Nullius in verba

Steve Job's Christmas message for our friends in pharma

2011-12-25T12:26:00.001-08:00

I am at the end of Walter Isaacson's excellent biography of Steve Jobs and it's worth a read even if you think you know a lot about the man. Love him or hate him, it's hard to deny that Jobs was one of those who disturbed our universe in the last few decades. You can accuse him of a lot of things, but not of being a lackluster innovator or product designer.

The last chapter titled "Legacy" has a distillation of Jobs's words about innovation, creativity and the key to productive, sustainable companies. In that chapter I found this:

"I have my own theory about why decline happens at companies like IBM or Microsoft. The company does a great job, innovates and becomes a monopoly or close to it in some field, and then the quality of product becomes less important. The company starts valuing the great salesmen, because they're the ones who can move the needle on revenues, not the product engineers and designers. So the salespeople end up running the company. John Akers at IBM was a smart, eloquent, fantastic salesperson but he didn't know anything about product. The same thing happened at Xerox. When the sales guys run the company, the product guys don't matter so much, and a lot of them just turn off."

Jobs could be speaking about the modern pharmaceutical industry. There the "product designers" are the scientists of course. Although many factors have been responsible for the decline of innovation in modern pharma, one of the variables that strongly correlates is the replacement of product designers at the helm by salespeople and lawyers beginning roughly in the early 90s.

There's a profound lesson in there somewhere. Not that wishes come true, but it's Christmas, and while we don't have the freedom to innovate, hold a stable job and work on what really matters, we do have the freedom to wish. So with this generous dose of wishful thinking, I wish you all a Merry Christmas.

Autism studies among the Asian-American diaspora.

2011-11-15T12:47:00.001-08:00

Last week's issue of Nature had a special section on autism research. One look at the series of articles should convince anyone how complex the determination of causal factors for this disorder is. From a time when pseudoscientific environmental factors (such as "frigid" mothers) were supposed to play a major role, we have reached a stage where massive amounts of genetic data are uncovering tantalizing hints behind Autism Spectrum Disorders (the title itself pointing to the difficulty of diagnosis and description) without a clear indication of causes. Indeed, as pointed out in the Nature articles, some researchers think that the pendulum has now swung to the other side and environmental factors need to be taken into account again.

All the articles are worth reading, but for me the most interesting was a piece describing the research of psychologist Simon Baron-Cohen (brother of the colorful actor Sacha Baron-Cohen) who believes that there is a link between autistic children and the probability of their having technically-minded parents like engineers or scientists. Baron-Cohen's hypothesis has not been validated by rigorous studies but it's extremely intriguing. He thinks that the correlation may have to do with the existence of a "systematizing" brain, one which is adept at deciphering and constructing working relationships in mechanical and logical systems, but which is simultaneously rather poor at grasping the irrational, ill-defined nature of human relationships. Baron-Cohen's hypothesis would be consistent with the lack of empathy and human understanding sometimes found among autistic individuals who also seem to have an aptitude for mathematics, science and engineering.

The moment I read the article, I immediately thought of the substantial Asian-American diaspora in the US, especially Indian and Chinese. I don't have precise statistics (although these would be easy to obtain) but I would think that the majority of Indians or Chinese who emigrated to the US in the last twenty years or so are engineers. If not engineers then they would mostly be scientists or doctors, with businessmen, lawyers and others making up the rest. Chinese and Indian engineers and scientists have always been immigrants here, but the last twenty years have undoubtedly seen a dramatic increase in their numbers.

Now most of the Asians who migrated to the US in the last few years have children who are quite young. From what I read in the Nature article, it seems to me that this Asian community, especially concentrated in places employing large numbers of technically-minded professionals like Silicon Valley and New Jersey, might provide a very good population sample to test Baron-Cohen's hypothesis between autism in children and their probability of having parents who are engineers or physical scientists. Have there been any such studies indicating a relatively higher proportion of ASDs among Asian-American children? I would think that geographic localization and a rather "signal-rich" sample to test Baron-Cohen's hypothesis would provide fertile ground. And surveys conducted with these people by email or in person might be a relatively easy way to test the idea. In fact you may even gain some insight into the phenomenon by analyzing existing records detailing the ethnicity and geographic location of children diagnosed with autism in the last two decades in the US (however, this sample may be skewed since awareness of autism among Asian parents has been relatively recent).

If the prevalence of autism among recent Chinese and Indian children turns out to have seen an upswing in the last few years (therefore contributing to the national average), it would not prove Baron-Cohen's hypothesis but it would certainly be consistent with it. And it would provide an invitation to further inquiry. That's what good science is about.

Age is of course a fever chill?: Why even older scientists can make important contributions

2011-11-08T07:31:00.001-08:00

A ditty often attributed to Paul Dirac conveys the following warning about doing scientific work in your later years:

Age is of course a fever chill
That every physicist must fear
He is better dead than living still
When past his thirtieth year

Dirac was of course a member of the extraordinary generation of physicists who changed our understanding of the physical world through the development of quantum mechanics in the 1920s and 30s. These men were all in their 20s when they made their revolutionary discoveries, with one glaring exception - Erwin Schrodinger was, by the standards of theoretical physics, a ripe old thirty-eight when he stumbled across the famous equation bearing his name.

When we look at the careers of these individuals we could be forgiven for assuming that if you are past thirty you will probably not make an important contribution to science. The legend of the Young Turks has not quite played out in other fields of science though. Now a paper in PNAS confirms what we suspected, that since the turn of the twentieth century there has been a general increase in the age at which scientists make their important discoveries. What is more surprising is that this increase exists more across time than across fields. The study looks at Nobel Laureates, but since many people who make Nobel Prize worthy discoveries never get the prize, the analysis applies to others too.

So what does the paper find out? It finds out that in the early years of the last century, young men and women made contributions in every field at a relatively young age, often in their twenties. This was most pronounced for theoretical physics. Einstein famously formulated special relativity when he was a 26-year-old patent clerk, and Heisenberg formulated quantum mechanics when he was 24. The same was true for many other physicists including Bohr, Pauli, Dirac and De Broglie and the trend continued into the 70s, although it was less true for chemists and biologists studied by the authors.

The reasons postulated in the paper are probably not too surprising but they illustrate the changing nature of scientific research during the last one hundred years or so. It is easiest for a brilliant individual to make an early contribution to a theoretical field like theoretical physics or mathematics, since achievement in such fields depends more on raw, innate ability than skills gained over time. In an experimental field it's much harder to make early contributions since one needs time to assimilate the large body of experimental work done and to learn the painstaking trade of the experimentalist, an endeavor where patience and perseverance count much more than innate intelligence. As the paper puts it, deductive knowledge lends itself more easily to innate analytical thinking skills visible at a young age than inductive knowledge based on a large body of existing work. This is true even for theoretical physicists where fundamental discoveries have become extremely hard and scarce, and where new ideas depend as much on integrating an extensive set of facts into your thinking process as on "Eureka!" moments. And this difference holds even more starkly for social sciences like economics and psychology where you find very few young people making Nobel Prize winning contributions. In these cases success depends as much on intellectual maturity gained from a thorough assimilation of data about extremely complex systems ("humans") as it does on precocity.

But if this were purely the distinction, then we wouldn't find young people making contributions even to experimental chemistry and biology in the early twentieth century. The reason why this happened is also clear; there was a lot of low-hanging fruit to be picked. So little was known for instance about the molecular components of living organisms that almost every newly discovered vitamin, protein, alkaloid, carbohydrate or steroid could bag its discoverer a Nobel prize. The mean age for achievement was not as early as in theoretical physics, but the contrast is still clear. Even in theoretical physics, the playing field was so rife for new discoveries in the 1930s that in Dirac's words, "even a second-rate physicist could make a first-rate discovery". The paper draws the unsurprising conclusion that there is much more opportunity for a young person to discover something new in a field where little is known.

This conclusion is starkly illustrated in the case of DNA. Watson and Crick are the "original" Young Turks. Watson was only 25 and Crick was in his early thirties when they cracked open the DNA structure, although one has to give Crick a pass since his career was interrupted by the war. What's important to note is that both Watson and Crick came swinging into the field with very little prior knowledge. For instance they both knew very little chemistry. But in this case this lack of knowledge did not really hold them back and in fact freed up their imagination because they were working in a field where there were no experts, where even newcomers could use the right kind of knowledge (crystallography and model building in this case) to make important discoveries. Watson and Crick's story points to a tantalizing thought- that it may yet be possible to make fundamental contributions at a young age to fields in which virgin territory is still widely available. Neuroscience comes to mind right away.

Since this is a chemistry blog, let's look at the authors' conclusions as they apply to chemistry. Linus Pauling provides a very interesting example since he plays into both categories. The "early Pauling" made his famous contributions to chemical bonding in his twenties, and this contribution was definitely more of the deductive kind where you could indulge in much armchair analysis based on principles and approximations drawn from quantum theory. In contrast, contributions by the "late Pauling" are much more inductive. These would include his landmark discovery of the fundamental elements of protein structure (the alpha helix and the beta sheet) and the first description of a disease at a molecular level (sickle cell anemia). Pauling did both these things in his 40s, and both of them needed him to build up from an extensive body of knowledge about crystallography, chemical bonding and biochemistry. It would be hard to imagine even a Linus Pauling deducing protein structure the way he deduced orbital hybridization.

If we move to more inductive fields then the relatively advanced age of the participants is even more obvious. In fact in chemistry, in contrast to mathematics or physics, it's much harder to pinpoint a young revolutionary precisely because chemistry more than physics is an experimental science based on the accumulation of facts. Thus even exceptional chemists are often singled out more for lifelong contributions than for lone flashes of inspiration. Even someone as brilliant as R. B. Woodward (who did make his mark at a young age) was really known for his career-wide contributions to organic synthesis rather than any early idea. It's also interesting that Woodward did make a very important contribution in his late 40s - to the elucidation of the Woodward-Hoffmann rules- and although Hoffmann provided a robust deductive component, inspiration for the rules came to Woodward through anomalies in his synthesis of Vitamin B12 and his vast knowledge of experimental data on pericyclic reactions. Woodward was definitely building up from a lot of inductive knowledge.

An additional factor that the authors don't discuss is the contribution of collaborations. From a general standpoint it has now become very difficult for scientists in any field to make lone significant contributions. In fact one can make a good case that even the widely cited lone contributions to theoretical physics in the 1920s involved constant collaboration and exchange of ideas (mostly through Niels Bohr's institute in Copenhagen). This was far from the case for most of scientific history, when you had people like Cavendish, Lavoisier, Maxwell, Faraday, Kekule and Planck working alone and producing spectacular results. But things have significantly changed, especially in the case of experimental particle physics and genomics where even the most outstanding thinkers can often work only as part of a team. In such cases it may even be meaningless to talk about the young vs advanced age dichotomy since no one individual makes the most important discovery.

Finally, one rather disturbing reason that could potentially contribute to an even greater advancement of age in the context of important discoveries is left undiscussed. As the biologist Bob Weinberg lamented in an editorial a few years ago, the mean age at which new academic researchers receive their first important research grant has been advancing. This means that even brilliant scientists may be held back from making important discoveries simply because they lack the resources. While this trend has really been visible in the last decade or so, it could contribute as an unfortunate factor to the age-corrected generation of novel ideas. One only hopes that this does not make things so bad that scientists are forced to consider contributing to their fields in their 70s.

Ultimately there's one thing that age brings that's hard to replace with raw brilliance, and that's the nebulous but invaluable entity called 'intuition'. As scientific problems become more and more complex and interdisciplinary, it is inevitable that intuition and experience will play more important roles in the divining of new scientific phenomena. And these are definitely a product of age, so there may be something to look forward to when you grow old after all.

The future of science: Will models usurp theories?

2011-10-05T08:53:00.000-07:00

This year's Nobel Prize for physics was awarded to Saul Perlmutter, Brian Schmidt and Adam Riess for their discovery of an accelerating universe, a finding leading to the startling postulate that 75% of our universe contains a hitherto unknown entity called dark energy. All three were considered favorite candidates for a long time so this is not surprising at all. The prize also underscores the continuing importance of cosmology since it had been awarded in 2o06 to George Smoot and John Mather, again for confirming the Big Bang and the universe's expansion.

This is an important discovery which stands on the shoulders of august minds and an exciting history. It continues a grand narrative that starts from Henrietta Swan Leavitt (who established a standard reference for calculating astronomical distances) through Albert Einstein (whose despised cosmological constant was resurrected by these findings) and Edwin Hubble, continuing through George Lemaitre and George Gamow (with their ideas about the Big Bang) and finally culminating in our current sophisticated understanding of the expanding universe. Anyone who wants to know more about the personalities and developments leading to today's event should read Richard Panek's excellent book "The 4 Percent Universe".

But what is equally interesting is the ignorance that the prizewinning discovery reveals. The prize was really awarded for the observation of an accelerating universe, not the explanation. Nobody really knows why the universe is accelerating. The current explanation for the acceleration consists of a set of different models, none of which has been definitively proven to explain the facts well enough. And this makes me wonder if such a proliferation of models without accompanying concrete theories is going to embody science in the future.

The twentieth century saw theoretical advances in physics that agreed with experiment to an astonishing degree of accuracy. The culmination of achievement in modern physics was surely quantum electrodynamics (QED) which is supposed to be the most accurate theory of physics we have. Since then we have had some successes in quantitatively correlating theory to experiment, most notably in the work on validating the Big Bang and the development of the standard model of particle physics. But dark energy- there's no theory for it that remotely approaches the rigor of QED when it comes to comparison with experiment.

Of course it's unfair to criticize dark energy since we are just getting started on tackling its mysteries. Maybe someday a comprehensive theory will be found, but given the complexity of what we are trying to achieve (essentially explain the nature of all the matter and energy in the universe) it seems likely that we may always be stuck with models, not actual theories. And this may be the case not just with cosmology but with other sciences. The fact is that the kinds of phenomena that science has been dealing with recently have been multifactorial, complex and emergent. The kind of mechanical, reductionist approaches that worked so well for atomic physics and molecular biology may turn out to be too impoverished for taking apart these phenomena. Take biology for instance. Do you think we could have a complete "theory" for the human brain that can quantitatively calculate all brain states leading to consciousness and our reaction to the external world? How about trying to build a "theory" for signal transduction that would allow us to not just predict but truly understand (in a holistic way) all the interactions with drugs and biomolecules that living organisms undergo? And then there's other complex phenomena like the economy, the weather and social networks. It seems wise to say that we don't anticipate real overarching theories for these phenomena anytime soon.

On the other hand, I think it's a sign of things to come that most of these fields are rife with explanatory models of varying accuracy and validity. Most importantly, modeling and simulation are starting to be considered as a respectable "third leg" of science, in addition to theory and experiment. One simple reason for this is the recognition that many of science's greatest current challenges may not be amenable to quantitative theorizing, and we may have to treat models of phenomena as independent, authoritative explanatory entities in their own right. We are already seeing this happen in chemistry, biology, climate science and social science, and I have been told that even cosmologists are now extensively relying on computational models of the universe. Admittedly these models are still far behind theory and experiment which have had head starts of about a thousand years. But there can be little doubt that such models can only become more accurate with increasing computational firepower. How accurate remains to be seen, but it's worth noting that there are already books that make a case for an independent, study-worthy philosophy of modeling and simulation. These books extol philosophers of science to treat models not just as convenient applications and representations of theories (which are then the only fundamental things worth studying) but as ultimate independent explanatory devices in themselves that deserve separate philosophical consideration.

Could this then be at least part of the future of science? A future where robust experimental observations are encompassed not by beautifully rigorous and complete theories like general relativity or QED but only by different models which are patched together through a combination of rigor, empirical data, fudge factors and plain old intuition? This would be a new kind of science, as useful in its applications as its old counterpart but rooting itself only in models and not in complete theories. Given the history of theoretical science, such a future may seem dark and depressing. That is because as the statistician George Box famously quipped, although some models are useful, all models are wrong. What Box meant was that models often feature unrealistic assumptions about all kinds of details that nonetheless allow us to reproduce the essential features of reality. Thus they can never provide the sure connection to "reality" that theories seem to. This is especially a problem when disparate models give the same answer to a question. In the absence of discriminating ideas, which model is then the "correct" one? The usual answer is "none of them", since they all do an equally good job of explaining the facts. But this view of science, where models that can be judged only on the basis of their utility are the ultimate arbiters of reality and where there is thus no sense of a unified theoretical framework, feels deeply unsettling. In this universe the "real" theory will always remain hidden behind a facade of models, much as reality is always hidden behind the event horizon of a black hole. Such a universe can hardly warm the cockles of the heart of those who are used to crafting grand narratives for life and the universe. However it may be the price we pay for more comprehensive understanding. In the future, Nobel Prizes may be frequently awarded for important observations for which there are no real theories, only models. The discovery of dark matter and energy and our current attempts to understand the brain and signal transduction could well be the harbingers of this new kind of science.

Should we worry about such a world rife with models and devoid of theories? Not necessarily. If there's one thing about science that we know, it's that it evolves. Grand explanatory theories have traditionally been supposed to be a key part- probably the key part- of the scientific enterprise. But this is mostly because of historical precedent as well a psychological urge for seeking elegance and unification. Such belief has been resoundingly validated in the past but it's utility may well have plateaued. I am not advocating some "end of science" scenario here - far from it - but as the recent history of string theory and theoretical physics in general demonstrates, even the most mathematically elegant and psychologically pleasing theories may have scant connection to reality. Because of the sheer scale and complexity of what we are trying to currently explain, we may have hit a roadblock in the application of the largely reductionist traditional scientific thinking which has served us so well for half a millennium

Ultimately what matters though is whether our constructs- theories, models, rules of thumb or heuristic pattern recognition- are up to the task of constructing consistent explanations of complex phenomena. The business of science is explanation, whether through unified narratives or piecemeal explanation is secondary. Although the former sounds more psychologically satisfying, science does not really care about stoking our egos. What is out there exists, and we do whatever's necessary and sufficient to unravel it.

Book Review: Robert Laughlin's "Powering the Future"

2011-10-02T18:34:00.000-07:00

In the tradition of physicists writing for the layman, Robert Laughlin has emerged as a writer who pens unusually insightful and thought-provoking books. In his "A Different Universe" he explored the consequences and limitations of reductionism-based physics for our world. In this book he takes an equally fresh look at the future of energy. The book is not meant to be a comprehensive survey of existing and upcoming technologies; instead it's more like an assortment of appetizers designed to stimulate our thinking. For those who want to know more, it offers an impressive bibliography and list of calculations which is almost as long as the book itself.

Laughlin's thinking is predicated on two main premises. The first is that carbon sources are going to eventually run out or become inaccessible (either because of availability or because of legislation). However we will still largely depend on carbon because of its extraordinarily fortuitous properties like high energy density, safety and ease of transportation. But even in this scenario, simple rules of economics will trump most other considerations for a variety of different energy sources. The second premise which I found very intriguing is that we need to uncouple our thinking on climate change from that on energy instead of letting concerns about the former dictate policy about the latter. The reason is that planetary-level changes in the environment are so vast and beyond the ability of humans to control that driving a few more hybrids or curbing carbon emissions will have little effect on millennial events like the freezing or flooding of major continents. It's worth noting here that Laughlin (who has been called a climate change skeptic lately) is not denying global warming or its consequences here; it's just that he thinks that it's sort of beside the point when it comes to thinking about future energy, which will be mainly dictated by economics and prices more than anything else. I found this to be a commonsense approach based on an appreciation of human nature.

With this background Laughlin takes a sweeping and eclectic look at several interesting technologies and energy sources including nuclear energy, biofuels, energy from trash, wind and solar power and energy stored beneath the sea. In each case Laughlin explores a variety of problems and promises associated with these sources.

Because of dwindling uranium resources, the truly useful form of nuclear energy for instance will come from fast breeder reactors which produce their own plutonium fuel. However these reactors are more susceptible to concerns about proliferation and theft. Laughlin thinks that a worldwide, tightly controlled system of providing fuel rods to nations would allow us to fruitfully deploy nuclear power. One of his startling predictions is the possibility that we may put up with occasional Chernobyl-like events if nuclear power truly becomes cheap and we don't have any other alternatives.

Laughlin also finds promises and pitfalls in solar energy. The basic problem with solar energy is its irregular availability and problems with storage. Backup power inevitably depends on fossil fuel sources which sort of defeats the purpose. Laughlin sees a bright future for molten salt tanks which can very efficiently store solar energy as heat and which can be used when the sun is not shining. These salts are simple eutectic mixtures of potassium and sodium nitrates with melting points that are conveniently lowered even more by the salts' decomposition products. Biofuels also get an interesting treatment in the book. One big advantage of biofuels is that they are both sources and sinks of carbon. Laughlin talks about some recent promising work with algae but cautions that meeting the sheer worldwide demand for energy with biofuels that don't divert resources away from food is very challenging. Further on there's a very intriguing chapter on energy stored under the sea. The sea provides a stupendous amount of land beneath it and could be used for energy storage through novel sources like high-density brine pools and compressed natural gas tanks. Finally, burning trash which has a lot of carbon might appear like a useful source of energy but as Laughlin explains, the actual energy in trash will provide only a fraction of our needs.

Overall the book presents a very thought-provoking treatment of the nature and economics of possible future energy sources in a carbon-strapped world. In these discussions Laughlin wisely avoids taking sides, realizing how fraught with complexity and ambiguity future energy production is. Instead he simply offers his own eclectic thoughts on the pros and cons of energy-related topics which may (or may not) prove important in the future. Of the minor gripes I have with the volume is the lack of discussion of promising recent advances in solar cell design, thorium-based fuels and next generation nuclear reactor technology. Laughlin's focus is also sometimes a little odd and meandering; for instance at one point he spends an inordinate amount of time talking about interesting aspects of robotic technology that may make deep sea energy sequestration possible. But these gripes detract little from the volume which is not really supposed to be an exhaustive survey of alternative energy technologies.

Instead it offers us a very smart scientist's miscellaneous musings on energy dictated by commonsense assumptions based on the simple laws of demand and supply and of human nature. As responsible citizens we need to be informed on our energy choices which are almost certainly going to become more difficult and constrained in the future. Laughlin's book along with others will stimulate our thinking and help us pick our options and chart our direction.

The flame of life and death: My favorite (insufferable) chemical reaction

2011-09-27T14:48:00.000-07:00

For me, the most astounding thing about science has always been the almost unimaginably far-reaching and profound influence that the most trite truths about the universe can have on our existence. We may think that we are in charge of our lives through our seemingly sure control of things like food, water, energy and material substances and we pride the ability of our species to stave off the worst ravages of the natural environment such as disease, starvation and environmental catastrophe. We have done such a good job of sequestering ourselves from the raw power of nature that it's all too easy to take our apparent triumph over the elements for granted. But the truth is that we are all without exception critically and pitifully beholden to a few numbers and a few laws of physics.

And a few simple chemical reactions. Which brings me to my favorite reaction for this month's blog carnival. It's a reaction so elementary that it will occupy barely a tenth of the space on a napkin or t-shirt and which could (and should) be productively explained to every human being on the planet. And it's a reaction so important that it both sustains life and very much has the potential to end it.

By now you might have guessed it. It's the humble combination of hydrocarbons with oxygen, known to all of us as combustion.

First the reaction itself which is bleedingly simple:

C_nH_2n+2 + (3n+1)/2 O₂ → (n+1) H₂O + n CO₂ + Energy

That's all there is to it. There, in one line, is a statement about our world that packs at least as much information into itself as all of humanity's accumulated wisdom and follies. A hydrocarbon with a general formula C_nH_2n+2reacts with oxygen to produce carbon dioxide, water and energy. That's it. You want a pithy, multifaceted (or two-faced, take your pick) take on the human condition, there you have it. While serving as the fundamental energy source for life and all the glory of evolution, it's also one that drives wars, makes enemies out of friends, divides and builds ties between nations and will without a doubt be responsible for the rise, fall and future of human civilization. Faust himself could have appeared in Goethe's dream and begged him to use this reaction in his great work.

First, the hydrocarbon itself. Humanity launched itself onto a momentous trajectory when it learnt how to dig carbon out of the ground and use it as fuel. Since then we have been biding our time for better or worse. The laws of quantum mechanics could not have supplied us with a more appropriate substance. Carbon in stable hydrocarbons is in its most reduced state, which means that you can get a bigger bang out of your buck by oxidizing it compared to almost any other substance. What billions of controlled experiments over the years in oil and natural gas refineries and coal plants have proven is that you really can't do better than carbon when it comes to balancing energy density against availability, cost, ease of handling and transportation and safety. In its solid form you can burn it to stay warm and to produce electricity, in its liquid form you can pump it into an incredibly efficient and compact gas tank. For better or worse we are probably going to be stuck with carbon as a fuel (although the energy source can wildly differ).

The second component of the chemical equation is oxygen. Carbon is very fortunate in not requiring a pure source of oxygen to burn; if it burned, say, only in an environment with 70% or more oxygen that would have been the end of modern civilization as we know it. Air is good enough for combusting carbon. In fact the element can burn under a wide range of oxygen concentrations, which is a blessing because it means that we can safely burn it in a very controlled manner. Varying the amount of oxygen can also lead to different products and can minimize the amount of soot and toxic byproducts. The marriage of carbon and oxygen is a wonderfully tolerant and productive one and we have gained enormously from this union

The right side of the combustion equation is where our troubles begin. First off, water. It may seem like a trivial, harmless byproduct of the reaction but it's precisely its benign nature that allows us to use combustion so widely. Just imagine if the combustion of carbon had produced some godforsaken toxic substance in addition to carbon dioxide as a byproduct. Making energy from combustion would then have turned into a woefully expensive activity, with special facilities required to sequester the poisonous waste. This would likely have radically altered the global production and distribution of energy and human development would have been decidedly hampered. We may then have been forced to pick alternative sources of energy early on in our history, and the face of politics, economics and technology would consequently have been very different.

Moving on we come to what's almost ubiquitously regarded as a villain these days- carbon dioxide. If carbon dioxide were as harmless as water we would live in a very different world. Sadly it's not and its properties again underscore the profound influence that a few elementary facts of physics and chemistry can have on our fate. The one property of CO2 that causes us so much agony is the fact that it's opaque to long-wavelength infrared radiation and absorbs it, thus warming the surroundings. This is not a post to discuss global warming but it's obvious to anyone not living in a cave that the issue has divided the world like no other. We still don't know for sure what it will do, either by itself or because of the actions taken by human beings from merely perceiving its effects. But whatever it is, it will profoundly alter the landscape of human civilization for better or worse. We can all collectively curse the day that the laws of physics and chemistry decided to produce carbon dioxide as a product of combustion.

