Random thoughts

In Memorium: H. G. Khorana (1922-1911)

2011-11-17T00:18:00.000-08:00

I came to know of Khorana’s work from the pages of Science Reporter even before Neil Armstrong walked on the moon.

I was however not aware of how exactly he had deciphered the triplet genetic codons when I lined up in front of the Bose Institute in Calcutta on a winter afternoon in 1973. It was the Bose Memorial lecture, and Khorana was the speaker. Like most other lectures at Bose Institute, my fellow second year undergraduate student Siddhartha and I were expecting a small turn out, mostly of stuffy professors and a few graduate students. We were not prepared for the spectacle: an unruly crowd of at least 1,000 were trying to get a glimpse of this man, who was ushered from a black Ambassador into the lecture theater by a gang of burly security people. After a delay of another hour or so, it was announced that Professor Khorana had requested that the lecture be moved to a larger hall where the entire crowd could be accommodated, and so the timing of the lecture was delayed by 3 hours. The new venue would be at the Saha Institute of Nuclear Physics, a few blocks away, where there was a large enough lecture hall to accommodate the huge gathering.

There was a stampede. By the time Siddhartha and I arrived at the new venue, the crowd was almost breaking down the collapsible gate at the front entrance. Since we were both rather thin, we were able to slip through the chain-link fence behind the building and gain admission through the back door. Khorana arrived, along with a galaxy of professors. Behind him was a long blackboard, on which a professor had neatly written out the table of triplet codons. There were eulogies upon eulogies. I felt that the thin short man with a rather well defined jaw line, sporting a plain brown jacket and a dark tie, was shrinking more and more unto the table as eulogies were heaped upon him. My vivid memory is that of the top of his triangular head, because his face was mostly turned down in embarrassment.

When at last it was Khorana’s turn, the little man nearly sprang up from his chair, and charged ahead without spending so much as even one sentence of pleasantry. For an hour he blazed at the blackboard with a piece of chalk, explaining the intricacies of a mind-boggling series of ingenious experiments that had led to the deciphering of the genetic code, and an almost immediate Nobel Prize in Physiology and Medicine. He was dynamic in a manner I had never seen someone lecturing before then. Newspapers the next day ran an full page article on Khorana and his discoveries, and how he failed to obtain a job in India when he tried to return after his PhD in England and a postdoctoral stint in Switzerland.

Nearly twenty years later, I was in my first month at MIT, in an elevator at the ground floor of B56. The door was about to close when slid in Khorana, his wet hair still dripping a little. I nervously smiled at him. He smiled back, “From India?” and immediately began to ask me a staccato series of questions about what am I doing in Ethan’s lab. So far as I recall, his lab could be reached from the fourth floor along a walkway to the chemistry building. We came out of the elevator, I trying to explain as briefly as I could the questions I was then addressing and my experimental plans. He listened attentively and asked a few probing questions. Of course like everyone who meets “Gobind” for the first time, I was in awe: this was the man who once took up an entire fat issue of the Journal of Biological Chemistry and published a series of papers announcing the “Total Synthesis” of a gene—a feat that has never been repeated in the history of science for its sheer “weight”.

I used to see him often after that day, returning from his daily swim to his office, and also at 4 PM seminars, where he was a regular. But I did not get to talk to him again until the departmental retreat somewhere in New Hampshire (the location eludes me now). At that meeting Khorana spoke about his then recent results on using bacteriorhodopsin to understand how light is perceived and “decoded” into chemical and electrical signals. I had asked a few questions, and had expressed some concerns about the apparent differences in the time scale of electron transition actuated by the photon and the enzymatic reactions that ultimately triggers—whether the models he was using were sufficient to span the time scale difference. At lunch Khorana sought me out. After a brief discussion on the topic of his talk, he started asking me detailed questions on how my work was progressing. Amazingly, he appeared to remember nearly everything I told him about my work on the first day at the elevator. Gradually the conversation turned to his early life in Punjab, near Lahore in undivided India; how he would run from one school to another ahead of the district inspector, because he was trusted by the headmaster to present the best face forward. He also spoke about his time in post war Switzerland as a postdoc, where for a while he did not receive any salary, but managed to obtained free board at a monastery and survived for several months on milk and bread. His easy personality, and keen interest in other people’s work was a marvelous example. I had last seen him a few weeks before I had left MIT for my first job at the University of Rochester in 1991. He was trying to figure out how to calculate the dose of UV radiation from a conversion table in the handbook of nucleic acid chemistry, when he looked up and asked me when I was leaving.

Some fourteen years later, I had the honor of reviewing a grant proposal that he wrote. That was just before I heard that he apparently has been taken ill. I had been dreading this day; he passed away on November 9.

On Growth and Emergence

2011-11-13T09:57:00.000-08:00

It is often thought by people who are casually concerned with the environment and its degradation that it is important to live in harmony—in a steady-state of sorts; they ignore the primary characteristics of living organisms: living organisms grow.

One tends to imagine the idealized steady-state population dynamics of animals and plants in isolated geographical regions the ideal for human population. Unfortunately the reality is different. Nearly always such steady-state communities are extremely vulnerable to external influences; they lose their robustness because there is little selection pressure to keep such “robustness” genes in the population in the absence of changing circumstances.

Even in steady-state populations, individual organisms grow—either in number (where death rate balances growth rate) or in size (think of the massive conifers in old growth forests). Large conifers that have been around since Buddha walked the earth are still growing. The meristematic cells at the tips of their main shoot or branches are continuously dividing and are contributing to their growth in size.

To make this analogy somewhat more general, economic systems, which are indeed properties inherent of living systems (more appropriately, of communities of living systems), grow.

When economies do not grow, they become vulnerable. Free economies, like ant hills, tend to grow in fits and bursts.

On one late Fall evening in a lonely corridor across the hallowed halls of MIT, Philip Morrison, the wheel-chair bound astrophysicist, explained to me that ant hills grow by a few rather simple rules. Rule 1: make mounds. So numerous ants begin making numerous mounds over a range of area. Some mounds grow a little bit faster and others a bit slower just due to random fluctuation. Rule 2: Go to the nearest fastest growing mound. Probably they see the shadows of nearby mounds and thus find the locally tallest mounds. A recursive application of rules 1 and 2 will tend to generate a few very tall mounds with the most number of ants.

So do the economies. The fastest growing economies tend to whip up the businesses to participate and concentrate. This is true of geographical localization of economies as well. Think for example of the silicon valley, or the biotechnology mesa of San Diego.

Here comes the next analogy: self-organized behavior of crystal growth. Crystals also grow using rather simple rules of thermodynamic energy minimization. Rare and minor initial fluctuations in the rates of growth of a few crystal nuclei tend to determine the overall size distribution of crystals arising in a super-saturated sugar solution. Now, shake the solution a bit. Some of the growing crystals break up; the nuclei are redistributed. In a while a different distribution of size arises.

So it is with economies in recession. Recession has the effect of shaking up the economies. Bright folks left unemployed in Torrey Mesa in San Diego go to the medical school complexes in Alabama or biotech incubators in Madison and take root their. So too for global economies.

Very much like the dreams of the universal communes of communist manifesto, the most natural direction for the future of global economies lie in the migration of people and economies across the current archaic national boundaries. The difference here is that we are talking of pure capitalistic economy, accepting its boom and bust cycles as natural growth processes. I do not however agree that we will need to accept the social alienation that is generally associated with this view of capitalism. I believe there is room for active role of the nation states to alleviate human suffering, to act as buffers, and to promote human migration, spread of education and in promoting social acceptance associated with this migration.

