Field of Science

Why healthcare might not have benefited from a Steve Jobs-style disruptor

Steve Jobs holding a non-emergent object
The website Stat has an article titled "Why healthcare needs a Steve Jobs-style disruptor". The article which is by a physician named Damon Ramsey focuses on Jobs' ability to rethink design and to reinvent many of the ways in which we interact with the digital world. Ramsey thinks that Jobs would have had much to offer our current healthcare system with its convoluted regulatory mechanisms and information systems; it draws inspiration from an account by Jobs's sister in which she recounts him sketching out new designs for hospital systems even on his deathbed.

It's a pleasing vision, and Jobs was certainly a visionary who will go down as one of the most important people in the history of modern civilization, but I actually don't think that someone like him will be a disruptor in healthcare. The main reason is that healthcare is very different from electronics and computer science in terms of the complexity and predictability of its essential elements. Jobs might certainly have been useful in designing some of the electronic interfaces in hospitals, but that's a very limited part of the system. A major part of healthcare lies in the process of drug discovery, and in this vast arena I think Jobs would have been far less effective. In fact his working philosophy might have even been a hinderance.

Jobs' main achievement was to make computers and other electronics easy to use: even more than Bill Gates he brought computer technology to the masses. He was probably the best interface designer of his time, and he also had a genuine capacity to see the interconnections between various aspects of software and hardware.

And yet Jobs was designing his iPhones and Macs based on extremely well understood principles of software and hardware engineering. He certainly needed to think creatively in order to understand how to make these principles play well with each other, but he did not have to worry about the truth of the principles themselves. In addition the systems he was looking at were very modular, so most creative ways to package them together would work since they would not suffer from unexpected interactions. Put simply, there was very little chance that Jobs's devices would blow up.

In contrast, biological systems are startlingly non-modular and non-linear. Getting them to work is not a matter of designing interfaces. Not only do we not yet understand how to discover new drugs well, but we don't know how to do that because we lack an understanding of the human body to begin with. The "software" in case of drug discovery would be the genome which dictates the actual workings of the cell. The "hardware" is the universe of proteins that serve as workhorses for regulating every single important process in our body, from reproduction to the immune response. Unlike a microprocessor in which the welding together of software and hardware is a matter of engineering, welding together the software and hardware of the human body is currently impossible, simply because we are ignorant both about the nature of these components and their interactions.

I think Steve Jobs would have been completely befuddled if he had been confronted with the task of reinventing drug discovery. In fact one wonders if he would have fundamentally misunderstood the problem; it's worth noting that some people think that he died an early death because he wasted critical time in refusing standard chemotherapy for his cancer, opting to pursue untested "alternative" cures instead (although he does seem to have regretted his decision later). Knowing what we do about his philosophy, I get the feeling that he preferred the simple to the complex, the intuitive to the un-intuitive and the predictable to the chaotic. iPads and Macs are all of the former, biological systems are all of the latter. Notwithstanding his drive and intelligence, a Steve Jobs in drug discovery might have likely have taken his team down some very dark and interminable alleys.

The challenges that Jobs met were very impressive, but they were primarily engineering challenges which could be solved by putting together a bunch of smart people in a room and giving them enough money. The systems he was looking at were largely homogeneous, did not involve too much unexpected feedback and were non-emergent. The challenges that healthcare faces - and this includes the regulatory, economic and informational challenges which the article mentions - deal with highly emergent systems composed of very unexpected feedback and non-linear phenomena arising from extremely heterogeneous and diverse players. Solving those systems is not a matter of designing a better mousetrap, it's one of understanding what a mouse is in the first place. Steve Jobs would not exactly have been the right candidate for unraveling that particular pickle.

Here's that prospective drug design study you asked for...

Improving ligand binding selectivity by
electrostatic optimization
Here's a rare beast: a set of ten prospective molecular design studies from Roche, mostly made possible by a combination of modeling and crystallography. It's a valuable contribution to the field in my opinion, especially since people are always asking about prospective successes of molecular modeling and because companies are reluctant to divulge that kind of data. I especially liked the authors' emphasis on qualitative rather than quantitative aspects of modeling approaches; this is a subtlety not always appreciated by critics and is in fact one that goes to the heart of chemistry as a predictive science.

