Field of Science

A potentially revolutionary new technique for chemical structure determination


I am a big believer in science as a tool-driven rather than an idea-driven revolution, and nowhere do you see this view of science exemplified better than in the development of instrumental techniques in chemistry - most notably NMR and x-ray diffraction. NMR and crystallography were not just better ways to see molecules, but in their scope, their throughput, their cost and their speed, they opened up whole new fields of science like genomics and nanomaterials up to investigation that their developers couldn't even have imagined.

So it is with some interest that I saw a paper from the Nelson, Gonen and Rodriguez labs at UCLA and the Stoltz lab at Caltech that describes a new way to rapidly determine the structures of organic molecules. And I have to say: very few papers in recent times have made me sit up and do a double take, but this one did. At one point in the paper the authors say they were "astounded" by the ease of the technique, and I don't think that word is out of place here at all.

Until now, crystallography has been the gold standard for all kinds of structure determination; it gives you as direct a view of molecules at the atomic level as possible. But the very name "crystallography" implies that you need to get your sample into a crystalline state, and as any chemist who has worked with a headache-inducing list of assorted powders, gels, oils and tars knows, being crystalline is not the natural state of most molecules. In most cases your samples are thus simply not in a convenient form for crystallography.

That's why NMR has been the primary technique for routine organic structure determination. But NMR is still relatively slow and depends on having a machine that's expensive and sometimes breaks down. You also cannot do NMR on a benchtop, and getting the sample in a pure enough condition in the right solvent is also key to good structure determination. Then there are all the problems attendant with shimming, water suppression and other artifacts that NMR presents, although sophisticated software can now take care of most of these. Nonetheless, as powerful as NMR is and will continue to be, it's not exactly a rapid, plug-and-play system.

That's why this recent paper is so promising. It describes a crystallographic technique that uses cryo-EM and micro-electron diffraction (micro ED) for efficiently finding out the structure of organic molecules. Electron diffraction itself is an old technique, pioneered for instance by Linus Pauling in the 1930s, but this is not any old ED, it's micro ED. Cryo-EM already won the Nobel Prize two years ago for determining the structures of complex proteins, but it has never been routinely applied to small molecule structure determination. This new technique could change that landscape in a jiffy. And I mean in a jiffy - the examples they have shown take a few minutes each. The first molecule - progesterone - went from powder to pattern in less than 30 mins, which is quite stunning. And the resolution was 1 Å, and you can't ask for more. Up to twelve samples were investigated in a single experiment.

But what really made me sit up was the variety of starting points that could be investigated. From amorphous powders to samples straight out of flash chromatography to mixtures of compounds, the method made quick work out of everything. As mentioned above, amorphous powders and mixtures are the rule rather than the exception in standard organic synthesis, so one can see this technique being applied to almost every chemical purification and synthetic manipulation done in routine synthesis or structure determination. For me the most amazing application however was the determination of a mixture of four different molecules: no other technique in organic chemistry which I know can do mixtures in a few minutes with such high resolution with such little material.

There are undoubtedly still limitations. For one thing, cryo-electron microscopes are still not cheap, and while sample preparation is getting better, it's also not instantaneous in every case. I also noticed that most of the compounds this study looked at were rather rigid, with lots of fused and other rings; floppy molecules will likely cause some trouble, and although thiostrepton is an impressive-looking molecule, it would be interesting to see how this works for beasts like rapamycin or oligopeptides. In general, as with other promising techniques, we will have to see what the domain of applicability of this method is. 

Nonetheless, this is the kind of technique that promises to take a scientific field in very novel directions. It could accelerate the everyday practice of organic chemistry in multiple fields - natural products, chemical biology, materials science - many fold; and at some point, quantity has a quality of its own. It could allow the investigation of the vast majority of compounds that cannot be easily coaxed into a crystal or an NMR tube. And it could perhaps even allow us to study conformational behavior of floppy compounds, which from first-hand experience I know is pretty hard to do.

If validated, this technique also exemplifies something I have talked about before, which is how scientific tools and discoveries build on each other; in other words, how scientific convergence is a key driving force in science. When cryogenics was invented, nobody foresaw cryo-electron microscopy, and when cryo-EM was invented, nobody foresaw its application to routine organic synthesis. And so it goes on, science and technology piggybacking in ever-expanding spirals.

Lessons from Tom Steitz, surveyor of molecular empires (1940-2018)



The ribosome is one of the most important and complicated molecular machines ever devised by evolution. Functioning as the factory and assembler for making proteins from RNA, it is as important as DNA itself and is found in every life form on planet Earth. If we find life on another planet, along with some form of DNA, it is almost certain to contain some kind of ribosome.

Tom Steitz, Venki Ramakrishnan and Ada Yonath won the Nobel Prize for chemistry in 2009 for cracking the structure of the ribosome. I was saddened to hear that Steitz passed away a few days ago. Incidentally, his demise comes after Venki Ramakrishnan published his memoir on his ribosome odyssey, a journey that both starred and owed a lot to Tom Steitz.