What if the most vibrant of Chinese or Indian businesses find partners in Greece or Italy, and a portion of teeming Indonesian masses were to set up houses in population depleted Europe?

Perhaps the biggest barriers to internationalism are the color of our skin and the shapes of our jaws.

A sense of time

2011-09-06T20:44:00.000-07:00

Raymond Depardon’s iconic photograph of a couple with their son on a scooter in Saigon, 1972, brings back a rush of imagery of those days. A sense of time, perhaps, has been missing in my life.

I used to suck in history. I was more interested in Fourier transform and Maxwell’s demon and pseudouridine in tRNA-gly.

The road to immortality seemed in those days to be paved with one scientific insight that survives the test of time. A delusion that comes of not knowing the history of time.

Absence of Heroism and the Road Inward

2011-07-29T19:09:00.000-07:00

The debt crisis, largely artificial because it is not that the US government is unable to pay its dues but that it is not allowed to pay, is a failure of the political leadership to be rational.

This emerging trend of irrational governance is apparent in the US, Japan, and in Europe (see “Turning Japanese” The Economist July 30, 2011).

In the US at least, this is partly the result of electing into office a vocal minority of fiscal extremists, the Tea Party representatives. But it would be overly simplistic to stop there. One needs to probe the reason as to why the extremists got elected in the first place.

In a psychological sense, all extremists appear to suffer from various degrees of delusion of grandeur, a narcissistic view that the ills of the society can be bettered by making heroic demonstrations.

We in the US have had little occasion to be heroic lately. We fight a war for which no sacrifice has been required for the vocal middle class, because we have let the poor and the minority to die in it; we get a tax rebate instead. The face of the war does not leave much room for heroism either, because we fight an enemy that is not afraid of death as the ultimate sacrifice—a supposedly Western prerogative that has received much mythological support in our culture. What is worse, we are now led by a black intellectual, who is often identified as a half-Moslem. Racial inferiority and religious antagonism are the most difficult cultural instincts to overcome. If the media are to be believed, our businesses are increasingly run over by the Chinese and the Indians; Latinos are on the rise; we don’t even have a rocket science any longer. Where should we now vent our delusions of being a hero?

The answer presented to us is simple: dismantle the status quo. This Samson-like act of narcissism appears preferable even at the risk of collapsing the institutional dome of legitimacy above us.

My DNA: The Rashomon Factor

2011-07-11T21:53:00.000-07:00

So here I am, having both paternal and maternal ancestries traced to the central Asian mountains and valleys, to the Hunzas and the Persians. How did I get here?

The 64 : 36 admixture of European and Asian polymorphic markers in my genome has evidently been preserved over many generations, because there is no European history known in either of my lineage within at least 10 generations. Were it the case that there was a single homozygous European who married a homozygous Asian, then their child would have both markers. Since there are many more Asians than Europeans in Bengal, and if all were homozygous Asians, then in every subsequent generation there is an overwhelming probability that the descendent of that lineage will breed with a homozygous Asian, thus at every subsequent generation the proportion of European markers will be halved (if the markers are all unlinked). This is akin to successive back-crosses with the Asian stock. Thus, after 10 generations, 2^(-10) or only 1 in approximately 1,000 or 0.1% of the European markers, if all are unlinked, will still exist.

The actual proportion might be somewhat more, because of linkage and linkage disequilibrium, which can be calculated, which will lead to loss of heterozygosity at the rate of (1 – r)^t, where t is the number of generations and r is the recombination frequency between marker pairs. But the frequency of retention under the above simplifying assumption will be far below 64%. This is because r for most marker pairs (~700,000 markers if randomly distributed over 23 chromosome pairs) would be approximately 0.04 for human chromosomes (~1 centiMorgan per megabase pairs). Therefore, the erosion will be approximately at a rate of (1 – 0.04)^t, which translates to 0.96^t. For 10 generations, we need to divide 0.1% by approximately 66%, which leads to a retention of 0.15% of the heterozygous markers on average. Although I arbitrarily chose 10 generations (i.e., t = 10), it is probably true that anyone in my ancestry mating with a person homozygous for European markers goes far deeper into the past because the very first Europeans in historical times came to Bengal only about 20 generations ago. The overwhelming conclusion is that my assumptions are incorrect. Where are they incorrect?

The main assumptions were that there was one rare mating between a European and an Asian, and that most people in Bengal are homozygous for Asian markers. Both are nearly certainly incorrect.

The heterozygosity of markers over many generations, in the absence of direct natural selection due to selective advantage (unlikely because it would predict an enormous selective advantage to rare heterozygous markers), is probably the result of selective breeding or kin-selection—the inevitable result of the caste system in India. It is because of this selective breeding and kin-selection that the heterozygous markers were conserved over many generations. Therefore in a moment of somewhat dampened literary inspiration, I am compelled to moderate my romantic scenarios of a Hunza couple eloping together and settling in Bengal, or a wayward Yemeni sailor marrying an Asian woman.

The reality is likely to be quite different. The most likely scenario is that my ancestors descended from individuals in south central Asia, the inhabitants of Afghanistan, Persia, and central Asian plateaus at some remote Vedic or pre-Vedic time, through selective marriages among a small number of communities who rarely married into the indigenous Asian stock. This ensured that the members of these communities are all highly heterozygous. If nearly all of these people are heterozygous at most markers, then the chance that any individual will be heterozygous at any marker is nearly 50%. The observed 64 : 36 distribution of markers is close enough to this expectation, if one assumes a slight bias towards marrying into families with more European (i.e., Brahmin) than Asian markers. Thus, for my ancestors, intermarriages largely restricted within the community in most generations with only rare breeding with non-Brahmins (having somewhat higher frequency of Asian markers) is a good explanation for my lineage.

This scenario is well attuned to an oral myth of the Vaidya or Baidya communities of Bengal. Tradition has it that the ancestor of the Vaidya caste was the result of an illegitimate union between a Vaishya woman by the name of Birabhadra and a Brahmin Galava Muni. The latter was reputed to be a Vedic Brahmin, apparently from the area currently known as northern Pakistan/Afghanistan (but see also: this). The child born became known as Dhanavantri. Since the child had no legal father, (s)he belonged to the family of his/her mother. Of course that is only one of the narratives, and there are several competing narratives. One fact is clear: the Vaidyas generally intermarried among their own communities, thus maintaining their genetic heterogeneity.

This is all a remarkable congruence of oral tradition and science, perhaps even more interesting than my romantic story of the eloping Hunza couple.

My DNA: My Ancestry

2011-07-03T23:37:00.001-07:00

My DNA result is out. I have 64% European and 36% Asian markers, which put me squarely in the Indian subcontinent, somewhat more heterogeneous than the upper caste Brahmins who have roughly 80% or more European and ~20% or less Asian markers on average. This is not surprising, because I am not a Brahmin, but am supposed to be a Vaidya, or, historically a class of Brahmins who were shunned from wed locks with other Brahmins for either reasons of envy, for accepting fees for medical treatment (you see, the Brahmins are supposed only to receive the gifts of gratitude and never a fee for labor) or, more likely, because a wayward Brahmin in my remote ancestry fell for a lower caste boy or girl…

I seem not to have any known marker for any debilitating disease, or even a carrier of any known disease markers. I might be more than average sensitive to Warfarin, a blood thinner given in cases of blood clot diseases or stroke, too much of which could cause bleeding, and knowing this the doctors would be cautious in case they catch me on a stretcher one of these days.

