Duplicate duplicate...And the sad case of hexacyclinol

Unrest is brewing in the world of chemistry, because a piece of research is raising eyebrows, and hackles, of those who think that it represents possibly dishonest science. The case also showcases the dilemmas in modern scientific progress, which have been illustrated before by some other famous cases. I think it would be worth it for me to elucidate the nature of the current entertaining fracas. But after a very short introduction to the art and science of organic synthesis.

* Magic in moleculeland and showdown in the house of hexacyclinol:

'Total synthesis', the multistep synthesis of complex organic molecules with practical and medicinal benefits, has been one of the cornerstones of the scientific foundation of the modern world. Look everywhere around you, and you see materials that have been manufactured tediously by organic chemists, one step and one bond at a time, since many decades. The greatest impact of this endeavor has been in the pharmaceutical industry, and most of today's important drugs would not exist if it were not for the patience and ingenuity of the organic chemist, nor could we hope to get future pharmaceutical products. Without synthesis of natural and artificial molecules, we would essentially be losers in our fight against disease.

So much for the practical aspect. The other reason why organic chemists synthesize molecules is for the sheer intellectual challenge. Building a complex molecule is like building the Eiffel tower or like painting the Sistine chapel, where not only does every bit and piece have to be put in its exact place, guided by known chemical principles, but the result, efficiency, and methods also have to be aesthetically pleasing. Many chemists are drawn to the synthesis of especially natural molecules, because they are dazzled by the beauty of nature's architectures, and want to make every effort to top nature in her magnificent constructions. Many have come close, if not surpassed, the rich and astonishing diversity of nature's creations.

So did James La Clair of the Xenobe Research Institute (?) want to synthesize a molecule called hexacyclinol, whose structural beauty and complexity only seasoned organic chemists can truly appreciate. It is a metabolite from a fungus isolated a few years ago, from a dead piece of wood in Siberia. Many of the top selling drugs of recent years have incidentally been based on molecules isolated from such obscure terrestrial and marine organisms in exotic locations, a resounding case for preserving biodiversity.

A couple of months ago, his synthesis appeared in one of the two top chemistry journals in the world. I am not a seasoned organic chemist, but when I saw the structure and synthesis, my first reaction was 'Wow'. But further reading of the paper made my jaw drop lower down. The synthesis was 30 steps, something not uncommon in today's synthetic protocols, although still a formidable feat. What was dazzling was the fact that authoring the paper was one man- La Clair. Today's syntheses are massive endeavors, usually involving at least four to five graduate students and post-docs who have toiled for months, if not years, on such a complex product. One man's crusade in synthesizing such a molecule would have been hard to believe even in the maverick days of the 30s, when rebels determined to overturn sacred cows could toil obsessively in their laboratories. Frankly though, I was not completely qualified to judge the synthesis, but I was astonished at the fact that one man had done all the work of procuring, synthesizing, and then characterising this gigantic succesion of molecules in the synthesis. Suddenly I remembered having seen La Clair in a session from the annual meeting of the American Chemical Society. I remembered his clever remarks in the session which he had chaired, which involved praising my friend's synthesis and saying that 'my friend is ahead of the bug that usually synthesizes the molecule by several steps'.

My astonishment and puzzlement at the solitary achievement of La Clair was justified when I came across Dylan's Tenderblog, where he pointed out the dubious nature of some of the steps and statements in the paper, followed by a world-class barrage of invective, hilarious comments, and astute observations. I was ROFL when I was reading these comments.

However, now, it seems that La Clair may have become A La Carte indeed. A chemist by the name of Scott Rychnovsky at the University of California Irvine, predicted that some structural data for the molecule actually matched the calculated data for a totally different molecule.
Note that the molecule which La Clair synthesized already existed. Its structural data was already known, and a structure had already been deduced from that data. What Rychnovsky did was use powerful computers and the methods of computational chemistry (my turf!) to conversely calculate the structural data from the molecule. What he got did not correspond to the observed data. Instead, he came up with a totally different structure which would correspond to the observed data. In a mammoth effort now, John Porco of Boston University has actually synthesized the alternative structure which according to Rychnovsky, should correspond to the observed data. Voila! It does.

Now what does this mean?? For one thing, it could mean that La Clair synthesized the wrong molecule. But remember, Rychnovsky's structural data calculated for La Clair's structure does not actually correspond to that structure. However, in his paper, La Clair has done the usual routine of presenting the experimental structural data for his molecule, comparing it to the original experimental data acquired when the molecule was isolated from its fungus, and then noting the exact correspondence between them, concluding that his structure is the same as the original one. This is standard and age-old scientific protocol; come up with something, then see if the data for that something matches the known data. If it does, you do have what you say you have. But again, according to Rychnovsky, La Clair's structure should NOT give the structural data which La Clair has presented. So there's a disconnect between La Clair's structure and its synthesis, and La Clair's structural data. Now, the structural data already exists (from the original isolation study) and so cannot be fabricated. Thus, by the rules of Aristotelian logic, that imperfectly perfect science, the fault lies with La Clair's synthesis. Ergo, the skeptics conclude, La Clair could not have synthesized the molecule which he claims he did. Ergo, La Clair's synthesis is not what he says it is.