Over more than two decades, Steitz, Ramakrishnan, Yonath and others used laborious techniques to carefully obtain more complicated and better structures of this beast of a molecule. And a beast it certainly was; the 40S subunit of a eukaryotic ribosome contains 1900 nucleotides and 33 proteins. While protein crystallography is now routine, solving the structure of a multiprotein assembly like the ribosome is incredibly daunting even now, and is a tribute to both the perseverance and the creativity of these scientists. Crystallography is the ultimate example of marathon running in science, something that at its highest levels can easily take a decade and long hours in the lab. Even before he attacked the ribosome, Steitz had already established a reputation as one of the world's top crystallographers, doing a detailed study of the enzyme hexokinase for instance. Among other findings, his work revealed that the ribosome is composed mainly of RNA rather than proteins; another boost for the RNA world theory for the origins of life.

I have fond memories of Steitz from my time as a postdoc at the University of North Carolina, Chapel Hill. In 2010, a year after he won the prize, he was a visiting lecturer at UNC. Four or five of us had a chance to sign up for a private breakfast with him in a small room at the faculty club. There wasn't a trace of ego in Steitz's interactions with us, but what I remember best was his unending curiosity regarding each of our research projects (not surprisingly, he was particularly interested in some cryo-EM work a colleague of mine was doing). It was clear that Seitz was no prima donna, but a scientist's scientist who was not resting on his laurels but seeking new adventures.

The New York Times has a good obituary of Steitz that showcases many of his qualities. After his PhD he trained at the famed MRC Laboratory of Molecular Biology, an institution started by Watson, Crick, Perutz and others that has produced more than fifteen Nobel Laureates. The article talks about the atmosphere in the institute, where Nobel laureates sat next to graduate students during tea and lunch in the cafeteria and constantly talked science. One thing that struck Steitz was how much time they spent talking about experiments rather than doing them; later he realized that they were basically enforcing a process of ruthless elimination on the experiments by discussing them beforehand, so that they would pursue only the most promising ones. That's a good lesson.

I remember another MRC-related anecdote that Steitz told us during our breakfast eight years ago; he was constantly surprised how the famous scientists at the MRC asked seemingly stupid or simple questions whose answers were not as obvious as we think. For instance, he remembers Max Perutz asking everyone what a eukaryote was; the question led to an unexpectedly fascinating discussion about the molecular differences between eukaryotes and prokaryotes. Steitz emphasized to us how important it is to keep on asking simple questions and setting our egos aside, a lesson that many of us sadly don't imbibe.

Steitz's wife Joan is an equally eminent biologist in her own regard. She was awarded a Lasker Prize this year and has done much to advance RNA science in addition to serving as a role model for women in science. When Steitz was looking for a faculty position he was offered one at Berkeley, but they declined to offer Joan - a protégé of James Watson - one, so Steitz turned down the job, and the couple moved to Yale where both of them acquired prestigious positions.

Tom Steitz was a scientist's scientist and an honorable man who did much to advance progress in molecular biology and the cause of honest, sound science. He will be missed.

Big discoveries from little things


That's physicist Albert Michelson, at the University of Chicago in 1894, saying that fundamental physics was essentially finished. In the fifty years after Michelson's talk, physics discovered the following: special and general relativity, quantum theory, nuclear fission and the expansion of the universe. And it was just getting warmed up. The famously acerbic Wolfgang Pauli would have probably called Michelson's prediction as "not even wrong".

Michelson clearly was woefully wrong in saying that the main task of physics would henceforth simply be more accurate measurements. And yet it would be wrong to take him to task for a clearly mistaken view, for at least two reasons. Firstly, physics in 1894 explained an enormous range of phenomena. From Newtonian mechanics that explained everything from apples falling down to the motion of planets to thermodynamics which explained everything from the increase in disorder in physical systems to the practical workings of steam engines, physics clearly had proved itself to be a spectacularly successful science, so there was good reason to think that most of the fundamentals had been worked out. 

Secondly, the kinds of things physics was being unable to explain then could be seen as little more than annoying anomalies and exceptions; the behavior of glowing blackbodies, the slight anomaly in the motion of mercury around the Sun, the absence of the luminiferous ether. In fact, Michelson himself would perform an experiment just three years later, in 1887, that would lead to a very important negative result: the lack of detection of the ether that had been predicted as a medium for the propagation of light and other electromagnetic radiation which Maxwell had worked out.

Neither Michelson nor anyone else could have seen the profound new worlds hidden in these seemingly mundane anomalies. Problems with blackbody radiation led to the birth of Planck's quantum theory, and problems with the ether and with the anomalous orbit of Mercury led to Einstein's special and general theories of relativity. And at least in one sense Michelson's highlighting of more and more accurate measurements was spot on: the difference between the perihelion of Mercury predicted by Newton's theory of gravity and what was actually measured was tiny - Newton's prediction was off only by a millionth of one percent (which meant that Mercury would arrive at its perihelion only half a second later than what Newton predicted), but that little deviation hid a stunningly different and new view of nature that took Einstein's genius to uncover.

Rather than mocking Michelson's 1894 statement as a foolish failure of prediction or the product of tunnel vision, it's more important therefore to recognize what it implies. Firstly, it's clear that nobody and not just Michelson could have known how different the future of physics would be, giving currency to Niels Bohr's statement that prediction is difficult, especially about the future. But more importantly, it's enlightening to realize how seemingly mundane experimental anomalies can lead to completely new ways of looking at the world. 