I seem to be a slow metabolizer of caffeine, which explains why I spend so much time in cafés.

So far that is almost all I know that is of significance to my health…the rest are all typical.

The real fun begins when I look at my maternal and paternal ancestries.

Maternal ancestry is provided by the mitochondrial DNA sequence, which rarely changes, and is always contributed by the mother (never the father). Thus my mitochondrial DNA ancestry forms a continuous chain up the line of my mother’s mother’s mother’s mother’s…..mother the Eve in Africa. The same with yours.

The funny thing is that the mitochondrial DNA does change sometimes, but very very rarely. When it does, and the mitochondrion still functions, then the mutated (changed) mitochondrial DNA “diverges” in sequence a little bit from the previous generation, and this changed sequence is then inherited down the line, until all females in that line have all male children, in which case the mitochondrial DNA chain is annihilated. This provides a way to sleuth out the maternal ancestry of the current population on the earth because if my mitochondrial DNA is related to yours then we must have shared the same maternal lineage, and by checking this we can actually chart the migration patterns of groups of people across the globe.

My mitochondrial DNA belongs to the so called haplogroup R6, which is a minor part of a very ancient lineage R that arose in Southeast Asia not long after the first human migrations out of Africa into Asia, who then migrated to Europe, Australia, and the Americas. The haplogroup R arose some 60,000 years ago in Asia, before migration to Europe, Australia and the America; therefore it is found in all these places except in Africa. R6 is a variant of the the original R. R6 is quite rare, and is now found most frequently among some tribes in the mountainous regions of Afghanistan-Pakistan-India border and also in small pockets near Tamil Nadu of southern India and in northern Sri Lanka (source: Metspalu et al. BMC Genetics 2004, 5:26 doi:10.1186/1471-2156-5-26).

Therefore, a woman in my distant ancestry from either the mountains of Kashmir or Afghanistan region, or from Southern India, or one of their common ancestors, must have migrated to the plains of north-eastern Bengal, perhaps over many generations through bearing daughters who migrated slowly, or perhaps it was a single romantic affair that led to one couple eloping together and settling in Bengal, producing a daughter who bore another daughter, and so on. While eye and skin colors are not at all known to be inherited through the mitochondrial DNA—the mitochondrial DNA merely asserts the maternal inheritance line—other genes that do might also have descended from this couple. My maternal grand mother (who was born in north-eastern India in current Assam, in the Dibrugarh area, so far as I recall), from whom I must have inherited my mitochondrial DNA, had bluish green eyes and fair skin, something like what is seen among the tribes of Kashmir region of India, Afghanistan and Pakistan. But the couple might also have come equally likely from southern India, where the incidence of bluish-green eyes is rarer though.

How about my paternal line? This is even more interesting. My paternal line, derived from my Y chromosome, which was given to me by my father (by his father, and so on up to some Adam in Africa), who were all from the Chittagong region of current Bangladesh, belongs to a very rare group H1a*. The haplogroup H, from which H1a* is derived, is mainly restricted to the Indian subcontinent, mostly among the tribes of India and is rarely (~10%) found among the Brahmins, but also its variants are found among the Central Asians including the Afghanis, the Romani gypsies of the Balkans, some central Asians and Iranians, among the Saudis (including their royal families), and in Yemen, and a somewhat distant line in Cambodia/Vietnam. But if one looks more closely at the specific rare variant H1a*, then one finds the closest similarity to a group of "Balkarians" (a Turkish people of the Caucasus mountains), southern Iranians, and Serbians, all of whom contain the mutation M82 in H1a subgroup that is the closest ancestor of H1a* which is mine. Further derivatives of H1a, such as H1a1, H1a2, and H1a3 are found in Nepal, and Southeast Asian countries including Bali, Indonesia and Cambodia, but these are in parallel lineages to that of H1a*, all derived from the common H1a, which likely originated in Northern India or Central Asia.

Whatever I know of my immediate paternal ancestry, my great great grandfather was childless, and adopted a child who was my great grandfather. The only surviving photograph of my great grandfather shows him to be a man of about 50, who was reputed to have had greenish brown eyes, as did my father and as does my daughter.

Was there a lost sailor from Yemen who married a village girl in southern Bengal during his oceanic voyages along the spice route? Or was there a Balkarian soldier in the army of Babur who descended on the Bengal delta and married a woman who produced a son who provided the Y chromosome that ultimately gave rise to my great grandfather?

When I download the entire DNA marker set of my genome (some 700,000 of them) and do principal component analysis (PCA) against all known DNA markers of the world, my DNA markers appear to cluster on the first and second eigen vector spaces right near where the DNA of the indigenous people of central Asia (north of Afghanistan), closest to the Burushos of the Hunza valley of Pakistan-Afghanistan, appear to originate.

These are the stuff of which epic novels are made!

----
*The above account, as might be expected after a reading, is colored with quite a flight of fancy. To get a slightly more nuanced scientific perspective, read the next entry, My DNA: The Rashomon Factor.

The Beginnings of my Stirring

2010-10-17T20:09:00.000-07:00

My first stirrings, so far as I remember, came when I happened to get my fifth year birthday present from my mother, a book (in Bengali), called Manus Elo Kotha-hote? (How did man come about?). This book was a treat. Until that time I had never heard of dinosaurs; there was no TV show (I had not seen a TV until I was 17 years old), no radio show, no books on dinosaurs before this; my parents and relations never studied science, so they never talked about dinosaurs before—in fact I don’t think they even knew of their existence before I got the book, which they also read along with me.

By the time I was in fourth grade, I was reading science fiction stories, translated from other languages into Bengali. I remember specifically “The Time Machine” and “From the Earth to the Moon”. Around this time, but likely even before this time, while still in the third grade, I had accidentally discovered that when plant parts, such as green leaves and stems or flower petals, are pounded into a mash, mixed with fountain-pen ink, bottled and put into a dark place, they change color—-sometimes the ink becomes discolored, sometimes blue ink became red or straw yellow or orange. I was doing this because I loved to paint, but had access to limited pigment colors for doing watercolor. So I thought mixing plant parts with ink might generate interesting color. But the process was messy, and I did not want people to throw the mixtures away. So I put them in a box and hid them within the space within a drain pipe between my bedroom and the balcony, thinking that no one will try to clean the dry drain pipe. Well, that led to my fascinating observations, which caused no end of wonder, and I did not figure out as to why until late in college.

But there were other leads. I loved animals; specifically I used to watch birds, which were plentiful in variety in the little tropical town where I lived. I first became aware of serious dangers that wild flora and fauna in India faced around the time I was in the eighth grade, through reading about in Sandesh, the monthly literary magazine for children which was edited by Satyait Ray, the noted film director from Bengal, from the writing of a Bengali naturalist whose pen name was "Jeeban Sardar". I do not know who he was, but my guess is that he might have been someone in Bose Institute. In any case, his writings deeply influenced me when I was in the middle school and was instrumental in my choosing science at the end of eighth grade--before that I was quite set on becoming an archeologist and was going to study history.

