Thursday, November 17, 2011

In Memorium: H. G. Khorana (1922-2011)

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.

Sunday, November 13, 2011

On Growth and Emergence

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.

Tuesday, September 6, 2011

A sense of time

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.

Friday, July 29, 2011

Absence of Heroism and the Road Inward

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.

Monday, July 11, 2011

My DNA: The Rashomon Factor

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.

Sunday, July 3, 2011

My DNA: My Ancestry

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 caf├ęs.

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.