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.

The 100 most highly cited papers of all time: Tools, not ideas

A rather obscure paper by biochemist
Oliver Lowry is the most highly cited
scientific paper of all time
(Image: beckerarchives)

Nature has published a comprehensive list of the top 100 most highly cited papers of all time and the list is well worth a look for what it reveals about what's really important in science, what people perceive as being important and in fact how science progresses.

I like the list because it confirms something that I have written about on the blog a few times: science is as much a tool-driven revolution as an idea-driven one. This is evidenced by the fact that almost all of the most highly cited papers in that list are about useful techniques rather than great ideas and discoveries. Thus the expansion of the universe, the structure of DNA and the theory of relativity don't rank on the list but Sanger's gene sequencing method, an algorithm for comparing protein and DNA sequences (ClustalW) and a popular statistical technique do. And the dominance of many of these came about because of computers, so the selection also speaks very highly to the rise of computer technology.

Now one can argue that the reason the structure of DNA does not rank on the list is because its importance is so obvious that it has become a textbook fact and does not need to be cited. This is true, and the list does nothing to denigrate the significance of such household ideas (and it also does not elevate the importance of tools above ideas). But what it does convey is that the really visible papers are those which gave researchers practical tools rather than profound ideas. It also tells us that what's in the textbook is not always what's used the most by scientists in their day to day work, even if it may be an important component of their background knowledge.

The selection is dominated by papers from protein biochemistry, bioinformatics and statistics. The most highly cited paper documents the use of the Folin phenol reagent which even researchers consider a "tad outdated". This big enchilada leads the pack with a whopping 305,000 citations; the next best paper with 213,000 citations is a dot on the horizon by comparison. The genomics revolution meant a huge unmet need both for methods to quantify, isolate and sequence biomolecules and to process, compare and analyze these sequences. Not surprisingly, specific lab protocols for isolating and studying biomolecules and computer algorithms for analyzing their information content rank at the top of the list. The latter phenomenon is a great example of two technological revolutions - cheap software and hardware and the applications they engender - piggybacking on each other.

Statistics and crystallography - two other disciplines with huge practical ramifications - also feature prominently on the list. Computers were again tremendously important in the practical realization of these disciplines. For instance the program SHELX made it possible to analyze complex diffraction data from x-ray diffraction. Similarly the original paper describing the Kaplan-Meier test is highly cited: today the reason the Kaplan-Meier test is so popular is partly because it has found critical use in fields like clinical trials, but more importantly because it has been incorporated in popular software tools like Matlab and R which even non-statisticians can use efficiently. As statistics becomes more user friendly it is likely that these papers will be even more highly cited, but the people who cite them might just be using their products the way a gardner uses a lawnmower without really understanding how it works.

Computational chemistry also makes an appearance and density functional theory (DFT) which has caused a revolution in the accurate and fast calculation of molecular properties is what raises the profile of the field. The two most highly cited papers in this area include one by by Lee, Yang and Parr and another by Becke. The interesting thing about the amalgamation of these two methods is that they have now become ensconced in an abbreviation (B3LYP) which is used as part of a recipe by thousands of graduate students, postdocs and professional researchers to do all kinds of quantum chemical calculations, from simple energy determinations to complex reaction studies. But the prominence of B3YLP also goes to the heart of the reason why a paper can be highly cited: it becomes so firmly enmeshed into a standard arsenal of tools that most people start blindly citing it and using it as a black box. I have used the technique myself dozens of times including in a few papers, but I don't remember the last time I took a look at the original paper.

One of the most puzzling facts about the list is the almost complete absence of papers from physics and astronomy. Maybe I am missing something here but the absence tempts me to reiterate something that I have noted before: that chemistry and biology, much more so than physics, are about tools rather than ideas. Nonetheless I find the paucity of physics papers puzzling since there is no reason a priori why physics should be devoid of practical tools nor why ideas in physics should not be highly cited. One intriguing point noted in the article is that physicists might be less prone to citing each other's papers than biologists, and if true this is really a cultural phenomenon responsible for the absence of physics papers on that list.

Nevertheless the list is quite readable. It tells us that science is ultimately as much about the mundane use of tools and techniques as it is about the genesis and distribution of profound ideas. Sadly the former view is not half as much appreciated by the general public as the latter. The list provides a great counterpoint to the idea of science as a series of paradigm shifts. It tells us that in science, as in many other fields, what matters ultimately is what we can use.

High-throughput method for detecting intramolecular hydrogen bonds (IHBs)

We have talked about the importance of intramolecular hydrogen bonds (IHBs) as motifs to hide polar surface area and improve the permeability of molecules a couple of times here. The problem is that there's no high-throughput method for detecting these in, say, a library of a thousand molecules. The best method I know is temperature and solvent dependent NMR spectroscopy but that's pretty time consuming. Computational methods can certainly be useful but they can sometimes lead to false positives by overemphasizing hydrogen bonding between groups in proximity.