Jeeban Sardar used to take long walks in the Dam Dam and Salt Lake areas and describe over the years how birds and small mammals were disappearing. Remember that in 1960s Salt Lake areas of Calcutta were quite deserted and mostly devoid of settlements; he described how the place was changing. Subsequently I was an avid follower of the natural history columns in Science Today and Science Reporter, monthly popular science magazines published in India. While in high school, I would escape from classes and go to the riverside and try to collect fossils, rocks and mud skinks, and watch dolphins dunking in the water. In 10th grade science fair, I organized a booth that, through posters, which were painted in watercolor by my mother under my direction, tried to make other students and their parents aware of the disappearing bird life in Bengal.

By the time I was in 11th grade, I was passionately interested in nature conservation. But I had also realized that nature conservation was a full time scientific career, and I was not sure whether I had the right 'stuff' to make nature conservation a career.

While in 10th grade I had a chance encounter with an old copy of Time Life magazine, from early sixties, with Sophia Loren on the cover—Princess from Hong Kong was released then—in which there was an article on the new science of immunology. There was a two-page spread of a ball and stick model of an antibody, with Linus Pauling beaming across it.

That was a watershed moment. The dry pages of organic chemistry I was cramming for my high school examinations came alive with that article. I am yet to decide which was more attractive to me in that magazine, Sophia Loren or the model of antibody!

I decided that I must do what these ‘scientists’ do—the whole concept of a scientist being incredibly romantic to me, having never seen any scientist in real life at that time. In another year, I accidentally came upon “The Double Helix” by Watson in the British Council Library on Theatre Road, whose Rs.15 annual membership I purchased (which my father approved reluctantly) because it was the only library that I could access, to which I would walk a mile from home, take a train for an hour, take a bus for 40 minutes, then walk another few miles, and return the same way, on days that I didn’t have classes in school because the Maoist extremists would shut down the schools. I am grateful to the Maoists for making possible these trips; otherwise I would have probably become a physician in a provincial town. The Double Helix sealed my future.

I discussed this with Dr. Sivatosh Mukherjee, then the head of the department of Zoology in Presidency College, when I was in 11th grade (having been introduced to him by a PhD student of his from Chandernagore), even before I was admitted to Presidency as a first year student, and suggested to him a hare-brained idea about finding out why certain 'cold blooded' animals were disappearing faster than others--having to do with their immune compromization due to greenhouse effect and high temperature (in 1970-71, they had already detected massive greenhouse effects, and popular science magazines were awash with articles about them.

Professor Mukherjee was amused but not discouraging. He suggested I talk to Dr. Kanailal Mukherjee (KLM), a professor of immunology in the department of biochemistry of Calcutta University.

From Chandernagore I took the train, and long journey by bus to somewhere in near Park Circus, spending nearly four hours each way, to his research lab in a clinic. There, after trying to get his appointment (I had no access to telephones in those days) for three weeks (so 3 visits), I got his audience. He was extremely encouraging to me. I am sure he knew the naïveté of my idea, yet he was encouraging to the extent that he invited me to work in his lab along with one of his female PhD students.

The student was quite attractive but totally ruthless in critiquing me while I made numerous mistakes; but she also used to bring delicious food for me because she knew I used to come from very far away and did not have much money. Unfortunately I do not recall her name any more. I shadowed her for 3 months, 3 days a week; in this I was lucky because our school was closed indefinitely (those 3 months, as it turned out) due to the Maoist Naxalite disturbances. I owe it to them.

At the end of the year, I wrote up my National Science Talent exam's project report based on this research experience--no result really, but it had an original theory, however naive it was it was mine own. I got the scholarship. Based on this I convinced my father that I did not want to be a physician, and so despite having obtained admission to medical colleges, I went to study physiology, with physics and chemistry at Presidency--this is what Sivatosh Mukherjee and KLM had suggested to me given my interests. My chief interest was to become a molecular biologist, with the view of understanding how the environment affects life.

While in Presidency, I along with my friends organized a weekly seminar program on current progress in biology, including conservation biology, at USIS. We once invited Dr. R. L. Brahmachary to speak on difficulties with conservation in war torn central Africa. He pointed out that India was equally vulnerable.

During the summer after my first year in college, I went to Delhi university and worked for a few months in the laboratory of Professor Duraiswami, a biochemist. It was a most incredible experience to me. Professor Duraiswami treated me as an adult and opened the whole lab to me. He told me to do whatever I wanted. I read random papers for a while, then decided to study the binding of actinomycin D, an antibiotic, with DNA. I designed two biophysical experiments, one involving viscometry, another equilibrium binding kinetics using spectrophotometric shifts in absorbance, worked out the algebra, and conducted the experiments successfully. One incident I vividly remember. He gave an Ostwald viscometer and told me not to break it. Within a few hours I broke it. He smiled, gave me another one, and told me that now that I knew how to break it I would not break another one. Indeed, he was correct. This simple philosophy has since guided my own behavior with respect to my students when many years later I had my own laboratory.

Upon returning to Presidency college, I fast-talked our head of the department into giving me a corner of his laboratory, a viscometer and some chemicals, to study the hydrodynamics of protein shape change as a function of partitioning into two polar solvents. Unfortunately this was too ambitious for the modest facilities we had and my limitations of knowledge of statistical mechanics (which I had to acquire entirely by reading by myself and talking to a senior student of physical chemistry whom I happened to know because he came from the same town as I did); so these experiments, although fun, did not go anywhere.

I end here, because after graduating with a B.Sc. I went to New Delhi to study MSc; so after this period I became a card-carrying scientist.

A Father's Day

2010-06-21T00:01:00.000-07:00

Father died. It was a dark Monday evening in his room; it was a brilliant Monday morning in my car as it sped through the foothills of San Bernardino Mountains. The distant peaks were shadows over the horizon on the right and on the left west wind from Los Angeles brought the brown fog that curled low over the sprawling valley glittering under a dry desert sun.

Death came creeping up the stairs to father’s bedroom with three windows overlooking the tall coconut palms swaying in the moist wind. Low cloud hung heavy with warm rain in the stifling heat of late monsoon. He had felt it coming for the past five days; he had told Shikhadi last Friday when he was returning from his evening stroll by the river, “It’s been so many years; now it is time.” “Why talk like that?” She had rebuked him gently. “You’re so fit, you have many more years before you. You’ll have to see your grand daughter’s wedding.”

Time that began to wait for him seventy-nine years ago came slowly into his bedroom over that Sunday and finally on that Monday evening. The fever came on Sunday but went away later that day. On Sunday evening and throughout Monday he had slowly tried to move about the room, flexing his feet and arms, standing up by the bed then sitting down; he looked for the shadow of death on his wrinkled face in the mirror. He had felt it crawl up his bed in the early afternoon; he’d asked mother to call his younger son back from work.

Kanchu had rushed home immediately, anxious at this unusual request. Late in the afternoon, the sky became menacingly dark, the palm trees swung in rhythms in the blowing wind, the egrets scattered against the rush of cloud, thunder struck over and over and one crashed with a terrific report nearby. The power failed. Rain came first in large drops over the hibiscus leaves, then in a torrent that roared on the rooftop for over an hour. He felt death crawl up his legs and he asked Kanchu to massage them a little. He fell asleep. Brother called up the doctor, who asked for a blood test—to be drawn tomorrow. Kanchu paced on the porch downstairs while father slept. Mother sat beside him on the bed. At eight, he woke and asked mother for a little water.

“Can you sit up to drink?”