The review deals with ten early discovery projects involving diverse targets where a variety of modeling techniques were used to improve affinity, selectivity, solubility, pharmacokinetic properties and a bunch of other desired druglike characteristics.

Some of the applications (filling hydrophobic pockets with small aromatic substituents or designing 'steric bumps' to get selectivity against other protein subtypes) are relatively straightforward while others (scaffold hopping, getting affinity by generalized electrostatic optimization, homology modeling) are more challenging and interesting. Here is a table displaying target type, approach and impact of the various protocols.



Most of the projects benefited from early crystallographic data and in fact make a case for getting this kind of data as early as possible, even when you have relatively weak hits (as I have found out through experience, you can get a perfectly reasonable co-crystal structure with a 10 ┬ÁM hit). At the same time, crystallographic data can sometimes actually surprise and tell you where you went wrong; for instance there is an example of a tryptase inhibitor whose scaffold was redesigned and found to be favorable through modeling, only to realize from the crystal structure that the scaffold was in fact flipped through 180 degrees. That particular example illustrates that occasionally you can get the right answer through the wrong process, although knowing this fact as early as possible itself is quite useful.

Homology models pose a particular challenge for modeling; as I described in a previous post, a small change in the torsional angle of even a single residue can impact your ligand binding prediction. In this review the authors make a good case for using homology models even as crude aids. The crux of the matter is generating good hypotheses, and even crude models can help us do that. In this particular case, based on an initial lead, the model was used to predict a position to add polarity to the molecule. This led to a sulfonamide being replaced by an amide and a spiro ring system which retained potency and good properties.

The last few cases deal with ligand-based optimization in which the lack of 3D protein structural information required the use of 3D ligand overlays. The authors make another important point here: in one of their case studies they used a simple 'shape envelope' instead of detailed QSAR analysis to guide ligand design. As they point out, doing ligand overlaps for detailed QSAR analysis can be very tricky; the devil is in the molecular details and small differences in atom placement might throw you off. There have been several articles bemoaning the limitations of QSAR in recent years, so this sounds like a safe thing to do.

There are some obvious limitations to using such techniques which I am sure the authors are well aware of. Their list features hits, not misses, and many of the techniques which may have worked in these particular cases may not have worked in others. In addition, the review does not explore whether there is in fact a causal relationship between the technique used and the result obtained since other hypotheses aren't always explored. Nevertheless, it is unrealistic to expect researchers to try out every single hypotheses in a project, and what I find most useful in any case about this article is that it provides us with a checklist of things to try and conjectures to test. Science is about ideas, not answers, and as with anything else in drug discovery, if one thing fails you just hold your head high and try another.

The review concludes with a set of lessons which I think are valuable guidelines to think about in any molecular design project. The importance of the first lesson cannot be overemphasized: qualitative statements can often be more useful than quantitative analysis. I can't say this statement doesn't make me beam with pleasure. It is an antidote to those who think of chemistry as physics and expect quantitative predictions. As the case studies here demonstrate, not only are quantitative predictions often a fool's errand but in many cases they aren't even necessary. 

This is a point that I think is often lost on the critics of molecular modeling. The goal of modeling is not just to make detailed predictions; it is to cull unnecessary directions of inquiry, save labor, guide researchers into previously unexplored areas of thinking and generate hypotheses that can be quickly made and tested. It is to help think about molecular design in the broadest possible way. This is value that goes far beyond being able to rank order your latest deck of hits, and it's something to keep in mind the next time an experimentalist asks you whether you can do that.

The other lessons are also worth remembering: use molecular design to shape medicinal chemistry space, employ the principle of parsimony (and Occam's razor), annotate whenever possible (even simple visualization of molecular interactions can be eye-opening), realize the domain of applicability of your techniques (occasionally by stress-testing them) and perhaps most importantly, stay close to experiment. That last part is something all good modelers should know; don't use quantum chemical torsional calculations when you can look up features in the CSD, don't use homology models when you can convince the crystallographer to get you even a low-resolution crystal structure, don't use fancy scaffold morphing software when the medicinal chemist tells you that he or she can rapidly make alternative scaffolds. 

