind of work. But I am not quite convinced yet that it is decreased flexibility that leads to more potent inhibition. For one thing, inhibition is not direct binding, and there are a variety of factors including changes in cell permeability and off target effects that could lead to the observed changes in inhibitory - not binding - affinity. Secondly, there were 152 mutants, and it's not clear to me how many were tested for flexibility: in other words, I am not sure there were enough controls to determine whether the flexibility-inhibition correlation really holds up. For instance, many of the mutants were inactive: were there instances in which some of these were actually less flexible and challenged the hypothesis? Another way to put it is to ask what the right null model for this dataset is. 

Thirdly, decreased or increased inhibition can be a result of both more conformations as well as conformational selection. For instance, two macrocycles can have similar conformations, but in one case a particular conformation more suitable for binding could be more stable (perhaps because of an intramolecular hydrogen bond) and represented to a higher degree in solution, making it easier for a protein target to pick it out. Lastly, it is not clear whether the improved affinity could simply have been a result of better interactions: although that seems unlikely for the sp2 vs sp3 pair above, it is nonetheless a factor that could be operating in other cases.

Entropy is an important consideration in drug design, but it's also trickier than it sounds to both understand its effects and implement its benefits. To their credit the authors acknowledge that rigidity is a necessary but not sufficient condition for increased affinity, and other studies seem to bear it out. Macrocyclization can also be counterintuitive: for instance in my own studies I found out that dictyostatin which is a macrocycle seems more flexible than its corresponding acyclic counterpart discodermolide. In that case it was fairly straightforward syn-pentane interactions which made the acyclic molecule rigid. In other cases it could be the opposite. In any case, this study serves as an interesting starting point for exploring the impact of flexibility on drug affinity, but it also serves to illustrate how thick the jungle of SAR really is.

An open letter to my fellow industry scientists: Why the March for Science must be led by us

On April 22nd, scientists, science-lovers and people who care about evidence-based reasoning are going to participate in protests and marches around the country. The flagship march will take place in Washington DC, but there are sister marches in Boston, San Francisco, Atlanta and Raleigh, to name a few cities.

There has been a lot of debate and commentary on what the objectives of the march should be, how political it should get and what it generally should or should not do. Some think that scientists should not politicize the march, others think that there is no way the march could not be political. I am participating in the march myself and wish it all success, but one thing is clear to me: the march will not succeed in its objectives if industry scientists do not participate in it in large numbers.

For me, it is very clear why this is the case. First of all, a few words about the motives and reasoning of the march. The objective of the march is to send a resounding message to the politicians and people of this country about respecting scientific facts and divorcing them from political ideology. However the people who need to hear the message about science the most are Donald Trump's supporters, especially ones in the rural areas of this country. If we don't reach them, we would spend the day feeling happy and smug about ourselves, wander around with like-minded people, and come home after patting each other's backs without really having accomplished much, feeling secure in our secure worlds. We would have done almost nothing to change the mind of the average person living in rural Alabama.

The only way to not have our efforts fail is to understand the details of the bridge we need to build to mend our relationship with those who may think differently. We are more similar than we think. Many people who are suspicious of science are far from dumb, but they are suspicious of certain fields of science such as climate science and evolution while being supportive of areas like space exploration. I don't think there is any evidence that the average American is against scientific research as a whole. But those who are suspicious of specific areas think that not only do these ideas infringe on their deeply held religious beliefs, but that they are part of a grand liberal agenda to ram sweeping government policies down their throats. They also think especially of academic scientists as liberal, ivory tower intellectuals who have their heads in the clouds and who don't care about the welfare of the common man. The victory of Trump was in large part a victory against these perceived intellectual elitists.

Firstly, what we need to convince these people is that many of the facts unearthed by science, even in areas like climate change and evolution, are independent of the political beliefs of the people who discover these facts. That means pointing out, first of all, that there are religious and conservative scientists who work in these fields, and that these scientists also support the facts independent of their religious or political beliefs. The continuing head of the NIH, Francis Collins, is a devout Christian for instance who fully supports evolution and important fields like stem cell research. The better we can do in separating scientific facts from the beliefs of the people who find out these facts, the better we will be able to reach the people who need to know them the most. At the same time, we should admit that some scientists do politicize science, and that we need to have an honest dialogue with each other about how we can keep science as neutral as possible. We also need to admit that extreme politicization of science can take place on both the left and the right.

Most importantly, however, we need to convince the people who need to hear about science the most that science is far from being limited to ivory tower academics, and to fields like evolution or climate change. Even if we completely ignored those fields, there is zero doubt that science has had a profound impact on the standard of living of the very people who are suspicious of it during the last few decades. Even if you completely took liberal academics out of the equation, science still pervades every aspect of everyone's lives. The best way to convince them of this is to move away from pure and basic science to applied science.

That's where industry scientists come in. Forget, for a moment, abstract academic matters like dark energy and directed gene evolution and the fine-tuning of computer climate models, forget what Thomas Kuhn said about science, forget what stuffy scientific epistemology and ontology are all about, and focus on one stark fact: Science has directly, immeasurably and irrevocably impacted the lives of rural and urban populations alike through its research into fossil fuels, into agriculture, into infrastructure such as roads and bridges, into oil refining, into plastics and textiles, into improving water and air quality, and into lifesaving drugs and vaccines against cancer, polio and infectious diseases. Most of this innovation was made possible by the creativity and passion of industry scientists, ranging from Wallace Carothers to Gertrude Elion. 

Throughout recent history, companies like Bell Labs, IBM, Lockheed, Ford, GE and Exxon have been fonts of scientific innovation and progress. This kind of science is not just sewn into the fabric of everyday American life from Boston, MA to Savannah, GA, but it should also appeal to his or her patriotic instincts, since it's what has allowed the United States to become a powerhouse of technology and finance after World War 2. Even if you are suspicious of global warming or evolutionary theory, you should be able to appreciate the profound influence science has had on your way of life by bringing you transistors, the Saturn V rocket, nitrogen fertilizer, painkillers, petroleum cracking, nylon, Ford F-150 trucks, Portland cement and the iPhone. These are not liberal or conservative inventions. These are scientific inventions. They are enabling beyond measure. Even if you think they haven't really helped lift you out of poverty, without them your fate would be unimaginable.