Finally we come to the piece de resistance. None of this would have mattered if it weren't for the most important thing combustion produces- energy (in fact we wouldn't have been around to give a fig). In this context combustion is exactly like nuclear fission; twentieth-century history would have been very different if all uranium did was break up into two pieces. Energy production from combustion is what drives life and human greed. We stay alive by eating carbon-rich compounds - especially glucose - which are then burned in a spectacularly controlled manner to provide us with energy. The energy liberated cannot be used directly for our actions and thoughts. Instead it is used to construct devilishly clever chemical packages of ATP (adenosine triphosphate) which then serves as the energy currency.

Our bodies (and those of other creatures) are staggeringly efficient at squeezing oxidation-derived energy out of compounds like glucose; for instance in the aerobic oxidation of glucose, a single glucose molecule can generate 32 molecules of ATP. Put another way, the oxidation of a gram of glucose yields about 4 kilocalories of energy. This may not seem like a lot until we realize that the detonation of a gram of TNT yields only about 1 kilocalorie (the reason the latter seems so violent is because all the energy is liberated almost instantaneously). Clearly it is the all-important energy term in the combustion equation that has made life on earth possible. We are generously contributing to this term these days by virtue of quarter pounders and supersizing but our abuse does not diminish its importance.

The same term of course is responsible for our energy triumphs and problems. Fossil fuel plants are nowhere as efficient in extracting energy from carbon-rich hydrocarbons as our bodies, but what matters is whether they are cheap enough. It's primarily the cost of digging, transporting, storing and burning carbon that has dictated the calculus of energy. Whatever climate change does, of one thing we can be sure; we will continue to pay the cheapest price for our fuel. Considering the many advantages of carbon, it doesn't seem like anything is going to substitute its extraordinarily fortuitous properties anytime soon. We will simply have to find some way to work around, over or through its abundance and advantages.

If we think about it then, the implications of combustion for our little planet and its denizens are overwhelming and sometimes it's hard to take it all in. At such times we only need to take a deep breath and remember the last words spoken by Kevin Spacey's character from "American Beauty":

"Sometimes I feel like I'm seeing it all at once, and it's too much, my heart fills up like a balloon that's about to burst... And then I remember to relax, and stop trying to hold on to it, and then it flows through me like rain and I can't feel anything but gratitude for every single moment of my stupid little life..."

That's right. Let's have it flow through us like rain. And watch it burn.

Image source

Book Review: "Feynman"

2011-09-19T08:53:00.000-07:00

With his colorful personality and constant propensity to get into all kinds of adventures, Richard Feynman is probably the perfect scientific character to commit to comic book form, so in one way this graphic novel is long due. What is remarkable is how powerfully Jim Ottaviani and Leland Myrick harness this unique medium to accurately dramatize the life and qualities of this genius. Both authors are uniquely qualified for this endeavor, having already penned graphic portraits of Niels Bohr, Robert Oppenheimer and Leo Szilard.

Ottaviani and Myrick manage to capture the essential characteristics that made Feynman such a cherished teacher, scientist, friend, colleague, and public personality. Most importantly, the book succeeds in vividly bringing out Feynman's quintessential quality of almost obsessively staking out his own iconoclastic path both in science and in life. The biography is really a memoir akin to "Surely You're Joking Mr. Feynman" since it features Feynman's own account of his life, work and intellectual development. The great strength of the book is that it uses close-ups and color to highlight key words and moments from Feynman's life. While the biographical information in the book has been covered in other works and most notably in Feynman's own memoirs, the comic book form has a very different impact because of the combined literary-visual effect it has on the viewer.

For instance, in describing Feynman's time at Los Alamos, one can actually see people's bewildered faces as they struggled to comprehend both his genius in solving intractable physics problems and his wildly successful attempts at safe-breaking. There are evocative close-ups of Feynman's father teaching him to appreciate and truly understand nature during walks in the park, of Feynman encouraging his sister to learn science and his wonderful and tragic relationship with his first wife. Also included are Feynman's strip-club forays (during which he solved physics problems), his famous dunking of the Challenger space shuttle's O-rings into a glass of cold water to demonstrate their failure (again rendered much more dramatic by the graphic medium) and some fairly detailed albeit brief discussions of his pioneering work in quantum mechanics.

I was especially convinced of the power of the graphic form during the parts dealing with Feynman's lectures about scientific wonder and humility. As he paced the podium at Caltech and stressed the importance of holding oneself to an absolute standard of integrity, successive panels of the book zoomed in on his face. This device which is commonly employed in comic books imparts a heightened sense of importance to the words in a way that would not be evident on simply reading them. The other idea used in the comic medium is to intersperse the narrative with divergent panels; for instance, Feynman's eloquent description of science as a great game of chess intersects with snapshots of a chess game played by two people in a park where his father has taken him for a walk.

The minor gripe I have with this comic account is that the faces of different characters are sometimes not easily distinguishable. In addition the narrative would have had a bigger impact if the characters resembled their real life counterparts. But these minor points detract little from the volume's novelty. Ottaviani and Myrick have done a wonderful job in making a unique scientist and human being come alive in these pages. With the mountains of literature written about Feynman one would think that there's nothing new that could be said or done. But this "dramatic picture" of Richard Feynman, as his friend Freeman Dyson calls it, will occupy a proud place on the shelves of Feynman fans. Knowing his fondness for fun, Dick would undoubtedly have approved.

Nobel Prizes 2011

2011-09-08T06:29:00.001-07:00

So it's that time of the year again, the time when just like Richard Feynman and Paul Dirac, three lucky people get to mull over whether they will incur more publicity by accepting the Nobel Prize or rejecting it.

Predicting the Nobel Prizes gets easier every year ((I said predicting, not getting your predictions right) since there's very little you can add in the previous year's list, although there are a few changes; the Plucky Palladists can now happily be struck off the list. As before, I am dividing categories into 'easy', and 'difficult' and assigning pros and cons to every prediction.

The easy ones are those regarding discoveries whose importance is (now) ‘obvious’; these discoveries inevitably make it to lists everywhere each year and the palladists clearly fell into this category. The difficult predictions would either be discoveries which have been predicted by few others or ones that that are ‘non-obvious’. But what exactly is a discovery of ‘non-obvious’ importance? Well, one of the criteria in my mind for a ‘non-obvious’ Nobel Prize is one that is awarded to an individual for general achievements in a field rather than for specific discoveries, much like the lifetime achievement Academy Awards given out to men and women with canes. Such predictions are somewhat harder to make simply because fields are honored by prizes much less frequently than specific discoveries.

Anyway, here's the N-list

2. Computational chemistry and biochemistry (Difficult):
Pros: Computational chemistry as a field has not been recognized since 1999 so the time seems due. One obvious candidate would be Martin Karplus.
Cons: This would definitely be a lifetime achievement award. Karplus did do the first MD simulation of a protein ever but that by itself wouldn’t command a Nobel Prize. The other question is regarding what field exactly the prize would honor. If it’s specifically applications to biochemistry, then Karplus alone would probably suffice. But if the prize is for computational methods and applications in general, then others would also have to be considered, most notably Ken Houk who has been foremost in applying such methods to organic chemistry. Another interesting candidate is David Baker whose program Rosetta has really produced some fantastic results in predicting protein structure and folding. It even spawned a cool game. But the field is probably too new for a prize.

3. Chemical biology and chemical genetics (Easy)
Another favorite for years, with Stuart Schreiber and Peter Schultz being touted as leading candidates.
Pros: The general field has had a significant impact on basic and applied science
Cons: This again would be more of a lifetime achievement award which is rare. Plus, there are several individuals in recent years (Cravatt, Bertozzi, Shokat) who have contributed to the field. It may make some sense to award Schreiber a ‘pioneer’ award for raising ‘awareness’ but that’s sure going to make a lot of people unhappy. Also, a prize for chemical biology might be yet another one whose time has just passed.

4. Single-molecule spectroscopy (Easy)
Pros: The field has obviously matured and is now a powerful tool for exploring everything from nanoparticles to DNA. It’s been touted as a candidate for years. The frontrunners seem to be W E Moerner and M Orrit, although Richard Zare has also been floated often.
Cons: The only con I can think of is that the field might yet be too new for a prize

5. Electron transfer in biological systems (Easy)
Pros: Another field which has matured and has been well-validated. Gray and Bard seem to be leading candidates.

Among other fields, I don’t really see a prize for the long lionized birth pill and Carl Djerassi; although we might yet be surprised, the time just seems to have passed. Then there are fields which seem too immature for the prize; among these are molecular machines (Stoddart et al.) and solar cells (Gratzel).

MEDICINE:

1. Nuclear receptors (Easy)
Pros: The importance of these proteins is unquestioned. Most predictors seem to converge on the names of Chambon/Jensen/Evans.

2. Statins (Difficult)
Akira Endo’s name does not seem to have been discussed much. Endo discovered the first statin. Although this particular compound was not a blockbuster drug, since then statins have revolutionized the treatment of heart disease.
Pros: The “importance” as described in Nobel’s will is obvious since statins have become the best-selling drugs in history. It also might be a nice statement to award the prize to the discovery of a drug for a change. Who knows, it might even boost the image of a much maligned pharmaceutical industry...
Cons: The committee is not really known for awarding actual drug discovery. Precedents like Alexander Fleming (antibiotics), James Black (beta blockers, antiulcer drugs) and Gertrude Elion (immunosuppresants, anticancer agents) exist but are far and few in between. On the other hand this fact might make a prize for drug discovery overdue.

2. Genomics (Difficult)
A lot of people say that Venter should get the prize, but it’s not clear exactly for what. Not for the human genome, which others would deserve too. If a prize was to be given out for synthetic biology, it’s almost certainly premature. Venter’s synthetic organisms from last year may rule the world, but for now we humans still prevail. On the other hand, a possible prize for genomics may rope in people like Carruthers and Hood who pioneered methods for DNA synthesis.

3. DNA diagnostics (Difficult)
Now this seems to me to be a field whose time is very much due. The impact of DNA fingerprinting and Western and Southern Blots on pure and applied science, everything from discovering new drugs to hunting down serial killers, is at least as big as the prizeworthy PCR. I think the committee would be doing itself a favor by honoring Jeffreys, Stark, Burnette and Southern.

4. Stem Cells (Easy)
This seems to be yet another favorite. McCulloch and Till are often listed.
Pros: Surely one of the most important biological discoveries of the last 50 years, promising fascinating advances in human health and disease.
Cons: Politically controversial (although we hope the committee can rise above this). Plus, a 2007 Nobel was awarded for work on embryonic stem cells using gene targeting strategies so there’s a recent precedent.

4. Membrane vesicle trafficking (Easy)

Rothman and Schekman

Pros: Clearly important. The last trafficking/transport prize was given out in 1999 (Blobel) so another one is due and Rothman and Schekman seem to be the most likely canidates. Plus, they have already won the Lasker Award which in the past has been a good indicator of the Nobel.

PHYSICS

I am not a physicist
But if I were
I would dare
To shout from my lair
“Give Hawking and Penrose the Prize!”
For being rock stars of humungous size

Also, Anton Zeilinger, John Clauser and Alain Aspect probably deserve it for bringing the unbelievably weird phenomenon of quantum entanglement to the masses. Zeilinger's book "Dance of the Photons" presents an informative and revealing account of this book.

I have also always wondered whether non-linear dynamics and chaos deserves a prize. The proliferation and importance of the field certainly seems to warrant one; the problem is that there are way too many deserving recipients (and Mandelbrot is dead).

Thoughts on personalised medicine

2011-08-31T08:40:00.001-07:00

This is a piece I had written up for the annual report of this year's Lindau Meeting of Nobel Laureates. The final version had to be significantly edited because of space limitations so I thought I would post the full version here.

The future of personalized medicine

In this year’s Lindau meeting, the Israeli biochemist Ciechanover expressed great hope for the future of personalised medicine, an age in which medical treatments are customized and tailored to individual patients based on their specific kind disease.

In some ways personalised medicine is already here. Over centuries of medical progress, astute doctors have fully recognized the diversity of patients who are suffering from what appears to be the same disease. Based on their rudimentary knowledge of disease processes, empirical data and experience, physicians would then prescribe different combinations of medicines for different patients. But in the absence of detailed knowledge of disease at the genetic and molecular level, this kind of approach was naturally subjective; it continued to rely on extensive personal experience and ad hoc interpretations of incompletely documented empirical data.

This approach saw a paradigm shift in the latter half of the twentieth century as our knowledge of DNA and genetics revealed to us the rich diversity and uniqueness of individual genomes. Concomitantly, our knowledge of the molecular basis of disease led us to recognize molecular determinants unique to every individual. We are already taking advantage of this knowledge and harnessing it to personalize therapy.

Take the case of the anticancer drug temozolomide for instance. Temozolomide is prescribed for patients with a particularly pernicious form of brain cancer with poor prognosis. The drug belongs to a category of compounds called alkylating agents, a common class of anticancer drugs in which a reactive chemical group is transferred onto DNA in cancer cells, rendering them incapable of efficient cell division and causing their death. The problem is that because of its key role in sustaining life processes, DNA division is tightly controlled. Any kind of modification of the kind caused by temozolomide is treated as DNA damage and- for good reason- life has evolved multiple mechanisms to reverse such damage. In this case the body produces an enzyme that strips DNA of the reactive functionality attached by the drug. Thus the body unwillingly helps cancer cells by reversing the drug’s action. The understanding of this mechanism has led doctors to personalize temozolomide treatment only for individuals who have low levels of the drug-resisting enzyme. For other patients that produce high levels of the enzyme, temozolomide will unfortunately not be effective and doctors will have to turn to other drugs.

We will undoubtedly witness the proliferation of such advances in personalizing individual treatments in the future. But what appears to be an even more promising approach is to start at the source, at the fundamental genomic sequences that dictate the phenotypical changes associated with enzymes and proteins. The deciphering of the human genome has opened up exciting and promising new avenues for mapping differences in individual genomes and harnessing these differences in drug discovery. The most important strategy has been to compare genomes of individuals for single nucleotide polymorphisms (SNPs) which are changes in single base pairs in the DNA sequence. In fact much of the genetic variation between individuals and populations arises from these single nucleotide changes. SNPs have been of enormous value in tracing genetic diseases and generally categorizing variations in our species. They are typically utilised in genome-wide association studies in which the genomes of members of a certain homogeneous population with and without a disease are compared. Knowing the differences can enable scientists to pinpoint genetic markers responsible for the disease. These genetic markers can then be linked to phenotypes like enzyme overproduction or deficiency that are more directly related to the disease. In addition SNPs are unusually stable and remain constant between generations, providing scientists with a relatively time-invariant handle to study genetic disorders. One of the most notable instances of using SNPs to determine propensity toward disease involves the so-called ApoE gene in Alzheimer’s disease. Two SNPs in this gene lead to three alleles- E2, E3 and E4. Each individual inherits one maternal and one paternal copy of the ApoE gene and there is now solid evidence that the inheritance of the E4 allele leads to a greatly increased risk of Alzheimer’s disease.

In the long run, SNP’s may provide the foundation for much of personalised medicine. This is because SNPs also often dictate individuals’ propensity toward drugs, pathogens and vaccines. Thus in an ideal scenario, one might be able to predict a patient’s response to a whole battery of drugs using knowledge of specific SNPs associated with his or her disease.

Unfortunately this ideal scenario may be much farther than imagined. For one thing, we have still only scraped the surface of all possible SNPs, and there are already an estimated three million out there. But more importantly, the difference between knowing all the SNPs and knowing their causal connections to various diseases is almost like the difference between a list of all human beings on the planet on one hand and everything about their lives on the other; their professions, origins, hobbies, political views, family lives. Knowing the former is far from understanding the latter.

In this sense the problem with SNPs illustrates the problems with all of personalised medicine. In fact it’s a problem that plagues scientific research in general, and that’s the dilemma of separating correlation from causation. The problem is even more acute in a complex biological system like a human being where the ratio of extraneous unrelated correlations to genuinely causative factors is especially high. Simply knowing the SNP variations between a healthy and diseased individual is very different from being able to pinpoint the SNP that is directly connected to the disease. The situation is made exponentially more complex by the fact that these putative determinants usually act in combination with each other. Thus one has to now account not only for the effect of an individual SNP but also for the differential effects of its combination with other SNPs. And as if this complexity were not enough, there’s also the fact that many SNPs occur in non-coding regions of the human genome, leading to even bigger questions about their exact relevance. Sophisticated computers and statistical methods are enabling us to sort through this jungle of data, but as of now the data itself clearly outnumbers our ability to intelligently analyse it. We need to become far more capable at distinguishing signal from noise if we are to translate genetic understanding into practical therapeutic strategies.

In addition, while a certain kind of SNP may be able to determine disease tendency, there are also many false positives and negatives. Only a small percentage of SNPs are typically linked to a condition, especially when it comes to complex conditions like cancer, diabetes and psychological disorders. Many SNPs may simply be surrogate SNPs that have little to do with the disease themselves but which have come along for the ride with other SNPs. It is a difficult task to say the least to separate the wheat from the chaff and hone in on the few SNPs that are truly serving as disease determinants or markers. In such cases it is instructive to borrow from the example of temozolomide and remember that ultimately we will be able to untangle cause and effect only by looking at the molecular level interaction of drugs and biomolecules. No amount of data sequencing and analysis can really be a substitute for a robust study designed to directly demonstrate the role of a particular enzyme or protein in the etiology of a disease. It’s also worth noting that such studies have always benefited from the tools of classical biochemistry and pharmacology, and thus practitioners of these arts will continue to stand on an equal footing with the new genomics experts and computational biologists in unraveling the implications of genetic differences.

Finally, there’s the all-pervasive question of nature versus nurture. Along with genomics, one of the most important advances of the last decade has been the development of epigenetics. Epigenetics refers to changes in the genome that are induced by the environment and not hard-coded in the DNA sequence. An example includes the environmentally stimulated silencing or activation of genes by certain classes of enzymes. Epigenetic factors are now known to be responsible for a variety of processes in diseases and health. Some of these factors can even operate in the fetal stage and influence physiological responses in later life. While epigenetics has revealed a fascinating new layer of biological control and has much to teach us, it also adds another layer of complexity to the determination of individual responses to therapy. We have a long way to go before we can perfect the capability to clearly distinguish genetic from epigenetic factors as signposts for individualized therapy.

The future of personalised medicine is therefore both highly exciting as well as extremely challenging. There is much promise to be had in mapping the subtle genetic differences that make us react differently to diseases and their cures, but we will also have to be exceedingly careful in not leading ourselves astray with incomplete data, absence of causation and confirmation bias. It is a tough, but ultimately rewarding problem which will lead to both fundamental understanding and new medical advances. It deserves our attention in every way.

Image source

It's not blackmail if...

2011-08-21T16:49:00.000-07:00

I have stayed away from the Anna Hazare story mostly because I have had mixed feelings about it and because it's not really been high on my list of interesting topics. However I have to say that I am bamboozled by those who call Hazare's fast-unto-death "undemocratic" and say that he is "blackmailing" the government. Blackmail is when you force someone to do something against their will and threaten to harm them if they don't accede. Hazare is threatening to harm himself, so I don't see how it is blackmail. Now sure, people can call it blackmail because he is indirectly trying to harm the government by encouraging people to come out on the street in throngs. But how can he be held responsible for what the people do and do not decide to do based on his protests?

In fact, the way I see it, it is precisely in a free democracy that everyone has a right to openly demand whatever he or she wants out in the street. And they also have a right to kill themselves if they think their demands are not met. And equally importantly, the government has every right to refuse their demands. The government has absolutely no obligation to give in to Hazare's demands until there is a formal majority that seeks it from them through a democratic process. If they cave in to Hazare's protests it's really their problem, not his.

Plus of course, I personally think that a little "blackmail" is pretty mild treatment for the kind of power-bloated politicians steeped in corruption that seem to define India's polity. But that's a different matter. First and foremost, I don't see how it's blackmail, and I don't see why the government has to give in to Hazare's demands. The way I see it, Hazara's protests are a sign of a healthy democracy at work and I for one feel quite satisfied.

What is chemical intuition?

2011-07-19T05:18:00.001-07:00

Recently I read a comment by a leading chemist in which he said that in chemistry, intuition is much more important than in physics. This is a curious comment since intuition is one of those things which is hard to define but which most people who play the game appreciate when they see it. It is undoubtedly important in any scientific discipline and certainly so in physics; Einstein for instance was regarded as the outstanding intuitionist of his age, a man whose grasp of physical reality unaided by mathematical analysis was unmatched. Yet I agree that "chemical intuition" is a phrase which you hear much more than "physical intuition". When it comes to intuition, chemists seem to be more in the league of traders, geopolitical experts and psychologists than physicists.

Why is this the case? The simple reason is that in chemistry, unlike physics, armchair mathematical manipulation and theorizing can take you only so far. While armchair speculation and order-of-magnitude calculations can certainly be very valuable, no chemist can design a zeolite, predict the ultimate product of a complex natural product synthesis or list the biological properties that a potential drug can have by simply working through the math. As R B Woodward once said of his decision to pursue chemistry rather than math, in chemistry, ideas have to answer to reality. Chemistry much more than physics is an experimental science built on a foundation of rigorous and empirical models, and as the statistican George Box once memorably quipped, all models are wrong, but some are useful. It is chemical intuition that can separate the good models from the bad ones.

How then, to acquire chemical intuition? All chemists crave intuition, few have it. It's hard to define it, but I think a good definition would be that of a quality that lets one skip a lot of the details and get to the essential result, often one that is counter intuitive. It is the art of asking the simple, decisive question that goes to the heart of the matter. As in a novel mathematical proof, a moment of chemical intuition commands an element of surprise. And as with a truly ingenious mathematical derivation, it should ideally lead us to smack our foreheads and ask why we could not think of something so simple before.

Ultimately when it comes to harnessing intuition, there can be no substitute for experience. Yet the masters of the art in the last fifty years have imparted valuable lessons on how to acquire it. Here are three I have noticed:

1. Don't ignore the obvious: One of the most striking features of chemistry as a science is that very palpable properties like color, smell, taste and elemental state are directly connected to molecular structure. There is an unforgettably direct connection between the smell of cis-3-hexenol and that of freshly cut grass. Once you smell both independently it is virtually impossible to forget the connection. Chemists who are known for their intuition never lose sight of these simple molecular properties, and they use them as disarming filters that can cut through the complex calculations and the multimillion dollar chemical analysis.

I remember an anecdote about the chemist Harry Gray (an expert among other things on colored coordination complexes) who once deflated the predictions of some sophisticated quantum chemical calculation by simply asking what the color of the proposed compound was; apparently there was no way the calculations could have been right if the compound had a particular color. As you immerse yourself in laborious compound characterization, computational modeling and statistical significance, don't forget what you can taste, touch, smell and see. As Pink Floyd said, this is all that your world will ever be.

2. Get a feel for energetics: The essence of chemistry can be boiled down to a fight unto death of countless factors that rally either for or against the free energy of a system. When you are designing molecules as anticancer agents, for hydrogen storage or solar energy conversion or as enzyme mimics, ultimately what decides whether they will work or not is energetics, how well they can stabilize and be stabilized and ultimately lower the free energy of the system. Intimate familiarity with numbers can help in these cases. Get a feel for the rough contributions made by hydrogen bonds, electrostatics, steric interactions and solvent influences. This is especially important for chemists working at the interface of chemistry and biology; remember, life is a game played within a 3 kcal/mol window and any insight that allows you to nail down numbers within this window can only help. The same goes for some other parameters like Van der Waals radii and bond lengths. Linus Pauling was lying in bed with a cold when he managed to build accurate models of the protein alpha helix, largely based on his unmatched feel for such numbers.

A striking case of insights acquired through thinking about energetics is illustrated by a story that Roald Hoffmann narrates in a recent issue of "American Scientist". Hoffmann was theoretically investigating the conversion of graphene to graphane, which is the saturated counterpart of graphene, under high pressure. After having done some high-level calculations, his student came into his office and communicated a very counter-intuitive result; apparently graphane was more stable per CH group than the equivalent number of benzenes. What happened to all that discussion of unsaturation in aromatic rings contributing to unusual stability that we learnt in college? Hoffmann could not believe the result and his first reaction was to suspect that something must be wrong with the calculation.

Then, as he himself recalls, he leaned back in his chair, closed his eyes and brought half a century's store of chemical intuition to bear on the problem. Ultimately after all the book-keeping had been done, it turned out that the result was a simple consequence of energetics; the energy gained in the formation of strong carbon-carbon bonds more than offset that incurred due to the loss of aromaticity. The fact that it took a Nobel Laureate some time to work out the result is not in any way a criticism but a resounding validation of thinking in terms of simple energetics. Chemistry is full of surprises- even for Roald Hoffmann- and that's what makes it endlessly exciting.

Another example that comes to my mind is an old paper by my PhD advisor which refuted an observation indicating that a group in cyclohexane was purportedly axial. In this case unlike the one above, the intuitive and commonly held principle- that substituents in cyclohexanes are equatorial- turned out to be the right one, again based on some relatively simple NMR-assisted computational energetic analysis. On the other hand, the same kind of thinking also led to thediscovery that the C-F groups in substituted difluoro-piperidines are axial! Sometimes intuition leads to counter intuition, and sometimes it asserts itself.

3. Stay in touch with the basics, and learn from other fields: This is a lesson that is often iterated but seldom practiced. An old professor of mine used to recommend flipping open an elementary chemistry textbook every day to a random page and reading ten pages from it. Sometimes our research becomes so specialized and we become so enamored of our little corner of the chemical world that we forget the big picture. Part of the lessons cited above simply involve not missing the forest for the trees and always thinking of basic principles of structure and reactivity in the bigger sense.

This also often involves keeping in touch with other fields of chemistry since an organic chemist never knows when a basic fact from his college inorganic textbook will come in handy. Most great chemists who were masters of chemical intuition could seamlessly transition their thoughts between different subfields of their science. This lesson is especially important when specialization has become so intense that it can sometimes lead to condescension toward fields other than your own. Part of the lesson also involves collaboration; what you don't have you can at least partially borrow.

Ultimately if we want to develop chemical intuition, it is worth remembering that all our favorite molecules, whether metals, macrocyles or metalloproteases, are all part of the same chemical universe, obeying the same rules even if in varied contexts. Ultimately, no matter what kind of molecule we are interrogating, Wir sind alle chemikers, every single one of us.

Lindau 2011: What do scientists do after winning the Nobel Prize?