As the review concludes:
"Best practice in molecular design is best practice in all sciences: a relentless focus on clarity, simplicity and good experimental design. What is special about molecular design is the need to build solid hypotheses and to simultaneously foster creative thinking in medicinal chemistry. If we accept this, our focus may shift from the many semi-quantitative prediction tools we have to methods supporting this creative process. Further improvements in computational methods may then have less to do with science than with good software engineering and interface design. The tools are a just means to an end. Good science happens when they are appropriately employed."
A means to an end indeed. Modeling is a poor master but can be a very useful servant.

Carlo Rovelli's "Seven Brief Lessons on Physics": A beautiful and poignant meditation on the laws of physics and our place in the cosmos

Every once in a while it's a good idea to stand back from the daily necessities of our lives and look back and marvel at what we as human beings have accomplished in our understanding of ourselves and our universe. In very few instances is this wonder more apparent than in an appreciation of the discoveries that physics has made regarding space and time.

In this short and highly readable book, Italian physicist Carlo Rovelli leads us through a tour of what he thinks are seven of the foremost ideas (or "lessons') in physics. These are ideas which have not just furthered our understanding of our material world but which have also expanded our consciousness and connected us to our origins and future. Rovelli’s writing is often poignant and beautiful, simple and without frills and from the heart, and I would be lying if I said the experience wasn't uplifting. Personally I would have included an extra eighth lesson on chaos theory and complexity since I think those are going to be key scientific issues in the 21st century. Also, there is little new per se in here which would not be familiar to physics aficionados. But as it stands Rovelli's offering is a marvelous feast which should ignite a renewed sense of inspiration regarding the reach and beauty of science even in hardened veterans.

The first lesson is about Einstein's general theory of relativity which saw yet another towering validation this year with the discovery of gravitational waves. The Russian physicist Lev Landau called it the "most beautiful theory" and I would say there would be few contenders for that title. The basic equation of the theory fits on a napkin, and the essentials of the framework are both startling and elegant. As Rovelli explains, Einstein's major breakthrough was to realize that Newton's gravitational field is not a field at all but is spacetime itself. That one insight suddenly elevated all of physics to a completely new level and it opened up previously unimaginable vistas - black holes, neutron stars, radio astronomy, the Big Bang - to deep exploration. Here's Rovelli on the essential craziness of Einstein's equation: "Within this equation there is a teeming universe. And here the magical richness of the theory opens up into a phantasmagorical succession of predictions that resemble the delirious ravings of a madman, but which have all turned out to be true."

The second lesson concerns the other big revolution of twentieth century physics - quantum mechanics. Relativity is astonishing but its basic tenets are easy to understand. In contrast, even the basic tenets of quantum theory - wave particle duality, entanglement, the uncertainty principle - have left even the theory's great founders befuddled. Quantum mechanics is unique in the history of science as a theory which is spectacularly successful in its practical applications while at the same time continuing to be virtually impenetrable in its philosophical implications. It opened up vast new areas of modern life to understanding; without it computers, chemistry, electronics and molecular biology would be inconceivable. And yet the sheer weirdness of its laws continues to defy every commonsense expectation. Rovelli zeroes in on one of the essential qualities of quantum mechanics when he says that its laws "do not describe what happens to a physical system but only how one physical system affects another". I find it interesting that the same emphasis on the philosophy of interactions which lies at the heart of quantum theory also underlies the science of emergent complex systems like the weather, the stock market, biochemical networks and social networks.

The third chapter talks about the Big Bang theory and the architecture of the cosmos. Rovelli wrote just before the discovery of gravitational waves otherwise he would have included them in his discussion but he talks about many other wonders revealed by Einstein's theory combined with many of the tools of modern physics such as radio telescopes and particle detectors. The culmination of applying relativity to the universe must surely be the discovery of the accelerated expansion of the universe, although the presence of what we call "dark matter" leaves something to be desired.