It's only by talking about these very practical and amazing innovations that you can convince the average American of the value of science. Whether you are a Clinton supporter or a Trump supporter, a Methodist or an atheist, poor or rich, gun lover or hater, for or against abortion, it is simply impossible for your life or that of your parents and grandparents to not have been radically impacted for the better because of improved medicines, better roads and automobiles, better clothing and housing and better means of communication. At the heart of every single one of these innovations is science, firmly rooted in observable fact and independent of politics and religion. At the same time, this is where we can loop back from these highly applied advances to basic science which may sound very esoteric. For instance, Einstein's relativity is what makes GPS possible. Basic research into organic synthesis is what makes new drugs possible. And it would be impossible to understand cancer and AIDS without understanding evolution. But even if you didn't care about the process that goes into these developments, you can still care about the fruits themselves.

I therefore want to issue an open appeal to my colleagues in industry. To scientists from Exxon, Dow, Pfizer, Kraft, GM, Raytheon, Genentech, GE, Monsanto, Coca Cola and the umpteen number of small startups doing research in pharmaceuticals, food science, agriculture, electronics and tech; don't just participate but lead the March for Science. Show up with your families. Come out in large numbers; it's a Saturday so you don't even need to take a day off. Since academia is a niche, show the country that you and your colleagues actually constitute the majority of scientists in this country. Leave aside your political differences and come together to show everyone how your work and that of your intellectual forefathers has profoundly changed the average American's life for the better, and how it has turned his nation into the most technologically advanced civilization on earth. Forget about politics for a moment and remember the joy that each one of you feels in the shared moment of scientific discovery, a moment completely divorced from your political beliefs. It certainly helps that unlike leading academic centers, the leading industrial research centers you work in are more uniformly distributed throughout the country and not just limited to the coasts. A strong showing of industry scientists would thus automatically disperse the science march over a much wider area. 

My fellow industry scientists, here is our chance to try to convince our fellow countrymen, and especially ones with whom we have strong political disagreements, that irrespective of what they think about its political trappings, science is a fantastic truth-finding practical tool that influences and will keep influencing their way of life through its contributions to the most practical matters related to energy, transportation, housing, and healthcare. Here is our chance to convince the average American how she could be a part of this revolution, and how you are ready to do what you can to communicate not just the wonders of science to her but to enable her to participate in its fruits. Reassure her that you are willing to have an honest dialogue about how the government can do more to retrain her for this new technological age, to try to make sure that her kids can go to college and become technically enabled, to become a part of the same adventure that put a man on the moon, helped the United States win World War 2, and ended polio and smallpox. 

Seen from the angle of these practical innovations, science has been the great equalizing force in American life, reaching Americans of every political stripe and disagreement. That is what makes it so special, so important for our future, so much worth fighting for, and most importantly, so much worth sharing with those who we think are so different from us.

I'll see you there.

Darwin Day: A personal offering

Two hundred and eight years ago this day, Charles Darwin was born. The vision of life that he created and expounded on transformed humanity's perception of its place in the universe. After Copernicus's great heliocentric discovery, it was Darwin's exposition of evolution and natural selection that usurped human beings from their favored place at the center of the universe. But far from trivializing them, it taught them about the vastness and value of life, underscored the great web of interactions that they are a part of, and reinforced their place as both actor and spectator in the grand game of the cosmos. Not only as a guiding scientific principle but as an all-encompassing element of understanding our place in the world, evolution through natural selection has become the dominant idea of our time. As the eminent biologist Theodosius Dobzhansky put it quite simply, nothing in biology makes sense except in the light of evolution. Evolution is a fact. Natural selection is a theory that is now as good as a fact. Both evolution and natural selection happen. And both of them owe their exalted place in our consciousness to a quiet, gentle and brilliant Englishman.

Today it is gratifying and redeeming to know how right Darwin was and how much his theory has been built upon, and frustrating to keep on realizing how those professing religious certainty threaten to undermine the value of his and others' careful and patient discoveries. Especially in the United States evolution has become a bizarre battleground of extreme opinions and mudslinging, a development that seems to be in step with the tradition of coloring any and every issue with a political hue. In this country, it seems today that you can hardly utter an opinion without attaching a label to it. You cannot simply have an opinion or take a position, no matter how grounded in fact it is; your position has to be Republican, Democrat, Libertarian, Neo-Conservative, Socialist or Atheist. If none of these, it has to be Centrist then.

When it comes to evolution, attaching the label of "Darwinism" has obscured the importance and power of the theory of natural selection. On one hand, those who defend the label sometimes make it sound as if Darwin was the beginning and end of everything to do with evolution. This is simply untrue; in his creation of the theory of natural selection, Darwin was a little like Martin Luther King. The Civil Rights movement owed an incalculable debt to King, but King was not the Civil Rights movement. On the other hand, those who oppose the Darwinist label make it sound like all of us who "believe" in evolution and natural selection have formed a cult and get together every weekend to worship some Darwin idol.
Unfortunately both these positions only serve to obfuscate the life and times of the man himself, a simple, gentle and brilliant soul who painfully struggled with reconciling his view of the world with prevailing religious sentiments and who thought it right to cast his religious views aside in the end for the simple reason that his findings agreed with the evidence while the others did not. Darwin Day should be a chance to celebrate the life of this remarkable individual, free from the burdens of religion and political context that his theory is embroiled in today. Because so much has been said and written about Darwin already, this will be more of a personal and selective exposition. Since I am a lover of both Darwin and books, I will tell my short story of Darwin as I discovered him through books.