Ergo, La Clair has committed scientific fraud, or that's what they are saying at least.

La Clair claims that most of his work was done in an institute named Bionic Bros' in Germany. This name sounds to me like something from an Asimov novel, a cross between a robotics company and a bagel bakery (I am thinking of Einstein Bros. of course) where an obscure genius toiling in an obscure institute with a funny name, comes up with a breakthrough to create artificial life or something similar.
Supporting the skeptics' conclusion is the dubious nature of some of La Clair's statements and experimental steps, which I would leave an experienced organic chemist to pontificate on.

To be frank, strictly speaking, the verdict is still out on the La Clair affair. La Clair himself says now that the structural data for both the molecules could be exactly the same. To my humble chemist's mind, this seems highly unlikely, given the very different structures of the two. But as it is the case, whether I or La Clair or the critics are wrong in this case, science will progress either way. No offense to La Clair. If he is right, we will be wiser anyway.
That's the good thing about doing science. Whatever happens, science always wins.

* I replicate, therefore I am:

But this case is illustrating some of the inherent problems of scientific peer review. Scientific results should crucially be testable. But who is going to go to the trouble of testing a 30 step synthesis, or any such mammoth endeavor? And mind you, dozens of such syntheses are published every month. All the reviewers can do is check for internal consistency and past conformity based on their own knowledge and experience. Nature has recently published a nice article, narrating the problems with the all-important replication of data that is paramount in the scientific method. How can you check each and everything in a paper? Even if you can, does failure to replicate mean shoddy work on your own part, or a fundamental problem in the original author's work? And more importantly as the article points out, scientific research has subtle details in the exact protocol, including elements introduced by the skill (or lack of) the experimenter. Such elements can hardly be evaluated, and are never mentioned in a paper. What if these subtleties are playing a large role in the results?

The Nature author recounts the efforts of several journals now going to be devoted to methods, as well as websites where readers can rank papers based on their own efforts in duplicating the data from those papers. As the author says though, this could have the adverse effect of having to include too many similar pieces of work, a fact that may make the journal less attractive for authors and readers alike.

Another quite different matter concerns the nagging question; Why do they do it? Is their behaviour an inevitable consequence of today's cut throat world of competition in science, the high-pressure world of publish-or-perish that is so emotionally taxing, that sometimes scientists just lose it a little and falsify their results with the hope that they won't be detected. In La Clair's case, hexacyclinol was one example among a dozen other interesting examples. But what about the celebrated case of Woo-Suk Hwang, the Korean celebrity, the scientist who became the lifeblood and then the pariah of his ilk with his work on stem cells and cloning. Surely he could not have assumed that crucial work such as his would not be subjected to the closest scrutiny possible. That scientists would not keep the midnight oil burning in their laboratories to validate his results. How can someone who does work of that calibre afford to be dishonest to any degree and think he would get away with it? What about another celebrated case, that of Jan Hendrik Schon, the trailblazing Bell Labs researcher who promised to revolutionise electronics, semiconductor and superconductor technology. Not in one but in sixteen papers did he duplicate the exact same graph. How could he think he would escape unscathed and in fact be lionized? The question defies explanation. However, if any kind of serious study found out that it is emotional strain and pressure that brings about such behaviour, then does our entire way of doing science deserve a second and serious look? Or do we just dismiss these few cases as bad apples?

I believe that psychologists should find this avenue of investigation a very fertile paradigm of study. In the 1930s, a publicised and comprehensive psychological study tried to document what kind of men and women become scientists. What is their personality, their origins, childhood influences that turned them toward science and inquiry? Maybe the time is ripe for a similar study asking a different question: What are the adverse effects of the framework of modern scientific research and peer review?

But in the end, I think that the Nature author says it best when he points out that the marvelous expositor of science Nobel laureate Peter Medawar once pointed out that all scientific papers are frauds, because they paint a false picture of science progressing in an orderly fashion from hypothesis, testing, confirmation, to theory or law! As the great philosopher Paul Feyerabend pointed out to the chagrin of others, science is an anarchic enterprise. As the Nature article enumerates, since the actual process of science is much more messier than is depicted, maybe the evaluation of the process should also be more messier. I agree. Let evaluation also be an anarchic enterprise.

The more the messier. The messier the merrier.