In my view, the fifty years that followed Michelson's statement, although now rightly regarded as a triumph of theoretical physics, should be viewed as an even greater triumph of experimental physics. Both the old quantum theory invented by Planck and the new quantum theory invented by Heisenberg and others arose from small, anomalous observations in seemingly obscure and minor areas of physics. So did relativity. Without the exceedingly accurate measurement of the error in the predicted vs measured anomaly of Mercury's orbit, who knows how long it would have taken general relativity to come along.

The development of physics following Michelson's statement gives one hope that the biggest discoveries in science will continue to be hidden in some of the smallest discrepancies in experiment. This is especially true of biology where we are now in a position to detect very small differences in protein and gene expression. Experimentalists should keep on looking for minor anomalies in their observations; flies in the ointment; nagging little differences in numbers that should be explained by the existing theoretical framework but are not. Sometimes it will be nothing, often it will simply be a result of statistical error or random noise, but occasionally, just occasionally, it could be a glimpse of the crack of light from a door that opens on to a whole new world.

On Nobel Prizes, Diversity And Tool-Driven Scientific Revolutions

First published on 3 Quarks Daily.
The Nobel Prizes in science will be announced this week. For more than a century the prizes have recognized high achievement in physics, chemistry and medicine. Some scientists crave the prizes so much that they get obsessed with them. A prominent, world-famous chemist once had lunch with my graduate school advisor. After a few minutes he went off on a tirade against the Nobel committee, cursing them for not giving him the prize. He never got it, and he never got over it. The Nobel can bring fame and recognition, but it can also make the lives of those who live for them miserable.
A human prize created by a human committee based on the will of a human who established it to atone for a better method of killing people should not cause people such agony. And yet, in many ways, the prizes reflect all that is good and bad about human nature. The physicist Phillip Lenard later turned out to be a Nazi who denounced Einstein and his relativity. The celebrated Werner Heisenberg wasn’t a Nazi, but he controversially participated in work toward an atomic weapon in Germany during the war. Fritz Haber made an even more damning pact with the devil. Haber and his collaborator Carl Bosch kept alive, by one measure, one third of the world’s population by inventing a process to manufacture ammonia for fertilizers from nitrogen in the air. Haber won the Nobel Prize for chemistry in 1918, right after he had spent the First World War inventing chemical weapons that led to the deaths of tens of thousands. António Moniz who won the prize in medicine in 1949 pioneered the highly controversial procedure of lobotomy which, even though it seemed like a good idea then, incapacitated thousands. And William Shockley who co-invented the transistor and inaugurated Silicon Valley later became infamous for promoting racist theories of intelligence. The moral landscape of Nobelists even in science is unambiguous, so one can imagine how much worse it would be and in fact is in areas like peace and economics.
There are also all the other human problems which have been highlighted with the prizes. The ratio of those who deserved the award but did not get it to those who did must be at least a hundred to one, although it’s at least possible to make an honest argument that those who did get it largely deserved to. Some spurned candidates have taken it in their stride and jest about it. The astronomer Jocelyn Bell-Burnell should have received the prize for the discovery of pulsars – rotating neutron stars; instead only her PhD advisor Anthony Hewish shared it. But Bell-Burnell has taken the fifty-year controversy in good humor, joking that it’s better that people ask her why she didn’t win it than why she did. The fallout from the controversy might have affected more than just Bell-Burnell: the astrophysicist Fred Hoyle who deserved a share of the 1983 prize for his groundbreaking work deciphering the synthesis of the elements in stars was sidelined, and some think it might have been for his vigorous public advocacy of Bell-Burnell.
Most egregious is the three-person rule which prevents many other worthy individuals from getting the prize almost every year. In one case, just like the chemist who was complaining to my advisor, one bitter scientist who felt especially ignored for the lack of recognition of his work on MRI took out a full-page advertisement in the New York Times protesting the omission. Even otherwise world-renowned scientists are not immune to wanting even more recognition. Robert Burns Woodward, by a very broad consensus the greatest organic chemist of the 20th century, wrote a remarkable letter to the Nobel committee protesting the chemistry prize in 1973 which was published in The Times of London, telling them that they had committed a grievous error by not including him among the winners; Woodward in fact had already won the prize in 1965 for his seminal contributions to the synthesis of complex organic substances like chlorophyll, and he would have undoubtedly won another one in 1981 with Roald Hoffmann had he not died the year before.