2011-06-29T14:39:00.002-07:00

Most of us know about the prize-winning work of this year's Lindau Nobel Laureates, but how many of us keep track of what they did after winning the coveted honor? Scientists' lives after the Nobel Prize change dramatically. As former Lindau attendee Richard Ernst put it, they are now expected to be oracles on everything from international politics to religion, even when their knowledge of most other things is as limited as that of other people. There is no common thread; after winning the Prize, scientists' lives become as varied as those of all of us and in some cases a little more interesting. Here's a short portrait of life after the Nobel Prize illustrated with a select few examples...

Read the rest of the post on the Lindau blogs site...

Lindau 2011: From designing airplanes to designing proteins

2011-06-29T14:39:00.001-07:00

An inspiration from the birth of aviation

A few weeks ago I visited the small coastal town of Kitty Hawk in North Carolina. Kitty Hawk is where the Wright brothers made their epoch-making first powered flight. Big stones mark the start and end points of the flight. There is a huge monument on top of a hill where they took off and then there are three stones at varying distances at ground level. The three stones indicate the distances covered on every flight; the brothers clearly got better at flying on every attempt.

The Wright brothers' story is inspiring not only because of the watershed in human history which they orchestrated but also because it shows the evolution of a technology at its best. The projects which the brothers undertook cost a few hundred dollars and should serve as a beacon of inspiration in this era of "big science" involving hundreds of millions of dollars. The brothers had a bicycle workshop in which they fashioned many of the components of their infant gliders. They drew inspiration from Otto Lillienthal who had been the first aviation pioneer to make successful glided flights; tragically, Lillienthal was killed on one of his flights, but not before saying "Kleine Opfer müssen gebracht werden!" ("Small sacrifices must be made!").

One of the most important lessons that the Wrights learnt from Lillienthal's adventures was the great value of building 'toy' models. Toy models start from the simplest possible systems which retain the essential features of a phenomenon and then work their way towards greater complexity. This philosophy has been used by many other pioneers of technology, including the scientists and engineers who made the moon landings possible...

Read the rest of the entry at the Lindau blogs website...

Lindau 2011: The beginning

2011-06-29T14:38:00.001-07:00

This year I am privileged to be invited again to write for and attend the 61st Meeting of Nobel Laureates in Lindau, Germany. This year's meeting is dedicated to Physiology or Medicine and the list of attendees provides a glimpse of the diversity and impact of biomedical research. These men and women have made enormous contributions to our understanding of biological systems, from elucidating structures and pathways to providing tools of inestimable value. My first post just went up and I will be linking to others as I write more. Here's the first one.

From messy to magical: Preparing for the future of medicine

In the early 1940s, as war raged over the continent, the British mathematician Freeman Dyson and the Indian physicist Harish Chandra were taking a walk in Cambridge. Harish Chandra was studying theoretical physics under the legendary Paul Dirac while Dyson was getting ready to spend a depressing time calculating bombing statistics at Bomber Command.

“I have decided to leave physics for mathematics”, quipped Harish Chandra. “I find physics messy, unrigorous, elusive”. “That’s interesting”, replied Dyson. “I am planning to leave mathematics for physics for exactly the same reason.” Leave their respective disciplines the two did, and both of them had highly distinguished careers in their new fields at the Institute for Advanced Study in Princeton.

I narrate this story because I can imagine almost exactly the same conversation taking place today between a biomedical researcher and any other kind of natural scientist. In fact it’s interesting to compare the status of medicine today with the status of physics when Dyson and Harish Chandra had their conversation. By 1940 physics had underwent a great revolution in the form of quantum mechanics and relativity. Yet there was much to be done and the “second revolution” was in the making. In retrospect it’s clear that very little was known about the strong and weak nuclear forces and nothing was known about the particle “zoo” that would be uncovered in the next few years. It took the efforts of many brilliant individuals to unify crucial concepts and make the whole structure look more consistent and complete.

Medicine in the year 2011 is like physics in the year 1940. Just like physics it has had a recent revolutionary past in the advent of molecular biology. Just like physics there is much of it that is “messy, unrigorous, elusive”. And it’s exactly these qualities that make it a field ripe for another revolution. The future beckons for medicine and biology today as it did for physics in 1940.

Putting the filosophy back into fysiks

2011-06-18T14:21:00.000-07:00

How the Hippies Saved Physics: Science, Counterculture, and the Quantum Revival- David Kaiser

Does philosophy have a place in serious science? Many of the founders of modern physics certainly thought so. Einstein, Bohr, Heisenberg and Schrodinger were not just great scientists but they were equally enthusiastic and adept at pondering the philosophical implications of quantum theory. To some extent they were forced to confront such philosophical questions because the world that they were discovering was just so bizarre and otherworldly; particles could be waves and vice versa, cats (at least in principle) could be alive and dead, particles that were separated even by light years appeared to be able to communicate instantaneously with each other, and our knowledge of the subatomic world turned out to be fundamentally probabilistic.

However, as quantum theory matured into a powerful tool for calculation and concrete application, the new generation of physicists in general and American physicists in particular started worrying less about "what it means" and much more about "how to use it". American physicists had always been more pragmatic than their European counterparts and after World War 2, as the center of physics moved from Europe to the United States and as the Cold War necessitated a great application of science to defense, physicists turned completely from the philosophizing type to what was called the "shut up and calculate" kind; as long as quantum mechanics agrees spectacularly with experiment, why worry about what it means? Just learn how to use it. Yet this only swept epistemological questions under the rug.

Curiously, there emerged in the 1970s a quirky and small group of physicists in the Bay Area who tried to resurrect the age of philosopher-scientists. In "How the Hippies Saved Physics", David Kaiser wonderfully tells the very engaging story of this "Fundamental Fysiks" group and how it kept alive some of the deep philosophical questions that had haunted the founding fathers. The "Fysicists" came from a variety of backgrounds, but all of them had been dissatisfied; both by the dismal job market for physicists after the Cold War craze and more importantly by the purely practical approach toward physics which they learnt in graduate school. Interestingly they combined their deep questions about physics with the emerging hippie counterculture of the 60s and 70s and it's pretty clear from the book that they had great fun doing this; after all this was an age when non-conformity was encouraged. Discussions of physics concepts blended seamlessly with Eastern mysticism, forays into LSD-induced mind experiments, New Age workshops at the Esalen Institute in California and meanderings into telepathy, consciousness and parapsychology. Books like Fritjof Capra's "The Tao of Physics" which explored parallels between modern physics and Eastern religions only helped the movement. The small group of physicists was also fortunate to get funding from some unlikely sources, including self-help guru Werner Erhard and even the CIA who was interested in possible connections between ESP and physics. Not surprisingly, mainstream physicists often ignored and sometimes actively condemned such activities

However, as Kaiser describes in this fascinating volume, this ragtag group of countercultural philosopher-scientists achieved at least one crucial goal; they kept questions about the philosophical implications of quantum theory alive at a time when most physicists eschewed and disdained such questions. Gradually, they managed to get a handful of mainstream physicists interested in their philosophizing. Much of the connection of this philosophy to real physics centered about a remarkable result called Bell's theorem which essentially reinforced the spooky properties of quantum systems by showing that information in quantum systems can flow instantaneously between particles. Remarkably, this seemingly otherworldly idea of "quantum entanglement" (which gave some of the founding fathers heartburn) now lies at the foundation of some of the most cutting-edge areas of modern physics, including quantum computation and the new discipline of quantum information science. What was considered far-flung by mainstream physicists and kept alive by the Fundamental Fysiks group is now serious physics for many. In fact, at least a few physicists who put Bell's theorem to experimental test are regarded as candidates for a Nobel Prize (these especially include John Clauser, Alain Aspect and Anton Zeilinger who shared the prestigious Wolf Prize- often a forerunner to the Nobel Prize- in 2010).

In the end Kaiser wants to make the case that by keeping such once-disparaged philosophical concepts alive, the Fundamental Fysicists "saved physics". I am a little skeptical of this claim. They certainly managed to nurture and publicize the concepts, but it was the harnessing of these concepts by "real" physicists who were involved with the nuts and bolts of calculation and experiment that actually saved the concepts and kept them from turning into a purely philosophical mishmash. In addition, a lot of concepts that the New Age physicists bandied about belonged squarely in the realm of pseudoscience and the trend continues; people like Deepak Chopra commit gross violations of quantum mechanics on a daily basis. Unfortunately the line between science and non-science can be thin and one of the most intriguing discussions in Kaiser's book is this so-called "demarcation problem". How does one know if today's philosophy is tomorrow's cutting edge science or just noisy mumbo-jumbo? It's not always easy to say.

Nonetheless, I think Kaiser and the Fysicists make a really great general case for why philosophical questions in science have their own place and should not be rejected. For one thing, they are always fascinating in themselves and demonstrate the endless human quest for meaning and reality; as recent discussions indicate, the philosophical conundrums in physics have been far from answered and continue to be explored through even more bizarre ideas like parallel universes and multiple dimensions. And as this wonderful book shows, at least in some cases these discussions may lead to key advances by influencing mainstream physicists who validate them by subjecting them to the ultimate arbiter of truth in science- hard experiment.

Lindau 2011: The beginning

2011-06-06T08:02:00.001-07:00

From messy to magical: Preparing for the future of medicine

Time to make science popularization popular

2011-06-03T12:46:00.001-07:00

When I was in college, “science popularization” was a dirty phrase. Popularizing science was considered the domain of the intellectual lightweights of science. You were interested in science popularization because you were not very good at “real” science itself. More disturbingly, this attitude was the corollary of a larger set of beliefs which saw “science” as tantamount to academic scientific research and nothing more. This view relegated not just popularization but to a lesser extent even teaching to the side. All this was quite surprising especially considering that Pune is the home of astrophysicist Jayant Narlikar, one of the foremost popularizers of science of his generation. But of course, even Narlikar’s “scipop” activities were admired because of his status as a first-rate scientist. The popularization was simply a side-product of his real scientific achievements.

When I came to America two things struck me. First, that science popularization enjoyed vigorous participation and appreciation from both scientists and non-scientists. And second, that some of the clearest writing about science came from people without formal scientific backgrounds. There are indeed many famous science writers like Carl Sagan, Stephen Jay Gould, E O Wilson and Steven Weinberg who have impeccable scientific credentials, but there’s an equal number of others like Carl Zimmer, Robert Crease, Richard Rhodes, James Gleick, Rebecca Skloot and George Johnson who have written first-rate books on science and its history and philosophy, and whose grasp of basic science rivals that of experts in the field. With the rise of blogs and online media, science popularization has enjoyed an even bigger audience and entire conferences like ScienceOnline are organized and attended by science writers and journalists who are fundamentally science popularizers. I attended ScienceOnline 2011 this year and was very impressed by the scientific passion and drive for science communication that I saw in all the non-scientists attending the conference. Most of these people had basic degrees in science but very few of them were professional scientists.

In this post I want to address the troubling attitude about science popularization that existed among my fellow students in college. I already consider my college years a thing of the past, so recent college graduates should definitely voice their observations and opinions in the comments section. Have things changed?

As I noted above, the real problem with the attitude toward science popularization is that it is endemic of a more troubling larger view of science as being equivalent to research and nothing else. But this view is just plain wrong. Even a cursory glance at the history of science reveals that while research has been the primary driving force within science, teaching, scientific funding, scientific collaborations and even rivalries, the impact of social factors on the direction of research and yes…science popularization, have all played a key role in science’s transformation of the modern world. This history reveals a simple fact that is sometimes forgotten; science is very much a social activity. The image of the lone scientist toiling away in his lab and making a great discovery with immediate impact on society was never really true, and is not true at all in this era of expensive science, international collaborations and interdisciplinary research. These days it’s not enough to have a great idea; one needs to sell it to academic institutions, government agencies, private corporations and other funding bodies.

But most importantly, one needs to sell it to the public. And this is true even if the sale is not actually conducted from a park bench by every individual scientist. The sale is necessary because not only has the majority of scientific research in history been funded from the public coffer but because that funding will stop flowing if the public is not convinced of the value of research. We are already seeing this happening in the US. A country which has been the largest public supporter of science until now is struggling to hold on to the public purse strings through its government agencies, in part because of a fundamentally bad economy but also because public support for basic science has been increasingly tainted by multiple factors including the declining quality of education, fundamentalist religion and a growing inability to separate long-term prosperity from short-term benefits.

The only solution to this problem is better science communication. No number of brilliant scientific research ideas by themselves are ever going to reach the public and solve the problem if they are not presented in a digestible form. In that sense, science “popularization” is really nothing but science “communication”, although the former entails fancier pitches. Hopefully the latter word conveys a much bigger and obvious sense of urgency. Thus henceforth I will refer to science popularization as science communication.

Once the key dependence of scientific support on a public that mostly is not formally scientifically educated becomes clear, the important of science communication cannot be underestimated. Communicate science, otherwise doing science will slowly but surely become an uphill battle. My friends who were erstwhile scientists should have realized that their future as science doers depends in an important way on the science communicators that they disparaged. Perhaps that should have generated more respect for the communicators.

Indeed, even within science the importance of “explanation” has been widely recognized. Scientists who were masters of explanation may not always be as well-known as the movers and shakers of science but within the community their importance is unquestioned. Most people won’t recognize the name of Harvard physicist Sidney Coleman who contributed much more to science by way of teaching, critiquing and explaining than he did through original research. Robert Oppenheimer was similar. At the height of his powers, Oppenheimer once said that the business of theoretical physicists was to explain to each other what they could not understand. Niels Bohr, a scientist who had an almost maddening obsession to state scientific facts accurately, used to stress to his brilliant students and colleagues that they could not claim to have understood the thorny subtleties of quantum mechanics if they could not explain them to each other in “plain language”. Richard Feynman quipped that one could not really hope to have understood something if he or she were unable to explain it to the average layman on the street. It may not be obvious, but all these scientists were implicitly extolling the key value in science of what we are calling science “popularization”.

But assuming that my friends had understood the importance of communication, that may have still led them to their second misunderstanding; that only scientists who are accomplished in research are capable of the best scientific communication. As I have noted before, even a factual examination tells us otherwise; there are as many first-rate formally untrained science communicators as there are trained ones. This leads right away to the larger fallacy stated above; the assumption that knowing or doing science necessarily means spending all your time in actual scientific research.

It’s important to spend some time discussing this fallacy since it also implicitly assumes that being steeped in the fundamentals, getting trained at the best universities or under the best scientists or being the valedictorian of your class are all equivalent to great scientific creativity and necessarily imply an actual research career. This is not the case at all, not just among non-scientists but even among scientists. As the case of Coleman and Oppenheimer reveals, the history of science reveals a multitude of (largely unsung) first-rate scientific “critics”, those who had an excellent grasp of their field but who could not, for one reason or other, achieve creative genius commensurate with their intellect. But Coleman and Oppenheimer were still exceptional scientists. How about science journalists who graduated with degrees in history, english and philosophy and then penned top-notch scientific volumes? The bigger point really is that science, just like many other things, is basically a set of complex ideas that can be digested by virtually anyone if they really apply their mind to it. People who can understand the tortuous meanderings of politics or the vagaries of sports statistics really shouldn’t have much problem understanding scientific basics, and this is proven for example by people who have edited excellent scientific entries on Wikipedia. Most of these people lack formal scientific training and yet have a knowledge of many scientific ideas that rivals that of the best scientists. And yet are we going to cast them aside because they are not professional scientists and will not win the Nobel Prize? There’s another key point; people may sometimes realize relatively late in their career that their real talents lie in other aspects of science like teaching and communication and not research. In fact this happens all the time (and we should be honest enough to own up to it) since many of us don’t really know what we are truly good at until late in our career. Should we then just give up these other scientific activities because we are supposed to fit within only one narrow box? Would we have dissuaded Isaac Asimov (“The Great Explainer”) from writing all those wonderful science books because he was not publishing top scientific papers? Such thinking reflects a very impoverished view of the institution of science and its role in society.

The real big truth is that not only can you understand science very well without being a great scientist but that there is nothing wrong with it. Every field needs its critics, explainers, teachers and creators. As described above, science has always been a multifaceted social activity, and it is unreasonable to assume that anyone who is competent to delve into one of its many corners should also be competent enough to delve into any other.

We live in an age where more people believe in astrology and ghosts than in evolution. In this age the importance of science communication is as or even more relevant than that of actual research, whether this communication is done by scientists or anyone else. When you are trying to discover antibiotics against rapidly evolving bacteria or viruses and when the public which ultimately funds your research is skeptical of this very evolution, you better realize the key role that the communicators of science are going to play in helping you achieve your goals. None of the great ideas that are created by “real” scientists are ever going to have an impact if they are going to reach ignorant and closed minds. Nor are most scientists involved in research going to have the time necessary to communicate science on a regular basis. On the other hand, most people can grasp and appreciate scientific facts when these facts are carefully and patiently communicated by dedicated professionals.

In such cases, it’s best to leave communication to those who do it best and nurture and encourage their potential. We owe them a lot. It does not matter whether they are actual scientists or writers or just scientifically minded members of the public. Science is inherently a social phenomenon accessible to anyone with an open mind; as Oppenheimer put it, what we don’t understand we need to explain to each other. We want to get the message across. The identity of the messenger should not matter.

Originally posted at Critical Twenties

One more thing we can learn from Linus Pauling

2011-04-30T15:27:00.000-07:00

What makes a successful scientist? The question is hard to answer, not because there is no general consensus but because the precise contribution of specific factors in individual cases cannot always be teased out. Intelligence is certainly an important feature but it can manifest itself in myriad ways. Apart from this, having a good nose for important problems is key. Perhaps most important is the ability to persevere in the face of constant frustration and discouragement. And then there is luck, that haphazard driving force whose blessings are unpredictable but can be discerned by Alexander Fleming's famous "prepared minds".

But aside from these determinants, one factor stands out which may not always be obvious because of it's negative connotation; and that is the good sense to realize one's weaknesses and the willingness to give up and marshal one's resources into a more productive endeavor. Admitting one's weaknesses is understandably an unpleasant task; nobody wants to admit what they are not good at, especially if they have worked at it for years. That kind of attitude does not get you job offers or impress interviewers. Yet being able to admit what qualities you lack can make your life take a radically successful direction. And lest we think that only mere mortals have to go through this painful process of periodic self-evaluation and subsequent betterment, we can be rest assured. It was none other than Linus Pauling who went through this soul-searching. And we are all the wiser for his decision.

When Pauling graduated from Oregon State University in 1922, he had already shown great promise. At that point he had had an excellent overall education in mathematics and physics and compared to his peers in the United States was mathematically quite outstanding. In 1926 he won a Guggenheim fellowship to study in Europe under the tutelage of Arnold Sommerfeld in Munich, with trips to the great centers of physics in Copenhagen, Gottingen and Zurich included as part of the package. There Pauling met the founders of quantum mechanics, almost all of whom were about the same age, and realized that maybe his talents in physics and mathematics were not as great as he thought. There is a story, probably apocryphal, that the famously acerbic Pauli dismissed one of his papers on quantum mechanics with two short words- "Not interesting".

At this point Pauling made what was one of the the wisest decisions of his life; he decided to focus not on physics but on chemistry. He swallowed his frustration at being beaten by the best and brightest of his generation in physics and realized the great value of striking out into new territory. Why? Because his mathematical and analytical abilities, while being of considerable value in physics, would be of wholly unique import in chemistry. At that point and to some extent even today, gifted mathematicians and quantitative thinkers are quite common in physics but less so in chemistry and biology. That is precisely what makes them more valuable in the latter disciplines. In addition, Pauling had always had an empirical and experimental bent, demonstrated by his earlier research in crystallography. So chemistry it was, and the rest is history. Pauling ended up making contributions to chemistry whose significance easily paralleled that of contributions made by Heisenberg, Pauli, Dirac and Schrodinger to physics.

There are two key lessons to be drawn from Pauling's story. The first lesson is to know when to let go, to know what path on the famed fork not to take. History would likely have been quite different if Pauling had decided to be stubborn and spent the rest of his career trying to outcompete his fellow theoretical physicists. But the bigger lesson is extremely valuable for scientists wanting to make discoveries. Take a skill-set which is valuable but not groundbreaking in one discipline, and then apply it to another discipline where it will lead to novel insights and real breakthroughs. Or to put in another way, move from a crowded field where you may share your particular talent with dozens of others to one which is sparser and where your talent will be more unique, productive and appreciated. The other related lesson is to capitalize on pairs of skills, each of which by itself may not be unique but whose combination turns out to be explosive in a particular field. For instance Pauling combined his deep grounding in physics with an encyclopedic memory and a remarkably wide knowledge of chemistry's empirical facts. There were a few chemists who could marshal one or the other talent, but almost nobody could serve up Pauling's powerful one-two punch. One can find similar analogies in combinations of diverse skills like computer science and molecular biology, or electrical engineering and neuroscience.

The history of science abounds with success stories stemming from this kind of recipe. Physicists venturing into biology constitute the best example. Francis Crick was a good physicist, but he probably would not have become a great one had he stayed in physics. Instead Crick had the wisdom to realize the value of applying his physicist's mind to problems in biology and became one of the greatest biologists of the century. Walter Gilbert trained under the theoretical physics virtuoso Julian Schwinger and would have been a first-rate physicist, but applying his talents to biology enabled him to become one of the founders of molecular biology. There are also more exotic examples. The quantum physicist Tjalling Koopmans who fathered a well-known theorem in quantum chemistry did so well in econometrics that he won a Nobel Prize. In fact just like biology, economics has been another field which has been thoroughly enriched by thinkers who would have been good mathematicians or physicists but who became great economists (although the application of strict mathematical modeling in economics can lead to a world of pain). There are more local and specialized examples too. A professor of mine who is world-renowned in the physical organic chemistry of surfactants and lipids told me that he considered working in protein chemistry but realized that the field was too crowded; lipids, on the other hand, were under-explored and could benefit from exactly the kind of talents he has.

This is precisely the reason why biology is such a fertile playing field for outsiders of all stripes, from biologists and computer scientists to engineers. The kind of complex systems that biology deals with can only be unraveled through a variety of talents which people from diverse disciplines bring to the table. On one hand you need reductionist, quantitative scientists to set biology on a rigorous theoretical basis but you also need 'higher-level' thinkers who can tie together threads from disparate empirical phenomena. That's why both mathematicians and doctors continue to make valuable contributions to the field. The same can be said of chemistry. Quantum chemists like Pauling did much to root chemistry in physics, yet the sheer complexity of chemistry (after all the Schrodinger equation can be solved exactly for no atom bigger than hydrogen) demands more intuitive thinkers who can devise approximations and include empirical parameters to improve chemical prediction. Similarly, organic chemists like Stuart Schreiber and Peter Schultz were excellent synthetic chemists, but it was in the application of synthetic chemistry to biology that they found unexplored terrain and great riches.

The lesson for young scientists seems to be clear. The most explosive discoveries can result from applying talents suitable for one field to a whole new different field. And perhaps this is not surprising. Nature is not hostage to the boundaries of disciplinary convenience devised by fallible human beings and does not divide itself into rigid compartments titled "Physics", "Biology", "Approximation" or "Analytical Solutions". Nature encompasses phenomena whose analysis spans a continuum. It is hardly surprising then that she yields her secrets best to those who are more than willing to use each and every tool of analysis to criss-cross her myriad domains.

Dirac, Bernstein, Weinberg and the limits of reductionism

2011-04-19T18:49:00.001-07:00

Jeremy Bernstein is a physicist and science writer who has worked with some of the leading physicists of the twentieth century and has penned highly engaging volumes about science, scientists and society which I have enjoyed reading. I was thus disappointed to read his review of a new book on quantum theory by Jim Baggott in the Wall Street Journal which opens thus:

In 1929, theoretical physicist Paul Dirac announced: "The general theory of quantum mechanics is now complete. . . . The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known." The discipline at the point was four years old. Dirac himself was just 27. But eight decades later, we see that his optimistic evaluation was too modest. In addition to a "large part of physics and the whole of chemistry," the theory now is extended to a significant part of biology, essentially all of electronics and nuclear physics, and a large part of astrophysics and cosmology.

Really? A significant part of biology and the whole of chemistry? Both chemists and ecologists may be interested to know this. Let's take stock of this viewpoint since it highlights a quote by Dirac which has been marshaled all too often in support of reductionism. It's time to put the quote in context. Paul Dirac was one of the greatest scientists of the twentieth century and perhaps of all time, but he was no chemist or biologist. He made that statement about quantum mechanics in 1929 when quantum mechanics was at the height of its powers. The complete theory had just been developed by Heisenberg, Born, Schrodinger, Dirac and others and it had turned into physics's crowning achievement. At the same time scientists like Pauling and Slater were applying the theory to chemistry. Suddenly the world seemed to be at physicists' feet and there seemed to be no limit to what physics could achieve.

But this was not the case. The optimism about reductionism endured for the next couple of decades when physicists made monumental contributions to chemistry and molecular biology. And yet the waning years of the millennium indicated that the reach of reductionism was distinctly limited. We were just getting warmed up. As we made forays into expansive fields of chemistry and biology like self-assembly, chemical biology, population genetics, ecology, systems biology and neuroscience, it became clear that the essence of complex systems was emergence. Emergent properties seemed to demand understanding at their own levels and could not be reduced to interactions between particles and fields. At the level of every science there emerged foundational laws, not reducible to deeper principles, that served as the bedrock for that particular science. Today, as we encounter new horizons in the study of signaling networks, brain plasticity and chaotic ecological systems, it's clear that we will have to find and formulate fundamental laws specific to every system and science. No, if anything, Dirac's statement was not too modest but too ambitious; as spectacular as its predictions have been, "a significant part of biology" and chemistry cannot be explained on the basis of quantum theory.

In fact, although I am not an expert in cosmology, the extension of quantum predictions even to cosmology seems surprising to me. Isn't gravity the other dominant force that needs to be taken into account when formulating cosmological explanations? And isn't the welding of quantum theory and gravity the great unsolved problem of physics? To me the inclusion of large parts of cosmology and astrophysics under the quantum fold seems premature.

Interestingly, this abiding interest in reductionist statements reminds me a of minor debate about reductionism between Freeman Dyson and Steven Weinberg that took place in the 90s. Dyson who has been critical of reductionism for a while penned an expressive piece arguing against reductionist philosophy in the New York Review of Books. In reply, Weinberg who has been an arch reductionist replied with his own spirited rebuttal. This rebuttal has been discussed in Weinberg's engaging collection of essays "Facing Up: Science and its Cultural Adversaries".

Weinberg defined what he thought were two distinct critiques of reductionism. One was the critique of reductionism as a working principle. The other was a more fundamental, philosophical critique of reductionism as being unable to account for higher-order phenomena even in principle. Weinberg thus was making a distinction between reductionism in practice and reductionism in principle. According to him, scientists like Dyson who criticized reductionism really had a problem with the former manifestation of reductionism, as a working principle that did not really allow them to solve problems in chemistry, biology, economics or psychology. In contrast, reductionism in principle was alive and well and was being the unwitting victim of the anti-reductionists' axe. In essence Weinberg was saying that, sure, even if quarks cannot directly help you to solve the mysteries of chromosomes, they still surely account for chromosomal properties in principle.