When you read about his life for the first time, Charles Darwin does not evoke the label of "genius", and this superficial incongruence continues to beguile and amaze. His famous later photographs show a bearded face with deeply set eyes. His look is gloomy and boring and is not one which elicits the image of a sparkling, world-changing intellect and incendiary revolutionary taking on an establishment steeped in dogma. Darwin was not a prodigy by the standards of his English contemporaries William Hamilton or Lord Kelvin, nor did he particularly excel in school and college. He went to Cambridge, of course, but most well educated Englishmen went to Cambridge or Oxford. At Cambridge, although he studied religion, Darwin had one overriding quality: curiosity about the natural world. He consummately nurtured this quality in field trips and excursions; as one famous story goes, Darwin once held two beetles in two hands and popped one of them in his mouth so that he could free one hand for catching a third very attractive one which he had just noticed. He indulged in these interests much to the chagrin of his father who once said that he would not amount to anything and that he would be a disgrace to his family.

As is well-known, Darwin's story really begins with his voyage of the Beagle when he accepted a position on a ship whose melancholic, manic-depressive captain Robert Fitzroy wanted an educated, cultured man to keep him company on a long and dangerous voyage that circumnavigated the world. For Darwin this was a golden chance to observe and document the world's flora and fauna. One of the best illustrated expositions of Darwin's voyage is in Alan Moorhead's "The Voyage of the Beagle" which is beautifully illustrated with original drawings of the wondrous plants, animals and geological formations that Darwin saw on the voyage. Darwin's own account of the voyage is characteristically detailed and modest and depicts a man enthralled by the beauty of the natural world around him. By the time he set off on his historic journey, young Charles had already been inspired by his teacher Charles Lyell's book on geology that talked about geological changes over vast tracts of time: in time, “Principles of Geology” would become a seminal text and a touchstone of the Great Books program. As is also rather well known, evolutionary ideas had been in the air for quite some time by then (as marvelously documented in Rebecca Stott's recent book "Darwin's Ghosts", which traces evolutionary thinking back to Aristotle and even before), and Darwin certainly was not the first to note the rather simple fact that organisms seem to have changed over time, a view that nonetheless and naturally flew in the face of religious dogma. Most importantly, Darwin was well aware of Thomas Malthus's famous argument about the proliferation of species exceeding the resources available to them, an idea whose logical extension would be to conjecture a kind of competition between species and individuals for finite resources. The "struggle for survival", taught today in school textbooks, a phrase that became much maligned later, nonetheless would have been obvious to a man as intelligent and perceptive as Darwin when he set off on his voyage.

Biology, unlike mathematics or physics, is a science more akin to astronomy that relies on extensive tabulation and observation. Unlike a theoretical physicist, a biologist would be hard-pressed to divine truths about the world by armchair speculation. Thus, painstakingly collecting and classifying natural flora and fauna and making sense of its similarities and differences is a sine qua non of the biological sciences. Fortunately Darwin was the right man in the right place; endowed with a naturally curious mind with an excellent memory for assimilation and integration, he was also unique and fortunate to embark on a worldwide voyage that would enable him to put his outstanding faculties to optimum use. Everywhere he went he recorded meticulous details of geology, biology, anthropology and culture. His observation of earthquakes and rock formations in South America and his finding of fossils of giant mammals lend credence to his beliefs about organisms being born and getting extinguished by sometimes violent physical and planetary change. His observation of the Pacific and Atlantic islanders (especially the ones on Tierra del Fuego) and their peculiar customs underscored the diversity of human life along with other life in his mind. But perhaps his best known and most important stop came after several months of traveling, when the ship left Ecuador to dock at the Galapagos Islands.

Again, much has been written about the Galapagos Islands and about Darwin's Finches (most notably by Jonathan Weiner in his “The Beak of the Finch”). The truth is subtler, both simpler and more interesting than what it is made out to be. Darwin had mistaken his famous finches for other species of birds. It was only after coming back that his friend, the ornithologist John Gould, helped him to identify their correct lineage. But finches or not, the birds and the islands provided Darwin with a unique opportunity to study what we now know as natural selection. The islands were separated from each other by relatively small distances and yet differed significantly in their geography and flora and fauna. On each island Darwin observed similar plants and animals that were yet distinct from each other. As in other places, he also observed that species seemed to be adapted to their environment. Geographic isolation and speciation were prominent on those hot, sweaty and incredibly diverse landmasses.

After five years of exhaustive documentation and sailing Darwin finally returned home for good, much changed both in physical appearance and belief. His life following the voyage has been the subject of much psychological speculation since he settled down with his cousin Emma and never ever left the British Isles again. He also seemed to have been stricken with what today is noted by many authors as a kind of psychosomatic illness because of which he was constantly ill with abdominal and other kinds of pains. After living in London for some time, Darwin retired to Down's House in Kent where he peacefully lived the rest of his life with a kind and loving wife, playing with his children, taking walks along the path at the back of his house named the "Sandwalk", corresponding with intellectuals around the world and constantly interrupting his research with salutary visits to spas and resorts for "natural" treatments that were often of dubious value.

But peaceful as his life was, psychologically Charles Darwin was fomenting a maelstrom of revolution that was to have earth-shaking implications. Another fact that is frequently emphasized in contemporary discourse is his hesitation to not publish his ideas for another twenty-five years. Darwin was planning to write it for a while, but was finally jolted into writing it when he received a letter from an obscure young naturalist named Alfred Russell Wallace who was living a hard life of science and natural history exploration in Indonesia. Wallace had read some of Mr. Darwin's papers and manuscripts and had been struck by the similarity of his ideas to his own. Would Mr. Darwin comment on them? Darwin finally realized that he had to act to prevent getting scooped but characteristically credited Wallace in his published work.