There is also a pronounced lack of women winning the prizes, especially in physics which has not seen a woman win for fifty years. While disappointing, to some extent this is not surprising since women haven’t been represented in higher physics education and the physics workforce because of systematic barriers; Princeton University did not admit female physics students in its astronomy graduate programs until the 1960s; the problem really should be addressed at a much lower level. Fortunately there have been an increasing number of women in physics and other sciences in the last twenty years, so hopefully in a few years we should start seeing women represented in the list. The prizes have also been overwhelmingly won by scientists from the United States and Europe: this fact is even less surprising since these countries are where most pioneering scientific research after the Second World War has taken place. The only Asian country which has been well represented has been Japan, and the Japanese have progressed in science and technology after their virtual destruction in World War 2 at breakneck speed. Chinese, Indian and other scientists have won a few of the prizes, but it’s always been for work done in the United States or Europe. It’s noteworthy therefore that three years ago, Tu Youyou became the first Chinese scientist and woman who won a Nobel Prize for work done in China; she won for the discovery of the antimalarial drug artemisinin. If China, India and other countries pour money into their scientific institutions and train the next generation of scientists, if they bring the same spirit of adventure, risk-taking and perseverance that has animated scientists in the United States and Europe, it’s inevitable that they will start producing Nobel-quality research within a few decades.
The history of the Nobel Prizes also offers an interesting window on changing developments in science. For me, the most promising insight they offer is of science as a tool-driven rather than as an idea-driven revolution. If you ask most of the public who their favorite scientists are, they are likely to be theoretical scientists like Einstein, Newton, Galileo and Hawking. And yet, as brilliant as these scientists’ work is, the actual work of uncovering new facts is done by experimentalists and not theorists, and yet the popular conception of science is biased toward theorists. For instance, let’s consider Nobel Prizes in physics where the demarcation between theory and experiment is well defined. By my count, among the 73 prizes awarded since the end of the war, no less than 27 have been awarded for new techniques; these include bubble chambers, laser spectroscopy and scanning tunneling microscopy, all of which have revolutionized many branches of physics. Science develops through both new tools and both ideas, but the image of science in the public mind is rather skewed and consists of singular minds coming up with great ideas. The truth is both more mundane and more important; experimentalists are the ones who actually find new things, while theorists are the ones who predict or explain them. You seldom get a Nobel Prize for explanation. You can get one for prediction, but as Niels Bohr rightly said, prediction is very difficult, especially about the future, so there have been very few genuinely groundbreaking predictions even in physics that were later verified by experiments. Paul Dirac’s prediction of antiparticles stands out as being especially remarkable, although it might have exaggerated the role that beauty and elegance play in theoretical ideas and set up an entire generation in physics for believing that truth equals beauty. In chemistry and medicine it’s far easier to accept the idea of science as a tool-driven revolution, partly because most chemical and biological systems are too complex to be reduced to first-principles explanations the way they can be in physics.
The image of singular minds also leads to the other big misconception regarding Nobel Prizes and science in general; the belief that lone geniuses do most of what’s important in science. In a trivial sense this has always been false since nobody invents or discovers something from scratch and everybody stands on the shoulders of giants. But it’s also becoming false in a big way, and tool-driven revolutions in science are largely responsible for the increasingly gaping discrepancy. The Higgs boson which was recognized a few years ago came out of the minds of at least six people, but its discovery was enabled by hundreds working at the Large Hadron Collider (LHC) in Geneva. Similarly, the discovery of gravitational waves for which three physicists were rightly awarded the prize last year was made possible using giant detectors that were constructed, operated and maintained by hundreds of researchers. Research now also spans multiple disciplines, and many important discoveries will not fit cleanly within the categories of physics or chemistry unless the definition of the disciplines themselves is expanded. Clearly there was no way Alfred Nobel and his contemporaries could have seen this evolution of science into a highly interdisciplinary endeavor collectively practiced by hundreds of people from different countries. And yet even in 2018 the prizes seem to be stuck in Nobel’s time. To keep the prizes relevant, it is imperative that they be expanded to honor entire teams spread across many fields. Perhaps a compromise would be to go the way of the much maligned peace prize, where both individuals and entire groups are recognized in the same year; the prize awarded to Al Gore and the IPCC for climate change would be a good example.
At the same time, I am also troubled by some who seem to take the other extreme position of saying that individuals should never be awarded the prize. This seems to me to be a kind of postmodern position that is driven more by communal ideology than facts. One of the signature features of scientific research is its diversity. Science may be done by large teams, but it will continue equally to be done by lone individuals. Even though they may stand on the shoulders of giants, singular minds like Einstein and Pauling do occasionally come along who see much further than anyone before. I certainly do not think Peter Higgs shouldn’t have been awarded the prize; I simply think that the LHC collaboration of scientists, engineers and technicians should also have been recognized.
Ultimately the Nobel Prize is a human institution, and like Thomas Jefferson, it embodies both glory and folly. To some this may make it imperfect and unworthy of recognition, but to me, the fact that the prize embodies the same complexity that makes humans so human is exactly what makes it so special, and worth celebrating.

A meeting with V. S. Naipaul


I met him at a Starbucks outside the Tower of London. It was pre-arranged. I had told him I was an independent blogger. He told me he preferred to talk to independent writers these days; the mainstream media was more trouble than what it was worth. It helped that I wrote for a site that he regularly read and admired. 