But to me such a distinction is meaningless beyond a point. The working scientist in his or her everyday scientific life really only cares about reductionism as a working principle, not as final causation. The fact that quarks can account for chromosomes in principle is not very consequential; a biologist could care less if there were goblins manipulating the fundamental constituents of biological systems. In addition, a lot of biology and chemistry progresses through the construction of models which are not even required to reflect the presence of the very fundamental laws. At the very least, the extolling of reductionism as being able to ultimately account for all kinds of phenomena is a trivial statement; it's like saying that everything is made out of atoms. So what? That hardly helps us cure cancer.

Ultimately, I suspect the argument may be more about semantics, about the meanings of the words "explain" and "account for". But the last word actually belongs to Paul Dirac. In his quote, Bernstein left out something crucial that Dirac said. Yes, Dirac did seem to claim that quantum mechanics could explain "the whole of chemistry", but he also said later that

"...The difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble. It therefore becomes desirable that approximate practical methods of applying quantum mechanics should be developed, which can lead to an explanation of the main features of complex atomic systems without too much computation."

It's those words "approximation", "complex" and "computation" that encompass the essence of chemistry, biology and all the other sciences which Dirac did not mention.

He may have been right after all.

A singular lament

2011-04-18T05:24:00.000-07:00

When I was in high school I used to play keyboards in a band. While my own sweet PSR series Yamaha gave me much pleasure, I used to often salivate over some of the high-end models which I could not afford. Among these, keyboards made by the Kurzweil company used to seem especially sophisticated and insanely expensive and the most I could do was occasionally try these out when I attended concerts arranged by friends who were professional musicians.

I had absolutely no idea then that the founder of the keyboard company was really known for things that your average keyboard designer could not possibly dream of. Ray Kurzweil- child prodigy, engineering genius and inventor of several socially significant technologies like the flatbed scanner and a machine that reads out to the blind, multimillionaire, bestselling author, winner of the National Medal of Technology, founder of myriad start-ups- is best known today as one of the world's most high-profile soothsayers. In the pantheon of thinkers who think of technology as a panacea to all our troubles, Kurzweil is certainly at the forefront. In his 2005 book "The Singularity is Near" he laid out an astonishing version of the future in which mankind's intelligence will seamlessly fuse with machine intelligence in an unprecedented, warp-speed event called the "singularity". This would happen no later than 2029. Hearing this, it would be easy to dismiss Kurzweil out-of-hand without further thought as yet another loony new-age guru until you find out that many quite accomplished and clear-thinking individuals including Bill Gates, inventor Dean Kamen and the founders of Google take him quite seriously.

So who exactly is this Raymond Kurzweil? Filmmaker Barry Ptolemy decided to find out and the result is "Transcendent Man", a film about Kurzweil which I watched yesterday with a mixture of fascination and disappointment. The film is playing in selected cities but the DVD and a digital download are already available on the movie's site. Ptolemy probes into Kurzweil's life and finds a brilliant, articulate, curious, sad, haunted man who sheds tears over his father's grave, collects cat figurines and undergoes monthly blood tests. Along the way, several individuals who either agree or disagree with Kurzweil are interviewed. Philip Glass's haunting, edgy score adds to the allure of this unique individual. Overall Ptolemy does a good job of bringing out Kurzweil's essence, although the Glass score could not help but occasionally remind me that Errol Morris would have done an even better job with the film.

A child prodigy who built a music-composing computer when he was 17, Kurzweil holds dozens of award-winning patents worth millions. But beneath the success flows a silent undercurrent of emotional upheaval. Kurzweil is a man who had such a close relationship with his father and such a profoundly negative view of death that he has resolved to bring him back from the dead by recreating him from memories and memorabilia about him. He is someone who pops about 200 pills a day in the hope of staying alive at least until the day when his intelligence and personality can be downloaded into a computer so that he could discard this wretched, mortal body that we are all cursed with. And he sincerely believes that the day will arise when our only identity will be online and that using nanotechnology and AI, we will expand our intelligence to span the entire universe in a kind of grand cosmic denouement that will make the universe come alive and allow the human species to achieve immortality.

Yes, it is easy to dismiss Kurzweil as someone who has discovered an unusually liberating new controlled substance. And yet Kurzweil is not your garden variety wild-eyed rapture-seeking bearded madman. In fact, not having seen much of Kurzweil before, I was struck by how reasonable and self-assured he appears. Absent are the strenuous gesticulations, defensive maneuvers, dismissive put-downs and jargon-flinging that are the mainstay of snake-oil salesmen like Deepak Chopra. Kurzweil seems genuinely familiar with much of today's cutting-edge research in artificial intelligence, nanotechnology, genomics and medical science and lays out his thoughts rather carefully. The problem is that the probability space of his prognostications is highly expansive and inhomogeneous. There are predictions that seem to be within the realm of possibility in a very general sense. There are those which are at least based on currently existing technology. And then there are those that are not just out there but demonstrate a decided failure on Kurzweil's part to think things through. Unfortunately that last category dominates Kurzweil's thinking to such a significant (and often fatally flawed) extent that while fascinated, I ended up ultimately underwhelmed with both the man and the film.

First of all, let me lay down the areas where I do agree with Kurzweil. Unlike some others I don't think he is a "sophisticated crackpot"; it seems to be more a case of blinkered vision that's based on some generally accepted principles. Technological innovation can indeed be exponential and unpredictable. As Kurzweil puts it, it took a very short while (and a very startled Gary Kasparov) before a computer was able to defeat a human expert at chess. The twentieth century was the epitome of amazingly rapid technological advancement and most of today's innovations would seem like miracles for someone from 1900. The twenty-first century is very likely to witness future such miracles. Most importantly, I agree with Kurzweil that perhaps the defining technological event of this century would be the integration of the human body with electronics. This would likely start with simple but breakthrough implements that enable physically and mentally disabled people to access the world around them but would then probably lead to astonishing inventions that allow us to remotely manipulate objects through embedded electronic components. My agreement with Kurzweil also extends to breakthrough medical diagnostics enabled by nanotechnology that allow us to diagnose and treat diseases like cancer at a very easy stage. Nanoparticles are already being used for drug delivery and there is every reason to believe that disorders would be treated in the near future by injecting cell-sized nano-'robots' that are about as intelligent in sensing and manipulating their chemical environment as you can imagine. Yes, I am on board with Kurzweil in sharing a sense of wonder at all these possibilities and I suspect that's the main reason why so many reasonable people seem to hear him out.

So where's the glitch? As Neil Gershenfled who knows Kurzweil and directs the Center for Bits and Atoms at MIT puts it, "What Ray does consistently is to take a whole bunch of steps that everybody agrees on and take principles for extrapolating that everybody agrees on and show they lead to things that nobody agrees on," because "they just seem crazy."

That is indeed the gist of what's wrong. To me Kurzweil's thinking seems to suffer from two main…drawbacks (to put it mildly), even ignoring the fantastic nature of his predictions. First of all, he seems to regard historical precedent as virtually sacrosanct. As with many others, Kurzweil's starting point is Moore's Law which basically applies not just to microelectronics and transistors but also to technologies like genome sequencing and brain-mapping. I think pretty much everyone agrees that the time is not far at all when we could get our genomes sequenced for 100$ apiece. The rate of progress in mapping the activities of single neurons is also very impressive and likely to accelerate. Technology has indeed manifested itself exponentially. But that does not mean that there are no limits and that every successive stage is as facile as the previous one. Just because we have gotten through eight exponential cycles of technological expansion in thirty years does not automatically mean that the next eight cycles are going to be equally smooth. They may possibly be, but it may well be that the next four cycles are a breeze and then we get really stuck at the fifth stage. Or it may be virtually impossible to overcome the obstacles that we encounter in the third stage. A computer simulating chess is very different from a computer simulating a human brain. Given the complexities of the systems we are dealing with, it's virtually impossible to predict the exact course of events that progress might take, no matter how rosy a picture of limitless technological adaptation the past sets up before us. Especially when it comes to our view of future technology, Kurzweil should be the first one to tell us that the past is far from a perfect guide to the future (Or as Niels Bohr put it far more succinctly, "Prediction is difficult...especially about the future").

This brings me to the second and most important problem with Kurzweil's predictions, which is that for all his acumen, the man seems to be almost completely unconcerned with details. You know, the things that can actually matter in developing any kind of science and engineering. This leads to him virtually ignoring all the ways in which thing can go wrong. Consider this: one of the central events in Kurzweil's journey to the singularity will occur when we are able to reverse-engineer the human brain. Chew on that a bit. Reverse-engineering the brain entails mapping every connection, every axon, synapse and dendrite inside our remarkable 3-pound 'thin-bone vault'. And why exactly is Kurzweil so optimistic about this astonishing development? Why, because not only are we making unprecedented progress in mapping neuron activity, but the essence of neural reverse-engineering will be based almost entirely on capturing the genome sequence that codes for the brain. There is so much wrong with this viewpoint that I will leave it to others (for instance see Derek Lowe, PZ Myers, Luysii) to demolish the argument and emphasize the complexity of the brain. I have no doubt that deciphering the genomic basis of neuronal connectivity will be a landmark discovery, but for all his engineering genius, Kurzweil seems to be woefully ignorant of the sheer complexity of biology. With this viewpoint he also affirms his membership in the group of starry-eyed optimists who are completely enamored with the "omics" revolutions. These optimists seem to equate data with meaning.

The genome is the raw material, the starting point for any kind of biological organization. If the genomics revolution has taught us anything, it's how impoverished our knowledge of biology remains even after sequencing the genome. Most importantly, we have light years to go before we can understand the complex signaling networks that functional proteins form with each other and with genes, the subtle and fine-grained interdependencies of the components and networks with each other and the non-linear and startlingly indirect effects that perturbing these networks can have on physiological processes. Add to these layers of complication the control that epigenetic modifications exercise and you have a Dante's version of the hell of biological complexity that goes far beyond anything the genome sequence can tell us.

And this is where Kurzweil ultimately disappoints. Anyone (and certainly an engineer) who is studying or engineering complex systems knows how much the details matter. Every bench scientist or code-writer knows how the most unexpected and annoying details can thwart the design of simple experiments. And let's not even get started on the details of the technical, existential and ethical problems that true AI would engender. It would be one thing if Kurzweil discussed these problems and gave reasons for why he doesn't think they matter. But it's quite another when he steers virtually clear from and does not even allude to details and pitfalls. In the absence of recipes for identifying details and solving problems, prognostications are castles in the air, ephemeral beasts whose existence is at the mercy of hard reality. In fact, the same self-assured demeanor that impressed me before later started giving the impression of a man who has cocooned himself into his own little world of beliefs so fully that his world is impervious to doubt. Kurzweil's faith is unwavering, criticisms just don't seem to count.

Among his predictions are the end of aging, the distinct transfer of human intelligence into machines and the unbounded expansion of human intelligence into the entire universe. Many have relegated such dreams to the long-standing bin of human hubris. I myself am not too bothered about the part about hubris; if humans really wanted to give up their conceit and stop asserting their dominance over nature, they have long-since lost the chance. I also don’t have a problem with technological optimism and I take a rather dim view of the criticism of technology as a cure to all our woes; that’s precisely how we as a species have been developing and using technology since the discovery of fire, and as far as we do it responsibly and realistically, it’s a little hypocritical to scream foul murder now when someone proposes grand technological solutions to humanity’s most pressing problems.

No, what disturbs me most about Ray Kurzweil is that, quite apart from his blithe indifference to details and problems, it appears that in his quest to make mankind immortal, Kurzweil is somehow falling prey to the same fears that haunt him. He seems to evince a genuine distaste of death (he wouldn't be the first one) and much of his feelings seem to be motivated by the profound feeling of loss he faced after his father's death. He says that we lure ourselves into a false feeling of satisfaction by constructing all kinds of myths and comforting stories around death. Perhaps, by postulating mankind's and his own immortality by 2029, Kurzweil is doing the same thing?

Hedgehogs and foxes in chemistry

2011-04-13T08:34:00.000-07:00

Isaiah Berlin's parable about hedgehogs and foxes has long since served as a thought-provoking lens for looking at science and scientists. Berlin quoted the Greek poet Archilochus who said that "the fox knows many things, but the hedgehog knows one big thing". Scientists who spend most or all of their careers drilling down deep into one field, problem or idea are hedgehogs. Scientists who instead spend their careers sniffing out and solving interesting problems from several areas are foxes. How does the dichotomy apply to chemists?

At the outset, one thing seems clear: chemistry is much more of a fox's game than a hedgehog's. This is in contrast to theoretical physics or mathematics which have sported many spectacular hedgehogs. It's not that deep thinking hedgehogs are not valuable in chemistry. It's just that diversity in chemistry is too important to be left to hedgehogs alone. In chemistry more than in physics or math, differences and details matter. Unlike mathematics, where a hedgehog like Andrew Wiles spends almost his entire lifetime wrestling with Fermat's Last Theorem, chemistry affords few opportunities for solving single, narrowly defined problems through one approach, technique or idea. Chemists intrinsically revel in exploring a diverse and sometimes treacherous hodgepodge of rigorous mathematical analysis, empirical fact-stitching, back of the envelope calculations and heuristic modeling. These are activities ideally suited to foxes' temperament. One can say something similar about biologists.

The dominance of foxes in chemistry is demonstrated through its long history. Robert Boyle, the first modern chemist who is widely credited for separating chemistry from alchemy, is of course universally known for Boyle's Law but also made contributions to understanding combustion, respiration, color and electricity. The father of modern chemistry, Antoine Lavoisier, discovered the all-pervasive law of conservation of mass, preceded Mendeleev in putting together a tentative classification of elements and pioneered chemical book-keeping (stoichiometry). Similarly, the great chemists of the nineteenth century- Davy, Wöhler, Liebig, Kekule, Mendeleev- were all foxes who, while known for one or two important discoveries, worked in diverse facets of their chosen discipline. Chemical foxes also proliferated in the twentieth century, with Lewis, Langmuir, Curie, Fischer and Sanger being typical examples. Linus Pauling was the ultimate fox, but more on that below.

This does not mean that chemistry has no use for hedgehogs. Far from it. If there's one field of applied chemistry which has reaped riches from hedgehogs' talents, it's crystallography and especially protein crystallography. Crystallography also belongs to physics and biology, but it has enough of a crucial chemical component for crystallographers to call themselves chemists. Among crystallographers, Max Perutz was a hedgehog par excellence. Perutz spent his entire career shining his intellect like a laser beam on the structure of hemoglobin. It was largely his efforts that turned hemoglobin into one of the best studied proteins that we know and it was because of his extensive studies on it that we gained insights into some of the most general and important concepts in protein science, including cooperative effects and allostery. The chemists who won the Nobel Prize two years ago for their solution of the ribosome structure were also supremely focused hedgehogs. Special mention must be made among this trio of Ada Yonath, the "mother" hedgehog who made the ribosome her life's mission and stuck with it longer than anyone else. There are also hedgehogs in some other subfields of chemistry. For instance, Rudolf Marcus who spent his lifetime developing a comprehensive theory of electron transfer processes comes close to being a hedgehog. Similarly, Peter Mitchell is known for one big thing- the development of the fundamental theory of chemiosmosis which is of paramount importance in understanding biological energy transfer.

In every science there are also a few unique individuals who seem to be able to magically morph into both hedgehogs and foxes. The greatest chemist of the century belonged to this class. During his life, Pauling was known especially for the astounding diversity of his contributions and this puts him squarely into the fox camp. But remarkably, the hedgehogs could also claim him as one of their own since the depth of his contributions easily rivals the breadth of his interests. If Pauling had made no other contribution except his theories of chemical bonding, he would have still been hailed as one of the century's great chemical hedgehogs. That Pauling managed to be a fox and still made hedgehog-like contributions to at least three key fields (quantum chemistry, protein structure and molecular medicine) attests to the stature of his accomplishments. Among twentieth century scientists, Enrico Fermi is the only individual in my opinion who commanded both depth and breadth of this magnitude.

It is much harder to locate hedgehogs among organic chemists. The greatest of organic chemists, R B Woodward, was undoubtedly a fox, albeit one of the highest caliber. Other leading figures in the field like Corey, Stork, Djerassi, Westheimer, Breslow and Danishefsky have also been first-rate foxes. Interestingly, there are hedgehogs among synthetic chemists but they are not as well-known. One that comes to mind is the chemist John Sheehan who spent fifteen years of his life trying to synthesize penicillin. Even the great Woodward had stayed away from this molecule's perilous, highly strained beta lactam ring. Sheehan recounted his single-minded obsession in a highly readable book with a fitting title- "The Enchanted Ring". Another organic hedgehog was H C Brown who devoted his career to perfecting the chemistry of boron. Yet another example is George Olah who has had a fifty-year love affair with the chemistry of carbocations. Also, as Derek Lowe hints, organometallic chemistry may yet be a field full of hedgehog riches. The chemists who developed palladium-catalyzed reactions and olefin metathesis were very hedgehog-like.

Many leading contemporary chemists on the other hand are exceptionally gifted foxes. Harry Gray, Stephen Lippard, Stuart Schreiber, George Whitesides, David Baker, Jean-Marie Lehn, Ad Bax, Alan Fersht, Jacqueline Barton, Martin Karplus, Roald Hoffmann, Paul Schleyer, Christopher Dobson, C N R Rao, Donna Blackmond, Chad Mirkin, Eiichi Nakamura, Fraser Stoddart, Ken Houk and Dieter Seebach are but a few examples of individuals who have made first rate contributions to diverse areas of chemistry. In fact, there can be no better tribute to their identity as foxes than the fact that many of them could also be easily classified as physicists or biologists.

We mentioned the quintessential nature of chemistry as a field of dreams more attractive to foxes rather than hedgehogs. Why is this so? In chemistry unlike physics, overarching general principles are not as important as specific instances and diverse manifestations of these principles. Key unifying principles of course exist and are taught to every budding college chemist, but they are often not as deep compared with general laws in physics or theorems in mathematics. For instance, the theory of acids and bases or that of hybridization is undoubtedly a unifying theory, but it's more a set of rules derived through a mix of theoretical analysis and empirical facts. Few would equate acid-base theory with Maxwell's laws of electromagnetism, the laws of thermodynamics or the theory of Lie groups in terms of depth, fundamental importance and universal applicability. In addition, unifying concepts in chemistry (free energy, crystal field theory, conformational analysis, oxidative phosphorylation, solubility laws) are usually fathered by several individuals and not just one. The ideal of the lone thinker shunning himself or herself from society and heroically wresting nature's secrets from her grasp through single-minded pursuit is an ideal that is alien to chemistry's nature and practice. Finally, many key chemical contributions consist of methods or instrumental advances (NMR, crystallography, gene sequencing, chromatography, PCR) that are necessarily the work of many people.

Does the future of chemistry belong to hedgehogs or foxes? I see no reason for the trends of the past five hundred years to change. Chemistry will essentially remain a game for foxes. This will be even more true in the future than it was in the past because the hottest fields in chemistry like energy, nanotechnology, chemical genetics and drug discovery are especially fox-friendly. However, occasional hedgehogs of the kind described above will also remain an integral part of its development. Foxes will be needed to explore the uncharted territory of chemical discovery, hedgehogs will be needed to probe its corners and reveal hidden jewels. The jewels will further reflect light that will illuminate additional playgrounds for the foxes to frolic in. Together the two creatures will make a difference.

How (not) to get tenure

2011-04-05T10:15:00.000-07:00

Over at the blog Cosmic Variance, there are two (1, 2) excellent and informative posts on how to get tenure and how to kill your chances of getting it. While the tips and caveats apply mainly to physics positions (and primarily for large, research-focused universities), most of the points will be valid for chemistry positions too. Two especially stood out for me:

1. You may think diversity in research counts, but it does not, at least not for tenure: This is the age of interdisciplinary research where an ability to transcend boundaries is key to solving important scientific problems. Thus you may think that a track record of having worked on diverse projects may help. Apparently not for tenure; tenure committees still seem to be more impressed with hedgehogs rather than foxes. They don't want a "dabbler"; they want someone who has proven his or her expertise in a single, narrowly defined area of research. Personally I find this approach disappointing, not only because thinkers working on diverse projects can enrich a department but because scientific progress itself needs all kinds of tinkerers, from the ones obsessed with a single problem for fifteen years to ones having their fingers in several scientific pies. Sure, being able to probe to the core of your chosen speciality is important and in fact is indicative of sustained scholarship, but the capacity to think outside the box and apply your knowledge to a variety of problems is increasingly important. The way I see it, tenure committees seem to be stuck in the transition period between the age of specialization and that of diversity. In twenty years perhaps they will start to appreciate diversity more, but for now, the lesson seems to be that narrow specialization is much more important, at least for getting tenure. Once you get tenure of course you can break free of such constraints.

2. Interests outside actual research don't count, and paradoxically, interests related to research may harm your prospects: This point was even more revealing. Yes, you can have hobbies (thank you!), but the more unrelated a hobby is to your research, the more benign it will seem to the tenure committee. The good news is that cooking and horse-riding are good. The bad news is that blogging and textbook writing are bad. If you are blogging in an area related to your work, there is a much greater chance for the committee to think that you are wasting your time which could be more fruitfully spent in actual research. Similarly, textbook writing will be frowned upon, even if you write a best-selling textbook. Basically any time away from research by definition is time that can be spent on research, and that's how tenure committees think. This is not too different from the attitude that certain PhD advisors have toward their unfortunate graduate students, but that's how it is.

However, there are probably ways in which you can try to put a positive spin on your blogging and other activities in a way that makes the committee appreciate your efforts in these areas. Recently I attended ScienceOnline2011 and there was a session in which tenured professors who thought that their blogging actually helped their tenure process gave some valuable advice on pitching blogs in tenure applications. First of all, try to convince the committee that blogging is not just a pastime but a valuable way to communicate science. Thus, you could possibly make a good case that skills gained from such communication could and do help you in the classroom. Secondly, try to convey the impact of your blogging on department visibility by citing references to your blogs in the media and in scientific journals. International citations could especially help. Ultimately, however, I don't think any of these strategies would work in the majority of cases since again, none of these activities contribute to actual research as much as they do to teaching and outreach, aspects of science that are usually considered less important by tenure committees.

Are you depressed yet? Well, all this is probably not as unfair as it sounds. Think a little from the perspective of the tenure committee. They are going to run the risk of hiring someone who will hang around for thirty or more years and become a permanent department fixture. Thus they want to be absolutely sure that they hire someone who has demonstrated scholarship (and funding potential). The fact is that if you can prove your mastery in one speciality, the committee can be more confident of your potential in tackling other complex problems. They want someone who can do sustained work in a single area for half a dozen years and bring in the bacon.

At the same time, tenure committees need to awaken to the new reality where an ability to appreciate and work in diverse disciplines is as important as the ability to delve deep in one specialty. As for blogs and textbook writing, while I find the attitude disappointing, it again makes sense. Departments hire you first and foremost for your research and publishing potential. They may treat your blogging and other related activities with mild interest at best but one cannot blame them, at least in the first few years, for relegating such activities to the side when it comes to considering you for tenure.

It is also worth noting that the caveats listed above mostly apply to research-oriented universities. Blogging, textbook writing and diversity may all be appreciated more in institutions equally or more focused on teaching. But there it is; a picture that's disappointing but sensible in its own way. Say goodbye to your utopian childhood impression of science as a career in which you are free to pursue any line of activity and work in any area that interests you. At least until you get tenure, you will have to stick to a narrowly defined set of constraints and toe the line.

After that the world's your oyster. Almost.

The cult of organic synthesis

2011-03-25T09:42:00.001-07:00

In 1828, Friedrich Wöhler synthesized urea - a substance hitherto thought to be produced only by living organisms - from simple inorganic substances. The discovery was a watershed in the history of science. In one fell swoop it shattered the widespread doctrine of vitalism which held that there is something fundamentally different between the animate and inanimate worlds. Wöhler was the triumphant messenger, heralding great expectations for the new adventurers while shattering the dreams of keepers of the faith.

Only ten years before in 1818, a different kind of vitalism was being conceived. That was the year when Mary Shelley published "Frankenstein; or, The Modern Prometheus"."Frankenstein" did for the science fiction genre what Wöhlerdid for chemistry. It infused the vivid imaginations of generations of writers, thinkers and movie-makers with notions of reanimating dead matter.

Now fast-forward to 1960. Woodward synthesizes chlorophyll. Chlorophyll. The substance which more than any other fuels life on this planet. There are telling similarities betweenWöhler's synthesis of urea, Shelley's creation of "Frankenstein" and Woodward's synthesis of chlorophyll. All three speak to man's mastery over Nature. All three embody a conscious or unconscious sense of hubris. And all of them tell us that the allure of vitalism is still alive, albeit in a very different sense. The chemists of Wöhler's generation strove to annihilate the distinction between living and non-living. But the synthetic chemists of Woodward's generation want to do one better and are closer to the brilliant, troubled protagonist of Shelley's novel; they want to not only starkly state the difference between life and death but they want to become the creators of both.

Wöhler's urea and Woodward's chlorophyll demonstrate the second reason for the cultish status of organic synthesis. The first was the cult of personality, but the second is the cult of psychology. There is a truly seductive feeling of power in being able to synthesize a substance like chlorophyll whose constitution seemed for years to be among Nature's most closely guarded secrets. A creature who could unravel the workings of this most fundamental of nature's engines would announce himself to be a true master of creation. What better way to make this announcement than to not only tease apart the strands of this secret but to create it from scratch? In fact it's worth noting the other landmark Nobel Prize winning discovery related to photosynthesis: the unraveling of the structure of the photosynthetic reaction center protein by Harmut Michel, Johann Diesenhofer and Robert Huber. As important as it was, the psychological impact of even this discovery cannot compare to the creation of chlorophyll through human ingenuity.

That is why, among all the chemical sciences, organic synthesis still enjoys a unique status. It harkens back to one of man's most primitive desires, to remake the world in his image; to first closely study, then mimic, and finally improve over nature. There can be no higher accolade for a species than to be congratulated for being able to trump it's very creator. This accolade is manifest in the Nobel committee's tribute to Woodward as well as to organic synthesis when itnoted that "It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here Nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second." In addition organic synthesis not only creates the molecules of life but it saves life, and the production of novel drugs further drives the image of synthesis as an instrument of human triumph.