Once-a-day cocktail for HIV

One of the biggest problems with AIDS treatment always has been patient compliance. Viral levels can be reduced in a patient and maintained at that level only if you hit the virus early, hard, and repeatedly so. But because of the number of times that one has to take the drugs, many patients fail to keep up with this strict routine. There was a point when patients had to take drugs as many as 18 times a day, a grotesque regimen. If this fails to happen for even a couple of days, not only does the virus come back with a vengeance, but the diabolically chimeral creature develops resistance to that drug combination by clever mutations. After this, even the same previously highly effective treatment fails to have any efficacy.

The usual combination therapy of drugs consists of two drugs that inhibit the viral enzyme called reverse transcriptase which codes for viral DNA, and one which targets an enzyme called HIV-protease, which is reponsible for processing viral proteins into a form suitable for forming the viral coat. Both enzymes can rapidly develop resistance to these drugs through mutations, in an exquisite though unfortunate example of Darwinian evolution (People who think evolution is necessarily a slow process and therefore cannot be observed need only to look at HIV among other things)

In what I see as a major advance in HIV treatment, the FDA has finally approved a once-a-day capsule with a combination of three best selling drugs. The treatment still costs 1000$ a month, but this is assuredly affordable for well to do people in the developed world. The problem of making it available in India and Africa still persists, and I don't know if there's any easy way out, because given the income levels of many HIV patients especially in Africa (which are essentially none), there is no difference for them between paying 1000$ and paying a million dollars. Short of making the treatment free to at least some, I don't see any easy way out for pharmaceutical companies and governments.

In any case, this is an important new development, and I am proud that one of the three drugs (Emtricitabine®) is the one that was co-discovered by my advisor. Does this mean he will be away even longer than usual? Boo hoo.

Cyanide poisoning failed, student died

Rationale for smoking cigarettes while working in the lab- hydrogen cyanide can combine with tobacco to produce a foul smelling compound that can be an early warning for cyanide exposure.

Drawbacks- a dozen other things can combine with cigarettes and explode.

But who cares. We always plan for the worst and hope for the best, don't we? Must rush and remind my experimentalist friends of this fact. As for me, I can generate as much CN- as I want and be blissfully safe from it...

Update: My cigarette loving friend from Mexico has just admitted that he does not see much of an advantage in saving himself from cyanide poisoning, at the risk of dying from lung cancer or third degree burns. He would rather not smoke cigarettes near his apparatus. People are getting wiser. I am happy.

The reach of the penguins

This Ig Nobel Prize gem missed my attention before...

Polar Biology presents...*drum rolls*....the secrets of Penguinnnn Pooooooh!





God forbid them from becoming interested in elephants.
[Hat Tip: Everyday Scientist]

Fat fatter fattest

Reference: Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14

Note how Georgia and Washington are the only states to get catapulted from <10% to 20-24%. Another incentive for me to finish my PhD. and escape from the state with an abundance of the dark side of the meat as fast as I can.

The other day, someone asked me to truthfully say how frequently I eat fast food of the insidious type (namely burgers, fries, and their lofty fatkin).
The answer is, once every three or four months, and that too only to break the monotonous drudgery of Maggi Noodles and Curds-Rice with Bedekar Mango Pickle (those who are raising eyebrows...we can negotiate a non-disclosure deal later, but I am speaking the truth about the frequency). And from what I am reading in the engaging The Omnivore's Dilemma, I think that it's going to be a long long time, if at all, before I touch those Chicken Nuggets again.

The Ghosts of Molecules Past?

We are finally filing a patent for a compound on which we have been working since May 2005 or so...or rather, on which our collaborators at Imperial College in London have been working on. That is one of the downsides of computational chemistry (or upside actually). You design compounds on your computer that will target some protein implicated in a disease. That process takes perhaps a couple of weeks at the beginning. After which you fling your designer drug in the experimentalists' face. It's them who then have to keep the midnight oil burning for months; first to come up with a decent strategy to synthesize your molecule, and then give it to the biologists, who in turn take a few more months to test it in cell assays. By the time the compound shows activity, the next ice-age very well might have come and gone. Then you work on some more modifications during the interglacial, after which the experimentalists lock themselves up for one more extended round of geological time. Clinical trials and other events are way off into the next evolution of the Universe after the big crunch.
This is not intended as a put down to the experimentalists, but actually an appreciation of the lengths they have to go to in order to get some results. Also, the computational side of things is not always so easy or so quick, but on a relative basis, it can usually be less lengthier than the experimental side, and also less labour-intensive.

But that's why I decided to do computational chemistry; so that I would have to worry only about the thinking and leave the actual doing to everybody else who works at the bench. It would have been the perfect realisation of my indolence. Alas! I found out that even in computational chemistry, I am not spared the tribulations of learning programs, evaluating data, and actually typing on the keyboard, not to mention walking light years across campus to talk shop with the biologists. So much for the ennui for couch rumination.