The fourth lesson tells us how the findings of quantum mechanics led to an explosion of understanding of the building blocks of the cosmos in the postwar years. Quarks and electrons, Higgs bosons and neutrinos all make important appearances in this story. The culmination of all this progress was the Standard Model of particle physics, essentially a kind of periodic table which lists all known particles and their properties. And yet unlike general relativity the Standard Model is incomplete. Many of the particles' parameters are poorly understood, and the model itself is incompatible with general relativity. In addition there are ugly infinities arising in the theoretical treatment of all those particles which have to be tamed by artificially imposed mathematical order. These deficiencies make the Standard Model very much of a model. It is in the Standard Model that we start to glimpse the first troubling signs of how much more we have to discover in fundamental physics. But in trouble lies opportunity and glory, and in one sense the Standard Model only points to the bounty of undiscovered delights which must surely lie ahead.

The fifth lesson tackles one of the greatest scientific facing science, the marriage of general relativity with quantum mechanics; a marriage which as of now seems to end in violent, unholy divorce every time we attempt it. Interestingly there is not a word about string theory, probably because Rovelli himself works on a rival theory called loop quantum gravity. There is a capsule description of the theory which emphasizes again the fact that the framework is less about objects themselves and more about their interconnections. In this case the connections are between tiny quanta of space - which are themselves space.

The sixth lesson takes us on a journey into one of the most exciting frontiers of modern physics: the union of thermodynamics, quantum mechanics and relativity. This union is wondrous and critical because it can help us understand perhaps the deepest question we can ponder: the fact that time seems to flow only in one direction. As Rovelli explains, the arrow of time seems to be inextricably linked with the flow of heat. The second law of thermodynamics and its postulated increase of entropy tracks with the forward arrow of time, although on an individual particle level this arrow is reversible. Figuring out these conundrums of time and thermodynamics will undoubtedly take us into some very novel territory. In this context Stephen Hawking's discovery of radiation emanating from black holes is surely a promising springboard. Time, thermodynamics, quantum mechanics, relativity, statistics; it's all here, and it's all tantalizing.

The seventh lesson ties it all up together as Rovelli talks about the ultimate entity that allows us to figure all this out - the human brain. He ponders the delectable paradox that an entity which is composed of particles and fields and quanta can also decipher its own mysteries. Understanding this self-recursive extrapolation should keep us occupied for as long into the future as we can imagine, and it's also what should make us cherish our unique existence as sentient beings on this planet. And yet, as unique as we are, Rovelli reminds us in closing that our lowly origins from elemental life forms and the ordinariness of our planet, our solar system and our galaxy should not blind us to what might be the greatest lesson of all: humility and wonder.

"Here, on the edge of what we know, in contact with the ocean of the unknown, shines the mystery and the beauty of the world. And it's breathtaking".

On gravitational waves and the virtue of patience

From MIT physicist and science writer Alan Lightman - author of the wonderful "Einstein's Dreams". He is describing how the scientists whose work led to the groundbreaking discovery of gravitational waves this month knew they were in for the long haul when they proposed the pie-in-the-sky project LIGO in the 70s. It also seems to be a message the country needs to embrace in the Era of Quarterly Expectations. (Hat tip: Tom Levenson)
"The world at large, and the United States in particular, has developed an unfortunate need for instant gratification. We live not only in the age of information. We live in the Age of the Now. We grow impatient with printers that cannot churn out 10 pages per minute, or with computer screens that take 30 seconds to boot up. We avoid investing in companies that do not promise payoffs within a few years. Federal research and development, as a fraction of gross domestic product, has been going down and down. Perhaps even our foreign policy has been plagued by a hurried view of the world, seeking immediate results. 
In science, as in many other precincts of the Age of the Now, too often we celebrate the instant discovery, the sudden breakthrough, the quick and glamorous result. Drever, Thorne and Weiss, and the many scientists and institutions that supported their dream, did not seek instant gratification. They had a vision, and they wandered the desert with that vision for 40 years."

When Einstein was wrong: Black holes

In today's New York Times physicist Lawrence Krauss has a rundown of the myriad cases in which even Albert Einstein was wrong about physical reality. His opposition to quantum mechanics was famous, but there were several others including gravitational lensing and  - at the beginning - even gravitational waves.

Curiously however, Krauss does not list what I believe was Einstein's biggest failure after quantum mechanics: his refusal to accept the reality of black holes. This failure is especially staggeringly ironic, since the gravitational waves which were discovered this week (which he did predict and which further confirmed his theory) came from the collision of two black holes (entities whose existence he explicitly rejected).