The new science of synthetic biology promises to satisfy the same craving. The deliberate synthesis and rearrangement of genes to create new organisms from scratch promises the same kind of psychological benefits that the total synthesis of complex substances afforded to both organic chemists and lay audiences. No wonder that discoveries by Craig Venter and others are heralded in the press as the dawn of a new age, and they undoubtedly are. But in terms of their goals, these spectacular advances simply constitute the extensions of an age that began in 1828. And the psychological need goes back even further, when man was living in caves and creating innovative tools, agricultural implements and clothing from animal hides.

It's just vitalism and Frankenstein writ large all over again.

The long grave dug?

2011-03-22T07:16:00.001-07:00

Every time there is any kind of nuclear incident, the media does a hit job on nuclear power. People who support nuclear power and try to put things in the right context become "pro-nuclear partisans". The New York Times's reporting during the aftermath of the tsunami has been appalling. Not all the reporting was bad, but coverage of the tens of thousands of deaths from the tsunami and earthquake was relegated to the side-lines while alarmist headlines about the nuclear accident were splashed on the front page every day. Plus the paper did a masterful job of pitching contradictory facts. For a long time it stuck with the line that the accident was comparable to Chernobyl. It certainly was serious, but there was absolutely no evidence for the comparison, nor was there any discussion of the fundamentally flawed design of the Chernobyl reactor in comparison to the Fukushima reactor which stood up admirably to a 8.9 magnitude earthquake followed by a gigantic tsunami.

Then two days back, The Times blithely flashed the confusing headline that the Japanese have "upgraded" the level of the accident to Three Mile Island levels. This made it sound like the disaster was now considered worse than before, which was in complete contravention of the facts and a masterful piece of obfuscation. The fact that the Japanese considered the accident to be milder than TMI before makes the Times's constant comparison to Chernobyl absurd and shamefully alarmist. While The Times is no longer trotting out the line about Chernobyl, it has not made any sustained effort to educate the public about the completely benign nature of TMI in terms of the consequences. In addition the paper had another confusing headline yesterday titled "Radiation Plume Reaches U.S., but Is Said to Pose No Risk". As Rosie Redfield notes on her blog, the studied ambiguity in the statement (someone says the plume poses no risk, but we won't say that explicitly) does nothing to put the risk in the right context.

The New Yorker is no less biased. In the most recent issue there are two pieces on nuclear energy. One is a moderate critique by the environmentalist Elizabeth Kolbert while the other is a rather extreme and emotional critique by Japanese writer Kenzaburo Oe. While Kolbert does not go overboard, she casually throws around some opinions about how nuclear reactors are not protected against terrorist attacks. This is in spite of the fact that American nuclear power plants are well-secured, terrorists would have a very hard time stealing nuclear material from a power plant even if they overwhelm security, they would have a hard time getting away unnoticed, and the stolen nuclear material would be extremely dangerous to handle andcapricious in its behavior in a weapon. Of course all this just ignores the fact that terrorists are so much more likely to smuggle in a weapon from abroad than they are to foolishly attack a US nuclear reactor for making one. Kolbert also has biased critiques of lack of evacuation plans for people around a nuclear reactor (ignoring accident probability, radius of evacuation and the amount of radiation released) and spent fuel storage (no discussion of reprocessing, quotes from the Union of Concerned Scientists which has long-since vigorously opposed nuclear power).

Oe is worse; adopting one of the oldest tricks in the anti-nuclear playbook, he makes no attempts to separate nuclear weapons from nuclear power and constantly conflates the two ("Lessons of Hiroshima"). Basically there is no balancing pro-nuclear perspective. The New Yorker should be ashamed of itself for this one-sided reporting.

All this is keeping in line with physicist Bernard Cohen's extensive writings. Cohen has been a tireless and rational promoter of nuclear power for more than three decades and his articles and books are thoroughly readable. If you don't have time for his books, you should definitely at least read his essay in a recent collection of essays expounding on the relationship between science and politics (Politicizing Science, 2003). Cohen analyzed various accidents and their coverage in the New York Times in the 70s (even before TMI). He found that while there was a clear correlation between the number of deaths and the subsequent coverage for all other kinds of accidents (low number of deaths corresponding with low coverage), when it came to nuclear accidents the Times went ballistic. The coverage was all out of proportion with the number of deaths- zero. That's exactly what's happening right now. In addition Cohen recounts routinely being ignored and even reprimanded when he wrote letters to journalists whose coverage of nuclear power contained numerous factual (not literary) mistakes. Even trying to correct thescience brought forth responses like "I don't tell you how to do research so you don't tell me how to do journalism". As Cohen sums it up:

"To attack the nuclear power industry, activists needed ammunition, and it was readily found. They only had to go through the nuclear power risk analysis literature and pick out some of the imagined accident scenarios with the number of deaths expected from them. Of course, they ignored the very tiny probabilities of occurrence attached to these scenarios, and they never considered the fact that alternate technologies were causing far more deaths. Quoting from the published scientific analyses gave the environmentalists credibility and even made them seem like technical experts."

The situation seems to be no better right now. Needless to say this distortion of the truth is not just appalling but it could be a certain recipe for disaster even as nuclear power needs to be a healthy component of the mix for combating climate change. Liberals always like to complain about how the conservative media distorts and cherry-picks the science on global warming. The litmus test of the liberal media's scientific integrity would be its coverage of nuclear power. Sadly it seems to have already failed this test multiple times.

A hundred years from now when we are possibly writing the epitaph for the human race, I wonder if one of the turning points on the road to perdition would be seen to be our inability to rationally balance the benefits and risks of the greatest source of energy that mankind has discovered.

"Quantum Man"

2011-03-18T11:22:00.000-07:00

I still remember the day when, as a kid, I first came across the irrepressible Richard Feynman's memoirs "Surely you're joking Mr. Feynman". Within a few hours I was laughing so hard that tears were coming out of my eyes. Whether he was fixing radios 'by thinking', devising novel methods of cutting string beans in a restaurant or cracking the safes at Los Alamos, Feynman was unlike any scientist I had ever come across. Feynman died in 1988 and James Gleick's engaging and masterful biography of him appeared in 1993. Jagdish Mehra's dense, authoritative scientific biography came out in 1996. Since then there has been a kind of "Feynman industry" in the form of tapes, books, transcripts, interviews and YouTube video clips. While this has kept Feynman alive, it has also turned him into a kind of larger-than-life legend who is more famous in the public mind for his pranks and other exploits than for his science. Most laymen will tell you that Feynman was a brilliant scientist but would be hard-pressed to tell you what he was famous for. It's time that we were again reminded of what most contributed to Richard Feynman's greatness- his science. Lawrence Krauss's biography fulfills this role. You could think of Gleick's biography as a kind of Renaissance painting, an elaborate piece of work where he gets everything accurate down to the eyebrows of the men, women and Gods. Krauss's biography is more like the evocative impressionistic art of the French masters, more of a lucid sketch that brings out the essence of Feynman the scientist.

The biography is essentially aimed at explaining Feynman's scientific contributions, their relevance, importance and uniqueness. Thus Krauss wisely avoids pondering over oft-repeated details about Feynman's personal life. He compresses descriptions of Feynman's childhood, the tragic story of his first wife's death and their extremely touching relationship and his time at Los Alamos into brief paragraphs; if we want to learn more we can look up Gleick or Feynman's own memoirs. What concerns Krauss more than anything else is what made Feynman such a great scientist. And he delivers the goods by diving into the science right away and by explaining what made Feynman so different. Perhaps Feynman's most unique and towering ability was his compulsive need to do things from scratch, work out everything from first principles, understand it inside out and from as many different angles as possible. Krauss does a great job in bringing out this almost obsessive tendency to divine the truth from the source. It manifested itself at a very early age when Richard was cranking out original solutions to algebra and arithmetic problems in school. And it was paramount in his Nobel Prize winning work.

Krauss succinctly explains how this intense drive to look at things in new ways allowed Feynman to do novel work during his PhD with John Wheeler at Princeton in which he formulated theories that described antiparticles as particles traveling backwards in time. Later Feynman also applied the same approach in using a novel method based on the principle of least action to explain the dizzying mysteries of quantum electrodynamics. Krauss does an admirable job in explaining the physics behind these contributions in layman's terms. Feynman's "sum over histories" prescription involved taking into consideration all of the infinite paths that a particle can take when getting from the beginning to the end point. This was a bizarre and totally new way of looking at things, but then quantum mechanics is nothing if not bizarre. As Krauss describes, the moment of revelation for Feynman came in a meeting where, using his techniques and intellectual prowess, he could finish in a few hours a complicated calculation for mesons that had taken another researcher several months. Krauss also narrates how Feynman brought the same freewheeling, maverick approach to thinking about superfluidity, beta decay, the strong nuclear force, gravity and computing and the book contains the most complete popular scientific treatments of Feynman's thoughts about these important problems that I have seen. The approach did not always work (as it did not in case of superconductivity) but it encouraged other physicists to think in new ways. In fact as Krauss lucidly narrates, Feynman's great influence on physics was not just through the direct impact of his ideas but also through the impact of his unconventional thinking which inspired students and other scientists to think outside the box.

As scientifically brilliant as Feynman was, Krauss also does not gloss over his professional and personal flaws and this biography is not a hagiography. Professionally, Feynman's independent spirit meant that he often would not read the literature and would stay away from mainstream interests which his colleagues were pursuing; while this greatly helped him, on more than one occasion it led to him being scooped. At the same time Feynman also did not care about priority and was generous in sharing credit. As for mentoring, while Feynman was a legendary teacher by way of example, unlike his own advisor John Wheeler he left few bonafide graduate students because of his compulsive tendency to solve problems himself. On a personal basis, probably the most shocking description concerns Feynman's womanizing. It's hard to say how much of it is true, but Krauss describes Feynman's affairs with colleagues' wives, his elaborate methods to seduce women in bars and the personal and emotional entanglements his womanizing caused. At least one fact is jarring; apparently when he was a young professor at Cornell, the boyish-looking Feynman used to pretend to be a graduate student so he could date undergraduates. This kind of behavior would almost certainly lead to strict disciplinary action in a modern university, if not something more drastic. In his early days Feynman was also known for not suffering fools gladly, although he mellowed as he grew older. Later on Krauss details Feynman's more publicly known activities, including his bongo playing, nude painting and his famous demonstration of the failure of the O-rings in the Challenger space shuttle disaster. Feynman's absolute insistence on honesty and truth in science and on reporting the negative results along with the positive ones also comes across, and should be a model for modern scientists. The biography does a good job of demonstrating that in science, true success needs fearlessness, determination and an unwavering belief in your ideas.

Ultimately, it's not Feynman's bongos, nude art and relentless clowning that make him a great man. However, since his death, he has often been perceived that way by the public largely due to the industry that has grown up around him. But Richard Feynman was defined first and foremost by his science and his striking intellectual originality that allowed him to look at the physical world in wholly unanticipated new ways. Krauss's biography performs a timely and valuable service in reminding us why, when we talk about Feynman, we should first talk about his physics.

Perspective...again

2011-03-16T08:26:00.000-07:00

No one advocated halting the manufacture of methyl isocyanate or shutting down the chemical industry after the Bhopal tragedy of 1984 which killed thousands more than any nuclear accident. The Gulf oil spill also did not provoke howls to terminate oil production. And of course, you don't hear calls for permanent evacuation of coastal communities because of the occasional tsunami that can wipe out these cities in a catastrophe much worse than a nuclear engineer's worst nightmare.

I cannot add much to what's being already said and I join millions in wishing the unfortunate citizens of Japan the very best. But even a serious accident like the one currently unfolding at the Japanese nuclear plant should not blind us to the bigger picture. Predictably, there have already been calls from alarmists to stop all nuclear building in the US. In keeping with the media's appetite for sensationalism, the Washington Post put an adequately fear-invoking and alarmist photo on their cover page. As others have noted, we don't regularly hear calls to halt oil and natural gas production after accidents that are much more damaging in terms of environmental destruction and human life compared to the one or two serious nuclear accidents we have witnessed. The only response after a crisis such as the present one should be to put together a review of reactor safety in other parts of the world and how it could possibly be improved to withstand such freak scenarios as the ones we are witnessing. But when presented with an unfortunate, unlikely case, human nature is to throw out the baby with the bath water.

Already people are comparing the current crisis to Chernobyl. This is a ridiculous comparison, partly because the current reactor and the contingency response have been much better than the ones during Chernobyl and partly because if you really want to cite the worst case scenario, you might as well hold up the Hindenberg as an argument against air travel. In case of Chernobyl the accident was of course the result of a combination of several factors, including a fundamentally flawed design and human inertia engendered by communist ideology that prevented rapid response. The number of deaths from Chernobyl cannot be known with certainty, but it's certainly less than deaths from any number of other industry-related accidents. One can be almost sure that the effects of the present accident are going to be far less severe because of more open communication and prompt response. In fact it's heartening that these reactors with 50-year old designs did relatively well in spite of being struck by one of the biggest earthquakes in recorded history. With modern designs where passive systems can cool the core in spite of loss of electrical power, one can be much more confident about containment of radiation (as an aside, I wonder why the seawater that was pumped into the Japanese reactor did not contain cadmium chloride for neutron absorption).

Here's one of the things the US should do. Just like they did after Chernobyl, top scientists in this country should put together a committee after the facts of the Japanese disaster become known. They should undertake a review of all the nuclear reactors in the US and write a reportdetailing their safety features as well as possible measures that can be included in the unlikely case of natural disasters like the one in Japan. There should be two versions of this objective, apolitical report. One version should be more technical and comprehensive and can serve as a blueprint for future action. The other version should explain the committee's conclusions in simple terms that can be understood by the public and by members of Congress. Finally, and this is key, this version should be publicized as widely as possible in an effort to educate the public about the true risks and benefits.

Ultimately the life and death of a technology is not decided by how harmful or beneficial its effects are but by simple economic tradeoffs. Automobiles and fossil fuels have killed hundreds of thousands, but nobody advocates their extinction simply because their benefits are perceived to greatly exceed their costs. A similar argument can be made for knives and guns. On the other hand, nuclear power which boasts an impeccable safety record compared to the chemical and fossil fuel industry still sets off alarm bells and brings forth calls for its demise. This is partly because of the irrational psychological gut reaction that people still associate with the words "radiation", "nuclear" and "meltdown" (an unfortunate consequence of the fact that the world's first exposure to nuclear energy was by way of nuclear weapons) but more importantly because of the simple fact that nuclear is not seen as an indispensable energy option even now.

What will it take for the situation to change? Perhaps when war in the Middle East decimates dependence on fossil fuels or when extreme climate change exacerbates our lifestyles to an unacceptable extent, we will finally accept nuclear energy as an energy-intensive, climate change-friendly power source whose risks must be evaluated and managed just like those of others. The only question is whether it would be too late then.

When Iron and Bacteria tragically collide: From the Middle Ages to the University of Chicago

2011-03-01T09:50:00.001-08:00

Science brings us the bizarre, tragic but medically fascinating story of Malcolm Casadaban, a microbiologist working with plague bacteria at the University of Chicago, who died unexpectedly in 2009 of a then-unexplained cause. Obvious culprits were the plague bacteria he worked with. But the bacteria had been specially attenuated to be harmless in humans. So how could they kill?

It turned out that Casadaban had been the victim of an unfortunate double coincidence where two extremely rare causes combined to produce a lethal combination. It turns out that the plague bacteria he was working with had been rendered impotent by knocking out specific proteins which metabolize iron. More specifically they were engineered by knocking out a gene called pgm which codes for a protein allowing the bacterium to absorb iron from its surroundings. Iron is as essential to bacteria as it is to humans, and in the absence of iron-absorbing proteins the bacteria were useless as pathogens. Except that in this case they were not. Casadaban also suffered from hemochromatosis, a rare genetic disorder known for hundreds of years that causes the body to lock down stores of iron resulting in iron overload. From here it's not hard to put two and two together; when the iron-starved bacteria were suddenly introduced to Casadaban's body and its ample stores of the metal, they came to life like Frankenstein resurrected. The sudden windfall of virtually infinite stores of iron gave them the nutrient they lacked, transofrming them into a fatal force that killed Casadaban.

Very unfortunate, but utterly fascinating from a medical standpoint. The reason I find it even more interesting is that it seems to at least superfically contradict an equally fascinating story from the Middle Ages, and in the process provides a plausible explanation for what happened. There is a remarkable and horribly tragic piece of history that possibly supports the evolutionary benefit of a debilitating condition like hemochromatosis. In the Middle Ages, when the Black Death struck Europe on a terrible scale, Jews were often accused of bringing this malady into people's homes through some kind of mystic powers. Thousands of Jews were killed for the sake of this superstitious belief. And the fact that Jews as a population seemed to be less affected by the plague only encouraged the paranoia and madness. One of the reasons that's traditionally offered for this relative immunity is the hygenic kosher conditions which Jews practised which made their homes less attractive to rats. But another hypothesized factor is the higher prevelance of the hemochromatosis gene among Jews, especially Ashkenazi Jews who are widespread among Jewish communities. It seems that just like other bacteria, the plague bacterium Yersinia pestis needs iron to survive. By locking up iron stores, the bodies of Jewish individuals denied this valuable nutrient to Yersinia, which made the germ less successful in colonizing its victims. Thus hemochromatosis, while causing harm by storing excessive iron, might have compensated for that harm by serving as a defense against the deadly plague. This theory is quite controversial and may indeed be wrong, but it underscores the basic point that diseases which may seem to be presently harmful could have served a useful purpose in the past by defending against infections. Since Yersinia is largely no longer a concern in the modern world because of medical advances, we see only its ugly side.

But this seems to contradict what we have just heard. If hemochromatosis could deny iron to iron-starved plague bacteria in the Middle Ages, how could the same condition have the opposite effect on even more iron-starved bacteria in Casadaban's body? I don't know the answer, but a plausible explanation is that the ultra iron-starved, genetically engineered bugs simply evolved to be much more efficient at scavenging iron from Casadaban's cells than normal plague bacteria. We have all seen how the phosphorus-starved bacteria in the arsenic fiasco are widely thought to have evolved an ability to mop up and zealously guard phosphorus stores even more efficiently. When the going gets tough, the tough gets going, especially in the bacterial world. It is well-documented how remarkably fast bacteria can evolve their biochemical machinery to tide over unfavorable circumstances and efficiently utilize low concentrations of essential nutrients down to the last atom. It won't be suprising at all if the impotent bacteria in Casadaban's unfortunate body simply retooled to forcefully rip out iron from his cells and proliferate. A small, routine step for bacteria with giant, terrible implications for a human being.

What an unfortunate story, but it's implications are utterly sobering. It tells us how much we still don't understand about the risks of modifying genomes of simple organisms. Genetically engineered organisms can combine with naturally engineered human bodies in bizarre, unexpected and tragic ways. We may have started to come to terms with the synthetic modification of life, but we still have a long way to go before we understand how the different parts of the natural and artificial worlds dynamically interact with each other in ways that we cannot anticipate. There's miles to go before we can sleep.

"Shine during the day, and let me shine at night"

2011-02-02T20:45:00.001-08:00

After the sound of my parents' voice, his voice is among the first ones I distinctly remember hearing after being born. For twenty three years as I grew up, his voice filled our home. It sustained, nourished and inspired me at every turn of my life. And while it will forever be a part of my soul, the source of those thundering notes himself has passed into history. Pandit Bhimsen Joshi is no more, and with him a part of my childhood has died. Yet his legacy will live on in the hearts of millions like me who will continue to marvel that men like him lived and gave so much to us.

Bhimsen's voice resonated in my ears almost from the moment that I was born. Like so many other things, I owe my introduction to this remarkable man and his work to my father. Over the course of the last thirty years, my father who has been a dedicated fan gathered over four hundred live recordings of Bhimsen concerts. They constantly permeated our house at all hours of the day. They spanned over fifty years of Bhimsen's own life and career and were gathered from multiple sources; from other die hard fans, from commercial sources and from Bhimsen's own students. Some recordings originated with the great man himself and made their way to our collection through a long-winded trail of ardent music lovers and collectors. Over time the collection became substantial and valuable. My exposure to Bhimsen was so constant that once at the age of six or seven, I accosted him even as he was paying a visit to a travel agency whose office was located in our apartment complex. Possessing none of the timidity that comes with age, I let out a delighted cry of recognition: "Aren't you Bhimsen Joshi? I of course recognized you right away!". I can still see the master smiling beneficently at me.

What was so special about Bhimsen? Simply put, there is not a single other singer I know from any musical tradition whose voice shimmered with such sheer unadulterated supreme motive power. Bhimsen's voice thundered. It leapt and bounded and bored through our hearts. It ripped apart the air between us and the source and stirred something elemental within our soul. It justified in every sense the etymology of Bhimsen's name; a towering musical version of the mythical Bhim whose physical prowess was legendary. It constantly stretched our imagination to believe that the human throat, that compact assembly of muscles, nerves and skin could produce frequencies and notes that were so formidably potent as to almost physically make us tremble the way the wind from a tornado would. When Bhimsen sang, it was as if the heavens roared, and the Gods listened. But to call the notes emanating from him as emerging from his throat would do him a disservice. Bhimsen's music seemed to arise from the collective movement of every single cell in his body, the Herculean labor of every electrical connection between his neurons. Yet there was extraordinary versatility; sometimes the sound seemed to emerge from the depths of an endless, cavernous labyrinth of musical complexities and powers, yet a fraction of a second later it would turn into lyrical threads of sheer silk, into ephemeral snowflakes being wafted on a delicate breeze of air. The result defied belief.

This belief was not sullied by any of the tales about him which had more than a shred of truth in them: his sometimes difficult relationships, his problems with alcoholism and his temperamental behavior. If anything, they served as a valuable reminder that this supremely gifted being was human after all. Similar to other great men, Bhimsen's flaws only enhanced his prowess and reputation and generated anecdotes enthusiastically bandied about by his fans as they listened to his performances late in the night in the Sawai Gandharva music festival which he pioneered. Every one of his habits, from contorting his face to comical proportions to wildly flinging his extremities around when traversing a particularly treacherous set of notes, was affectionately remembered.

With such a prodigious command of the musical canon at his disposal, Bhimsen could mold his voice to suit any mood, any Raga and any genre of song. My earliest exposure was to his "Abhangas" which were songs dedicated to Indian saints. Bhimsen spent most of his life and career in Pune, and many of the Abhangas were subsequently dedicated to Marathi saints like Dynyaneshwar and Tukaram. My father used to play these all the time and I was so taken with them that I used to frequently do my best to sing a flimsy resemblance of them in school events. One set of memories connected with the Abhangas vividly stands out. My father originally hails from the town of Ratnagiri in the Konkan region. In those days we used to visit our Ratnagiri relatives often. The trip used to entail hot, long, precarious drives through the Western ghats. Air conditioning in cars was non-existent and the condition of the roads often meant at least an eight-hour trip with a flat tire or two generously thrown in. Defying the instructions in the Bhagavad Gita, I used to look forward to the fruits and resented the journey. But the one factor that always kept me from despairing was the presence of Bhimsen's Abhangas which my father used to inevitably play on tape. The majestic Sahyadri mountains looming on the horizon and the green countryside sloping gently beneath us, the Abhangas used to imbibe the landscape with newfound grandeur. Sometimes it seemed that Bhimsen's booming voice would reverberate in the mountains forever, becoming an integral part of their billion year old history, enduring into their future till eternity. Maybe it did.

Every music lover has a listing of his favorite artist's most memorable renditions. With Bhimsen such a list is difficult to compile since the man could turn everything he touched into pure gold. Yet there inevitably are certain Ragas that stand out, ones to which only Bhimsen could do supreme justice. Considering the utter energy of his voice, what better Raga to pick than Miya-Malhar, the Raga of the Rains. The Raga could well have been crafted a thousand years ago exclusively so that Bhimsen could sing it one day and leave us awestruck. The legendary Tansen from King Akbar's court was said to be able to summon forth the rains at will by singing this Raga. Close your eyes and listen to Bhimsen singing Miya-Malhar, and one could easily believe the legend. The initial slow vilambit cadence evokes majestic pictures of clouds gathering. Very few leading singers could hit notes as low as Bhimsen could and sustain their voice at these frequencies. Bhimsen massages the aroha and awroha (the increasing and decreasing base notes) like water droplets massaged by clouds to gather together. As the speed progresses to medium, one can almost feel the glistening raindrops gradually falling down from the heavens and striking your skin. And then it comes, the roar of his voice, like a rain God who has unleashed his benign powers on earth's denizens. As the druta (fast) rhythm builds up to a crescendo with unbelievably swift and shimmering tanas, one can almost feel the grand symphony of thunder, lighting and water unfold, enveloping us in its all-consuming glory. If you believed in God, you could believe that his name was Malhar.

Malhar is just one of many gems. Another Bhimsen specialty is Raga Darbari which evokes a mixture of melancholy, peace and beauty, best heard at night. Bhimsen could also pay the ultimate tribute to Raga Malkauns, another night Raga which is supposed to evoke a sense of romantic love. A towering morning gem is Raga Todi. And then there's Raga Bhairavi, the Raga of conclusion, usually sung at the end of a concert; some of Bhimsen's best known tunes are from this Raga. A particularly memorable recording was a live recording from the 1950s in which Bhimsen sang Raga Malkauns in the famous Vitthal temple in the holy city of Pandharpur. Even today this rendition sends a shiver down my spine as it evokes a sublime sense of experiencing transcendent talent in a place where millions have worshipped, prostrated and found wisdom and inspiration. One can only imagine the unique juxtaposition created by the sacred idols and the music which undoubtedly would have swayed them had they been sentient beings.

But personally for me, the ultimate embodiment of Bhimsen is Raga Yaman-Kalyan. This is a relatively simple Raga, used in many film and folk songs. It is taught to students during the earliest stages of their musical instruction. There is a perfectly good reason for the universal presence of this set of notes. More than almost any other Raga, Raga Yaman-Kalyan imbibes you with deep feelings of happiness, peace and optimism. In my opinion there is no human being who ever lived who can do this Raga the kind of justice that Bhimsen did. When Bhimsen sings Yaman-Kalyan, you feel like all the darkness in the world has been penetrated by a glowing light which will burn bright forever. The light emerges from Bhimsen's soul and shatters your worries and troubles. It envelops the world around you with a warm glow that seems to illuminate the truth, beauty and dignity in everything that you see, touch and hear. Bhimsen singing Yaman-Kalyan is Jesus delivering the Sermon on the Mount.