I am tempted to say that we are filing a patent for a drug but how premature that statement would be is well summed up in this post by a Pfizer chemist:

"Another surprise is when people find out that I've been doing this since 1989 without getting any drug on the market. I think that some folks are just being polite when I tell that that this isn't unusual, thinking to themselves that I must be some kind of hack. But the general public has, as far as I've been able to see, a very exaggerated idea of how quick and easy it is to find a drug. When I say that if I found a wonderful new compound tomorrow that it might be on the market in about 2015, they think I'm delusional. I wish I were."

Another quote I found also applies to us lowly lab dwellers which the general populace could keep in mind:

"When I meet people with no particular scientific background and they find out what I do for a living, it seems that there are several things that they're usually surprised about. For one thing, many people seem to think that doctors discover new drugs. Some of them don't even think about the drug companies or their role - and if they do, they imagine a lot of doctors working there. Actually, as my readers in the industry can confirm, the only time that physicians really get involved is when the drug is headed into the clinic and dosing in humans. There's not an M.D. in sight while we're validating drug targets, screening compounds, and working to fix their selectivity and activity. (And there's that noisy subset that think that all drugs are discovered in NIH-funded academic labs, but we'll leave that one alone for now)."

In any case, the one thing that keeps cropping up an annoying number of times in such endeavors is luck. We were lucky that 4 out of 10 of our molecules showed activity; it could easily have been none. The whole process was exacerbated by the unfortunate death of one of our collaborators. It is revealing to what pernicious extent you must go to to get your hands on a new molecule that may or may not, probably may not, become a new drug.

The new compound is intended for women whose breast cancer is resistant to the standard treatment of Tamoxifen®, and it turns out there is a considerable number of these.
I hope this one does not end up as the ghost of a molecule past.

Obviously I cannot draw the structure of the molecule here, because then I would have to kill this blog to protect the secret.

Engineering evolving by natural selection

The marvelous Richard Dawkins gives a short account of contraptions made by a German engineer that gradually 'evolved' from crude starting materials. Include a wind harnessing system of propellors inspired by the principles of bird flight, and an 'intelligently designed' (!) foil that is engineered by 'natural selection' to minimize air drag. This presentation should put to rest one of the many misconceptions about evolution- that it is so 'random' and hinges upon such a fortuitous happenstance, that it simply could not have taken place naturally in such a 'short' time. An illuminating presentation lasting only a few minutes



These days, I have strongly started to think that it is relatively easy to harbour doubts about evolution if one has not read into it in some detail. For example, questions about the improbability of complex life arising 'randomly' by mutations from simple chemical precursors in a short period of time, is what can be only called the "argument from incredulity"- we find it hard to believe simply because we cannot readily imagine it. No wonder the 'intelligent designees' can hoodwink people in a hardbeat. A more incredulous stance would actually be the belief that simply because something is incomprehensible to us human beings means that it cannot have taken place in nature. Talk about smug and self-centered satisfaction!

A little glance into some of the details of evolution should be enough to convince us of the utter beauty, logic and very much probable simplicity of the process. In retrospect, evolution should look infinitely more simple and beautiful than the transcendental and much more complex process of some inconceivable super-designer designing such a complex world.

Pretty much says it...



Actually it's even worse; "What facts can we make up to support it?"
From What is pseudoscience?

Sam...

SAM…

I first met Sadashiv a.k.a ‘Sam’ Patil in the summer of 2000. The venue was Raman Hall, the auditorium of the Department of Physics at Pune University, and we were listening to a talk by Prof. Yashwant Waghmare, former director of IIT Kanpur, about the history of the Indian atomic energy program. Dr. Waghmare was describing how Homi Bhabha, the architect of modern nuclear India, pioneered nuclear reactor development in the rapidly developing nation in the 50s and 60s. The reactors were given the now well-known incandescent sounding names- Apsara, Cyrus, Pornima, Zerlina etc., each of which curiously is an acronym for a longer technical name. While Dr. Waghmare was describing this phase of the program, a bald man wearing a cap who was sitting in front of me suddenly got up and quipped, “Do some of these names reflect Bhabha’s Zoroastrian origins and inclinations?” Dr. Waghmare, having no idea, said so. Later, one of my friends introduced the man to me as ‘Sam Patil’. In his hand, he held a copy of Robert Jungk’s ‘Brighter than a thousand suns’. This early book is a somewhat idealistic (and even inaccurate in parts) history of the atomic pioneers. But it is a wonderful introduction to the topic for a beginner, and reads like a fast paced, nostalgic novel. The copy showed considerable wear and tear, an indication of having been read several times.

The man was much older than us, about my father’s age, but he insisted that we call him ‘Sam’, a play on his own nickname, 'Sham'. When I introduced myself, Sam asked me, “Are you Bhau Jogalekar’s son by any chance?” I was surprised that this man called my father by his old nickname, which only close relatives and friends use (Bhau literally means brother in Marathi). When I said that I was, he looked happy, and said that he and Bhau Jogalekar went back a long time, to college days. He said that he would meet me again, and asked me to say hello to my father on his behalf. After that, he launched into an enthusiastic espousal of Jungk’s book. Till that time, my knowledge of atomic energy was quite sketchy, and upon his recommendation, I borrowed the book from Prof. Rajeev Pathak (a well-known physicist, teacher and good friend) and was impressed by its heady description of the heydays of physics.