He felt death near his chest and slowly shook his head. Mother gave him a few sips of water.

“How do you feel now?” she asked.

“Better. Much better.” He closed his eyes.

He saw his village home now clearly, his mother sitting beside his father on the moss-blackened window ledge across his room in his ancestral home, swinging their legs slowly under the moonlit night. That was nearly seventy years ago and their image had faded, but now he saw them clearly. He then saw me as the town physician, coming home each afternoon for the siesta, eating lunch with him and in the evening sitting with him in the living room, chatting with visiting neighbors who came to pay respect and with occasional patients; he saw his grandchildren returning home in the evening from school, dragging their umbrellas on the ground, kicking a piece of rock all the way, with shoes worn out at the toe, then they would eat as he would sit talking to them before they rush to the field for a game of soccer or climb the rooftop to gossip with their neighboring friends.

My car was swinging into route ten towards LA, pushing through the morning traffic, it lurched forward to pass a line of trucks on the middle lane, then changed three lanes to turn sharply into the Claremont exit on the right, stopped briefly at the red down the ramp bottom, then made slowly into the Institute parking lot. I called home in San Diego over the cell-phone several times, but nobody answered because my son would be sleeping late for the last few days before his school reopens next week following the summer break. The dog heard my voice over the answering machine and rose anxiously; he went to my son’s room and watched him snore for a while then sat down.

It was dark outside in father’s room, and mosquitoes were beginning to fly in. Sitting beside him on the bed, mother was watching him sleep. She stood up to close the window.

He could now see the tall tamarind tree in his village home, by the large pond beside the gravestones of his parents. It was evening, and a storm was coming. The cloud hung low, waiting for a rain. He was playing on the steps, slippery with moss with small water-snails creeping under the shadows, leading into the pond’s dark water, where small fish darted to and fro, a lone dragonfly dived and made a round across the water beside the floating lily leaves, then returned to its perch on a small bamboo stick projecting out the water. He leaned forward and tried to catch the dragonfly but it flew away at his shadow, made another round then it returned to its perch. He stepped into the water over the slippery steps to get closer to the dragonfly, but slipped and fell into the cool water…he flailed wildly with his legs and arms to float but he was sinking, he couldn’t hold his breath any longer, he tried one last time to grasp at the bamboo stick but it was too far away, and he could now see his parents clearly across the water on the other side smiling to him and he let go.

I poured my morning coffee; the students were waiting in the next room for the nine-o’clock meeting when the call from India finally came.

The Spark

2010-06-15T22:33:00.000-07:00

“The spark had found in its wings
The rhythm of a momentary dance…”
--Tagore in Sphulinga (The Spark)

My mother died on the morning of the Bengali New Year, the first official day of summer. A bright day; the sun shone on the saffron colored wall lining the nursing home where she spent the last few days of her life, breathing through the oxygen tube.

After her cremation and other ceremonies that invariably accompany such passages, I had to leave India in a hurry. Although I wanted to carry with me a few snatches of her belongings, objects that possibly could have no meaning to anyone but she and by default now me, I did not take them with me due to a sense of deference to my brother’s family who lived in the same household with my mother. I should do that on my next trip, I thought.

Among her belongings there was a little hard-bound book of poems by Tagore, a collection of Bengali Haiku by the poet published posthumously, the collection entitled by the name of one of the poems—Sphulinga or The Spark.

A tidy mauve colored book jacket with a small print of Tagore’s own stylized painting that tastefully decorated the frontispiece.

It was not the book itself that interested me.

The book was a wedding gift to my mother. A short note accompanied it on the first page: “To Gopa, with best wishes”, then the scrawl of a simple name. A name that I never heard my mother talk about.

My mother took a course on Ancient Indian History and Culture, leading to a Master of Arts degree at the Calcutta University in the latter’s heyday. It was then a new and interdisciplinary program, an amalgam of history and fine art, literature and archaeology. The program was headed by Dr. Kalidas Nag, a renowned historian and Indologist. There was a string of visiting professors, among them was Professor Stella Kramrisch. She described to me how brilliantly irascible was Dr. Kramrisch, who would lecture to the students in fluent Sanskrit and fly into a rage, her hair tucked in a small bun that would bob up and down, as she would castigate her students for not following her exposition.

My mother wanted to be an archeologist, but to qualify one had to spend a stipulated period on fieldwork in remote locations, which was not open to women students in her time.

She did fairly well in her course—she once showed me a hand written appreciation by Dr. Nag—but for some mysterious illness she deferred her graduation for a year. Afterwards she got the opportunity to do PhD, but she didn’t. Instead she got married to my father, left Calcutta, and became a schoolteacher. At the age of twenty-six she became the principal of a high school, and retired in that position after 40 years of service.

As a child I had often heard allusions to this episode of sacrificing her career to marry my father. This would only come out on those instances when my mother would be annoyed with my father, usually due to a disagreement about how to raise their children.

There were other vague stories I had heard. That my father’s marriage was first arranged with my aunt, who is a year younger than my mother. But apparently my aunt refused to marry my father due to his short stature. Since my great grand mother had apparently promised that wedding to my father’s aunt, by then deceased, there was a sense of guilt in the family due to unmet promise, which had apparently compelled my mother to “volunteer” to marry my father. This version couldn’t be all true, because my mother would retort while quarreling with my father that he needn’t have wanted to marry her.

My aunt, however, tells me a different story, that my father was in love with my mother. So it could be that although my aunt was originally betrothed to my father, she realized the situation and made up a story so as not to stand between them. Whatever the reason, my aunt, though the second daughter, was married off first, which was quite an anomaly in those days. That period also coincided with my mother’s mysterious illness.

But I digress. I was curious to know who actually was the top student in my mother’s MA class before she deferred. This topic she would avoid. She had airily mentioned a man’s name once, on a summer night when a cool moisture-laden wind blew past the translucent curtain on the western window, who had become an archeologist and had left for France.

My mother was the paragon of a dutiful wife, valiantly accomplishing all that was required of her both within the family and outside. My father, an orphan who had lost both his parents by the age of ten, was devoted to my mother. And so was my mother to him. As they aged together their bond appeared to grow stronger. After my mother’s retirement from school, she turned her entire attention to my father and to the growing family of my brother. After the sudden demise of my father due to a stroke, my mother re-focused her attention to a life of writing historical works and memoirs with a similar single-minded devotion.

Somehow I had always associated the name inside the book of poems, scrawled in black fountain pen ink, to a mysterious man in my mother’s past. Tradition demanded that I never spoke to her about it. Some thirty years had elapsed between the time I had last thumbed that book in my mother’s bookshelf, having left the country, and my mother’s death. I had forgotten about the book; not really forgotten but it was not in the orb of my attention all these years.

On my flight back to San Diego after my mother’s funeral, I suddenly remembered about the book of haiku. I made up my mind to bring that book with me on my next visit home.

I returned nine months later. The book, Sphulinga, was not in my mother’s bookshelf downstairs. A number of old books were missing. In their place now stood shiny paperbacks by Jane Austen and Mario Puzo.

My sister-in-law said that she had discarded some old books, because they were quite tattered, were eyesores, and because bookworms eating those would spread to the new books.

The spark is now truly extinguished.

Synthetic Life, First Edition

2010-05-21T08:21:00.000-07:00

Ham Smith and Craig Venter, together with their coworkers, have made what is certainly the first ever living organism put together by a chemically synthesized genome.