For a long time it was considered a travesty that the Indian Government did not award Bhimsen the Bharat Ratna. Many leading minds lobbied for the award, although any one of Bhimsen's fans knew that his talent easily surpassed every honor that it could claim. But in 2008 the government finally redeemed itself by awarding him the Bharat Ratna. Even without the award Bhimsen's stature would have been wholly undiminished, but the government would have had to live with itself the way the Nobel committee has had to live with itself for not awarding Gandhi the Nobel Peace prize. The Ratna was a giant step for the administration, but in a way it was a small step for a man whose contributions to music had the stamp of permanence that no medal and government have. However, the government had already tacitly acknowledged Bhimsen's stature by giving him the opening lines of one of India's most famous national tunes- the ubiquitously sung and performed "Mile sur mera tumhara". Bhimsen's face juxtaposes with those of the Himalayas, perfectly indicating the power, reach and enduring legacy of his voice.

So how can we sum up Pandit Bhimsen Joshi? How can we even begin to encapsulate such a unique concentration of abilities in one man in words? His own contemporaries fully recognized his singular talents and realized that they would not see the likes of him for a long time. Perhaps the ultimate tribute was offered by the eminent vocalist Pandit Jasaraj who quipped on Bhimsen's eightieth birthday, "Eighty years ago, Bhimsen Joshi made a contract with the Sun God. He told the Sun, 'Shine during the day, and let me shine at night' ". Bhimsen did shine, at every moment of our lives and those of the future.

But personally for me, the sheer all-encompassing power of Bhimsen's works brings a tribute offered to another supremely talented individual to mind. The natural philosopher William Whewell (who coined the word 'scientist') said about the monumental Principia Mathematica:

"As we read the Principia we feel as when we are in an ancient armoury where the weapons are of gigantic size; and as we look at them we marvel what manner of man he was who could use as a weapon what we can scarcely lift as a burden...”

Whewell's quote sums up what I feel about Bhimsen Joshi. Bhimsen was the Newton of Hindustani classical vocal music.

Note: Cross-posted on Critical Twenties

A government center for drug discovery?

2011-01-23T13:35:00.001-08:00

The New York Times has an article about a new center for drug discovery that the government is going to set up in the face of the declining pace of new drug discovery in the pharmaceutical industry. We all know what's wrong with the industry, with the numero uno factor being the pursuit of short-term profit goals at the expense of basic science and long-term benefit. The question is, can the government make up for this shortfall?

Perhaps, if it's done right. But the vision for the new center does not inspire me with much confidence. The center seems to mainly be a result of NIH director Francis Collins's conviction that gene-based drug discovery is the wave of the future. Collins is disappointed with the fact that Big Pharma has been unsuccessful with "translational genomics" in spite of spending millions of man hours and dollars. He thinks that if done right, this kind of translational approach will result in new drugs. As he makes it clear in his book "The Language of Life", Collins is a longstanding proponent of genomics-based medicine.

But isn't this what everyone has been saying ever since genome sequencing became possible? We all remember the hype about genomics enabling a new generation of 'rational' drugs based on intimate knowledge of genes and their protein products. The fact that this vision has not panned out could partly be ascribed to the lackluster efforts and the constant waves of lay-offs in industry, but maybe there's also a deeper reason why the optimism has hit a wall. Maybe, and experts have been saying this for a while now, it's simply because taking a genomics-based approach to drug discovery ignores all the other complexities of biological systems like signal-transduction and epigenetics. Discovering the gene and protein is one thing, understanding the intricate interactions of the protein as part of a multi-layered cellular communication network is quite another. We are still struggling to understand the very basics of how proteins and genes link up in cells to enable complex physiological and behavioral responses, let alone rationally design drugs to block specific parts of those responses. In the absence of such understanding, simply pinning your hopes on the promise of 'translational genomics' seems to me to be another big sink for money and personnel.

So what else can a government center for drug discovery do which could be more concrete and fruitful? Ironically, the article contains part of the answer when it highlights the complexity of biological systems stated above.

Consider this remarkable fact; in the last century, only two breakthrough treatments for mental illness have been developed, lithium for bipolar illness and chlorpromazine (Thorazine) for schizophrenia. Many other successful antipsychotic drugs were spinoffs of thorazine. Also consider that even today we have little clue about how these drugs work, let alone how to rationally design them. Thorazine likely affects multiple neurotransmitter pathways involving serotonin, norepinephrine, dopamine etc. While we have made great advances in the last fifty years, brain chemistry remains as complex as ever. At a molecular level, the main problem is in understanding the basic mechanisms and specificity through which a molecule as simple as dopamine binds to only certain subtypes of a neurotransmitter receptor, stimulates multiple second-messenger pathways to different extents and elicits a complex behavioral response. In this case we know most of the genes and we know most of the protein products, yet we are light years away from understanding how Thorazine works. Lithium is an even more mysterious substance whose workings are almost akin to black magic. Instead of chasing the genes, thoroughly understand the action of a few of these drugs on a biochemical level and we can make significant inroads into understanding brain chemistry.

So if there's one thing a new government center for drug discovery can do, it should be to focus on these specific problems in the most general way rather than pool together resources for "translational genomics". Doing translational genomics will simply mean advancing work which industry is already involved in; it will largely be more of the same and there's good reasons why it may not work.

Here's what I think instead. If the center truly wants to do something productive that pharmaceutical companies cannot, let it put together a mini Manhattan Project type team focused on understanding a few specific problems, like how lithium works in the brain. The problems should be picked based both on their medical importance and their potential impact in enabling general understanding of the field. Just like the Manhattan Project did, get together the best people in the country from several disciplines who are experts at multidisciplinary thinking and problem solving. If you want to attack the lithium problem for instance, get together chemists, biologists, neuroscientists, pharmacologists, doctors and perhaps even a few physicists, mathematicians and computer scientists. Put them in a couple of large rooms (and maybe even seclude them in the majestic mountains of New Mexico) and give them enough funds. And then most importantly, give them almost complete freedom to brainstorm about specific problems. Let them consider every possible approach, from running basic biophysical experiments to the most advanced neural imaging techniques. Don't limit yourself to any one philosophy like translational genomics or any other currently fashionable mantra. Genomics can certainly be part of the mix but it should not be put on a pedestal. Combine the oldest tools of classical pharmacology with the newest tools of molecular biology. If the industry has been missing one thing, it's been the presence of bright young people who are given complete freedom to focus on their diverse ideas without strings attached and constant fear of unemployment. The government can give these men and women what industry has taken away from them in recent years.

The government has always been good at this kind of free-for-all interaction among talented scientists who are unencumbered by research funds and job insecurity. A new government center for drug discovery could be a great idea, but only if it provides the kind of freedom to operate that brings out the best in creative minds. Focusing on translational genomics to me seems to be another way to repeat what has been done and to waste more funds, time and personnel. Instead, do what the government does best; let them think, and let their minds soar.

How can we make the International Year of Chemistry successful?

2011-01-17T09:53:00.001-08:00

2011 has been designated by the UN as the"International Year of Chemistry". For the community of chemists the question is simple: What can we do to make this year successful and enhance the public's appreciation of chemistry? Here are three core aspects of chemistry which I think should be constantly highlighted:

1. Explain to the public the essential nature and unique philosophy of chemistry: As a field, chemistry is inherently more challenging to pitch to the public compared to physics or biology. If you are a physicist and you say to a layman that you are investigating the Big Bang, you don't have to say anything more to get his or her attention. A biologist who works on human evolution will get similar nods. But what about chemists? One of the reasons for the relatively dim public appreciation of chemical science was mentioned before; it is because the field apparently lacks "big ideas" that people can instantly latch on to (but see below). But what chemistry may lack in terms of the grand picture, it more than compensates for in terms of its identity as a "central science" and the sheer number of explanations and applications that it lends to almost every other discipline, from physics and biology to art and engineering. No other field does this in such a palpable way. In this sense chemistry is akin to engineering, but much more fundamental.

The chemist more than any other kind of scientist is a discerning arbiter of patterns and a patterner of chaos. One of the manifestations of this quality is in the beautiful structures that chemists draw and encounter every single day. Chemists look at structures the way artists look at mosaics of colors and architects look at geometric patterns. What other kind of scientist spends his or her professional workday doodling and evaluating lines, rings and their myriad intersections? In its ability for visualization and pattern analysis, chemistry comes closer to art than any other science, and the public needs to appreciate this supremely important aspect of the discipline.

But it is in its ability to make new things which never existed before that chemistry is wholly unique. In the last few years synthesis and especially total synthesis have taken some flak as somewhat self-serving activities geared toward factory-style publication and the nurturing of slave labor, but it cannot be denied that synthesis is what makes chemistry different from all other disciplines. No other science can boast the creation of new substances that have improved every facet of human life, from the conquest of disease to the feeding of the poor. Of course chemistry also led to poison gas and nerve gas but this was true of other discipline too. The fact remains that chemistry has modeled and sculpted the material world familiar to the layman more than any other science. Other fields provided valuable input to the principles behind synthesis, but the end products were those of chemistry alone, shining examples of the very ability of human beings to create, manipulate and improve. In the future chemistry promises us improved materials for alternative energy and designer drugs and biomolecules for treating disease. Convince the layman of the enduring centrality of synthesis, and you would have convinced him or her of the essential value of chemistry.

2. Push the origin of life as chemistry's "big idea": We mentioned above that chemistry seems to suffer from a lack of big ideas as compared to physics and biology and that this is partly responsible for its lackluster public perception. But as I indicated in my last post, there is actually a problem as big as any other which is primarily within the domain of chemistry. This is the origin of life within its broader framework of self-assembly. God must have been a molecular self-assembler, because without self-assembly the first components of life could not bond to each other and the first cells could not form and segregate their cargo, sparking the interactions and reactions that led to replication and metabolism. Darwin solved the second problem of what happens when life gets started, but not the first one of how it all began. Again, other sciences will continue to contribute to the unraveling of this problem, but the first step was uniquely chemical. A narrating of the origin of life as a quintessentially chemical question would also lead to a general exposition on self-assembly (important in diseases caused by protein misfolding) as well as a spirited homily on the central importance of weak interactions and hydrogen bonding.

3. Emphasize the crucial connections of chemistry with medicine and materials science again, and again and again...: It's official. The biggest practical contributions of chemistry to the betterment of human life have undoubtedly been in the discovery of new drugs and new materials. It is remarkable that every one of us benefits from these tangibles at every moment of day and night and yet fails to recognize the essential role that chemistry played in their creation. Since almost all of us know someone who has been afflicted or taken by a terrible malady, one would think that the public would be singing chemistry's praises for saving lives. Yet most people seem to think that it's doctors who discover new medicines. Quiz people about great medical advances and they would enthusiastically tell you about Alexander Fleming and Jonas Salk, but not about Gerhard Domagk or Gertrude Elion. This perception has got to change. Chemists are as responsible as doctors, if not more, for most of the live-saving drugs developed in the past century and will be responsible for many more in the coming one. The era of rational drug discovery was essentially ushered in by chemistry, and it will likely bring us novel advances in the form of designer proteins and small molecules as selective drugs against new threats. The public needs to know this crucial function of chemistry, and it can only be accomplished by drilling the facts into the public's mind eloquently and ad nauseam.

The other field where chemistry promises world-changing discoveries is in materials science and nanotechnology, especially as applied to energy. With climate change looming on the horizon, the next generation of breakthrough solar cells or other technologies may change the lives of millions, dramatically reduce our carbon footprint and impact the international geopolitical landscape. A central player in this seismic shift will undoubtedly be chemistry. The public now thinks very highly of nanotechnology but very few people realize that chemists have been practicing nanotechnology since their discipline gradually emerged from the shadows of alchemy. Polymers have revolutionized our lives as much as anything else. In the future polymers will contribute in novel ways such as drug delivery vehicles and smart materials in electronics engineering and space science. Organic electronics is another lucrative area of polymer science which will pay huge dividends in improving communications technology, leading to improvements in everything from healthcare to education. As the world inches closer to potentially devastating climate change and its global and social repercussions, chemistry will undoubtedly play its important role in saving the planet.

By bridging all other disciplines, enabling human progress and knitting the tapestry of the material universe, chemistry encircles the world. This is our chance to let everyone know.

Image source

An intimate portrait of India's people and their relationships

2011-01-11T10:44:00.000-08:00

In "India Calling: An Intimate Portrait of a Nation's Remaking", Anand Giridharadas takes a different tack from Thomas Friedman and others who have described the now familiar call centers and globalization that have turned India into an economic powerhouse. Instead Giridharadas decides to focus on the country's most important assets- its people and their changing attitudes towards the world, their families and themselves. Giridharadas has an unusual vantage point as an Indian who grew up in the US and who returned back to his country for a fresh look (although one wonders why he now lives in Cambridge, MA). The book is primarily about how India's new economic, political and social roles have changed Indians' relationships with themselves and their families. The most important consequence of the "New Order" is that Indians whose role in life was traditionally defined for centuries by their birth and their caste, class and gender are now seeking to make their own place in society rather than to "know" it. This is a great thing for a country where identity was defined for hundreds of years by where you came from rather than where you wished to go. As Giridharadas describes, in the new India someone from the lower caste can finally dare to dream beyond what was regarded as his indelible destiny.

To showcase these changing Indian identities, Giridharadas presents us with several "case studies" and describes the life stories of people drawn from a wide slice of Indian society. There's the poor boy in a small village who was born into a lower caste and decides to remake his identity by pioneering English language and "personality development" classes in his village and organizing a personality pageant. There's the "rat-catcher" whose job is to kill dozens of rats everyday in the slums of Mumbai. Then there's the Maoist, a member of the divisive Communist insurgency in India, who resents India's rise to wealth and fame but who has a complex relationship with the country he criticizes. The Maoist interestingly sees parallels between the old caste system and the new globalized order, with labor specialization replacing the role of labor-based caste. And in stark contrast, there's the Ambani family, India's richest business family whose clout extends over the entire Indian economic and political landscape. Giridharadas especially has an insightful portrait of Mukesh Ambani, one of the two Ambani brothers and one of the world's richest men whose empire stretches from petrochemicals to biotechnology. Giridharadas stresses how the Ambanis rose to prominence by cultivating relationships, a strategy that has helped them bribe slothful bureaucrats and journalists in creative ways that include paying for their children's education in Ivy League universities in the US. In an India where bribery is hardly an exception to the rule, the Ambanis' behavior is nothing novel. But one of the signs of a changing India is that while old-timers look with disgust upon the culture of bribery and corruption that the Ambanis have perpetuated, many young people see them as heroes who are cutting India's Gordian knot to an entrenched bureaucracy and socialist ethic and who are inspiring young Indians to dream big.

Further on, it is in describing the changing nature of the Indian family and relationships within it that Giridharadas really excels. Perhaps the two biggest changes in the Indian family during the last few decades have been the declining influence of parents on their children's lives and the empowerment of Indian women in middle-class families. This has led to new challenges and opportunities in the traditional Indian conception of marriage. Women are now regarded as men's equals in marriages and men are no longer supposed to be the sole bread-winners on whom their spouses precariously depend. Changing social mores have also awarded women an independence that was inconceivable for the older generation. Young men and women are now much more comfortable with casual sex and relationships. Indian women are now free to choose who they may or may not marry, or so it may seem. Yet as Giridharadas adeptly demonstrates, reality is more complex. Indian women and even men are still grappling with reconciling the modern with the orthodox. This has led to many of them living strange double lives where they have a wild time outside their homes but can instantly transform themselves into meek and dutiful sons and daughters in the presence of their parents. Ties to parents and family traditions are still too strong for many of India's young people to assert total independence. Thus an Indian woman who otherwise has a boyfriend and dictates the terms of her own life may still end up marrying a boy picked by her parents and sacrificing her freedom. The line between old and new is still not blurry enough for the young to casually transgress it, and it would be interesting to see how the changing dynamic between young people and traditions is played out in 21st century India.

Along with newfound independence come newfound problems. As young people are increasingly defying their parents and marrying for love, they are also increasingly become more intolerant of compromises and sacrifices. This has led to a spiraling divorce rate among young Indian families even as the taboos surrounding the word divorce have been as hard to abolish as that surrounding premarital sex. Giridharadas has a perceptive account of sitting in in an Indian court and watching divorce proceedings. Interestingly, contrary to popular belief, Indian divorces are no longer limited to the wealthy class and Giridharadas watches as a wide economic cross section of husbands and wives airs its woes in court. The reasons why these people are seeking divorce are varied and range from the unsurprising (marital infidelity, plain boredom) to the revealing (the husband becomes jealous when his wife starts making more money and living a more affluent lifestyle). Divorce in India promises to challenge traditional male-female hierarchies in marriage and social customs as acutely as any other modern liberating tendency.

As insightful as Giridharadas's book is, I have some minor complaints. Firstly, he says nothing about the negative repercussions of lowering standards in the educational system to accommodate the previously underprivileged. Liberation from the shackles of caste has been a wonderful thing for India, but on the flip side it has led politicians with vested interests to lower the standards of public education rather than to raise the standards of the lower castes through improvements in primary education. This is engendering divisive sentiments which the author does not discuss. Secondly, while Giridharadas eloquently describes changing perceptions of caste and class, he says almost nothing about how the changing dynamic has impacted religion and religious relationships which have always been a key part of the Indian identity. Thirdly, while he makes sincere attempts to be objective, Giridharadas cannot completely escape the biases of an Indian who did not grow up in India and who is coming back after a long time to inspect his former country much as an anthropologist would inspect a tribe. On one hand this has led him to offer us some fresh, out of the box perspectives, but on the other hand it has led him to quickly generalize from his own limited experiences. Indian is a complex and vast country, and even an observation that might apply to seventy percent of its citizens would still exclude a very significant portion of the population. Thus Giridharadas's observations should always be accepted as containing a significant element of truth but not the whole truth. Lastly, I found Giridharadas to be slightly verbose and rambling. Sometimes he seems to be too much in love with his words and phrases and belabors a point in too many different ways. This would have been fine for a work of fiction but it can tend to bore the reader and obscure clarity in a work of non-fiction.

Notwithstanding these minor gripes, I would strongly recommend the book. In a stream of books that have told us about India's economic and political rise, Giridharadas makes a valuable and rare contribution by focusing on the most important aspect of any country- its people and their changing relationships with themselves, their nation and the world.

Aliens, arsenic and alternative peer-review: Has science publishing become too conservative?

2010-12-09T19:06:00.001-08:00

In 1959, physicists Philip Morrison and Giuseppe Cocconi advanced a hypothesis about how we could detect signals from extraterrestrial civilizations. The two suggested monitoring microwave signals from outer space at the frequency of 1420 MHz. This frequency is the frequency of neutral hydrogen, the most abundant element in the universe and one which aliens would likely harness for communication. The paper marked the beginning of serious interest in searching for extraterrestrial life. A year later, Freeman Dyson followed up on this suggestion with an even more fanciful idea. He conjectured that a sufficiently advanced civilization might be able to actually disassemble a planet the size of Jupiter and use its parts to create a shell of material that would surround the parent planet’s solar system. This sphere would capture solar energy and allow civilizations to make the most efficient use of all such energy. The most telling signature of such an advanced habitat would be an intense infrared signal coming from the sphere. Thus Dyson recommended looking for infrared signals in addition to radio signals if we were to search for aliens. The sphere came to be known as a ‘Dyson sphere’ and became fodder for a generation of science fiction enthusiasts and Star Trek fans.

These two ideas and especially the second one sound outrageous and highly speculative to say the least. Can you guess where both were published? In the two most prestigious science journals in the world; the Morrison paper was published in Nature while Dyson published his report in Science. This was in 1960. I can say in a heartbeat that I don’t see similar ideas being published in these journals today, and this is a situation which we all should regret.

I bring up this issue because I think it indicates the significant changes in attitude about publishing novel scientific ideas that have occurred from 1960 to the present. In 1960 even serious journals like Nature and Science were open to publishing fanciful speculation, provided it was clearly enumerated. Now the demands for publishing have become more stringent, but also more narrowly defined. While this may have led to the publishing of more ‘concrete’ science, it has also dissuaded researchers from venturing out into novel territory. Most importantly, it has led the scientific community to put an unnecessarily high premium on ideas being right rather than interesting.

Science progresses not by being right or wrong but by being interesting. Most scientific ideas in their infancy are tentative, unsubstantiated and incomplete. Yet modern scientific publishing and peer review largely discourage the presentation of these ideas by insisting on convincing evidence that they are right. In most cases this emphasis on accuracy and complete validation is necessary to save science from itself; we have seen all too many cases of pseudoscience that looked superficially plausible but which turned out to be full of holes. Science usually plays it safe by insisting on unimpeachable evidence. But in my opinion this stringent self-correcting process has gone too far, and in our desire to err on the safer side we have erred on the extreme side. This is having a negative impact on what we can call creative science. The insistence on foolproof data and the public censure that researchers would face if they don’t provide it is deterring many scientists from publishing provocative results that are still in the early stages of gestation. Demands for conservative presentation are also accompanied by conservative peer review since reviewers fear backlash as much as authors. All this is unfortunate and is to the detriment of the very core of scientific progress, since it’s only when provocative ideas are published can other researchers validate, verify and refute them.

The furor about the recent paper on “arsenic-based” life brings these issues into sharp focus. Much of the hailstorm of criticism would have been avoided if the standards and formats of scientific publishing allowed the presentation of ideas that may not be fully substantiated but which are nonetheless interesting. By now we are all familiar with the torrent of criticism about the paper that has come from all quarters, from blog posts to opinions from well-known experts. What is clear is that the experiments done were shoddy and controls were lacking. But the criticism is detracting from the potential value of the paper. Irrespective of whether the claims of arsenic actually being incorporated in the bacterium’s replicative and metabolic machinery are true, the paper is undoubtedly interesting, if only as an example of a hitherto unknown novel extremophile. Yet it is in danger of simply being forgotten as one of the uglier episodes in the history of science publishing.

There is in fact a solution to this problem, one which I have been in favor of for a long time. What if there was a separate section specifically devoted to relatively far-fetched ideas and this paper had been published in that section? The paper would then likely have been taken much less seriously and its tenets would have been accepted simply as thought-provoking observations pointing to further experimentation rather than established facts. So here’s my suggestion; let the top scientific journals have a separate section entitled ‘Speculation’ (or perhaps ‘Imaginings’) which allows the presentation of ideas that are fanciful and speculative. The ideas proposed could range from purely theoretical constructs to the documentation and interpretation of unusual experimental observations. The only requirement is that they should be unorthodox and interesting, backed up by more or less known scientific principles, clearly defined and enumerated and contain testable hypotheses. Let there be a second type of peer-review process for these ideas, one which is as honest as the primary process but more forgiving of the lack of foolproof evidence.

The idea about Dyson spheres would fit in nicely in such a section. Another example that comes to my mind is an idea proposed by the biophysicist Luca Turin. Turin conjectured that we may smell molecules based not on their shape but on the vibrations of their bonds. The history of this idea is interesting since others had already proposed it earlier in respectable journals. Turin actually wrote it up and sent it to Nature. Nature deliberated for an entire year and rejected the paper. In this case Nature should at least be commended for taking so long and presumably giving careful consideration to the idea, but the point is that they wouldn’t have had a problem publishing it in a ‘Speculation’ section right away. Turin’s idea was interesting, novel, highly interdisciplinary, enumerated in great detail and backed up by well-known principles of chemistry and spectroscopy. It satisfied all the criteria of a novel scientific idea that may or may not be right. Turin finally published in a journal which only specialists read, thus precluding the concept from being appreciated by an interdisciplinary cross-section of scientists. There is now at least some evidence that his ideas may be right.

Interestingly, there is at least one entire journal devoted to the publication of interesting hypotheses. This is the journal ‘Medical Hypotheses’. Medical Hypotheses prominently lacks peer review (although they have instituted some peer review recently) and has occasionally come under fire for publishing highly questionable papers, such as those criticizing the link between HIV and AIDS. But it has also served as a playground for the interaction of many interesting ideas. The editorial board of Medical Hypotheses features highly respected scientists like the neurologist V S Ramachandran and the Nobel Prize winning neuroscientist Arvid Carlsson. Ramachandran himself has iterated the need for such a journal. Science and Nature merely have to devote a small section in each issue to the kinds of ideas that are published in Medical Hypotheses, perhaps with a higher standard.

It’s worth reiterating Thomas Kuhn’s notions of paradigm shifts in science here. Scientific paradigms rarely change by playing it safe. Most scientific revolutions have been initiated by bold and heretical ideas from maverick individuals, whether it was Darwin’s ideas about natural selection, Einstein’s thoughts about the constancy of the speed of light, Wegener’s ideas about continental shift or Bohr’s construction of the quantum atom. Not a single one of these ideas was validated by foolproof evidence when it was proposed. Many of them sounded outright bizarre and counter-intuitive. But it was still paramount to bring these ideas to a greater audience. Only time would tell whether they were right or wrong, but they were undoubtedly supremely novel and interesting. And almost all of them were published by leading journals. It was the willingness to entertain interesting ideas that made possible the scientific revolutions of the twentieth century. It seems to be a strange historical anomaly to find journals much more prone to publishing speculative ideas a hundred years ago than today. Today we seem to worship the safety of truth at the expense of the uncertain but bold reaches of novelty.

Of course, the existence of a second-tier of publication and peer review would undoubtedly have to be carefully monitored. There is after all a thin line between reasonable speculation and pseudoscience. The reviewers in this tier would have to pay even more careful attention than they usually do to ensure that they are not pushing baseless fantasies. But as we have seen in the case of the vibrational theory of smell and the case of arsenic-loving bacteria, it’s not that hard to separate legitimate science with uncertain truth value from mere storytelling.

Once the ground rules are established and the initial obstacles are overcome, the second tier of peer review would have many advantages apart from encouraging the publication of speculation. It would also make reviewers more comfortable in recommending publication; since the ideas are speculative anyway, they would not insist on complete verification and would not fear backlash if the ideas they had reviewed turn out to be wrong. Journal editors would similarly find it easier to approve publication. And the scientific community at large perhaps would not be as critical as it has been in the case of the recent paper because it too would accept the proposed ideas not as declarations of truth but as tentative exploration. But the greatest beneficiaries of the improved system would undoubtedly be the publishing scientists. Their minds would be much freer to dream and they would fear much less retaliation from the community for daring to do this. Most importantly, unlike the recent case, they would not be under pressure to make statements whose implications exceed the objective factual implications of their claims, and they would be happy to just present the claims as interesting observations that point the way towards further experiments.