Now here's a promising new method from Pfizer which could lend itself to high-throughput screening of IHBs. The authors essentially use supercritical fluid chromatography (SFC) to study retention times of molecules with and without IHBs. The solvent system consists of supercritical CO2 spiked with some methanol. They pick a judicious set of matched molecular pairs, each one of which contains a hydrogen bonded and non-hydrogen bonded version. They then look at retention times and find - not surprisingly - that the hydrogen-bonded versions which can hide their polar surface area have lower retention times on the column. 

They corroborate these findings with some detailed NMR studies looking at solvent and temperature dependent chemical shifts. At the beginning, when they plot the retention times vs the total polar surface area (TPSA) they get a nice correlation for non IHB compounds. For compounds with IHBs however, the TPSA is an imperfect predictor; what they find in that case is that a new parameter called EPSA based on the retention time is a better predictor of IHBs compared to TPSA.

This seems to me to be a potentially valuable method for quickly looking at IHBs in relatively large numbers of compounds, especially since we have now started worrying about how to get "large" molecules like macrocycles and peptides across membranes. And I assume every medium or large company will probably have access to SFC, so the technology itself should not pose a measurable barrier. One more handy tool to look at "beyond rule of five" compounds.

Reference: 

A High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding

Gilles H Goetz, William Farrell, Marina Shalaeva, Simone Sciabola, Dennis P Anderson, Jiangli Yan, Laurence Philippe, and Michael J. Shapiro

J. Med. Chem., Just Accepted

Publication Date (Web): March 18, 2014 (Article)

DOI: 10.1021/jm401859b

What did you say the error was??

I was looking at some experimental data for drug molecules binding to a pharmaceutically relevant protein.

The numbers reported were as percentages of binding relative to a standard which was defined to be 100%. Here's how they looked:

97.3 + - (plus or minus) 68.4
79.4 + - 96.1
59.5 + - 55.3
1.4 + - 2.5

Seriously, how did the reviewers allow this to go through?

Another entertaining exchange

You may remember that Manfred Christl who is emerging as a kind of vigilante of incorrect chemical structure determinations had debunked a previous claim and shown it to be a manifestation of a 100 year old reaction. There he goes again about the structure of some alleged cyclic allenes. But this time accompanied by a firm rebuttal; it's not often that you see the strong word "incorrect" in a scientific publication.



Are strained amides, where delocalization of the nitrogen electron lone pairs is not possible, still amides? Hell, yes!

References:
Manfred Christl, Bernd Engels (2009). Stable Five-Membered-Ring Allenes with Second-Row Elements Only: Not Allenes, But Zwitterions Angewandte Chemie International Edition, 48 (9), 1538-1539 DOI: 10.1002/anie.200803476

Vincent Lavallo, C. Adam Dyker, Bruno Donnadieu, Guy Bertrand (2009). Are Allenes with Zwitterionic Character Still Allenes? Of Course! Angewandte Chemie International Edition, 48 (9), 1540-1542 DOI: 10.1002/anie.200804909

Some slices from the literature

Not too much time this week to dwell in detail on papers, but here are some that I found interesting:

Richard Friesner and his colleagues at Columbia investigate the entropic contribution of arginine side chains by measuring local conformational dynamics by NMR spin relaxation. They compare these results to detailed MD simulations to infer that the aliphatic side chain maintains enough entropy for the charged amino group to fruitfully engage in rigid salt-bridge formation, thus minimizing the entropic penalty.

On the other side of the Atlantic, Angelo Vedani and his colleagues in Basel have derived a QSAR model for psychotropic drugs binding to the glucocorticoid receptor using their programs Yeti and QUASAR. The GR is a nuclear hormone receptor that can modulate a variety of key processes by binding small molecules. The model was validated on 110 compounds representing 4 chemical classes.

An interesting paper on the conformation of a common and important consensus tripeptide motif in a glycoprotein compares measured IR intensities and frequencies using a technique called ion-dip IR spectroscopy to frequencies calculated using high-level ab initio theory (MP2/6-311++G**). The Oxford authors do the comparison for the wild type motif as well as for two mutants and ask a "Why nature selected this specific motif" kind of question by looking at the viability of the resulting conformations. It looks fine, but I am a little skeptical about all those gamma turns that they see, a common artifact of inadequate treatment of solvation in both force field and ab initio approaches.

And again on the medicinal front, a group in Europe does some fragment-based computational design and find a PPAR agonist. Detailed knowledge of protein structure aids in explaining why one bioisostere works and another one does not.