In my mind however, Darwin's procrastination and its story sounds much simpler than the mystique and psychological speculation that sometimes envelop it. As we noted earlier, Darwin was a highly trained biologist and scientist of the first caliber. He knew that he would have to exhaustively document and classify the windfall of creatures, plant and rock specimens that he had collected on his voyage. Apart from thinking and writing about his Beagle collections, Darwin also maintained an astonishingly comprehensive and detailed research program on marine invertebrates and barnacles. More tellingly, he did experiments to find out if seeds are viable even when dispersed over long distances over salt-water. He visited gardens and zoos, and quizzed pigeon breeders about their profession. Much of this was in preparation for the grand act that was to follow. In case of the barnacles and marine creatures, Darwin's research was second to none. He published several extremely detailed books on the minutiae of these organisms; some of these had titles which would have put anyone to sleep.

And yet the level of detail in them reflects the extraordinary patience, power of observation and meticulous hard work that characterized the man, characteristics crucial for developing the theory of natural selection. Darwin was also very fortunate to have had several friends and colleagues who were experts in areas that he was not, who helped him classify and name all the material. Foremost among his correspondents were Charles Lyell and Joseph Hooker to whom he confided not just his scientific questions but also his emerging convictions about the interconnections and implications that were emerging from his research and writing. Also as noted above, John Gould accomplished the crucial task of reminding Darwin that his Galapagos birds were finches. With help from these collaborators and his own studies and thoughts on his observations, thoughts that filled literally dozens of rough drafts, scribblings and private diaries, Darwin finally began to glimpse the formation of a revolutionary chain of thought in his mind.

But Darwin did not rush forth to announce his ideas to the world, again for reasons that are obvious; Victorian England was a hotbed of controversy between science and religion, with many distinguished and famous scientists there and in other countries not just fervently believing in God, but writing elegant tomes that sought a supernatural explanation for the astounding diversity of life around us. Cambridge was filled with intellectuals who sought a rational framework for God's intervention. Darwin would have been quite aware of these controversies. Even though Darwin's grandfather (a more pugnacious character) himself had once propounded an evolutionary view, Darwin was finely attuned to the sensitive religious and social debate around him. Not only did he not want to upset this delicate intellectual and spiritual balance and get labeled as a crackpot, but he himself had not started his voyage as a complete non-believer. One can imagine the torment that he must have faced in those early days, when the evidence pointed to facts that flew in the face of deeply held or familiar religious beliefs. One of the factors that dispossessed Darwin of his religious beliefs was the stark contradiction between the observation of a cruel and ruthless race for survival that he had often witnessed first hand, and the image of an all-knowing and benign God who kindly reigned over his creations. As the evidence grew to suggest relationships between species and their evolution by the forces of natural selection that preserved beneficial characteristics, Darwin could no longer sustain two diametrically opposite viewpoints in his mind.

Opponents of evolution who want to battle the paradigm not from a scientific viewpoint (because they can't) but from a political one frequently raise a smokescreen and proclaim that evolution itself is too complex to be understood. The tricksters who propagate intelligent design further attest to the biochemical complexity of life and then simply give up and say that only an omniscient God (admittedly more complex than the systems whose complexity they are questioning) could have created such intricate beauty. The concept of a struggle for survival has also been hijacked by these armies of God who proclaim that it is this philosophy that would make evolution responsible for genocide, fascism and the worst excesses of humanity. This is a deeply hurtful insult to natural selection and evolution as only the most dogmatic believers can deliver.

One thing that constantly amazes you about evolution is its sheer simplicity. Stripped down to its essentials, the "theory" of evolution can be understood by any school child.
1. Organisms and species are ruthlessly engaged in a constant struggle for survival in which they compete for finite resources in a changing environment.
2. In this struggle, those individuals who are more adapted to the environment, no matter how slightly, win over other less adapted individuals and produce more offspring.
3. Since the slight adaptations are passed down to the offspring, the offspring are guaranteed to preserve these features and therefore are in a position to survive and multiply more fruitfully.
4. Such constant advantageous adaptive changes gradually build up and, aided by geological and geographical factors, lead to the emergence of new species.

It's almost like a simple three-step recipe that when followed keeps on churning out culinary wonders of staggering complexity and elegance. In my mind the beauty of evolution and natural selection is two-fold; firstly, as Darwin emphasized, the slightest adaptation leads to a reproductive advantage. Such slight adaptations are often subtle and therefore sometimes can sow confusion regarding their existence; notice the debate between driver and passenger mutations in fields ranging from evolutionary biology to oncology. But the confusion should be ameliorated by the second even more striking fact; that once a slight adaptation exists, it is guaranteed to be passed on to the offspring.

As Gregor Mendel hammered the mechanism for natural selection in place a few years after Darwin with his discovery of genetic inheritance, it became clear that not every one of the offspring may acquire the adaptation. The exact pattern may be complex. But even if some of the offspring acquire it, the adaptation is then guaranteed to confer reproductive fitness and will be passed on. This fact should demolish a belief that even serious students of evolution, and certainly laymen, have in the beginning; that there is something very uncertain about evolution, that it depends too much on "chance". The key to circumvent these misgivings is to realize the above fact, that while adaptations (later attributed to mutations) may arise by chance, once they arise, their proliferation into future generations is virtually certain. Natural selection will ensure it. That in my mind is perhaps Darwin's greatest achievement; he finally found a mechanism for evolution that guarantees its existence and progress. As for the struggle for survival, it certainly does not mean that it results in non-cooperation and purging of other individuals. As examples in the living world now document more than convincingly, the best reproductive fitness can indeed come about through altruistic leanings and cooperative behavior.

Every one of these factors and facts was detailed and explained by Darwin in "The Origin of Species", one of the very few original works of science which remain accessible to the layman and which contained truths that have not needed to be modified in their basic essence even after a hundred and fifty years. It was readable even when I picked it up as a callow young college student. No one who approaches it with an open mind can fail to be taken with its simplicity, elegance and beauty. One of the most extraordinary things about Darwin and something that continues to stupefy is how right the man was even when he lacked almost all the modern tools that have since reinforced basic evolutionary ideas. As one of Darwin's intellectual descendants, the biologist E O Wilson says, it is frustrating for a modern biologist to discover an evolutionary idea through his work, and then go back a hundred and fifty years and discover that the great man had hinted at it in his book.