I went home and told my father about Sam. He immediately recognized him; “O Sam, that happy-go-lucky man”. Then he told me about how he came to know him, back in the late 1960s.
Sam came from a well off family that had educational leanings. He secured admission for studying engineering in COEP, but got bored and dropped out after a year. During that time, many bright students were studying the sciences, and Sam decided to study physics, one of his pet interests. Accordingly, he did his BSc. in physics, and enrolled for his MSc. at Pune University. It was there that he met my father who was then doing his M.A. Sam became an occasional part of my father’s group which involved mostly hostelites and out of towners. Some of the members and acquaintances of that group included Anil Gore (Head of the Statistics Department), Naresh Dadhich (director of IUCAA) and Anil Awchat (the writer and social activist). Even though Sam had decided to study advanced physics, he was too much of a dilettante and free bird to pay attention to formal studies. Like before, he dropped out, and took up a carpenter’s profession, a previous hobby in which he could let his creative abilities manifest themselves. In fact, when I asked my father about him, my father pointed out several objects in our home, including a coffee table and an entire large wardrobe lined with rosewood paneling, which Sam had made for us. Sam’s interest in science shone through the furniture; the coffee table is shaped like a Mobius strip, that wondrous mathematical object which quite astonishingly has only one surface.

In spite of his profession as a carpenter, Sam’s real passions were two; the history of physics, and invention. He is the only person I have met in my life who was an actual, full-time, inventor. The problem was that just like many dilettantes, Sam never had the patience or the perspicacity to convert either physics or invention or carpentry into a serious, well-paying profession. Since his father was well off, he did not care much about money; at first because he could get it, and later simply because he had no need for it. Sam gave up all efforts at being well off himself, so that he could indulge in his hobbies. He was interested in science as much as anyone I have ever heard of. To slake his thirst for knowledge, he traveled all over the country, going to conferences, science congresses, and exhibitions, probing, asking questions, meeting and getting to know leading scientists, visiting their institutes, and collecting interesting physics based gadgets that piqued his inventor’s mind. He lived in a small, extremely dilapidated room on BMCC Road, and in that small room, he had dozens of gadgets that he had invented. These gadgets frequently were constructed from the simplest of materials, and used to demonstrate key principles like those of magnetism, mechanics, waves, and optics. I was quite struck by his interests and his inventions the first time I visited his place.

Sam knew that these inventions would not bring him money. As far as I know, the occasional carpentering that he did was his only source of income; perhaps he earned some meagre amount from informal sales of some of his toys. I am quite sure that all the money from this side-venture went into traveling, book buying, and building these toys. For Sam, books and these toys were his life. He used to travel around the city on his ramshackle bicycle, attending every exhibition or competition related to science that was ever organized. I remember meeting him several times; at a neuroscience meeting, at many physics competitions, at the Indian science congress, and at college exhibitions. He was a great and incessant talker (one of his qualities that used to irk my father!), and used to be ready to spend hours talking about his favourite topics with me or anyone else who was interested, quite oblivious to the inconvenience and impatience of his listeners. Inside his small shack, he used to spend almost all his time building toys and reading.

My father always lamented that Sam was a very intelligent man, who wasted his abilities by indulging in these ‘hobbies’ of his. He said that even as a carpenter, Sam would have been a success, if he had stuck with it seriously and professionally. To be frank, he did not always encourage me to spend a lot of time with Sam, because he feared that I might end up like him; a dilettante who is not a success in life (and even now, quite independent of Sam, he still does!) Many times when I did not study, both he and my mother used to say half-jokingly, “Don’t procrastinate; you will end up like Sam”. There was some truth in what they said, based both on Sam’s inclinations, and my own. What’s the use of knowledge if it’s not put to good use? What is the use of having ability, if one does not have staying power? Sam used to fondly remember circumstances when he had asked a question in the middle of a lecture to a famous scientist, which the learned man could not answer. My father used to say, so what; after all, is Sam the famous scientist?

Although my parents’ criticism of Sam was quite valid, I appreciated the fact that Sam was a man who truly followed his own destiny. I suspect that he was aware of all the things which people like my parents said about him, but he had long decided that they would not matter to him. He was a non-conformist who let his heart lead him to his true callings. He eschewed money, fame, or even respect from the supposed higher middle class of society, much of which gauges a man by his success and his social status. I liked him, and while receptive to my father’s warnings, was always ready to listen to him talk.