The complexities of the London tube have thwarted me on more than one occasion, and this time was no different.  I was a full fifteen minutes late. He was sitting in a cafe, his signature fedora on his head, but still dressed inconspicuously enough so as to seem like one of the many people thronging the cafe.
“Mr. Naipaul”, I said, extending my hand. “It’s a real pleasure to meet you.”
“Oh yes, please, I was expecting you. Please, call me Vidia”
Taken a little aback by the very informal moniker I was supposed to address him by, I exclaimed, “Ok, thank you. And so sorry”, I said, “I have to admit that the tube, as wonderfully efficient as it is, challenges me every time I visit the city.”
“Indeed. It was difficult to get around the first time I visited too, more than fifty years ago. Often when I thought I had made it to my destination, I realized I was back where I started. Shall we?”
We passed several tourists on our way inside the Starbucks. Inside, we ordered a regular coffee for Vidia and, for me, an American bastardization I had gotten used to since my graduate school days – a caramel macchiato. Vidia insisted on paying. Then, with a conspiratorial wink at me and the barista  – a woman who seemed like she had been around since before the advent of coffee shops – Vidia started toward the direction of the restrooms.
“Come with me”, Vidia said, leading the way. I was a bit confused: weren’t we supposed to get a table either inside or outside, where the weather was gorgeous, especially for a London summer? But I followed his lead.
At the very end of the hallway in which the restrooms were located Vidia stopped. Making sure nobody was around he pressed what seemed like a small photo frame of a bucolic mountain landscape hung on the wall. Suddenly the narrow wall swung open, and with a quickness belying the girth of his aging figure, Vidia disappeared into the void and beckoned me in. I was too stunned to say anything, and I followed him almost as a reflex action.
The door in the wall swung back and closed as fast as it had opened, and a bright light suddenly illuminated the hallway.
“Sorry about the mischief, but I have to guard against unexpected knocks on the door, even when I am seemingly past my prime.”
I still remained rather stunned to say anything.
There was another brown door at the end of the hallway. Vidia walked up to it and knocked. A few seconds later the door opened. Nadira Naipaul was gently smiling at us and welcomed us in. She was warm and welcoming, the picture of grace.
“Nadira, we have a guest with us today”. Vidia introduced me and briefly told Nadira about my background. I followed the two of them into the living room. The elegance of the room belied its simplicity. The walls were cream colored and easy on the eyes, and photos of various and sundry landscapes hung on the wall; a street scene in Trinidad, a sea of grass from England’s Lake District, and a weekend market in Agra with the Taj Mahal in the background. The apartment behind the wall seemed spacious. What caught my eye the most, however, was the low-slung Japanese table in the middle.
Vidia saw me staring at it and quickly said, “That’s where I write these days. I used to write at a desk for decades, but I have found recently that a low Japanese desk, a desk where you must sit cross-legged, imposes a kind of contemplative discipline that is hard to achieve with other seating arrangements. Would you like to give it a try?”
Of course, I said. I sat on one side, Vidia on the other. Nadira asked me if I would like some tea and went inside to fetch some. “So, what is it that you wanted to talk about?” Vidia asked.
“Well, I must apologize in advance, because this is undoubtedly a topic that many must have discussed with you, but I wanted to talk about identity. I wanted to talk about this both because it has been a central part of all your writings, and also because it’s something I can identify with myself.”
“Ah, identity”, Vidia exclaimed, a look of wistful familiarity compounded with some sadness evident in his eyes. “Yes, we all must grapple with identity at one point or another. We can certainly talk about it.”
“Well”, I said, “I must give you some personal background regarding why I wanted to bring up this specific topic.” Vidia indicated that he wanted me to continue at length.
“I am an Indian transplant in America. I came to the country for graduate school. I was steeped in American history, American science, American politics, throughout my upbringing in India. My parents were both college professors, both highly educated and literate, and our house was full of books, intellectual discussions, social occasions, laughter. America, especially, figured prominently in our dinnertime conversations, and people like Edison, FDR and George Washington Carver were greatly admired figures and regular topics of discussion. When I came to America, I realized I knew about many aspects of the country as well as the natives.”
“For the first few years I never felt the so-called identity crisis that is often talked about by immigrants, and I even laughed when other Indians in the United States indicated that they felt it. I felt at home in America. The public libraries, the basic rule of law, the respect for science and technology, the clean air, all left me feeling ecstatic; left me feeling that this was the greatest place in the world. Naturally during the first few years, just like other immigrants, I was eager to assimilate. However, in a somewhat paradoxical way, as I spent more time here, I started to ask myself, who am I, exactly, Indian or American or something in between, and does this even matter? And then – quite recently, I must admit – I read your wonderful book, ‘The Enigma of Arrival’, and that drove home the dilemma of identity in a fresh manner. My parents are no more now, and I certainly think of myself as American – or least Indian-American – and proudly call America home, but it is hard to let go of the dilemma entirely”
Vidia was quiet as I was saying this, nodding almost imperceptibly. “Yes”, he said, “the feelings you noticed weren’t alien to me, and I am sure you realized them when you were reading my book. I can certainly understand the gnawing dilemma of identity you must have felt. I am sure you understand that with me it was a case of a triple identity crisis, if you will. My grandfather came to Trinidad as an indentured Indian laborer, so I grew up with a motley collection of brown, black and white-skinned people in a very heterogeneous culture. Ideally I should have appreciated the cornucopia of racial and cultural complexity, but I was desperate to leave. Then I won a scholarship to Oxford, and I have lived in England for the last forty years. As you know, I have even been knighted, which is as English as it gets. And yet, if you ask me if I feel English alone, I would say no. There is a deep sense in which my mixed Indian-Trinidadian-English identity is indelible, and no amount of denial will peel away those layers and reveal a shining singular self.”
Glad to hear that he empathized with my thoughts regarding identity, I suddenly noticed Nadira standing next to us, holding a tray on which teacups made of elegant China were kept. I took a cup and added two spoonfuls of sugar in spite of the warnings about diabetes from my doctor; I wanted to make sure I was alert and attuned to anything Vidia was saying. “Can I join both of you?”, Nadira asked, “Of course”, I said. Company this charming was always welcome.
“Vidia and I were talking about identity”, I said. “Yes”, Nadira replied. “It’s a topic that Vidia and I never tire of discussing, especially in the context of his book, “The Enigma of Arrival”. “Exactly”, I said, delighted that Nadira and I shared the same taste in all things Naipaul. I recounted to Nadira what I had told Vidia. “I do understand”, Nadira said, “Each one of us has to square with different dilemmas of identity. As Vidia mentioned, he had to deal with a triple identity, I had to deal with a mixed Pakistani-English identity myself, and it seems you went through a similar experience.”