Science progresses by being the ultimate free-market of ideas; this has led to it being a highly social process where scientists build on each other’s work. But for this social process to work the ideas must be liberated from their initial nebulous beginnings. Ideas in the scientific marketplace come in different flavors, from boring and established to interesting and maverick. The current scientific publication and peer-review process imposes a straitjacket that ideas have to fit in in order to be ‘pre-selected’ for entry into this market. This keeps out some of the most interesting ideas and more importantly, dissuades thinkers from even pursuing them in the first place. The straitjacket does serve the valuable purpose of filtering flotsam but it is also filtering out too many other interesting things. Science is too haphazard and full of unexpected twists and turns to be entrusted to rigid rules of review and publication. We need to accept the liability of occasionally having a dubious idea published in order to keep open the possibility of also giving novel beginnings a public platform; the beauty of science is that the bonafide dubious ideas automatically get weeded out through scrutiny and so we should not have to worry about too many of them going on extended rampages. But the potentially good ideas can only be fleshed out by other scientists when they are allowed to be exposed to criticism, appreciation and ridicule. Even if the ideas themselves ultimately sink, they may serve as spores which lead to the germination of other ideas. And it is the germination of these other ideas that gets transformed into trees of scientific discovery.

We are all sheltered, invigorated and inspired by the branches of these trees. Let’s give them an opportunity to grow.

An eternity of infinities: the power and beauty of mathematics

2010-12-06T17:07:00.000-08:00

The biggest intellectual shock I ever received was in high school. Someone gifted me a copy of the physicist George Gamow’s classic book “One two three...infinity”. Gamow was not only a brilliant scientist but also one of the best science popularizers of the late twentieth century. In his book I encountered the deepest and most utterly fascinating pure intellectual fact I have ever known; the fact that mathematics allows us to compare ‘different infinities’. This idea will forever strike awe and wonder in me and I think is the ultimate tribute to the singularly bizarre and completely counter-intuitive worlds that science and especially mathematics can uncover.

Gamow starts by alerting us to the Hottentot tribe in Africa. Members of this tribe cannot formally count beyond three. How then do they compare commodities such as animals whose numbers are greater than three? By employing one of the most logical and primitive methods of counting- the method of counting by one-to-one correspondences or put more simply, by pairing objects with each other. So if a Hottentot has ten animals and she wishes to compare these with animals from a rival tribe, she will pair off each animal with its counterpart. If animals are left over in her own collection, she wins. If they are left over in her rival’s collection, she has to admit the rival tribe’s superiority in sheep.

What is remarkable is that this simplest of counting methods allowed the great German mathematician Georg Cantor to discover one of the most stunning and counter-intuitive facts ever divined by pure thinking. Consider the set of natural numbers 1, 2, 3… Now consider the set of even numbers 2, 4, 6…If asked which set is greater, commonsense would quickly point to the former. After all the set of natural numbers contains both even and odd numbers and this would of course be greater than just the set of even numbers, wouldn’t it? But if modern science and mathematics have revealed one thing about the universe, it’s that the universe often makes commonsense stand on its head. And so it is the case here. Let’s use the Hottentot method. Line up the natural numbers and the even numbers next to each other and pair them up.

1 2 3 4 5…
2 4 6 8 10…

So 1 pairs up with 2, 2 pairs up with 4, 3 pairs up with 6 and so on. It’s now obvious that every natural number n will always pair up with an even number 2n. Thus the set of natural numbers is equal to the set of even numbers, a conclusion that seems to fly in the face of commonsense and shatters its visage. We can extend this conclusion even further. For instance consider the set of squares of natural numbers, a set that would seem even ‘smaller’ than the set of even numbers. By similar pairings we can show that every natural number n can be paired with its square n², again demonstrating the equality of the two sets. Now you can play around with this method and establish all kinds of equalities, for instance that of whole numbers (all positive and negative numbers) with squares.

But what Cantor did with this technique was much deeper than amusing pairings. The set of natural numbers is infinite. The set of even numbers is also infinite. Yet they can be compared. Cantor showed that two infinities can actually be compared and can be shown to be equal to each other. Before Cantor infinity was just a place card for ‘unlimited’, a vague notion that exceeded man’s imagination to visualize. But Cantor showed that infinity can be mathematically precisely quantified, captured in simple notation and expressed more or less like a finite number. In fact he found a precise mapping technique with which a certain kind of infinity can be defined. By Cantor’s definition, any infinite set of objects which has a one-to-one mapping or correspondence with the natural numbers is called a ‘countably’ infinite set of objects. The correspondence needs to be strictly one-to-one and it needs to be exhaustive, that is, for every object in the first set there must be a corresponding object in the second one. The set of natural numbers is thus a ruler with which to measure the ‘size’ of other infinite sets. This countable infinity was quantified by a measure called the ‘cardinality’ of the set. The cardinality of the set of natural numbers and all others which are equivalent to it through one-to-one mappings is called ‘aleph-naught’, denoted by the symbol . The set of natural numbers and the set of odd and even numbers constitute the ‘smallest’ infinity and they all have a cardinality of . Sets which seemed disparately different in size could all now be declared equivalent to each other and pared down to a single classification. This was a towering achievement.

The perplexities of Cantor’s infinities led the great mathematician David Hilbert to propose an amusing situation called ‘Hilbert’s Hotel’. Let’s say you are on a long journey and, weary and hungry, you come to a fine-looking hotel. The hotel looks like any other but there’s a catch: much to your delight, it contains a countably infinite number of rooms. So now when the manager at the front desk says “Sorry, but we are full”, you have a response ready for him. You simply tell him to move the first guest into the second room, the second guest into the third room and so on, with the n^th guest moving into the (n+1)^th room. Easy! But now what if you are accompanied by your friends? In fact, what if you are so popular that you are accompanied by a countably infinite number of friends? No problem! You simply ask the manager to move the first guest into the second room, the second guest into the fourth room, the third guest into the sixth room…and the n^th guest into the 2n^th room. Now all the odd-numbered rooms are empty, and since we already know that the set of odd numbers is countably infinite, these rooms will easily accommodate all your countably infinite guests, making you even more popular. Mathematics can bend the laws of the material world like nothing else.

But the previous discussion leaves a nagging question. Since all our infinities are countably infinite, is there something like an ‘uncountably’ infinite set? In fact, what would such an infinity even look like? The ensuing discussion probably constitutes the gem in the crown of infinities and it struck infinite wonder in my heart when I read it.

Let’s consider the set of real numbers, numbers defined with a decimal point as a.bcdefg... The real numbers consist of the rational and the irrational numbers. Is this set countably infinite? By Cantor’s definition, to demonstrate this we would have to prove that there is a one-to-one mapping between the set of real numbers and the set of natural numbers. Is this possible? Well, let’s say we have an endless list of rational numbers, for instance 2.823, 7.298, 4.001 etc. Now pair up each one of these with the natural numbers 1, 2, 3…, in this case simply by counting them. For instance:

S1 = 2.823
S2 = 7.298
S3 = 4.001
S4 = …

Have we proved that the rational numbers are countably infinite? Not really. This is because I can construct a new real number not on the list using the following prescription: construct a new real number such that it differs from the first real number in the first decimal place, the second real number in the second decimal place, the third real number in the third decimal place…and the nth real number in the nth decimal place. So for the example of three numbers above the new number can be:

S0 = 3.942

(9 is different from 8 in S1, 4 is different from 9 in S2 and 2 is different from 1 in S3)

Thus, given an endless list of real numbers counted from 1, 2, 3…onwards, one can always construct a number which is not on the list since it will differ from the 1^st number in the first decimal place, 2^nd number in the second decimal place…and from the nth number in the nth decimal place.

Cantor called this argument the ‘diagonal argument’ since it really constructs a new real number from a line that’s diagonally drawn across all the relevant numbers after the decimal points in each of the listed numbers. The image from the Wikipedia page makes the picture clearer:

In this picture, the new number is constructed from the red numbers on the diagonal. It’s obvious that the new number Eu will be different from every single number E1…En on the list. The diagonal argument is an astonishingly simple and elegant technique that can be used to prove a deep truth.

With this comparison Cantor achieved something awe-inspiring. He showed that one infinity can be greater than another, and in fact it can be infinitely greater than another. This really drives the nail in the coffin of commonsense, since a ‘comparison of two infinities’ appears absurd to the uninformed mind. But our intuitive ideas about sets break down in the face of infinity. A similar argument can demonstrate that while the rational numbers are countably infinite, the irrational numbers are uncountably so. This leads to another shattering comparison; it tells us that the tiny line segment between 0 and 1 on the number line containing real numbers (denoted by [0, 1]) is ‘larger’ than the entire set of natural numbers. A more spectacular case of David obliterating Goliath I have never seen.

The uncountably infinite set of reals comprises a separate cardinality from the cardinality of countably infinite objects like the naturals which was denoted by . Thus one might logically expect the cardinality of the reals to be denoted by ‘’. But as usual reality thwarts logic. This cardinality is actually denoted by ‘c’ and not by the expected . Why this is so is beyond my capability to understand, but it is fascinating. While it can be proven that 2^ = c,the hypothesis that c = is actually just a hypothesis, not a proven and obvious fact of mathematics. This hypothesis is called the ‘continuum hypothesis’ and happens to be one of the biggest unsolved problems in pure mathematics. The problem was in fact the first of the 23 famous problems for the new century proposed by David Hilbert in 1900 during the International Mathematical Congress in France (among others on the list were the notorious Riemann hypothesis and the fond belief that the axioms of arithmetic are consistent, later demolished by Kurt Gödel). The brilliant English mathematician G H Hardy put the continuum at the top of his list of things to do before he died (he did not succeed). A corollary of the hypothesis is that there are no sets with cardinality between and c. Unfortunately the continuum hypothesis may be forever beyond our reach. The same Gödel and the Princeton mathematician Paul Cohen damned the hypothesis by proving that, assuming the consistency of the basic foundation of set theory, the continuum hypothesis is undecidable and therefore it cannot be proved nor disproved. This is assuming that there are no contradictions in the basic foundation of set theory, something that itself is 'widely believed' but not proven. Of course all this is meat and drink for mathematicians wandering around in the most abstract reaches of thought and it will undoubtedly keep them busy for years.

But it all starts with the Hottentots, Cantor and the most primitive methods of counting and comparison. I happened to chance upon Gamow’s little gem yesterday, and all this came back to me in a rush. The comparison of infinities is simple to understand and is a fantastic device for introducing children to the wonders of mathematics. It drives home the essential weirdness of the mathematical universe and raises penetrating questions not only about the nature of this universe but about the nature of the human mind that can comprehend it. One of the biggest questions concerns the nature of reality itself. Physics has also revealed counter-intuitive truths about the universe like the curvature of space-time, the duality of waves and particles and the spooky phenomenon of entanglement, but these truths undoubtedly have a real existence as observed through exhaustive experimentation. But what do the bizarre truths revealed by mathematics actually mean? Unlike the truths of physics they can’t exactly be touched and seen. Can some of these such as the perceived differences between two kinds of infinities simply be a function of human perception, or do these truths point to an objective reality ‘out there’? If they are only a function of human perception, what is it exactly in the structure of the brain that makes such wondrous creations possible? In the twenty-first century when neuroscience promises to reveal more of the brain than was ever possible, the investigation of mathematical understanding could prove to be profoundly significant.

Blake was probably not thinking about the continuum hypothesis when he wrote the following lines:

To see a world in a grain of sand,
And a heaven in a wild flower,
Hold infinity in the palm of your hand,
And eternity in an hour.

But mathematics would have validated his thoughts. It is through mathematics that we can hold not one but an infinity of infinities in the palm of our hand, for all of eternity.

Medicine! Poison! Arsenic! Life itself!

2010-12-02T17:59:00.000-08:00

A few months back when the Nobel Prize for chemistry was announced, a few observers lamented that unlike physics and biology, perhaps chemistry does not have any 'big' questions to answer. So here's a question for these skeptics. What branch of science has the biggest bearing on the discovery of an organism that utilizes arsenic instead of phosphorus? If you say "biology" or "geology" you would be wrong. The essential explanation underlying today's headline about an arsenic-guzzling bacterium is at the chemical level. The real question to ask is about the key molecular mechanisms in which arsenic substitutes phosphorus. What molecular level events enable this novel organism to survive, metabolize and reproduce? Of course the discovery is significant for all kinds of scientists including biologists, geologists, astronomers and perhaps even philosophers, but the essential unraveling of the puzzle will undoubtedly be at the level of the molecule.

Many years back I read a classic paper by the late Harvard chemist Frank Westheimer called "Why Nature Chose Phosphates". In simple and elegant terms, Westheimer explained why arsenic cannot replace phosphorus and silicon cannot replace carbon in the basic chemistry of life. In a nutshell, phosphates have the right kind of acid-base behavior at physiological pH. The single negative charge in phosphates in DNA hinders attack by water and hydrolysis without making the system so stable that it loses its dynamic nature. Arsenates, simply put, are too unstable. So are silicates.

And yet we have an arsenate-metabolizing bacterium here. Westheimer would have been delighted. Arsenic, the same stuff that was used in outrageous amounts in Middle-Age medicines and which later turned into the diabolical murderer's patent weapon of choice makes a new appearance now as a sustainer of life. First of all let's be clear on what this is not. It's not an indication that "life arose twice", it does not suddenly promise penetrating insight into extraterrestrial life, it probably won't win its discoverers a Nobel Prize and in fact it's not even technically speaking an 'arsenic-based life form'. The bacteria were found in a highly saline and alkaline lake with a relatively high concentration of arsenic where they were happily using conventional phosphorus-based chemistry. The fun started when they were gradually exposed to increasing concentrations of arsenic and increasing dilutions of phosphorus. The hardy little creatures still continued to grow.

But the real surprise was when the cellular components were analyzed and found to contain a lot of arsenic and very little phosphorus, certainly too less to sustain the metabolic machinery of life. This is a remarkable and significant discovery, although not too surprising. Chemistry deals with improbabilities, not impossibilities. Life forms utilizing arsenates were conjectured to exist for some time, but such almost total substitution of arsenic for phosphorus was not anticipated.

The work raises fascinating questions, not about extraterrestrial life or even about life's origins, but more mundane and yet probing ones about the basic chemistry of life. I haven't read the original paper in detail yet, but here are a few thoughts whose confirmation would lead to new territory:

1. The best thing would be to get an x-ray crystal structure of arsenic-based DNA. An x-ray structure of a molecule is as close as you can get to taking a photograph. That would be a slam dunk and would really catapult the discovery to the front ranks of novelty. The second-best thing would be to do experiments involving radioactively labeled phosphorus and arsenic, to find out the exact proportion of arsenic getting incorporated. Which brings us to the next point.

2. How much of the cellular components are trading phosphorus for arsenic? Life's molecules are crucially dependent on phosphate. Not just DNA but signaling molecules like kinases and AMP (adenosine monophosphate) are phosphorus-based. And of course there's ATP, the universal energy currency of the cell. What is fascinating to ponder is whether all of these key molecules traded phosphorus for arsenic. Perhaps some of them like DNA are using arsenic while others keep on using phosphorus. Checking the numbers and concentrations left over would certainly help to decide this. My guess is that the utilization of phosphorus was selective and not ubiquitous. Organisms rarely utilize all-or-none principles and usually do their best under the circumstances.

If arsenic is truly substituting phosphorus in all these signaling, genetic and structural components, that would really be something because it would create more questions. By what pathways does arsenic enter these molecules? How does it affect the kinetics of reactions involving them? And most important are questions about molecular recognition. There are hundreds of proteins that recognize phosphorylated protein residues and similar other molecules. Do all these proteins recognize their arsenic containing counterparts? If so, is this the result of mutations in most of these proteins?; it seems hard to imagine that simultaneous mutations in so many biomolecules to make them recognize arsenic would result in viable living organisms. A more conservative explanation is that most of these molecules don't mutate but still recognize arsenic, albeit with different specificities and affinities that are nonetheless feasible for keeping life's engine chugging. The molecules of life are exquisitely specific but they are also flexible and amenable to changing circumstances. They have to be so.

3. And finally of course, how does the protein expression systems of the bacteria cope with arsenic-based DNA? As mentioned above, arsenates are unstable. To counter this instability does DNA expression simply get ramped up? How does the altered DNA pack in chromosomes and how do proteins control the unpacking, packing, duplication and transcription of this unusual form of DNA? For starters, how does DNA polymerase (the enzyme that duplicates DNA) zip together individual arsenated nucleotides to construct complementary DNA strands for instance? How does the whole thing essentially hold together?

There are of course more questions. Whatever the implications, this is a significant discovery that would keep scientists busy for a long time. Like all truly interesting scientific discoveries it asks more questions than it answers. But ultimately it should come as no surprise. The wonders of chemistry combined with those of Darwinian evolution have allowed life to conquer unbelievably diverse niches, from methane-riddled environments to hot springs to sub-zero temperatures. In one way this discovery would only add one more feather into the cap of a robust and abiding belief- that life is tough. It survives.

Selenium for sulfur should be next (but I wouldn't wait around for silicon...)

In praise of contradiction

2010-11-23T10:57:00.001-08:00

Scientists usually don't like contradictions. A contradiction in experimental results is like a canary in a coal mine. It sets off alarm bells and compels the experimentalist to double-check his or her setup. A contradiction in theoretical results can be equally bad if not worse. It could mean you made a simple arithmetical mistake. Contradiction could force you to go back to the drawing board and start afresh. Science is not the only human activity where contradictions are feared and disparaged. A politician or businessman who contradicts himself is not considered trustworthy. A consumer product which garners contradictory reviews raises suspicions about its true value. Contradictory trends in the stock market can put investors in a real bind.

Yet contradiction and paradoxes have a hallowed place in intellectual history. First of all, contradiction is highly instructive simply because it forces us to think further and deeper. It reveals a discrepancy in our understanding of the world which needs to be resolved and encourages scientists to perform additional experiments and decisive calculations to settle the matter. It is only when scientists observe contradictory results that the real fun of discovery begins. It’s the interesting paradoxes and the divergent conclusions that often point to a tantalizing reality which is begging to be teased apart by further investigation.

Let's consider that purest realm of human thought, mathematics. In mathematics, the concept of proof by contradiction or reductio ad absurdum has been highly treasured for millennia. It has provided some of the most important and beautiful proofs in the field, like the irrationality of the square root of two. In his marvelous book "A Mathematician's Apology", the great mathematician G H Hardy paid the ultimate tribute to this potent weapon:

"Reductio ad absurdum, which Euclid loved so much, is one of a mathematician's finest weapons. It is a far finer gambit than any chess gambit: a chess player may offer the sacrifice of a pawn or even a piece, but a mathematician offers the game."

However, the great ability of contradiction goes far beyond opening a window into abstract realms of thought. Twentieth-century physics demonstrated that contradiction and paradoxes constitute the centerpiece of reality itself. At the turn of the century, it was a discrepancy in results from blackbody radiation that sparked one of the greatest revolutions in intellectual history in the form of the quantum theory. Paradoxes such as the twin paradox are at the heart of the theory of relativity. But it was in the hands of Niels Bohr that contradiction was transformed into a subtler and lasting facet of reality which Bohr named 'complementarity'. Complementarity entailed the presence of seemingly opposite concepts whose co-existence was nonetheless critical for an understanding of reality. It was immortalized in one of the most enduring and bizarre paradoxes of all, wave-particle duality. Wave-particle duality taught us that contradiction is not only an important aspect of reality but an indispensable one. Photons of light and electrons behave as both waves and particles. The two qualities seem to be maddeningly at odds with each other. Yet both are absolutely essential to grasp the essence of physical reality. Bohr codified this deep understanding of nature with a characteristically pithy statement- "The opposite of a big truth is also a big truth". Erwin Schrödinger followed up on his own disdain for complementarity by highlighting an even more bizarre quantum phenomenon- entanglement- wherein particles that are completely separated from each other are nonetheless intimately connected; by doing this Schrödinger brought us the enduring image of a cat helplessly trapped in limbo between a state of life and death.

The creative tension created by seemingly contradictory phenomena and results has been fruitful in other disciplines. Darwin was troubled by the instances of altruism he observed in the wild; these seemed to be contradicting the ‘struggle for existence’ which he was describing. It took the twentieth century and theories of kin selection and reciprocal altruism to fit these seemingly paradoxical observations into the framework of modern evolutionary theory. The history of organic chemistry is studded by efforts to determine the molecular structures of complex natural products like penicillin and chlorophyll. In many of these cases, contradictory proposed structures like those for penicillin spurred intense efforts to discover the true structure. Clearly, contradiction is not only a vital feature of science but it is also a constant and valuable companion of the process of scientific discovery.

These glittering instances of essential contradiction in science would seem perfectly at home with the human experience. While contradiction in science can be disturbing and ultimately rewarding, many religions and philosophies have come to savor this feature of the world for a long time. The Chinese philosophy of Yin and Yang recognizes the role of opposing and contrary forces in sustaining human life. In India, the festival celebrating the beginning of the Hindu new year includes a ritual where every member of the family consumes a little piece of sweet jaggery (solidified sugarcane juice) wrapped in a bitter leaf of the Neem tree (which contains the insecticide azadirachtin). The sweet and bitter are supposed to exemplify the essential combination of happy and sad moments that are necessary for a complete life. Similar paradoxes are recognized in Western theology, for instance pertaining to the doctrines of the Trinity and the Incarnation.

The ultimate validation of contradiction however is not through its role in life or in scientific truth but through its role as an insoluble part of our very psyche. We all feel disturbed by contradiction, yet how many of us think we hold perfectly consistent and mutually exclusive beliefs in our own mind about all aspects of our life? You may love your son, yet his egregious behavior may lead you to sometimes (hopefully not often) wish he had not been born. We often speak of 'love-hate' relationships which exemplify opposing feelings toward a loved one. If we minutely observe our behavior at every moment, such observation would undoubtedly reveal numerous instances of contradictory thoughts and behavior. This discrepancy is not only an indelible part of our consciousness but we all realize that it actually enriches our life, makes it more complex, more unpredictable. It is what makes us human.

Why would contradictory thinking be an important part of our psyche? I am no neuroscientist, but I believe that our puzzlement about contradiction would be mitigated if we realize that we human beings perceive reality by building models of the world. It has always been debatable whether the reality we perceive is what is truly 'out there' (and this question may never be answered); what is now certain is that neural events in our brains enable us to build sensory models of the world. Some of the elements in the model are more fundamental and fixed while others are flexible and constantly updated. The world that we perceive is what is revealed to us through this kind of interactive modeling. These models are undoubtedly some of the most complex ever generated, and anyone who has built models of complex phenomena would recognize how difficult it is to achieve a perfectly logically consistent model. Model building also typically involves errors, of which some may accumulate and others may cancel. In addition models can always be flawed because they don't include all the relevant elements of reality. All these limitations lead to models in which a few facts can appear contradictory, but trying to make these facts consistent with each other could possibly lead to even worse and unacceptable problems with the other parts of the model. Simply put, we compromise and end up living with a model with a few contradictions in favor of a model with too many. Further research in neuroscience will undoubtedly shed light on the details of model building done by the brain, but what seems unsurprising is that these models contain some contradictory worldviews which nonetheless preserve their overall utility.

Yet there are those who would seek to condemn such contradictory thinking as an anomaly. In my opinion, one of the most prominent examples of such a viewpoint in the last few years has been the criticism of religious-minded scientists by several so-called 'New Atheists' like Richard Dawkins and Sam Harris. The New Atheists have made it their mission to banish what they see as artificial barriers created between science and religion for the sake of political correctness, practical expediency and plain fear of offending the other party. There is actually much truth to this viewpoint, but the New Atheists seem to take it beyond its strictly utilitarian value.

A case in point is Francis Collins, the current director of the NIH. Collins is famous as a first-rate scientist who is also an ardent Catholic. The problem with Collins is not that he is deeply religious but that he tends to blur the line between science and religion. A particularly disturbing instance is a now widely discussed set of slides from a presentation where he tries to somehow scientifically justify the existence and value of the Christian God. Collins's conversion to a deeply religious man when he apparently saw the Trinity juxtaposed on his view of a beautiful frozen waterfall during a hike is also strange, and at the very least displays a poor chain of causation and inadequate critical thinking.

But all this does not make Collins any less of an able administrator. He does not need to mix science with religion to justify his abilities as a science manager. To my knowledge there is not a single instance of his religious beliefs dictating his preference for NIH funding or policy. In practice if not in principle, Collins manages to admirably separate science from storytelling. But the New Atheists are still not satisfied. They rope in Collins among a number of prominent scientists who they think are 'schizophrenic' in conducting scientific experiments during the week and then suspending critical thinking on Sundays when they pray in church. They express incredulity that someone as intelligent as Francis Collins can so neatly compartmentalize his rational and 'irrational' brain and somehow sustain two completely opposite - contradictory - modes of thought.

For a long time I actually agreed with this viewpoint. Yet as we have seen before, such seemingly contradictory thinking seems to be a mainstay of the human psyche and human experience. There are hundreds of scientists like Collins who largely manage to separate their scientific and religious beliefs. Thinking about it a bit more, I realized that the New Atheists' insistence on banishing perfectly mutually exclusive streams of thinking seems to go against a hallowed principle that they themselves have emphasized to no end- a recognition of reality as it is. If the New Atheists and indeed all of us hold reality to be sacrosanct, then we need to realize that contradictory thinking and behavior are essential elements of this reality. As the history of science demonstrates, appreciating contradiction can even be essential in deciphering the workings of the physical world.

Now this certainly does not mean that we should actively encourage contradiction in our thinking. We also recognize the role of tragedy in the human experience, but few of us would strive to deliberately make our lives tragic. Contradictory thinking should be recognized, highlighted and swiftly dealt with, whether in science or life. But its value in shaping our experience should also be duly appreciated. Paradox seems to be a building block in the fabric of the world, whether in the mind of Francis Collins or in the nature of the universe. We should in fact celebrate the remarkable fact that the human mind can subsume opposing thoughts within its function and still operate within the realm of reason. Simply denying this and proclaiming that it should not be so would mean denying the very thing we are striving for- a deeper and more honest understanding of reality.

Will-o'-the-wisp around 5 sigma: the hunting of the Higgs

2010-11-18T11:29:00.000-08:00

Mr. Hunter, we have rules that are not open to interpretation, personal intuition, gut feelings, hairs on the back of your neck, little devils or angels sitting on your shoulder.... - Capt. Ramsey ('Crimson Tide')

Particle physicists hunting for maddeningly elusive particles sometimes must feel like Mr. Hunter in the movie "Crimson Tide". The quarries which they are trying to mine seem so ephemeral, making their presence known in events with such slim probability margins, victims of nature's capricious dance of energy and matter, that intuition must sometimes seem as important as data. The hunt for such particles signifies some of the most intense efforts in extruding reality from nature's womb that human beings have ever put in.

No other particle exemplifies this uniquely human of all endeavors than the so-called Higgs boson. The man who bears the burden of imparting it its name is now a household name himself. Yet as the history of science often demonstrates, the real story is both more interesting and more complicated. It involves intense competition involving billions of dollars and thousands of careers of a kind rarely seen in science, and stories of glories and follies befitting the great tragedies. In his book "Massive", Ian Sample does a marvelous job of bringing this history to life.