Sometimes Sam used to come to my place and give me a book to read, or show me one of his inventions. He used to praise the Karanji or Patties that my mother used to offer him. My father used to meet him and, hiding his impatience, used to listen to our rants about Oppenheimer and Fermi. I think Sam was happy that he had renewed his old friend’s acquaintance through his friend’s son. I can say that he had also found a new friend in the son. He once gave me Silvan Schweber’s ‘In the shadow of the bomb’, an excellent contrasting study of Hans Bethe and Oppenheimer, based on their life, times, and personalities. Sam had a profound and diverse knowledge of the history of physics and also the events which accompanied its growth, an interest that he infectiously transmitted to me. He used to say that out of all the physics pioneers, his favourite was the Hungarian physicist Leo Szilard. The comparison and coincidence could not have been more apt. Szilard was a maverick scientist, a non-conformist, and a brilliant prophet. Just like Sam, Szilard was a peripatetic who lived out of a suitcase, never held a formal university post, and despised official academic scientific research. Yet, this genius in the shadows was more prescient and saw further into the future than anyone else, and today stands as one of the most important scientists of the century: the foremost herald of the atomic age (It was Szilard who, in 1933, long before fission in Uranium was discovered and long before anyone else thought about it, had the first inkling about possible and vast amounts of energy from a fission like process)

As my own knowledge about these matters grew, I used to take pleasure in telling Sam facts which he did not know, and seeing him chuckle at the mention of a particularly amusing one. He also read widely into every imaginable subject, and you could really discuss anything under the sun with him. He may not have been a scientist, but his enthusiasm for science outgrew that of most scientists that I have come across.

Probably the most memorable trip concerned the time when he took me out for a hearty breakfast at a small, typically Maharashtrian restaurant in front of Food World on Bhandarkar Road. After we finished eating, he brought out a wonderful and amusing toy that he had bought in Delhi. It consisted of two pink ‘magnetic hearts’ that swung on a small hinge on a long metal wire. One heart had the makeup and face of a girl, and the other of a boy. All you had to do was set the two hearts in circular motion. Like a couple who are angry at one another, the hearts would first swing away. Then, just like a couple who gradually make up with each other, the hearts would start coming closer, although in a haphazard manner. Finally, in a rib-tickling oscillatory motion, they finally settled down very close to each other in a diffident kiss. All these movements were governed by the intricate interplay and geometry of the magnets in the contraption. After witnessing the hearts’ endearing performance in the restaurant, I found myself hysterically laughing, and also being fascinated by the complex physics of magnetism that governed their motion. I could see that I shared my excitement with all the waiters in the restaurant. It is undoubtedly the simple, amusing things like these, that hide the most profound principles of science. That’s what makes it worth studying.

I met Sam many times, a few times in his dilapidated den of books and toys, many times in the most diverse events connected with science, and a couple of times when he visited my place. It was difficult to contact him because he neither owned a phone nor had an email address. Even when you visited him, more often than not he would be gone to some scientific event in or out of town.

When I visited India last December, I made up my mind to meet Sam. After coming to the US, I have updated myself considerably about science, history and technology, thanks to the magnificent library here. I was sure that Sam would love to hear tidbits from my bag of new facts. I would have contacted him much earlier if he had a phone. Because of his relative inaccessibility and other things that came up, meeting him kept on getting postponed, although I resolved to try to do it before I left.

On the morning of December 21, I woke up and was having coffee, when my mother gave me the news. Sam had died in an accident late the previous evening. He had been traveling on his cycle, when he collided with a speeding motorcycle. He passed away before he could make it to the hospital. I felt like our conversation, which had not even yet taken place, had broken off forever in midsentence. Sakal had his obituary as a small piece, in which they noted that he was an inventor. Sam would have liked that. I have kept the cutout.

I will always remember Sam as a man who went after his heart, and neglected the conventional dictates of society and worldly life. He may have been criticized and may not have been well off, but he was one of those who tossed tradition and convention aside, and did it cheerfully. He recognized why it is that mankind wonders at nature, at the cosmos, and human life. In him, I could get a glimpse of the raw, innocent curiosity that we should all have about the world around us. It is also a harsh and true fact that such sincere explorers are frequently not recognized by society as a valuable addition to its kind. But that is the price they pay for being mavericks.

Sam was in a significant way, responsible for introducing me to the heroes of physics and atomic energy, and inculcating a lifelong interest in the history and philosophy of science that will always give me solace; I believe this will be a connection that goes beyond my conscious awareness of it. The fact that I could not meet him before he passed away will always gnaw at my conscience to some extent, as would the cruel fact that he passed away in a tragic road accident. But after the incident, all my life, whenever I read or hear anything about Enrico Fermi or Leo Szilard, about the philosophy of science, or especially about a new, amusing invention, I will always ask myself,
“What would Sam think of this?”…

It was a little suprising for me to see ACS president Ann Nalley not just praise, but wholeheartedly believe in Bush's 'American Competitiveness Initiative', and his endorsements of the importance of science and technological research to the progress of the country which he listed in his state of the union address.