“I did. And as I told Vidia, I wonder sometimes whether it’s even worth feeling as if you have a conflict of identify, whether it’s something you should simply take in and become comfortable with rather than rationalize and overthink. And you know, you wonder about this even in the smallest instances; whether to speak in an American accent, how much to celebrate festivals from the old country, even something as seemingly trivial as whether to respond in your native language in kind on social media.”
“Yes, there is something to be said about the challenge of adopting to your new culture while being true to yourself.”, said Vidia, empathizing with my sentiment.
“There’s also something else I want to ask you about. What is identity, after all? How specific is it to one’s upbringing and family as opposed to one’s country? I say this especially in the context of the so-called ‘values’ that we speak of. For instance, if I ask myself what specific values I inherited from India, I would feel hard-pressed to find an answer. I would say that all the important values I have inherited are specific to my parents and family rather than to my country. At least the deep ones. The fundamental values I have gotten from my parents are ones like hard work, honesty, a thirst for knowledge and basic human decency. Is there something in here specific to India? I would think these are universal values, imparted by conscientious parents to their children around the world, in any country. If the deep and fundamental values I have are not specific to India, then what are? Diwali and Holi and Butter Chicken? Those sound rather superficial.”
Both Vidia and Nadira looked contemplative, and for a moment I worried whether I was boring them with my extended monologue. “I want to agree with you in principle; at least in terms of the notion of universal values that you speak of.”, remarked Vidia. “That being said, I think you are being too rational in your analysis here. It is quite difficult to truly speak of the values you imbibe when you grow up in a certain place, especially when you spend your impressionable years there. The real value of values, if you would forgive the expression, is intangible. It is the sum total of formative influences imparted by both your family and your country, the little things that you take for granted, the almost unconscious tics that you display; these are the lasting influences that are going to shape you as a person and contribute to your so-called identity.”
“I agree”, Nadira said. “There are all kinds of hidden influences that contribute to your identity, and through your actions later in life, you drop little hints here and there regarding those influences. For instance, as I am sure you know, Vidia’s father had a very deep and rather ambivalent influence on him; Vidia never even read the collection of letters between him and his father that was published a few years ago. This influence was a joint combination of his father’s identify as the son of an indentured Indian laborer in Trinidad and as an English-language journalist growing up as a subject in an English colony. Now of course, Vidia’s grandfather himself had been imported from India as a British colonial subject into a country where he became a different kind of British colonial subject. And he is also a Brahmin to boot, so there is another kind of caste-based identity embedded in this forest of identities. So you see how complicated this layering of identities gets?”
Vidia seemed a bit uncomfortable with Nadira’s explication, looking like he resoundingly agreed with it in principle while trying to stay away from the particulars. But he retorted, “She’s right. I think the best thing to say is that one always has many different identities; identities layered upon identities; identities fortifying identities; even identities contradicting other identities. It’s the essence of Walt Whitman’s quote about a person containing multitudes. That’s the way we all are. And we have to be comfortable with these splinters of identities.”
I took a cue from this discussion. As someone trained as a scientist, I thought I could bring a different idea of identity to the table. “I agree. Beyond a certain point it seems like it may be futile to analyze identity too rationally and minutely. But please humor me a bit here. I think of identity as something that goes beyond caste, creed, nationality, ancestry. I always think of human identity as embedded in a tapestry of biological identities, and I think we have to consider this aspect of identity at some point. I mean, think about it: whether as Indians or Americans or Englishmen, we are all part of a vast identity called ‘Homo sapiens’. And as Homo sapiens, we bear, as Darwin so memorably put it, “the indelible stamp of our lowly origins”. Our identities are intertwined with the identities of starfish and bears and orchids and earthworms and hummingbirds and barnacles that make up the grand edifice of evolution. The point I am making is that whatever our feelings about our national or ethnic identities, these are but a speck compared to the four billion years of identities that have manifested on our planet.”
“Wonderful, wonderful.”, Vidia remarked, and his face showed genuine appreciation. “I must confess I have always had trouble appreciating you scientific types. You know, during my travels in India, whenever people I met seemed quite confused about my identity as a Trinidadian-Indian-Englishman, I always took the easy way out and told them I was a chemistry teacher. Fortunately nobody asked me what I exactly taught, otherwise I would have been in trouble. Now, listening to you, I think perhaps I should have paid more attention to those meager science classes I attended in high school. ‘The indelible stamp of man’s lowly origins’. Wonderful. I could not agree more. However, I would say that it’s not always easy to subsume your proximate identity of caste and country, if you will, to this ultimate identity that you speak of. Everyone grapples with their own particular brand of identity. That differentiation of identities is itself a dilemma within a dilemma which we should all confront, much like the riddle wrapped in a mystery inside an enigma which that blue-blooded imperialist Churchill talked about in reference to the Soviet Union.”
The tea and pastries had gotten cold, the hour was late, Vidia seemed tired. “I think that if there is one take-home lesson from this discussion”, I said, “it would be that all of us, without exception, have to deal with multiple identities. Even if it’s not an identity of caste, it’s an identity of nationality. And even if it’s not one of nationality, even if your ancestors have lived in a country for hundreds of years and have never married outside their specific ethnicity, they still have to live with the multiple identities that have been bequeathed to them by evolution. We are all connected to each other in that regard.”
“Yes, as much as they try to deny it, not even those fervent evangelicals that I saw at the 1984 Republican convention in Dallas can escape from these multiple layers of identity!”, said Vidia. Nadira laughed.
“Indeed!”, I exclaimed. “Well, I think I don’t want to take up too much of your time. This has been a delightful conversation, and I am deeply grateful to you for your time.”
“We feel the same way. Make sure you send us your article, please.”, Vidia said. After bidding him and Nadira goodbye, he again walked me through the secret passageway and pressed a little button that opened the door in the wall. I grasped his hand and said goodbye, and made my way through the dimly lit Starbucks. Opening the door, I stepped out into the London night. The city was still alive, its multiplicity of identities glowing with anticipation.
Note: I never met V. S. Naipaul, although I am sure I would have loved to. But I did have a delightful dream about meeting him, about the secret passageway at the end of which was his home, about his charming wife Nadira, about a vigorous discussion about identity and his book The Enigma of Arrival (which, after waking up, I read enthusiastically). This is an elaboration of that dream. RIP, V. S. Naipaul.
This post was first published on 3 Quarks Daily.