The ingredients of the genome came from four bottles of chemicals, containing the equivalents of adenine (A), thymine (T), guanine (G) and cytosine (C), and a computer-stored information of the entire "tape" of the entire DNA sequence of Mycoplasma mycoides, a microorganism. (You can hear a podcast of Venter describing their work by clicking this link)

They chemically synthesized fragments of the genome in test tube, then used the "awesome power of yeast genetics" to stitch the fragments into a "complete" genome (with certain "water marks" and mutations created for specific purposes of identification and/or engineering) in baker's yeast (a totally different organism). Then the synthetic genome was introduced into a second microbe, Mycoplasma capricolum (as related to Mycoplsma mycoides as mouse is to humans) in various stages, debugged until the newly introduced synthetic genome took over the host cell and simultaneously the host genome was jettisoned.

What they now have is a completely new synthetic cell because most of the chemical building blocks of the new cell is now replaced by new molecules whose synthesis is directed by the synthesized genome.

This is a landmark technology achievement. It will also be touted as a landmark philosophical, psychological, ethical and moral watershed moment.

There is no doubt that it is a high moment in biotechnology. The scientific cleverness and engineering sophistication that went into this is of the finest order (I am still reading the pre-print and already much impressed).

However, its philosophical and extra-scientific implications are less than what some will surely claim.

There is no paradigm shift here: the concept has been consistent with scientific potentials of the day at least since 1991.

In fact, the crucial idea--that a host cell can be made to house a completely different genome and somehow be changed to the properties of the guest genome--was thinkable since a 1990 publication by Ron Davis in which his lab introduced full yeast genome into mouse cells, and I wrote a proposal to NSF, and got funded to introduce whole Arabidopsis chromosomes into yeast cells in stages by cell fusion (but did not succeed beyond the early stages due to technical reasons).

The fact that you can take over a host cell's "shell" ultimately by a new genome IS a challenging proposition which is first demonstrated by the present publication, and this is its most surprising novelty (beyond the technical tour-de-force).

None of it would likely persuade a sophisticated"believer" that man now can create life from fully inanimate objects (man cannot yet do so, because they needed living yeast cells and Mycoplsma capricolum cells, and M. mycoides genome information).

However, I can imagine now a fully synthetic life form being created some time in the future, where no previously living organism's "body part" materials will be used--in this direction recent work in Jack Szostak's laboratory in Harvard Medical School will be crucial. That synthetic organism will still have to use the "information" encoded in an already living organism's genome.

Perhaps the synthetic genome could use a mosaic of information from multiple organisms' genomes, and thus create a completely synthetic species. This would have to solve the issues of compatibility of gene regulation--a very difficult technical and theoretical problem. It will be a great achievement is successful.

Nevertheless, I still cannot imagine a completely synthetic organism in which both the genome (the software) and the "shell" (the hardware) are synthetic and did not exist before. Possible on paper, but not in reality. When that happens, man will have created life.

(If you click on the title, you should be directed to an editorial on the paper. IF you cannot access it, write in the comment and I will see what I can do)

$22

2010-05-16T09:42:00.000-07:00

If ever there were
perfectly good 1.5 hour
lost to giddiness,
it was last night; feel-good nevertheless.
Babies suckling,
Babies crying,
Babies laughing,
Babies thumping
floor, babies thumping
themselves, babies thumping
each other, babies thumping
giddy cats; babies galore,
Babies with tinker toys,
Babies with nothin' more
than themselves: little boys,
And girls, and goats,
And mooing cows...

The lesson: never believe again
Women of childbearing age
Declaring: Surely you'll enjoy, I presage,
documentary notwithstandin'....

The hero of the movie, if there's one,
Was the heroic rooster, who done
ignore
The cute baby on bed peacefully a-snore,
Posed for the camera hidden behind door!!

(Tickets for two--$22)

The Hungry Tide

2010-05-11T14:37:00.000-07:00

The Hungry Tide: A Novel by Amitav Ghosh

My rating: 4 of 5 stars
Amitav Ghosh, the author of The Circle of Reason and The Shadow Lines, weaves a complex fabric with some of the fundamentals of the deepest corners of our mind: the animistic instinct, the urge to discover, and the magnetism of finding one's roots. All this woven against a primitive landscape of water and silt, time set against tidal surges and mangrove forest, a flat land low against a stormy sky in the Bengal delta, a place that Ghosh brings alive with the apparent deftness of long familiarity. The plot is brilliant--a young woman smitten with the bug of a naturalist's passion is looking for the elusive fresh water porpoise in the riverine Sunderbans, an uneducated fisherman youth, his youthful wife and the locals with convoluted past in the backdrop of 1970s Bengal, create a drama that is wholly compelling yet mysteriously magical. Ghosh draws with broad swaths of a charcoal, as it were, constructing a dark world of primitive elements that probe deeply into our human self with the ease and flourish of a master craftsman. Magic is in the air and water, in the sky and in dolphin's breath. The story attains a crescendo in the form of a huge storm that changes not merely the landscape. A book written with deft craftsmanship and intimate knowledge. Read it.

View all my reviews >>

A Sea of Poppies

2010-05-08T20:49:00.000-07:00

Sea of Poppies by Amitav Ghosh

My rating: 2 of 5 stars
Apparently the first of a trilogy, Sea of Poppies has a meritorious plot. Beginning in the poppy plantations of north eastern India in 1830s, the novel explores pre-mutiny India under the East India Company rule, and follows its protagonists into a ship crossing the 'black waters' on its voyage to the Mauritius islands. Ghosh has done his homework well; his description of opium plantations is credible and so is his depiction of the landed gentry of precolonial Bengal and its contrast with its unsophisticated but wily new masters. Geography of 1830s Calcutta is fascinating to read. Where the book falls flat is in its overly dramatic, bollywood script of a story line, in its mix of authentic period pieces of linguistic constructs with lamentably modern colloquialisms given to post-bollywood mannerisms (and tollywood Bengali of 1980s) that ring hollow to the cognizant ear. Attempting to be Rushdiesque, Ghosh has fallen prey to the Bollywood film script genre (if that exists!). I bet someone in Bombay would be calling Ghosh's agent by this time. It would be a spicy flick; a sad loss, given that Ghosh had a plot as strong as any of his previous novels.

View all my reviews >>

I should've been an economist

2010-05-04T20:08:00.001-07:00

Had I read Asimov’s The Foundation series when I was in high school, or had I met an economist who was not a banker or a financial advisor but an economic theorist, I most likely would have chosen economics as a career option.

As it turned out, back in high school I thought economics is a boring field of stiff accountants, where you learn how to balance books and make investments. Since I equated money with vulgar incentives, a man-made device meant for corrupting the mind, I avoided all contact with economics though some contact with money was pleasurable. I knew no better until my late 30s, when I chanced upon Amartya Sen’s articles in the Scientific American.

Having always had that love for neat theories with the power of explaining large things, I gravitated towards biology because I thought the complexity of biology is ripe for theory. I was mistaken. In biology nearly anything goes. Evolution finds one solution among many. There are very few general principles.

Surely there are some principles. Evolution by natural selection on rare spontaneous variants is a powerful principle. Then the idea of information as an organizing principle is another. Coding theory. Mendel’s laws and Hardy-Weinberg equilibrium. Haldane’s rule. But these can be counted on one’s digits.