And yet as Darwin himself would have acknowledged, there is much in the book that needed to be modified, there was much that he could not explain. Darwin had no inkling of genes and molecular biology, nor could he come up with a convincing mechanism that explained the sheer age of the earth required for evolutionary processes to work their charm (the mechanism was found later with the discovery of radioactivity). The exact mechanism of passing on adapted characteristics was unknown. Major fossils of primates and humanoid ancestors had yet to be discovered. Quite importantly, random genetic drift which is completely different from natural selection was later discovered as another process operating in evolution. The development of viral and bacterial resistance in causing diseases like AIDS finally brought evolution to the discomfort of the masses. It was only through the work of several evolutionary biologists and geneticists that Darwin finally became seamlessly integrated with the understanding of life in the middle twentieth century. Genomics has now proven beyond a shade of doubt that we truly are one with the biosphere. But in the absence of all these developments, it is perhaps even more remarkable how many of Darwin's ideas still ring true.

There is another factor that shines through in "The Origin"; Darwin's remarkable modesty. One would have to search very hard in history to find a scientist who was both as great and as modest. Newton may yet be the greatest scientist in history, but he was nothing if not a petty, bitter and difficult man. Darwin in contrast was a symbol of kindly disposition. He doted on his children and told them stories. He loved and respected his wife even though their religious views gradually grew more distanced. His written correspondence with her was voluminous and fond. His correspondence with his collaborators, even those who disagreed, was cordial and decent. Never one for contentious public debates, he let his "bulldog" Thomas Henry Huxley fight his battles; one of them with Bishop Samuel Wilberforce ended in a famous showdown when the Bishop inquired whether it was through his father or mother that Huxley had descended from an ape, and Huxley countered that he would rather descend from an ape than from the Bishop. Darwin stayed away from these entertaining confrontations; as far as he was concerned, his magisterial work was done and he had no need for public glory. To the end of his life this kind and gentle man remained a wellspring of modest and unassuming wonder. His sympathetic, humane and sweet personality continues to delight, amaze and inspire reverence to this day.

In the later stages of his life Darwin became what he himself labeled as an agnostic but what we today would probably call an atheist. His research into the progression of life and the ruthless struggle that it engenders made it impossible for him to justify a belief in a paternal and loving deity. He was also disillusioned by popular conceptions of hell as a place where non-believers go; Darwin's father was a non-believer and yet a good doctor who treated and helped hundreds of human beings. Darwin simply could not accept that a man as kind as his father would go to hell simply for not believing in a version of morality, creation and life trotted out in a holy book. Probably the last straw that convinced Darwin of the absurdity of blind faith was the untimely death of his young daughter Annie who was his favorite among all the children. According to some accounts, after this happened, Darwin stopped even his cursory Sunday trips to church and was satisfied to take a walk around it while not at all minding his wife and children's desire to worship inside.

The second fact is also in tune with Darwin's kind disposition; he admittedly had no problem reconciling the personal beliefs of other people with his conviction about their falsity. Darwin's tolerance of people's personal faith and his unwillingness to let his own work interfere in his personal life and friendships is instructive; to the end he supported his local parish and was close friends with a cleric, the Reverend John Innes. Darwin's example should keep reminding us that it is actually possible to sustain close human bonds while having radically different beliefs, even when one of these is distinctly true while the other one is fantasy. Nurturing these close bonds with radical scientific ideas that would change the world for ever, Charles Darwin died on April 19, 1882, a content and intellectually satisfied man.

To follow, nourish and sustain his legacy is our responsibility. In the end, evolution and Darwin are not only about scientific discovery and practical tools arising from them, but about a quest to understand who we are. Religions try to do this too, but they seem to be satisfied with explanations for which there is no palpable evidence and which seem to be often contradictory and divisive. It is far better to imbibe ourselves with explanations that come from ceaseless exploration and constant struggle; the very means that constitute these explorations are then much more alluring and quietly fulfilling than any number of divergent fantasies that can only promise false comfort. And these means promise us a far more humbling and yet grand picture of our place in this world. Especially in today's age when the forces of unreason threaten to undermine the importance of the beautiful simplicity in the fabric of life that Darwin and his descendants have unearthed, we owe it to Charles Darwin to continue to be amazed at the delightful wonder of the cosmos and life. We owe it to the countless shapes and forms of life around us with whom we form a profoundly deep and unspoken connection. And we owe it to each other and our children and grandchildren to keep rationality, constructive skepticism, freedom and questioning alive.


I don't often write about Darwin and evolution here for a simple reason; there is literally an army of truly excellent authors and bloggers who pen eloquent thoughts about these subjects and the amount of stuff published about him will fill up entire rooms. You could probably put together a thousand-page encyclopedia simply listing works on Darwin. His original work as stated above is still very readable. Every aspect of his life and work - the scientific, the psychological, the social, the political and the personal - has been exhaustively analyzed. I have certainly not sampled more than a fraction of this wealth of knowledge, but based on my interest in Darwin and selected readings, I can recommend the following.

For what it's worth, if you want to have the best overview of Darwin's life after he came home from his voyage on the Beagle, I think nothing beats the elegance of language and wit of David Quammen's "The Reluctant Mr. Darwin". Quammen has exhaustively researched Darwin's post-Beagle life and work, and no one I have come across tells the story with such articulate enthusiasm, fondness and attention to detail in a modest sized book.