Months after Einstein put the capstone on his general theory of relativity, a German mathematical physicist serving in the First World War named Karl Schwarzschild applied his theory to the simple case of spacetime around a spherical star. Schwarzschild found that as you approached closer to the star, for a star massive enough you would encounter a region where gravity was so strong that you could not escape from it unless you were moving at the speed of light. Schwarzschild sent his calculations to Einstein who curiously accepted them without protest; they seemed simple and logical.

And yet Einstein never really explored the physical structure of Schwarzschild's solution, nor did he ever accept its profound implications. He regarded the solution mainly as a mathematical abstraction, much as some who did not quite believe in Copernicus's heliocentric model and regarded it only as a mathematical construction. Schwarzschild sadly died of an autoimmune disease on the Russian front in 1916. Einstein himself did not return to Schwarzschild's discovery, and it fell to a succession of young physicists unaffected by the biases of the old guard to investigate it to its logical conclusion.

The most famous among these were Subrahmanyan Chandrasekhar and Robert Oppenheimer. Chandrasekhar's (or Chandra as everyone called him) story is well known. While crossing the ocean from India to England in 1930, the 19 year old Chandra worked out what would happen when white dwarfs exceed a certain mass. This mass, now called the Chandrasekhar limit, would be the limiting mass for a white dwarf to support itself against its internal gravitational pull. Chandra found his own skeptical Einstein in the famous English astronomer Arthur Eddington, who in a meeting in 1935 excoriated him for developing a model of a star which did not make physical sense (to Eddington). Chandra who knew better than to waste his time battling the establishment wisely moved on, seeing his ideas vindicated half a century later.

Oppenheimer turned to gravitational collapse almost as a temporary diversion when he wanted to explore the ramifications of a theory of neutron cores set forth by the Soviet physicist Lev Landau. It was Oppenheimer who first worked out the full implications of a star which was so massive that it could not achieve any kind of steady state against gravitational collapse. In a seminal paper in 1939, Oppenheimer also introduced the now familiar idea of an observer falling past the so-called event horizon. Without calling them as such, Oppenheimer had discovered black holes and singularities, regions of spacetime where gravitational fields becomes infinite.

Ironically, in the same year that Oppenheimer published his calculations Einstein wrote a paper in the journal Annals of Mathematics titled "A Stationary System with Spherical Symmetry Consisting of Many Gravitational Masses". The paper - published only a month after Oppenheimer's - argued against Schwarzschild's conception of singularities. In it he tried to get away from the idea that a single body could create a gravitational field strong enough to cause such a prohibitive warping of spacetime. Instead he tried to replace such a single body with a collection of bodies exhibiting spherical symmetry. The crux of Einstein's argument that such a system would have to rotate at the speed of light in order to exhibit singularities. Needless to say Einstein was deeply mistaken, and the 1939 paper displayed exactly the kind of mathematical modeling free of physical reality that he thought Schwarzschild's equations for singularities did.

After the war both Oppenheimer and Einstein worked together at the Institute for Advanced Study in Princeton. There is no evidence indicating that they ever discussed black holes or their respective papers from 1939; there is no evidence that Oppenheimer objected to Einstein's paper or that Einstein explicitly told Oppenheimer that he rejected his conclusions. But what was happening was worse than opposition: it was indifference. Just like Einstein Oppenheimer lost all interest in black holes after 1939 and refused to have any discussion about them, although as their inventor he putatively at least believed in them. The two physicists who had been scientific revolutionaries in their younger days became arch conservatives in their older years.

It is a delicious reversal of fortune that the same black holes that Einstein explicitly rejected have been found to contain some of the deepest mysteries of physics, encompassing not just relativity but also quantum mechanics, thermodynamics and information theory. And now with the discovery of gravitational waves from colliding black holes, the scientific children which Einstein disowned have come back to smile at their father and say, "I told you so." This is irony of the highest order, and I suspect that Einstein with his great sense of irony about science and history would actually have enjoyed it.