Isn't Nalley (or others who hold similar views) counting her chickens before they are hatched? We must remember that the lofty sounding programme was only one of scores of such initiatives enumerated by Bush in the address. Well, there are State of the Union addresses and there are State of the Union addresses...out of all the topics that the president mandatorily has to cover in about an hour and a half, including health care, national security, and social security, I would think that it would not be surprising if science ranks low again in terms of actual efforts and concrete steps. I would think that we should wait; first of all for a practical and significant demonstration of this commitment to science and technology basic research, and secondly, to see that such proposals make it through without actually having been twisted, modified, and conveniently interpreted so much, that they have lost all semblance to the original. It is all too easy, and well-known, for politicians to have their sincere faith in the adage; 'It's only the thought that counts' (India Uncut)

Did you say research?

It's been about 3 years since I started off as a PhD. student, and by this time, I have become as they say, a sadder but wiser man. Even the perpetual reading about science and scientists that I indulged in ever since a kid is no match for what the flavour of scientific research actually tastes like. So here is a distillation of some common lessons that I learnt through rather uncommon and meandering, not to mention excruciating, ways. More will be forthcoming, of course, as I suffer more:

1. Research involves ideas, not answers: Probably the hardest thing to come to terms with. Unfortunately, the way we are taught science in school and college is as a set of results, theorems and laws. Start doing actual research, and one quickly realises that about ninety percent (and I am being highly optimistic here) of research is clerical work, donkey work, monkey work, whatever you would like to call it. It is the last ten percent that scientists usually can die for. But most of what is routinely done is a far cry from the world of cut and dried facts that are encountered in textbooks. The average scientist or student can well spend spend most of his or her time in going down blind alleys, solving mundane but intractable problems that seem to have sprung up out of the blue, troubleshooting errors that don't even seem related to what you are doing, and most excruciatingly, getting unexpectedly stranded at the very beginning of a project for ages so that it seems that you are never ever going to progress to the juicy, creative part. In fact, this is the single most important situation that drove me to tears; getting stuck up with something that I least expected, that is the most boring yet essential part of the project, and that by itself is anything but creative work as such. You tend to lose all hope if the beginning is where you seem to be stuck till the very end. And yet, you have to endure.

In a nutshell then, if you don't enjoy the doing much more than the fruits, which would be rare if they exist in the first place, research is not for you. If you think that you want to do research to build a better washing machine or mouse trap, or to mix more nutritious cereal, or to find quick fixes for practical problems plaguing humanity, think again, at least if you are thinking about academic research. That might never happen possibly till you are halfway through your career, and possibly till your grandson is halfway through his. Moreover, since science has become a highly collaborative effort these days, it is very rarely that one gets to sample a Eureka Moment, when he can revel in the ecstasy of an idea that is his and his alone. Enjoy the labours more than the fruit then, and don't expect practical results unfolding daily before your eyes. Throw in an infinite reservoir of patience and tolerance, and you could be well on your way to becoming a scientist. Otherwise, GE, IBM (Google?) and Lucent Technologies always beckon you, but most of what the public perceives of these companies is definitely not the kind of research I am talking about here. So that's a different ball game you want to be involved in then.

On a side note, there was a time when high quality academic style research was being pursued in these corporations. Note the bonanza of physics Nobel prizes gathered by IBM in the 80s for example. But predictably, as companies became more enamoured with stock holders than with the fruits of pure research, so have the standards of pure research in these companies declined over the years, and in fact that's a rift in American science that is being vigorously discussed today.

One key fact that today's politicians and administrators should keep on reminding themselves about, is that it is a hard and proven fact that most research that is hazy and improbable in its time usually turns out to have practical consequences, and sometimes enormous ones, in the future. The atomic bomb, microwave devices, semiconductors, medicines, MRI, lasers, and genetic engineering are but a few examples of the kind of research that started off as mere curiosity in the ways of the natural world, and led to multibillion dollar practical technologies.

2. It's hard to know what's important: James Bryant Conant holds the distinction of being one of America's top notch organic chemists, president of Harvard, and one of the leaders of the Manhattan Project...all this being possible in the 1930s of course. When his student Frank Westheimer, again a Nobel calibre chemist, went to him with an idea for a research project he had, he was told that if he was successful in the project, he would be a "footnote to a footnote" in the history of science. While Westheimer did turn out to be much more than a footnote in his career, the message here is clear and has been enumerated by a number of successful researchers- 'Work on important stuff'.
While it's easy to inculcate this Olympian ideal in your mind, it's only when you start doing research that you realise with a lot of consternation and ask the question- 'What's the important stuff??'. Usually, your advisor would have an idea about what's important. But more often than not, you may also land up with some speculative project that, IF successful, MAY turn out to be quite important. But science and progress being what they are, it's naive to expect that all these ifs and mays would materialize and especially till the end of your PhD. The compensation for this uncertainty, as I can testify to a minor extent, is the joy of discovery, no matter how trivial, and the excitement about the future that is compunded with the uncertainty. Also is the compensatory feeling that what you are doing is a part, no matter how small, of a grand enterprise that will bear frution someday. Moreover, echoing good old Tom's words, if you survive the tears and the frustration, maybe you too can beam with triumph someday and say "I have not failed...I have found ten thousand ways that do not work". But try telling that to your PhD. committee.