Sample excels at three things. The first is the story of the two great laboratories that have mainly been involved in the race to the finish in discovering nature's building blocks- Fermilab and CERN. CERN was started in the 60s to give a boost to European physics after World War 2. Fermilab was lovingly built by the experimental physicist Robert Wilson, a former member of the Manhattan Project who was a first-rate amateur architect and saw accelerators as aesthetic things of beauty. Secondly, Sample does a nice job of explaining the reasons that led to the construction of these machines, the most complicated that mankind has ever constructed. Only human beings would put billions of dollars and immense manpower on the line purely for the purpose of satisfying man's curiosity of plumbing the depths of nature's deepest secrets. Sample also lays out the very human and social concerns that accompany such investigations. Lastly, Sample was lucky enough to get an extended interview with Peter Higgs, a shy man who very rarely does interviews. Higgs grew up in Scotland idolizing Paul Dirac and shared Dirac's view of a unifying beauty that would connect nature's disparate facts. In the late 1960s he wrote papers describing what is now called the Higgs boson. The papers were well-accepted in the US and Higgs's name soon began to be bandied about in seminars and meetings. As described below however, Higgs was not the only one postulating the theory.

So what exactly is the Higgs boson? A complete understanding would naturally need a background in theoretical physics, but the best analogy for the layman was given by a British scientist. Imagine a room full of young women who are happily chatting. In walks a handsome young man. As long as he is not noticed he can move freely across the room, but as soon as the young women spot him they cluster around him, impeding his movement. It's as though the young man has become heavier and has acquired mass from the "field" of women surrounding him. The Higgs then is the particle that imparts specific masses to all the other myriad particles discovered so far including quarks and leptons through its own field. It should be evident why it's important. The Higgs would be the crowning achievement in the Standard Model of particle physics which encompasses all particles and forced known until now except gravity.

However, the history of the Higgs particle is complicated. Sample does a great job of explaining why the credit belongs to six different people who reached the same conclusion that Higgs did. It seems that Higgs was not the first to publish, but he was the first one to clearly state the existence of a new particle. However, the most comprehensive theory of the Higgs field and particle came out later. If Nobel Prizes are to be awarded, it's not at all clear what three people should be picked, although Higgs's name seems obvious. The sociology of scientific discovery is as important as the facts and again illustrates that science is a much more haphazard and random process than is believed.

The search for the Higgs gathered tremendous momentum in the 80s and 90s. It intensified after accelerator laboratories spectacularly discovered two particles named the W and Z bosons that are responsible for mediating the electromagnetic and weak interactions (the electroweak force). These particles were predicted by Steven Weinberg, Abdus Salam and Sheldon Glashow in the 60s, and their prediction surely ranks as one of the greatest theoretical successes in modern physics. Once the theory predicted the masses of these particles, they were up for grabs. No experimentalist worth his or her salt would fail to relish nailing a concrete theoretical prediction of fundamental importance through a decisive experiment. Sample captures the pulse-quickening inter-Atlantic races to find these particles especially between CERN and Fermilab. The importance of these particles was so obvious that Nobel Prizes came in quick succession both to the theorists and the experimentalists. However the existence of the Higgs is also essential for the successful formulation of the electroweak theory, and signatures of the Higgs are thought to be produced whenever W and Z bosons are created. It again becomes obvious why finding the Higgs is so important; its existence would validate all those successes and Nobel Prizes, whereas a failure to find it would entail a stunningly hard look at some of particle physics's most fundamental notions.

These days the Large Hadron Collider (LHC) is all over the news. Yet the most exciting part of Sample's book describes not the LHC but the Large Electron Positron collider (LEP) at CERN which was the largest particle accelerator in the world at the time. Unlike protons, electrons and positrons are fundamental particles and crashing them together produces 'cleaner' results. There were some fascinating events associated with the LEP. The behemoth's circumference was 27 kilometers and it crisscrossed the Swiss-French border, so authorities had to seek permission to build the accelerator underneath some homes. It seems that French law is special just like their cheese and language; apparently if you build a house in France, it means that you own the entire ground beneath the house, all the way to the center of the earth. Suffice it to say that some negotiation with the homeowners was necessary to secure permission for underground construction. At one point the intensity of the beams inside the mammoth machine started to wax and wane. After many days of brainstorming a scientist had a hunch; it turns out that the the gravity of the moon and the sun sets up tides inside the crust of the earth. These tides put the calibration of the machine off by a millimeter, too small to be noticed by human beings, but thunderingly large for electron beams. In another case, the daily departure of a train from a nearby station sent surges of electricity into the ground and affected the beams. It seems like when you are building an accelerator you have to guard against the workings of the entire solar system.

The story of particle physics is also fraught with tragedies. One of the biggest described in the book was the construction of the Superconducting Supercollider in Texas. The SSC was supposed to be the answer to CERN and got enthusiastic backing from Reagan and Bush Sr. Unfortunately the budget spiraled out of hand, the infighting intensified, congressmen remained unconvinced and the collider never got built in spite of spending billions and affecting thousands of careers of scientists who had relocated. The fiasco just proved that public support for even projects like the LHC is never a sure thing, and scientists don't always excel at public relations.

Then of course there are all the doomsday scenarios and concerns which were raised about the LHC, from the formation of black holes to the world ending in myriad other ways. As Sample describes, these concerns go back to an accelerator at Brookhaven National Laboratory which would impact large gold ions together at furious velocities. The would-be Nobel laureate Frank Wilczek raised the theoretical yet vanishingly small probability of forming 'strangelets', entities akin to the fictitious substance 'Ice-9' in Kurt Vonnegut's novel 'Cat's Cradle'. These strangelets would coalesce together matter around themselves and form a superstable form of dead matter that would rapidly engulf the entire planet. The concern about strangelets pales in comparison however to the possibility of 'vacuum decay', in which our universe is thought to be in a perfectly happy but metastable state like a vase on a table. All it takes is a little nudge or a massive kick from a high-energy particle collision in our case to dislodge the vase or universe from its metastable state into a stable state of minimum energy. Gratifyingly, not only would this state mean the end of life as we know it but it would also mean the impossibility of life ever arising. Yes, all these scenarios seem straight out of the drug-induced, overactive imagination of a demented mind, but at least some of them are within the realm of theoretical possibility. Unfortunately when the result is the destruction of the planet, the words "improbable" and "vanishingly small" will never do much to assuage the public's fears. It just indicates that physicists will always have to grapple with public relations issues vastly more complex than the LHC.

Finally, we get a fascinating overview of the kinds of things which scientists hope to see in the LHC. The problem is that the generation of particles like the Higgs is a very low-probability event and is usually only a side-product of some other primary event. The situation is made more complicated by the immense difficulty of observing such fleeting glimpses in a hideously complex background of noise generated by the creation of other particles. Scientists working on these projects have to keep their eyes and instruments peeled for the one in a trillion event that may bring them glory. Whenever an event is observed, the scientists have to calculate the realm of probability in which it belongs. Usually if the event is outside five standard deviations ('5 sigma') then it is extremely likely to be real and not have occurred by chance alone. Not surprisingly, the observation and communication of these events is a tortuous thing. Publicity has to be avoided before you confirm such fleeting bits of probability, but leaks inevitably offer. And the media has seldom shown any restraint in announcing such potentially momentous discoveries which would bring glory, prizes and money to their originators. Scientists working today also have to deal with the presence of blogs and other instant communication conduits. As Sample narrates, at least in one case a physicist at CERN posted preliminary LHC results on the blog Cosmic Variance, and all hell broke loose. Scientists have to tread carefully especially in this era of instant data dissemination.

All this makes the scientists engaged in such endeavors live on the edge, and to us they appear like the explorers who have their eyes peeled to the sky looking out for the stray signal that would announce the presence of extraterrestrials. The mathematics of the Higgs boson is of course much more sound than that of alien contact, but the scientists who are looking for it are hanging on to such flimsy wisps of probability and interpretation that they surely must be questioning their own sanity sometimes.

In the end, even physicists are all too human. As Capt. Ramsey says, our rules are not always subject to little devils and angels sitting on our shoulders. And yet it seems that scientists like the Higgs hunters sometimes would be tempted to trust the hairs on the back of their head, especially when those hairs stand up straight at the glimpse of a peak in the graph, that 5-sigma event which would change everything. Maybe, just maybe.

How about a graphite ring for getting engaged?

2010-10-29T17:03:00.000-07:00

Donald Sadoway is a professor of materials science and engineering at MIT. Over the last few years he has emerged as one of the most popular lecturers on campus. Even Bill Gates has referred to him as a fantastic chemistry teacher. His course titled "Introduction to Solid-State Chemistry" is so much in demand that in 2007 it had about 600 students and the school had to stream the lecture into another room. Fortunately all his lectures including the ones for 2010 are online. Sadoway is a great speaker and seems to have thought very carefully about what he wants to say in class. Definitely worth watching.

Check out his description of the structural differences between diamond and graphite and how they affect the radically different properties of the substances. It's one of the clearest explanations of the difference I have heard.

At the end, Sadoway mentions that since graphite is the most stable form of carbon at room temperature, wouldn’t it make sense to present a ring made of graphite instead of diamond to your love interest as a symbol of everlasting love? I think that makes sense although my fiancée will probably disagree.

A limitless life

2010-10-28T12:03:00.001-07:00

Cross posted at Critical Twenties

The Indian chemist Chintamani Nagesa Ramachandra Rao (known as C N R Rao) is one of the foremost solid-state and materials chemists in the world. His output- more than a thousand papers and forty books- is phenomenal by most scientific standards. He has been one of the founding fathers of the field in the last fifty years. There are very few living chemists in any field who have worked in such diverse areas. Rao’s work has been recognized by several honors, including election to the Indian science academies, the Royal Society and the US National Academy of Sciences. Very few scientists have influenced Indian science in the last half century to the extent that he has. In his native city of Bangalore he is virtually worshipped by some; I have seen a traffic intersection named after him.

Rao has now written an biography in which he catalogs his life and times in chemistry. It’s worth reading, especially if you want to get a glimpse of science in a developing country and the kind of efforts it takes to do research in such a place.

Rao grew up in post-independence India where the fledgling republic was striving to get its feet off the ground. India’s first Prime Minister, Jawaharlal Nehru, was probably the most scientifically literate and ambitious of all the country’s leaders and placed a premium on scientific and technological development. It was under his leadership that the Indian Institutes of Technology and many of the leading national laboratories were established. Rao grew up in the 1940s and did his undergraduate work at the Banaras Hindu University in the holy city of Banaras, situated along the banks of the Ganges River. As a 19-year old undergraduate he published his first paper in Science on electrical discharges. After graduation he applied to Linus Pauling for his PhD. However, Pauling was then vigorously engaged in deciphering the structure of proteins and was not involved with the kind of experimental physical chemistry that Rao was interested in. He referred Rao instead to John Livingston at Purdue University, who was a leader in electron diffraction.

After finishing his PhD at Purdue, Rao went to Berkeley for a postdoc where he was engrossed by the likes of Glenn Seaborg, Melvin Calvin and others who had made Berkeley a Mecca for chemistry and physics. His scientific output was already outstanding- about 30 papers in leading journals- and it would have been easy for him to get a top faculty position in the US. However, Rao wanted to return to India and got a faculty appointment at the Indian Institute of Science (IISc). He also got married to a woman (Indu) who has been a great source of strength and wisdom for him since then. Apart from a productive stint at the Indian Institute of Technology, Kanpur, Rao has spent his entire career at IISc and then at the Jawaharlal Nehru Centre for Advances Scientific Research (JNCASR) which he founded.

The next part of the book is the part that’s most interesting. By that point (late 50s), chemistry had been revolutionized by two great developments. One was the invention of key instrumental techniques like NMR spectroscopy and x-ray diffraction. The other development was the formulation of a theoretical framework for chemistry through quantum mechanics, pioneered by Pauling, Slater, Mulliken etc. These developments were virtually unknown in India and were almost non-existent in the university curriculum. Along with a small band of other chemists, Rao was instrumental in establishing these modern chemical concepts in India. He did this, firstly by being one of the first to teach courses in quantum chemistry, spectroscopy etc. and secondly by founding a vigorous program of modern chemical research. He was certainly one of the few pioneers of modern chemistry in post-independence India; one is reminded of the American school of modern physics which Robert Oppenheimer founded at Berkeley in the 30s. Rao’s perseverance in overcoming fundamental odds like the lack of equipment and the Indian bureaucracy is noteworthy. Rao also made solid-state chemistry respectable when work in that discipline was far from fashionable. His descriptions of the threadbare capabilities of Indian science and the efforts necessary to overcome these are intriguing and inspiring. It definitely took a lot of courage and was an enormous gamble for Rao to decide to establish his career in India during that time, especially when his career would certainly have flourished anywhere in Europe or the US. But it ultimately paid off and allowed Rao to make contributions that were far greater in terms of social and national impact compared to the contributions he would have been able to make elsewhere.

So how does one do high-quality research in a resources and cash-strapped developing country? Rao’s approach is worth noting. He knew that the accuracy of measurements he could do with the relatively primitive equipment in India could never compete with sophisticated measurements in Europe or the US. So instead of aiming for accuracy, Rao aimed at interesting problems. He would pick a novel problem or system where even crude measurements would reveal something new. Others may then perform more accurate measurements on the system, but his work would stand as the pioneering work in the area. This approach is worth emulating and should be especially emphasized by young scientists starting out in their careers: be problem-oriented rather than technique-oriented. Another key lesson from Rao's life is to not work in crowded fields; Rao would often contribute the initial important observations in the field and then move on while it was taken over by other scientists. This also keeps one from getting bored. Embodying this philosophy allowed Rao to work in a vast number of areas. He started with spectroscopic investigations of liquids, moved to inorganic materials and further worked extensively on organic materials. Among other things, he has made significant contributions to unraveling the structures and properties of transition metal oxides, ceramic superconductors and materials displaying giant magneto-resistance. All these had special physical and chemical properties which were directly a result of their unique structures. Rao co-authored an internationally recognized book- “New Directions in Solid-State and Structural Chemistry”- which encapsulates the entire field.

However, sometimes not having the right technique can prove significantly debilitating. In the 80s, the world of science was shaken by the discovery of ‘high-temperature’ superconductivity in a ceramic material. In fact Rao had synthesized the exact same material - an oxide of copper, lanthanum and barium - more than fifteen years before. However, the compound became superconducting at 30 degrees Kelvin and could be studied only in liquid helium. Unfortunately Rao was unable to do measurements at this temperature because the only relevant material available in his laboratory was liquid nitrogen, which boils at 77 K. If liquid helium had been available, Rao might well have been the first person to observe superconductivity in this material. In 1987, two scientists at IBM who discovered the phenomenon were awarded the Nobel Prize.

The later parts of the book deal with Rao’s experiences as a top government advisor and his relationships with several leading scientists including Nobel laureates like Nevill Mott and Philip Anderson. He also laments the current state of science education in India where most bright students prefer to study financially lucrative disciplines like information technology, business and medicine. The Indian middle class is still stuck in a peculiar frame of mind in which intelligence and achievement is necessarily measured by the amount of money you make. Understandably, many Indian middle class parents who themselves grew up in relative poverty want their children to be financially successful. But as Rao says, this attitude is adversely affecting the scientific future of the country and is siphoning off talent from science and technology research. For now, about the only solution to this problem is the infusion of funds in science education and research with a view to making these fields financially sustainable. Some steps in this direction have been taken with the establishment of the Indian Institutes of Science Education and Research (IISER), but much more needs to be done. Unfortunately, Rao has relatively few thoughts on practical policies which could bring about such a change. This is probably the most disappointing part of the book since Rao, with his enormous experience in Indian science and government, enjoys a unique vantage point and would have been the idea guide to offer solutions and policy recommendations. But apart from stressing the importance of science education and science, he has few deep thoughts on the problem.

The book ends with some interesting appendices and reflections. One is a “Letter to a Young Chemist” in which Rao succinctly catalogs the excitement of solid-state and materials chemistry. Another essay on science and spirituality is again disappointing; while Rao clearly sees no conflict between the two, the essay is only two pages long and superficial. The last essay titled “Science as a Way of Life” is a masterful exposition on the kind of attitude one needs to be a scientist, and the role of science in our society. Here Rao teaches by example. As attested by his colleagues and friends, he has been completely dedicated to science throughout his life and demands the same kind of unflinching commitment from his students and co-workers. He still spends almost every free minute in the lab and intends to follow the example of some of his scientific heroes in working till the last day of his life. While this intensity has often made him a demanding teacher and taskmaster, no one can accuse him of not walking the talk. Rao talks about the international community of scientists and how it has helped him. He also talks about prejudices still standing in the way of international cooperation, including the occasional racism he encountered at Purdue in the 50s, which can be rapidly dissolved by the bonds of scientific kinship.

The great thing about science is that like music and art it is truly without boundaries and constitutes an international community. As Rao himself has demonstrated, excellence in science does not ask for one’s nationality, religion, gender, sexual inclination or political views. All it asks for are an open mind, healthy skepticism, honest dedication and respect for knowledge and inquiry. As Rao’s life exemplifies, cultivating these qualities can lead to a life that is extraordinarily rewarding and enriching.

Link: An extended video interview of Rao on the Vega Science Trust website conducted by his friend, chemist Anthony Cheetham of UCSB and Cambridge. The interview is worth watching and covers Rao's life, science, public service and home life.

Ethics and Indian Science

2010-10-22T21:14:00.000-07:00

I have started contributing to the blog Critical Twenties which has been launched by an excellent cross-section of intellectually curious Indians scattered across the globe. You can read the description here. The blog is the initiative of Arghya Sengupta, a law student at Oxford University. The following is my first post at the blog and I will be linking here whenever I post.

The story is well-known by now. A graduate student named Heather Ames was doing cancer research at the University of Michigan. At one point she started noticing her experiments going horribly wrong. This started happening so often that the frustrated researcher almost began to question her own sanity. When she complained to her advisor her advisor would not believe it initially. At one point even her advisor suspected, based mostly on second-hand reports, that the young woman was sabotaging her own experiments to gain sympathy. One can only imagine her plight. Finally, by judicious recording of her experiments, she was able to prove beyond a shadow of doubt that someone was tampering with them. When she and her advisor reported the matter to the campus police, the police first gave the poor woman herself a lie-detector test. Only after they were convinced of her innocence did they launch a serious investigation. The winning strategy for catching the culprit turned out to be simple. A camera surreptitiously installed in the lab proved that the young researcher’s colleague, an Indian postdoc named Vipul Bhrigu, was cruelly sabotaging her experiments...

Read the rest of the post on Critical Twenties

"The most ludicrous system ever devised"

2010-10-19T10:37:00.001-07:00

That's Nobel laureate Harry Kroto on the peer-review system. Since he won his Nobel for fullerenes, Kroto has become a tireless promoter of science education and communication. This week's issue of Nature has a series of brief interviews with several Nobel laureates. One of the questions asked was about the peer-review system and whether it is an optimal one. Most laureates gave an analogy and paraphrased Churchill's quip about democracy: it’s a system full of flaws, yet better than the other alternatives. But Kroto went one step further:

Many people consider the peer-review system broken. Do you share their view, and do you have a solution?

The peer-review system is the most ludicrous system ever devised. It is useless and does not make sense in dealing with science funding when history abounds with a plethora of examples that indicate that the most important breakthroughs are impossible to foresee.

The science budget should be split into three (not necessarily equal) parts and downloaded to departments. The local institutions, and not government departments, should disburse funding as they are close to the coalface and can decide what needs support and what is in the long-term interest of the department. There should be no research proposals on which to waste time.

One part should go to young people chosen by their universities as the researchers on which their institution's future will depend — they have done the work, why waste time doing it again when people have no time and are too far away from the coalface and in general do not have the relevant expertise?

The second part should go to a group whose most recent report was excellent. This is the racehorse solution — if a scientist has just done some great work, let her or him run again.

Although I would have probably eschewed such strong words and do sympathize with the other laureates' perspective, my heart is with Sir Kroto. Revolutionary science has often been rejected by the peer-review system; it's worth noting that Enrico Fermi's paper on beta decay was rejected by Nature.

I myself have believed in having a separate section in leading science journals devoted to "improbable" science, speculative and brain-tickling ideas flung out for contemplation by the rest of the community. The section should make it clear that such ideas have not been validated, but then that's true of any scientific idea when it's being conceived. I seriously believe that such sections would provide a lot of food for thought for researchers who are willing to go out on a limb. Maybe the published, incomplete ideas will meet their own ideas to be synthesized into a more coherent whole.

Now of course that does not mean that any crackpot idea deserves to be published. There certainly needs to be a minimum standard for acceptance. For this there could be a second kind of peer-review, where reviewers are more forgiving and more creative in judging the merit of the proposed concept. These reviewers could judge the idea not on the basis of its validation but on the basis of its novelty, novelty that’s nonetheless grounded in sound basic principles of science (thus homeopathy would be instantly excluded). Such a two-tier system would then provide an opportunity for the publication of both “normal” science as well as potentially revolutionary science. An example that comes to my mind is Luca Turin’s novel idea about olfactory molecules being detected by vibration rather than shape. The idea certainly seemed grounded in basic physics and chemistry. Its publication would have pushed at least a couple of researchers to validate or disprove it. As it turns out it was rejected by a leading journal after a long wait.

As Freeman Dyson says, the most important scientists are often "rebels" who speak out against the conventional wisdom. Their far-fetched sounding pronouncements of today have often been transformed into the important discoveries of tomorrow. The least that science journals can do is to give their ideas a worldwide platform.

In praise of cheap science

2010-10-15T07:14:00.001-07:00

The era of ‘big science’ in the United States began in the 1930s. Nobody exemplified this spirit more than Ernest Lawrence at the University of California, Berkeley whose cyclotrons smashed subatomic particles together to reveal nature’s deepest secrets. Lawrence was one of the first true scientist-entrepreneurs. He paid his way through college selling all kinds of things as a door-to-door salesman. He brought the same persuasive power a decade later to sell his ideas about particle accelerators to wealthy businessmen and philanthropists. Sparks flying off his big machines, his ‘boys’ frantically running around to fix miscellaneous leaks and shorts, Lawrence would proudly display his Nobel Prize winning invention to millionaires as if it were his own child. The philanthropists’ funding paid off in at least one practical respect; it was Lawrence’s modified cyclotrons that produced the uranium used in the Hiroshima bomb.

After the war big science was propelled to even greater heights. With ever bigger particle accelerators needed to explore ever smaller particles, science became an expensive ‘hobby’. The decades through the 70s were dominated by high-energy physics that needed billion-dollar accelerators to verify its predictions. Fermilab, Brookhaven and of course, CERN, all became household names. Researchers competed for the golden apples that would sustain these behemoths. But one of the rather unfortunate fallouts of these developments was that good science started to be defined by the amount of money it needed. Gone were the days when a Davy or a Cavendish could make profound discoveries using tabletop apparatus. The era of molecular biology and the billion dollar Human Genome Project further cemented this faith in the fruits of expensive research.

We are now seeing the culmination of this era of big physics and biology. In recent years, university professors’ worth has exceedingly been measured by the amount of funding that they get. Science, long a relentless search to uncover the mysteries of life and the universe, has been transformed into a relentless search to find the perfect problem most likely to bag the biggest grant. Rather than focusing on the ideas themselves, the current system encourages researchers on proving their ‘worth’. The only true worth of a scientist is his quest and hunger for knowledge and his passion in transferring that knowledge to the next generation. All other metrics of worth are greatly exaggerated.

The accomplished chemist Alan Bard nails this problem in an editorial that castigates the current system for sacrificing the actual quality of research at the altar of the ability to bring in research funds. The editorial succinctly points out that in the race to secure these funds, scientists are often tempted to hype their research proposals so that the end product is more smoke and less fire. And of course, the biggest casualty is the education of further generations of scientists, those who are going to bring about the very technological and scientific advances that make our world tick. The result of all this? Young people are dissuaded from going into academic science; if their worth is going to be mainly judged in dollars (and that too only after they turn 40), they might as well work for the private sector.

Now of course nobody is arguing against scientists being able to file patents or apply for large grants. Money flowing in from these endpoints can sustain further research which today on the whole is more expensive. But as Bard’s article makes it clear, these activities are often becoming the primary and not the secondary focus of universities. That goes against the spirit of research and it undermines the very meaning of intellectual scholarship.

But most importantly, and Bard does not explicitly mention this, I think that the current environment makes it appear to young scientists just entering the game that they need to necessarily do expensive science in order to be successful. I think part of this belief does come from the era of big accelerator physics and high profile molecular biology. But this belief is flawed and it has been demolished by physicists themselves; this year’s Nobel Prize in Physics was awarded to scientists who produced graphene by peeling off layers of it from graphite using good old scotch tape. How many millions of dollars did it take to do this experiment?

Sure, low hanging scientific fruits accessible through simple experiments have largely been picked, but such a perspective is also in the eye of the beholder. As the graphene scientists proved, there are still fledgling fields like materials science where simple and ingenious experiments can contribute to profound discoveries. Another field where such experiments can provide handsome dividends is the other fledgling field of neuroscience. Cheap research that provides important insights in this area is exemplified by the neurologist V S Ramachandran, who has performed the simplest and most ingenious experiments on patients using mirrors and other elementary equipment to unearth key insights into the functioning of the brain. These scientists have shown that if you find the right field, you can find the right simple experiment.

Ultimately, few can doubt that cheap experiments are also more elegant, and one derives much more satisfaction from simply mixing two chemicals together to generate complex self-assembled structures than using the latest accelerator to analyze gigabytes of computer data, although the latter may also lead to exciting discoveries. The beauty of science still lies in its simplicity.

But as Bard’s article suggests, are university administrations going to come around to this point of view? Are they going to recruit a young researcher describing an ingenious tabletop experiment worth five thousand dollars or are they going to go for one who is going to pitch for a hundred thousand dollars worth of fancy equipment? Sadly, the current answer seems to be that they would rather prefer the latter.

This has got to change, not only because simple experiments still hold the potential to provide unprecedented insights in the right fields, but also because the undue association of science with money misleads young researchers into thinking that more expensive is better. It threatens to undermine everything that science has stood for since The Enlightenment. The function of academic scientists is to do high-quality research and mentor the next generation of scientist-citizens. Raising money comes second. A scientist who spends most of his time securing funds is no different from a corporate lackey soliciting capital.

Science, which has nurtured and sustained our intellectual growth and contributed to our well-being for four hundred years, is like an eagle held aloft by the wind of creativity and skepticism. How can this magnificent bird soar if the wind fueling its flight and holding it high starts getting charged by the cubic centimeter?