Janet Browne's magisterial biography of Darwin is definitely worth a look if you want to get all the details of his life. Browne pays more attention to the man than the science, but her work is considered the authoritative work, and there are nuggets of eloquence in it.
As a student in high school I was inspired by Alan Moorehead's "The Voyage of the Beagle" noted above which combines an account of Darwin's life and voyage with beautiful and full page illustrations.
Geting to evolution now, there's an even bigger plethora of writings. Several books have captured my attention in the last many years. I don't need to extol the great value of any (and indeed, all) of Richard Dawkins' books. If you ask me which ones I like best, I would suggest "The Selfish Gene", "The Extended Phenotype", "Climbing Mount Improbable" and "The Blind Watchmaker". For a journey into our ancestral history, Dawkins' strikingly illustrated "The Ancestor's Tale" is excellent. Speaking of ancestral history, Neil Shubin's "Our Inner Fish" charts a fascinating course that details how our body parts come from older body parts that were present in ancient organisms. So does his recent book "The Universe Within". Shubin provides scores of interesting tidbits; for instance he tells us how hernias are an evolutionary remnant. Another great general introduction to evolution is Carl Zimmer's "Evolution"; Zimmer has also recently written excellent books on bacteria and viruses in which evolution plays a central theme.

No biologist- not even Dawkins- has had the kind of enthralling command over the English language as Stephen Jay Gould. We lost a global treasure when Gould died at age sixty. His books are relatively difficult to read and for good reason. But with a little effort they provide the most sparkling synthesis of biology, history, culture and linguistic exposition that you can ever come across. And all of them are meticulously researched, although Gould’s political ideology sometimes has to be watched out for. Out of all these I personally would recommend "Wonderful Life", and if you want to challenge yourself with a really difficult unedited original manuscript written just before he died, "The Hedgehog, the Fox and The Magister's Pox". His collections of essays - "Full House" and "Eight Little Piggies" for instance - are also outstanding.

I don't want to really write about books which criticize creationism since I don't beat that horse much, but if you want to read one book about the controversy that rips apart intelligent design proponents' arguments, read Ken Miller's "Finding Darwin's God" which makes mincemeat out of the usual "arguments from complexity" trotted out by creationists which are actually "arguments from personal incredulity". He also has a book covering the Dover Trial. I have only browsed it but it seems to be equally good read. What makes Miller a tough target for creationists (and puzzling for evolutionists) is that he is a devout Christian.

This is an updated and revised version of a post originally written on Darwin's 200th birthday.

Why the world needs more Leo Szilards

The body of men and women who built the atomic bomb was vast, diverse, talented and multitudinous. Every conceivable kind of professional - from theoretical physics to plumber - worked on the Manhattan Project for three years over an enterprise that spread across the country and equaled the US automobile industry in its marshaling of resources like metals and electricity.

The project may have been the product of this sprawling hive mind, but one man saw both the essence and the implications of the bomb, in both science and politics, long before anyone else. Stepping off the curb at a traffic light across from the British Museum in London in 1933, Leo Szilard saw the true nature and the consequences of the chain reaction six years before reality breathed heft and energy into its abstract soul. In one sense though, this remarkable propensity for seeing into the future was business as usual for the Hungarian scientist. Born into a Europe that was rapidly crumbling in the face of onslaughts of fascism even as it was being elevated by revolutionary discoveries in science, Szilard grasped early in his youth both a world split apart by totalitarian regimes and the necessity of international cooperation engendered by the rapidly developing abilities of humankind to destroy itself with science. During his later years Szilard once told an audience, "Physics and politics were my two great interests". Throughout his life he would try to forge the essential partnership between the two which he thought was necessary to save the human species from annihilation.

A few years ago, physicist and author William Lanouette brought out a new, revised edition of his definitive, sensitive and sparkling biography of Szilard. It is essential reading for those who want to understand the nature of science, both as an abstract flight into the deep secrets of nature and a practical tool that can be wielded for humanity's salvation and destruction. As I read the book and pondered Szilard's life I realized that the twentieth century Hungarian would have been right at home in the twenty-first. More than anything else, what makes Szilard remarkable is how prophetically his visions have played out since his death in 1962, all the way to the year 2014. But Szilard was also the quintessential example of a multifaceted individual. If you look at the essential events of the man's life you can see several Szilards, each of whom holds great relevance for the modern world.

There's of course Leo Szilard the brilliant physicist. Where he came from precocious ability was commonplace. Szilard belonged to the crop of men known as the "Martians" - scientists whose intellectual powers were off scale - who played key roles in European and American science during the mid-twentieth century. On a strict scientific basis Szilard was perhaps not as accomplished as his fellow Martians John von Neumann and Eugene Wigner but that is probably because he found a higher calling in his life. However he certainly did not lack originality. As a graduate student in Berlin - where he hobnobbed with the likes of Einstein and von Laue - Szilard came up with a novel way to consolidate the two microscopic and macroscopic aspects of the science of heat, now called statistical mechanics and thermodynamics. He also wrote a paper connecting entropy and energy to information, predating Claude Shannon's seminal creation of information theory by three decades. In another prescient paper he set forth the principle of the cyclotron, a device which was to secure a Nobel Prize for its recognized inventor - physicist Ernest Lawrence - more than a decade later.

Later during the 1930s, after he was done campaigning on behalf of expelled Jewish scientists and saw visions of neutrons branching out and releasing prodigious amounts of energy, Szilard performed some of the earliest experiments in the United States demonstrating fission. And while he famously disdained getting his hands dirty, he played a key role in helping Enrico Fermi set up the world's first nuclear reactor.
Szilard as scientist also drives home the importance of interdisciplinary research, a fact which hardly deserves explication in today's scientific world where researchers from one discipline routinely team up with those from others and cross interdisciplinary boundaries with impunity. After the war Szilard became truly interdisciplinary when he left physics for biology and inspired some of the earliest founders of molecular biology, including Jacques Monod, James Watson and Max Delbruck. His reason for leaving physics for biology should be taken to heart by young researchers - he said that while physics was a relatively mature science, biology was a young science where even low hanging fruits were ripe for the picking.