This general lack of theories gave biology its charms too. Just when I think of myself as so clever having figured out something, there comes the unexpected surprise. During my own career there were many such surprises. Splicing; RNA enzymes; PCR (dang! I should’ve thought ‘bout it!!); combinatorial design; miRNA. Perhaps the prion fold as a “bit-flipping” memory molecule is just over the horizon; hope it turns out to be true.

Biotechnology has profited from these unexpected insights in due courses, and more will surely come. It is even more surprising how staid most research in successful biotech companies usually is, and, paradoxically, how invigorating research can be in many unsuccessful biotech companies. This happens so much so that some say, for a biotech company to succeed one doesn’t need good science. One only needs simple, practical solutions and managed development.

Nothing can be further than the truth. The truth is that one never knows what would succeed. So the initial investment, at least in terms of time, must be long and tolerant of blind alleys—merely because there are very few theories in biology—there is only chance and surprise—there are few principled risk factor calculators, unlike in hedge fund investment. When one doesn’t know what will work, the best that one can do is to nurture the creative energy of the scientists. Less the management, more the nurture, the better. Scientists in powerful positions in biotech know this well. Managers in powerful position rarely appreciate this. Venture capital fund managers are even less tolerant. The balance between the next quarter’s books and the creative energy of science is a tough one to achieve; tough to tolerate the latter in the absence of a theory.

Nothin’ beats the austere satisfaction of constructing a purely algebraic formalism of a paradox, resolving it by logic, and finding its application to a thing as complicated as the voting behavior of people; as Arrow’s impossibility theorem shows, for example. Imagine an ‘impossibility theorem for a peptide drug for HIV-AIDs treatment’!

I should’ve been an economist.

Dang!

Road Warriors

2010-04-17T12:27:00.000-07:00

Icelandic ash produces chaos in air travel. So it is time for the road warriors to have some enforced adventure (see the link on this blog's title).

I am reminded of a few adventures myself. That time in 1977, the express train from New Delhi gets stranded in Bengal-Bihar border due to some problem on the track. We wait for some four hours, walking around the train in the middle of nowhere. The track seems beyond salvage any time soon. An engine is apparently en route from the direction we have just come so our train can be hauled back to the previous junction in Bihar. So it is a choice between getting stranded in Bihar versus finding our own way to Calcutta. My friend and I jump ship. We walk along the railway track about five miles to the next town, catch a bus that travels along bumpy way through glacial moraines of Bihar and then the coal fields to a rail junction after some six hours. It is night by that time. We wait until the next passenger train rattles into the platform in the middle of night, its coal engine hissing. We set off, to arrive in Burdwan at the crack of dawn. Sweet tea and jhal muri along the way. What fun.

The Power of Sequencing

2010-04-15T23:52:00.000-07:00

Back in 1992 I was in a conference where someone famously powerful was proposing to sequence the genome of the model organism with which I used to study my favorite questions in research. Sitting in the dark hall I quickly made a back-of-the-envelope calculation: how long would it take to discover the function of an unknown gene, known only by its sequence, given the rate of gene function discovery for the first organism's DNA ever sequenced completely (the lambda virus) in 1979. The answer was several hundred centuries. So at the end of the talk, I announced the result of my calculation, and asked why not spend the money, millions of dollars, on simple investigator-initiated research that asks straight questions and gets straight answers. There was silence in the hall, and I felt smug and smart. Until the last talk in the conference, which announced the discovery of microarrays, for parallel measurement of RNA transcripts made from hundreds (at that time) of genes. Quite uncomfortably, I realized my mistake--the vice of linear extrapolation. That changed my mind.

So today I read and discussed a paper published this last January, which reported the successful identification of a gene that appears to harbor the causative mutations for Miller Syndrome (Google it, if you don't know it), a particularly debilitating rare and inherited disease that severely affects the lives of some children. The methods that the researchers used, based on sequencing nearly the entire protein-coding gene set of the patients, were unimaginable back in 1992--it would have been considered a science fiction dream in popular forums and would have been derided as madness in scientific company. But it is a reality today. What surprise will the next month bring?
[Update, April 16: Here is a link to an editorial on this paper published in today's Nature Genetics: http://www.nature.com/nrg/journal/v11/n5/full/nrg2783.html]

They say it is the cruelest month

2010-04-13T21:14:00.000-07:00

Today is the Bengali New Years day. It is not held on every April 13, because it goes by the lunar calendar. Vagaries of celestial bodies mean that my mother, who passed away on April 15 morning last year, on the Bengali New Year's day, has two more days to live as it were in the year since her passage. This year it was Winko's turn, but he just missed the New Year's day. He perhaps could have made it but it was better for his own sake that he didn't. I also wish that mother suffered fewer days the agony that she endured last. I miss Winko's silent paws as he paced behind me, up and down the room, as I am given to do often, and he so followed. A shadow. Funny. I miss my mother's distant look on the empty balcony, waiting for April nor'wester to break against the sky. Winko's paws, strangely soft, as soft as mother's hands on my forehead a distant memory. Kisses that I would disown when grown were to be sought again from a mouth with a hanging tongue. Selfless devotion? Yes, that. Dog and mother. That is why this pain in April.

A Hot Summer’s Bay

2007-12-16T15:47:00.000-08:00

The 1984 Cold Spring Harbor Symposium was an exceptional meeting for me in many ways. The first excitement was because I got to see so many Nobel Laureates in one place, including legends like Jim Watson and Barbara McClintock.

I still remember Jim’s obituary of Ahmad Bukhari, one of the cleverest molecular geneticists of the time, who had died recently of heart attack while jogging in Cold Spring Harbor…Jim was hardly in the expected somber mood. He managed to blurt out statements such as, “…who had ever heard of a scientist from Pakistan?” and immediately realizing it was not the right thing to say added emphatically, “He was really very, very good, as good as you get!” Evidently Watson had forgotten the Nobel winner Abdus Salam, the PhD advisor of his close associate and friend, also a Nobel laureate, Walter Gilbert. Rasika Harshey, once a postdoc with Bukhari, patched up the uncomfortable silence with a marvelous collection of slides of Bukhari (one in which he was all twisted up in telephone cables while trying to talk to two phones simultaneously) and the snowy windows of the lab in winter.

The meeting was also memorable for a compelling set of experiments reported by Howard-Flanders of Yale, and Jim Watson shouting from the back of the hall, “Francis and I considered a four-stranded DNA model thirty years ago…it does not work!” Later work has proved Watson correct, and yet Howard-Flanders was in the right track and would have probably discovered the real mechanism of DNA strand exchange in time were it not for his untimely death a few years later.

It was also the meeting where I saw Frank Stahl towering over Barbara McClintock, the two standing by the bay, a few geese waddling by. As I approached, I heard Frank exclaim, "...but no one understood what you wrote in those days...even now I don't understand them…you meant for no one to understand what you wrote!" McClintock shook her little walking stick in the air, "Franklin, you will never grow up!"

Hardly memorable at that meeting were two talks, one by Oliver Smithies laboratory reporting the first replacement of a gene in a mammalian cell line, and the other by Mario Capecchi’s lab reporting on recombination of introduced DNA in mammalian cells. The mammalian system was considered ‘dirty’ by most geneticists, and one did not “waste clean thoughts on dirty” genetics. Yeast and phage lambda were the chosen ones, mammalian cells and plants were at the edges of attention.