In my own experience then, most of the work I have done until now has involved mainly groping in the dark, massive amounts of clerical work that never end, and frustration heaped on top of more frustration. Why then, do we do this? Ask why people climb mountains, collect insects in the Brazilian rainforest, compose poetry, wait for eternity to meet their loved ones, arduously spend a Sunday in baking that exotic dish, and prove three hundred year old equations with no practical significance whatsoever, and we see the answer. It's the joy of the discovery that counts. But like other contrasting qualities, it's value is felt only when you go through its other wicked half- pain. And once in a while, yes, we do end up discovering a new kind of microwave oven too...

Science in a straitjacket

It's simple. If countries want scientific collaboration with other countries, they have to learn to empathize with the whole global enterprise of science and scientists, and understand its nature. If they really do, then they would understand that asking questions like the ones they asked to Prof. Goverdhan Mehta of IISc. before rejecting his visa application for attending a scientific conference in Florida, are not consequential, even if they are necessary as a formality. Asking a chemist "Can your work be used for making chemical weapons?", is like asking Isaac Newton, "Can your calculus be used for making missiles?". Although the answer to both questions is a resounding yes in principle, both the question and the answer don't make sense at all, because then that means that every scientist (or engineer for that matter) should in theory be considered a security risk. Dr. Mehta, an internationally recognised organic chemist and former director of the Indian Institute of Science, has said that he felt humiliated by the questioning at the US consulate, which seemed to hint that he was actually hiding information from them. On the other hand, this is not a new incident, and has happened scores of times before with lesser known scientists.

Almost any competent scientist, given enough time and resources, can harness his expertise for making weapons of mass destruction in one way or the other. Another trivial point is that you don't need to be a scientist in order to "work on WMDs". Even the most mundane technician at Los Alamos, for example, could be said to have "worked on the atomic bomb". So that's another inconsequential point. And the general point was already driven home more than enough during the Manhattan project, when the most "pure" of scientists built the atomic bomb. Science can of course, always be used for good and bad. But governments have to understand that by stifling the flow of scientific information because of the tenuous possibility that it may be used for dangerous purposes, they are stifling the much larger amount of good that can arise from the flow of that information. Of course, there do have been cases like the infamous A Q Khan case, where high profile top scientists have engaged in unethical and terrorist like acts. But one sparrow cannot make a bird, especially when the scientist in question has an unusually clean track record of being not just the leading organic chemist in his country, but also one who has done more than many others to further the national and international cause of science in peace. It's not surprising that many Indian scientists think that we should just stop all scientific collaboration with the US. In this age when national priorities have become particularly complicated, governments should put in extra efforts to separate the wheat of honest efforts and collaborations from the chaff of underhanded aims and insidious objectives, without colouring these issues with their own prejudices in the first place. Should we stop collaborating with all scientists because in theory, they can put their expertise to malicious use? There is a big difference between perceived and real threats, and now more than ever, we really need to weed out the differences between them.

Also, I do think that just like in other matters, there is bias based on nationality involved here too. A couple of years ago, there was a story about a well-known US chemist, who had wanted to demonstrate how easy it is for terrorists to order the chemicals necessary for making chemical weapons. To this end, he ordered a dozen or so of the basic chemical ingredients of nerve gases from Aldrich, the leading producer of laboratory chemicals in the world. Within a few weeks, he photographed himself sitting in his office, surrounded by canisters containing chemicals that would make enough nerve gas to wipe out a big city. While he obviously did this to make a point and in good faith, I did not hear about him being rejected a passport by the US State Department, or a visa by any other country. If an Indian scientist had done this, would he ever have received a US visa in his life?

Science has the potential to do many things, and politicians would do well not to interfere in the normal spread of pure knowledge that is necessary for progress in science. Governments are looking for completely risk free scenarios, and within that narrow and naive definition, no scientist is 'risk free'. But by imposing their own convenient norms and ignoring the big picture where pure and general scientific knowledge brings about much good, they are actually putting society at much greater risk in the future. Especially the current administration, with its false tunnel vision of pseudo pious motives (like their ludicrous and objectionable handling of the morning after pill related 'Plan B'), should take note. It's them who have to lose the most. And if you really want to shoot yourself in the foot, at least don't stand on someone else's feet.

P.S: Thanks for the previous good wishes by the way. The report went OK, and I stay alive for at least another year.