Szilard was not only a notable theoretical scientist but he also had another strong streak, one which has helped so many scientists put their supposedly rarefied knowledge to practical use - that of scientific entrepreneur. His early training had been in chemical engineering, and during his days in Berlin he famously patented an electromagnetic refrigerator with his friend and colleague Albert Einstein; by alerting Einstein to the tragic accidents caused by leakage in mechanical refrigerators, he helped the former technically savvy patent clerk put his knowledge of engineering to good use (as another indication of how underappreciated Szilard remains, the Wikipedia entry on the device is called the "Einstein refrigerator"). Szilard was also finely attuned to the patent system, filing a patent for the nuclear chain reaction with the British Admiralty in 1934 before anyone had an inkling what element would make it work, as well as a later patent for a nuclear reactor with Fermi.

He also excelled at what we today called networking; his networking skills were on full display for instance when he secured rare, impurity-free graphite from a commercial supplier as a moderator in Fermi's nuclear reactor; in fact the failure of German scientists to secure such pure graphite and the subsequent inability of the contaminated graphite to sustain fission damaged their belief in the viability of a chain reaction and held them back. Szilard's networking abilities were also evident in his connections with prominent financiers and bankers who he constantly tried to conscript in supporting his scientific and political adventures; in attaining his goals he would not hesitate to write any letter, ring any doorbell, ask for any amount of money, travel to any land and generally try to use all means at his disposal to secure support from the right authorities. In his case the "right authorities" ranged, at various times in his life, from top scientists to bankers to a Secretary of State (James Byrnes), a President of the United States (FDR) and a Premier of the Soviet Union (Nikita Khrushchev).

I am convinced that had Szilard been alive today, his abilities to jump across disciplinary boundaries, his taste for exploiting the practical benefits of his knowledge and his savvy public relations skills would have made him feel as much at home in the world of Boston or San Francisco venture capitalism as in the ivory tower.

If Szilard had accomplished his scientific milestones and nothing more he would already have been a notable name in twentieth century science. But more than almost any other scientist of his time Szilard was also imbued with an intense desire to engage himself politically - "save the world" as he put it - from an early age. Among other scientists of his time, only Niels Bohr probably came closest to exhibiting the same kind of genuine and passionate concern for the social consequences of science that Szilard did. This was Leo Szilard the political activist. Even in his teens, when the Great War had not even broken out, he could see how the geopolitical landscape of Europe would change, how Russia would "lose" even if it won the war. When Hitler came to power in 1933 and others were not yet taking him seriously Szilard was one of the few scientists who foresaw the horrific legacy that this madman would bequeath Europe. This realization was what prompted him to help Jewish scientists find jobs in the UK, at about the same time that he also had his prophetic vision at the traffic light.

It was during the war that Szilard's striking role as conscientious political advocate became clear. He famously alerted Einstein to the implications of fission - at this point in time (July 1939) Szilard and his fellow Hungarian expatriates were probably the only scientists who clearly saw the danger - and helped Einstein draft the now iconic letter to President Roosevelt. Einstein's name remains attached to the letter, Szilard's is often sidelined; a recent article about the letter from the Institute for Advanced study on my Facebook mentioned the former but not the latter. Without Szilard the bomb would have certainly been built, but the letter may never have been written and the beginnings of fission research in the US may have been delayed. When he was invited to join the Manhattan Project Szilard snubbed the invitation, declaring that anyone who went to Los Alamos would go crazy. He did remain connected to the project through the Met Lab in Chicago, however. In the process he drove Manhattan Project security up the wall through his rejection of compartmentalization; throughout his life Szilard had been - in the words of the biologist Jacques Monod - "as generous with his ideas as a Maori chief with his wives" and he favored open and honest scientific inquiry. At one point General Groves who was the head of the project even wrote a letter to Secretary of War Henry Stimson asking the secretary to consider incarcerating Szilard; Stimson who was a wise and humane man - he later took ancient and sacred Kyoto off Groves's atomic bomb target list - refused.

Szilard's day in the sun came when he circulated a petition directed toward the president and signed by 70 scientists advocating a demonstration of the bomb to the Japanese and an attempt at cooperation in the field of atomic energy with the Soviets. This was activist Leo Szilard at his best. Groves was livid, Oppenheimer - who by now had tasted power and was an establishment man - was deeply hesitant and the petition was stashed away in a safe until after the war. Szilard's disappointment that his advice was not heeded turned to even bigger concern after the war when he witnessed the arms race between the two superpowers. In 1949 he wrote a remarkable fictitious story titled 'My Trial As A War Criminal' in which he imagined what would have happened had the United States lost the war to the Soviets; Szilard's point was that in participating in the creation of nuclear weapons, American scientists were no less or more complicit than their Russian counterparts. Szilard's take on the matter raised valuable questions about the moral responsibility of scientists, an issue that we are grappling with even today. The story played a small part in inspiring Soviet physicist Andrei Sakharov in his campaign for nuclear disarmament. Szilard also helped organize the Pugwash Conferences for disarmament, gave talks around the world on nuclear weapons, and met with Nikita Khrushchev in Manhattan in 1960; the result of this amiable meeting was both the gift of a Schick razor to Khrushchev and, more importantly, Khrushchev agreeing with Szilard's suggestion that a telephone hot-line be installed between Moscow and Washington for emergencies. The significance of this hotline was acutely highlighted by the 1962 Cuban missile crisis. Sadly Szilard's later two attempts at meeting with Khrushchev failed.

After playing a key role in the founding of the Salk Institute in California, Szilard died peacefully in his sleep in 1964, hoping that the genie whose face he had seen at the traffic light in 1933 would treat human beings with kindness.