Capecchi, a former student of Jim Watson, who had done some pioneering biochemical work during his PhD in figuring out parts of the genetic code, had been trying to develop a gene knock-out strategy for mammalian cells so he could study the genetic basis of body patterning in mammals. Smithies, who had earlier discovered gel electrophoresis in the early 1950s, was interested in the genetic basis of human diseases. He wanted to knock out certain mouse genes to test if mutations in these genes could cause human diseases. Both of their experiments consisted of taking mammalian cells in culture, micro-injecting or introducing by other methods some DNA, bearing sequences similar to the target genes that they wanted to knock out, and studying what happens.

Their talks were deep into technical details on how long DNA sequence homology must be, whether little variations in the sequence might affect the outcomes, what kind of selectable marker genes are to be used and such technical considerations. These were scouting works, far removed from the elegant model building and testing that yeast and phage recombination geneticists were doing.

My friend Abed Chaudhury, originally from Bangladesh, whom I had met a few months earlier in Eugene, Oregon, had an exciting new result concerning a critical idea in DNA recombination…he was a flurry of ideas, hard to keep up with. In fact I, a late comer into the field, felt a little stupid in his presence; but we had other shared interests, in poetry and an ambition to translate Carl Sagan’s “Cosmos” into Bengali! And it was reassuring that Abed was always gracious. Abed and I dived into the harbor’s bay on a hot and sultry afternoon, but had to get off the water relatively quickly shivering—the water too cold for us used to our subcontinent’s warmth.

The Double strand break repair (DSBR) model was recently proposed by Terry Orr-Weaver, Jack Szostak, Rodney Rothstein and Frank Stahl, and this meeting saw a number of presentations for or against that model. The model was quite heretical, though a variant of sorts was proposed earlier by Mike Resnick. The surprising aspect of the model was the proposition that for DNA recombination both strands of one of the two recombining DNA molecules must be broken…this was thought to be rather unsavory…it left too much opportunity for the DNA strands to get lost in the process--a rather untidy way to accomplish “clean” recombination as observed by the fungal geneticists. So the DSBR model was not quite accepted yet. In this light, it was unusual that both Capecchi’s and Smithies’ groups had been using linear double stranded DNA with two out-ward facing ends (“ends out”) for targeting experiments whereas earlier work with yeast had shown that circles with “ends in” configuration worked nearly a thousand fold better. I remember walking away feeling vaguely interested that both Capecchi and Smithies groups got high frequency recombinants with “ends out” DNA.

Over the next 15 years, a string of papers from the laboratories of Capecchi and Smithies smoothened out most of the creases on gene knockout by homologous recombination in mammalian cells. The use of positive-negative selection was an important key. The use of large flanking DNA homology and the use of embryonic stem cells were others. The technique is now routine, and its use provides the ultimate test of a human gene’s function (confirmed in mouse).

Many interesting observations remain. While it is now relatively certain why “ends in” type of constructs do not work so well (probably because of the existence of a process called ‘non-homologous end joining’ or NHEJ, discovered only in the 1990s, which snares the introduced DNA into random locations in the genome), it is not clear why embryonic stem cells are one of the very few cell types where knock-out recombination can occur at high frequency. Noting that embryonic stem cells lack in some of the very same recombination gene activities that are thought to be important in the process, it is a rather curious observation.

This year’s Nobel Prize in Physiology or Medicine has gone to Capecchi and Smithies, to share with Sir Martin Evans who first isolated embryonic stem cells in mouse and used it for generating mice with knocked out genes.

It is interesting to note that the gene targeting methods were developed by these scientists merely as tools to investigate other larger questions. When they were developing these tools their work could not be published in flashy journals of science, and were generally thought to be unimaginative and not very fundable. Apparently, the US National Institutes of Health (NIH) had refused to support Capecchi’s work in 1981 and only in 1984 or 1985 could he obtain support from NIH for these studies.

Lesson: If you have a really good idea for a technology, it might be unfundable and it might not generate enough excitement immediately. The really important factor to consider, apart from the feasibility, is if you are successful will you make an incremental impact or a contribution that just was not possible before. If the latter, then beg or borrow, but do it. If the former, you’d better put on your thinking cap again. This time, first look for a big question in biology that you want solved, and then figure out a technique for solving it. Don’t put the cart (the technique) before the horse (biology or medical question).

The Anatomy of Rain

2007-12-15T20:55:00.000-08:00

The air is thick in the heat of a July afternoon. Acres and acres of rice field, squares, rectangles, swelter below as the sun glints into the eyes of the brahmini eagle soaring overhead, climbing higher and higher on hot circles of humid air, the heat opening spaces in the thick air for invisible water vapor rising from hundreds of ponds and rivers and paddy fields that dot the dark green landscape. A moorhen calls intermittently from shadows of the jute field, by the clumps of lantana brush that line the thatched huts along one edge of the rice fields, marking time like a muffled grandfather clock, here, here, now, now, lulls the rice fields into a somnolent haze.

At this hour, further south, summer heat drives into the sky more moisture-laden air from the brightly lit Bay of Bengal; and up north, the dry air from the Himalayan foothills, dusty and hot, sweeps down the Gangetic plains. The three air masses meet over the Bengal delta in the late afternoon, as the rows of farmhands swiftly gather bunches of delicate green rice saplings from the wet loam and replant them in knee-deep water, to outgrow the weeds, to draw nourishment left over by slimy filaments of anabaena, to dance in peristaltic waves in a distant October breeze—golden dreams on an acre of land—a new piece of fabric for the tiller’s child to dance with the drums. In rhythmic repose, the farmhands swing from right to left, lifting a bunch of saplings then replanting them with deft hands into the water, one, two, three…the sun beating down on their dark skin, sweat rolls down their bent backs.

As the three air masses collide high above their rice fields, massive piles of cumulonimbus roll forth, brilliant white with little dark interiors; they begin to rise rapidly, billowing in the wind, the eagle now a black dot against their bright forms; they reach higher and higher into the stratosphere, an anvil forming on their upper reaches, the cold rarefied air of the upper atmosphere squeezes the moisture out of the white cloud, billions of tiny dust particles begin to provide the surfaces on which moisture from the ponds, the bay, the rice fields, condenses, each a scherazade’s teardrop, the Precambrian dust of the high plateaus surrounded by dolphin’s breath and santhal women’s sweat, increasing in size from nanoliter to microliter as they rapidly succumb to gravity’s pull, forming fast moving dark puffs, move in layers at the tail end of a cooling breeze that now begins to flow over the rice fields, first slowly then rapidly, the sun is now obliterated by the dark forms, ominous, edged with menacing lightening that arcs across the western sky. Thunder rolls. The farmhands raise their bent backs to search the horizon; the cool air descends fast creating rapidly advancing pressure waves, the heads of the coconut palms begin to sway in unison, first gently then swiftly along the horizon’s edge, the ripple reaches the jute fields, the water on the pond begins to dance, the waves of wind stalls on the left as they move to the right, then again the left sways while the right stalls, a flock of white egrets disperses formation against the shear wind, the lean cow, in antelopean fear, its tail held erect, gallops over the bewildered dog.

And then the rain. The hard beating rain. The warm rain that pours forth from the darkened sky, that gushes in torrents. The farmhands take refuge under the mango tree and the rain drums down, the horizon obliterated by the mist of water vapor. The cow, dogs, goats, men and women, ghostly in the mist, soaked to their bones, shiver under the tree while the rain makes the dream of the rice fields come true.