Technological convergence in drug discovery and other endeavors




You would think that the Wright brothers’ historic flight from Kitty Hawk on December 17, 1903 had little to do with chemistry. And yet it did. The engine they used came from an aluminum mold; since then aluminum has been a crucial ingredient in lightweight flying machines. The aluminum mold would not have been possible had industrial chemists like Charles Hall and Paul Héroult not developed processes like the Hall-Héroult process for refining the metal from its ore, bauxite. More elementally, the gasoline fueling the flight was the result of a refining process invented more than fifty years earlier by a Yale chemist named Benjamin Silliman. There was a fairly straight line from the Bayer and Silliman processes to Kitty Hawk.

The story of the Wright brothers’ powered flight illustrates the critical phenomenon of technological convergence that underlies all major technological developments in world history. Simply put, technological convergence refers to the fact that several enabling technologies have to come together in order for a specific overarching technology to work. And yet what’s often seen is only the technology that benefits, not the technology that enables.

We see technological convergence everywhere. Just to take a few of the most important innovations of the last two hundred years or so: The computer would not have been possible without the twin inventions of the transistor and silicon purification. MRI would not have been possible without the development of sophisticated software to deconvolute magnetic resonance signals and powerful magnets to observe those signals in the first place. There are other important global inventions that we take for granted - factory farming, made-to-order houses, fiber optics, even new tools like machine learning - none of which would have materialized had it not been for ancillary technologies which had to reach maturation.

Recognizing technological convergence is important, both because it helps us appreciate how much has to happen before a particular technology can embed itself in people’s everyday lives, and because it can help us potentially recognize multiple threads of innovation that could potentially converge in the future - a risky but important vision that can help innovators and businessmen stay ahead of the curve. One important point to note: by no means does technological convergence itself help innovations rise to the top – political and social factors can be as or more crucial – but this convergence is often necessary even if not sufficient.

It’s interesting to think of technological convergence in my own field of drug development. Let’s look at a few innovations, both more recent as well as older, that illustrate the phenomenon. Take a well-established technology like high-throughput screening (HTS). HTS came on the scene about thirty years ago, and since then has contributed significantly to the discovery of new medicines. What made the efficient screening of tens of thousands of compounds possible? Several convergent developments: recombinant DNA technology for obtaining reasonable quantities of pure proteins for screening, robotic techniques and automation for testing these compounds quickly at well-defined concentrations in multiple wells or plates, spectroscopic techniques like FRET for determining the feasibility of the end results, and graphing and visualization software for mapping the results and quickly judging if they made sense. These are just a few developments: in addition, there are techniques within these techniques that were also critical. For instance, recombinant DNA depended on methods for viral transfection, for splicing and ligation and for sequencing, and robotic automation depended on microelectronic control systems and materials for smooth manipulation of robotic moving parts. Thus, not only is technology convergent but it also piggybacks, with one piece of technology building on another to produce a whole that is more than the sum of its parts, aiding in the success of a technology it wasn’t primarily designed for.