Gravitational waves, the man behind them, and two of the deepest puzzles confronting humanity

As we rightly celebrate the amazing discovery of gravitational waves announced yesterday amidst much fanfare, it’s critical to recognize the work of a stunning diversity of scientists, engineers, technicians and yes, even politicians, who poured forth sweat, toil and tears over more than twenty years to bring to fruition a measurement of almost unimaginable precision and sensitivity. Few quantities were ever unearthed from the soul of the universe with more care and patience.
And yet it’s equally paramount to step back for a moment and yet again stand in awe of the man who started it all and appreciate what exactly he did. Almost a hundred years ago Einstein put the finishing touches on his so-called field equations which described gravity in terms of the curvature of spacetime. It's an equation which can easily fit on a handkerchief, and yet one whose scope extends over a range of scales which beggars belief, from right here outside earth to the swirling dance of black holes to the entire large-scale structure of the universe. Even as they sat quietly in our textbooks and on our blackboards, those few symbols were orchestrating the workings of planets, galaxies and nebulae like a conductor wielding a baton whose length stretched across the entire universe.
Millions of man hours since 1915 have been spent in verifying, testing, extending and stretching every single aspect of those few scribbles, in bringing the accumulated wisdom of two thousand years of building machines and manipulating equations to bear on fulfilling one man’s amazing flights of fancy down to sixteen decimal places. Every one of those hours has validated that man and his fellow human beings’ dreams beyond any reasonable doubt. A rider on a light beam, a flash of awesome insight, a stroke of the pen and suddenly, a key that opened the door to an entire hidden reality filled with hitherto unimaginable wonders, some of which even the maker of that key did not believe in – black holes, neutron stars, gamma ray bursts, gravitational waves.
The grand challenge before us now is twofold. The first, longstanding one is to understand how it can possibly be that those few squiggles on a handkerchief describe not only the world that we know but the imagined future that will impinge on our collective consciousness for years to come; it is to figure out what Einstein’s contemporary Eugene Wigner called “the unreasonable effectiveness of mathematics in the physical sciences” (a phrase which must be one of the great understatements of all time). The fact that someone like Einstein can figure out what’s happening around a black hole - an object whose existence he wasn’t even aware of - by writing a few things on a blackboard or a piece of paper should give us all goosebumps.
The second challenge asks us to explain something equally amazing: how it is possible that a three-pound mass of blood, flesh and electrochemical impulses can divine those squiggles by pure thought; it is what Francis Crick called “the astonishing hypothesis”. The fact that a diminutive object composed of nothing more than the exact same atoms that constitute chairs, trees and air can evolve through random changes over billions of years and be housed in an entity which can then sit down and write down equations deciphering the symphony of the stars should also give us goosebumps.
Answering these two challenges will take all the combined wisdom and intuition that we have gained during two thousand years of scientific and technical exploration, along with completely new kinds of thinking that we can’t even imagine yet. For me these twin challenges are what make our continued existence over the next few millennia seem worthwhile. They are what make my spine tingle.
As for Einstein himself, if we had told him that we were still verifying his predictions one hundred years after he made them, I suspect he would have smiled and said exactly what he said then: "If you hadn't found gravitational waves I would have felt sorry for the Lord. The theory is correct."

Darwin and his vision of life: A personal offering



"You care for nothing but shooting, dogs, and rat- catching, and you will be a disgrace to yourself and all your family."

- Robert Darwin, to his son Charles.

Two hundred and seven 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 William Hamilton or Lord Kelvin, nor did he particularly excel in school and college. A Cambridge man who 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. 

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 book"Darwin's Ghosts"), 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. Like chemistry it is a synthetic rather than a purely analytical science. 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. The truth is more subtle, sometimes simpler and sometimes 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 land masses.

After five years of exhaustive documentation and sailing Darwin finally returned home for good, much changed both in physical appearance and belief. His following life 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 sometimes 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 is his hesitation to not publish his ideas for another twenty five years in the form of the famous "The Origin of Species". 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 a 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 circumventing 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 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 still 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.

LITERATURE ON DARWIN:

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.

Getting 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.

Out of all these I personally would recommend "Wonderful Life" and "The Mismeasure of Man", 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". In general, pick up any Gould book and you would have access to an extraordinary writer and mind. His collections of essays - "Full House" and "Eight Little Piggies" for instance - are also outstanding. One has to guard against the frequent intrusion of Gould’s political ideology into his writings, but as a man who could turn a phrase he had few peers.

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.