Since Szilard the common and deep roots that underlie the tree of science and politics have become far clearer. Today, when science and facts seem under attack and where truth constantly threatens to become a casualty, we need scientists like Szilard to stand up for science every time a scientific issue political ideology. When Szilard pushed scientists to get involved in politics it may have looked like an anomaly, but today it's not simply optional. All of us need to be involved in small and big ways. At the same time, it's worth noting that Szilard's motto for the interaction of science with politics was often one of accommodation. He was always an ardent believer in the common goals that human beings seek, irrespective of the divergent beliefs that they may hold. He was also an exemplar of combining thought with action, projecting an ideal meld of the idealist and the realist. Whether he was balancing thermodynamic thoughts with refrigeration concerns or following up political idealism with letters to prominent politicians, he taught us all how to both think and do. As interdisciplinary scientist, as astute technological inventor, as conscientious political activist, as a troublemaker of the best kind, Leo Szilard leaves us with an outstanding role model and an enduring legacy. It is up to us to fill his shoes.

Born on this day: Physicist Emilio Segrè, who changed the direction of the Manhattan Project

The road to mutually assured destruction unintentionally started in 1944, at the end of a mountain trail with flowers and snakes, with a man called The Basilisk. But he didn't know it then. In the fall of 1944, the sprawling, top secret atomic bomb project at Los Alamos faced a huge crisis. Ever since the laboratory had been set up in 1943, it had been working on two kinds of bombs. One would work on uranium which was being separated using cyclotrons at Oak Ridge, Tennessee. The other would work on plutonium which was being created in nuclear reactors in Hanford, Washington. The basic design for nuclear weapons had been worked out in 1942 and was simple in principle: slam together two lumps of uranium and plutonium using a "gun" so that they come together to create a critical mass, and the ensuing exponential chain reaction would guarantee a tremendous explosion. In 1944 it seemed like that design was well underway for both uranium and plutonium. 

Then in the fall of 1944 came news that this design would be useless for plutonium. Millions of 1944 dollars and the resources of thousands of workers and scientists were at stake. The laboratory's director, Robert Oppenheimer, felt so embattled that he briefly considered resigning. The man who delivered this bad news to Oppenheimer and the others was Emilio Segrè.

Emilio Segrè who was born today in 1905 was a member of the small band of brilliant physicists led by Enrico Fermi in Rome in the 1930s. Each member of the team had a nickname. Fermi was "The Pope" because of his infallible knowledge of physics. Segrè's sharp tongue and quick mind made others name him "The Basilisk". Segrè was part of all of Fermi's key experiments, including the ones leading up to his Nobel Prize. Segrè himself won a Nobel Prize later for his discovery of the antiproton. But in 1944, he must have been seen as the bearer of bad news. This news, however, galvanized the lab and forced it to explore a novel idea that became the basis of nuclear arsenals around the world.

At Los Alamos Segrè was assigned the task of measuring the neutron properties of uranium and plutonium and their byproducts. Because his work involved large quantities of potentially dangerous neutrons, he was put in a cabin several miles removed from the main laboratory. The cabin was at the end of a trail populated by rattlesnakes and beautiful flowers. What Segrè discovered in that cabin was that the plutonium bomb would fizzle out prematurely if it were assembled by the gun technique. Premature explosion had been considered by the Los Alamos scientists and was not thought to be a serious issue. The probability of premature explosion depended on the rate of neutrons spontaneously generated by the fissile mass. Left to themselves, uranium and plutonium have a small but fixed background rate of spontaneous neutron emission. During critical assembly, a high rate of neutron emission meant that the fission would start occurring before the critical mass was reached, and the result would at best be a small, inefficient explosion. It was thus essentially a contest between this rate and the speed with which the two pieces were brought together that would decide the fate of the bomb.

Physicists were not ignorant of the rate of spontaneous fission in uranium and plutonium and in fact had measured it to reassure themselves that it would not matter. However, they had reached this conclusion based on experiments on small quantities of uranium-238 and plutonium-239 produced in cyclotrons built by Ernest Lawrence's team at Berkeley. However cyclotrons cannot be used to make plutonium in any measurable quantity. By the time the Manhattan project picked up steam, Pu-239 was being produced in gram quantities in the nuclear reactors at Hanford.

What the physicists had not realized was the role that a rogue isotope of plutonium would play in thwarting their plans for a gun type bomb. It turns out that the spontaneous fission depends on the precise isotope under consideration. Plutonium-239 is produced by bombarding uranium-238 by neutrons. However there is another isotope of plutonium that is produced in the process: Pu-240. Pu-240 has a much greater spontaneous fission rate than Pu-239. The net rate depends on the ratio of the two isotopes.

The crucial discovery which Segrè made was that reactor-produced plutonium had a much higher percentage of Pu-240 than cyclotron-produced plutonium and therefore a much higher spontaneous fission rate. All the spontaneous fission rate measurements done by the physicists on cyclotron-produced plutonium were therefore useless for reactor-produced plutonium. The high spontaneous fission rate in reactor-produced plutonium would doom a gun type plutonium weapon to a premature fizzle. Chemical separation of the Pu-240 from the Pu-239 was also out of the question: chemically separating uranium 235 (the fissile isotope of uranium) from the more abundant uranium 238 was already a mammoth undertaking that strained the country's resources. Separating Pu-240 from Pu-239 would be almost impossible.

Segrè's bad news plunged the laboratory in a big crisis. Fortunately there was a physicist named Seth Neddermeyer who had proposed a backup alternative for assembling a plutonium bomb. This alternative was implosion and consisted of rapidly squeezing a sphere of plutonium inwards to criticality. Implosion would be much faster than a gun type assembly and the spontaneous fission rate would not be a problem. The laboratory was rapidly reorganized by Oppenheimer and Leslie Groves to make implosion a high priority.

Implosion was still a risky endeavor, so the first atomic bomb test that the world saw on July 16, 1945 was of the implosion bomb. Less than a month later, Nagasaki was destroyed by the same kind of bomb. And ten years later the United States and other countries were building terrible hydrogen bombs in which plutonium implosion was an essential mechanism. Since then thousands of hydrogen bombs have been added to the world's nuclear arsenals, placing humanity at the risk of instant obliteration. What Segre thought about this is lost to history.