Below is a table of just a few other primary drug discovery technologies that could not have been possible without ancillary convergent technologies.

Primary technology
Convergent enabling technologies
Combinatorial chemistry
LCMS for purification, organic synthesis methodology, hardware (solid phase beads, plastic, tubes, glassware) for separation and bookkeeping.
Molecular modeling
Computing power (CPUs, GPUs), visualization software, crystal structures and databases (PDB, CSD etc.)
Directed evolution/phage display
Recombinant DNA technology, hardware (solid phase supports), buffer chemistry for elution.
DNA-encoded libraries
PCR, DNA sequencing technology (Illumina etc.), hardware (solid phase beads, micropipettes etc.), informatics software for deconvolution of results.
NMR
Cryogenics, magnet production, software.

I have deliberately included NMR spectroscopy in the last row. A modern day organic chemist’s work would be unthinkable without this technique. It of course depends crucially on the availability of high-field magnets and the cryogenics techniques that keep the magnet cold by immersion in liquid helium, but it also depends fundamentally on the physics of nuclear magnets worked out by Isidor Rabi, Edward Purcell, Richard Ernst and others. Since this post is about technology I won’t say anything further about science, but it should be obvious that every major technology rests on a foundation of pure science which has to be developed for decades before it can be applied, often with no clear goal in mind. Sometimes the application can be very quick, however. For instance, it’s not an accident that solid phase supports appear in three of the five innovations listed above. Bruce Merrifield won the Nobel Prize in chemistry for his development of solid-phase peptide synthesis in 1984, and a little more than thirty years later, that development has impacted many enabling drug development techniques.

There are two interesting conclusions that emerge from considering technological convergence. The first is the depressing conclusion that if ancillary technologies haven’t kept pace, then even the most brilliant innovative idea would get nowhere. Even the most perspicacious inventor won’t be able to make a dent in the technology universe, simply because the rest of technology hasn’t kept up with him. A good example is the early spate of mobile phones appearing in the early 90s which didn’t go anywhere. Not only were they too expensive, but they simply weren’t ready for prime time because the wide availability of broadband internet, touchscreens and advanced battery technology was non-existent. Similarly, the iPhone and iPod took off not just because of Steve Jobs’ sales skills and their sleek GUI, but because broadband internet, mp3s (both legal and pirated) and advanced lithium ion batteries were now available for mass production. In fact, the iPod and the iPhone showcase convergent technologies in another interesting way; their sales skyrocketed because of the iTunes Music Store and the iPhone App store. As the story goes, Jobs was not sold on the app store idea for a long time because he characteristically wanted to keep iPhone apps exclusive. It was only flagging initial sales combined with insistent prodding from the iPhone team that changed his mind. In this case, therefore, the true convergent technology was not really battery chemistry or the accelerometer in the phone but a simple software innovation and a website.

The more positive conclusion to be drawn from the story of convergent technology is to keep track of ancillary enabling technologies if you want to stay ahead of the curve. In case of the iPod, Jobs seems to have had the patience to wait before USB, battery and internet technologies became mature enough for Apple to release the device; in spite of being the third or fourth mp3 player on the market, the iPod virtually took over in a few years. What this means for innovators and technologists is that they should keep an eye out on the ‘fringe’, on seemingly minor details of their idea that might have a crucial impact on its development or lack thereof. If you try to launch an innovative product before the ancillary technologies have caught up, you won’t achieve convergence and the product might well be doomed.

Of course, groundbreaking ancillary technologies are often obvious only in retrospect and are unexpected when they appear – Xerox’s mouse and GUI come to mind – but that does not mean they are invisible. One reason John D. Rockefeller became so spectacularly successful and wealthy is because he looked around the corner and saw not one but three key technologies: oil drilling, oil transportation and oil refining. Similarly, Edison’s success owed, in part, to the fact that he was an all-rounder, developing everything from electrical circuits to the right materials for bulb filaments; chemistry, electricity, mechanical engineering – all found a home in Edison’s lab. Thus, while it’s not guaranteed, one formula for noting the presence or absence of technological convergence is to cast a wide net, to work the field as well as its corners, to spend serious time exploring even the small parts that are expected to contribute to the whole. Recognizing technological convergence requires a can-do attitude and the enthusiasm to look everywhere for every possible lead.

At the very least, being cognizant of convergent technologies can prevent us from wasting time and effort; for instance, combinatorial chemistry went nowhere at the beginning because HTS was not developed. Molecular modeling went nowhere because sampling and scoring weren’t well developed. Genome sequencing by itself went nowhere because simply having a list of genes rang hollow until the technologies for interrogating their protein products and functions weren’t equally efficient. Developing your technology in a silo, no matter how promising it looks by itself, can be a failing effort if not fortified with other developing technology which you should be on the lookout for.

Technology, like life on earth, is part of an ecosystem. Even breakthrough technology does not develop in a vacuum. Without convergence between different innovations, every piece of technology would be stillborn. Without the aluminum, without the refined petroleum, the Wright Flyer would have lain still in the sands of the Outer Banks.