LEARNING TO LAY BRICKS...

Remember that subject (maybe Maths?) that you absolutely hated at first, and later, you not only accepted it as an interesting subject but also started liking it and truly appreciating it. Such has been the case with me and the field of Nuclear Magnetic Resonance spectroscopy (or NMR, as it is known to anyone even remotely associated with it)

I am not calling NMR a 'technique' which it definitely was earlier, but a field. That's because in the last 25 years, the 'technique' saw such rapid and profound developments, that it became the object of a lifetime of study. Four Nobel Prizes have been awarded to people associated with it, including one awarded to the progenitors of MRI, which is basically NMR; two more prizes manifestly seem to be in the pipeline. Today, there is not a single major academic or industrial laboratory in the world, which does not rely critically on NMR. And this is not limited to laboratories carrying on chemical research (the term itself not being limited anymore to things chemical) but also those engaged in solid state physics, materials science and engineering, biochemistry and biology, and last but not the least, medical research laboratories. The seed that was planted by physicists fifty years ago, has grown into an orchard, and if NMR were to suddenly disappear around the world, the growth of all the above sciences and more would quite certainly be severely thwarted.

At its heart, NMR is 'simply' a technique for determining the structures of molecules, any molecules. Molecules used as drugs or polymers. Molecules used to study biological function. Molecules that have become a menace to the environment. Molecules that would be part of the computer circuits of tomorrow. Molecules that would likely make up the 'biosuits' that would protect us from the destroyed ozone layer of the future...

The history of NMR begins with two physicists, Swiss emigre Felix Bloch, and American Edward Purcell. Both had worked on radar and the atomic bomb during WW2. Both were experts in probing the magnetic properties of matter. One of the reasons NMR is not 'intuitively' appreciated, like lasers for example, is because it has to do with magnetism. For some reason, I always believe that college students don't naturally recognise magnetism to be as fundamental a property of matter as its electrical or optical properties. The only thing which we usually think of when we hear the word 'magnet' is...a magnet. Or Iron at most. The fact is however, that at the atomic level, magnetism is as central to atoms and molecules as Coulombic attraction, or the photons that are exchanged during electronic transitions. Most importantly for NMR, and for us, is the fact that the most abundant molecule in the universe, hydrogen, has important magnetic properties, that are radically affected by the environment in which it is in. And in terms of weight, even more than carbon, it is hydrogen that makes life possible. The atom most commonly (but certainly not exclusively) observed in NMR is hydrogen. By noting certain key properties of hydrogen, chemists can make clever and correct guesses about the intricate structure of molecules.

Even though I am proud to be originally an organic chemist, maybe for foraying into NMR, it would have been better if I had been a physical chemist, or a physicist, or an electronics engineer, or even a mathematician. This sheer variety of professions points to the varied facets that NMR has. Unfortunately, or fortunately, for the organic chemist, NMR is, for the last fifty years, primarily a method for determining unknown structures. Organic chemistry has been the largest playing field for both the methods development and applications. However, for most organic chemists, NMR could well have been a toy mickey mouse, in one ear of which you insert your compound, and from the other ear of which you get the series of lines and peaks called a NMR spectrum, that challenges you to find what you just put in. For most, NMR is a black box in the true sense of the term.

And that's how it was for me. All through my BSc. and MSc. I took courses in NMR spectroscopy that were devoted to the singular objective of finding out unknown structures from NMR spectra. Two things severly stultified my growth in the field during that time; teachers with a remarkable knack for transforming anything interesting into everything boring, and the sheer patience that's necessary to analyse the spectra for finding the structure. Analysing NMR spectra is like analysing code from the Cold War; unless things are deceptively simple, one has to spend a lot of time, tenaciously finding connections and reviewing information from past analyses and chemical studies, to pursue the wily chemical structure. Some people, like my friend from Mexico, are geniuses at this. Will Hunting (Matt Damon) from the movie 'Good Will Hunting' was also a genius at it. He analysed an NMR spectrum of a complex molecule that was a homework assignment for his girlfriend, so that they could go to watch dog races. I was never interested in races, dogs' or otherwise, and lacked the magical presence of a girl to initiate me into deconvoluting black peaks on white ruled paper (On second thoughts, if the two of us had had NMR homework assignments, I would probably have asked her to do mine). This, combined with the paucity of a teacher who would bring me back on track, made me lose almost all interest in NMR.

Luckily, that was where it did not end. The lack of motivation for studying NMR, and the absence of dog races and girls, continued well into my first year of PhD. The mandatory NMR spectroscopy course I had to joust with yet again, gave me recurring nightmares. My Mexican friend's achieving a perfect score on almost every exam in the course really did not help, in spite of his encouragement that I was really good with many other things (how I manage to deceive...). However, again, this course was the typical organic chemists' structure determination NMR course.
When it became time for me to choose a lab and a mentor, my advisor called me into his office for that dreaded 'initiation' chat, which initiated new students into the dark dredges of graduate research work. To my pleasant surprise, everything has turned out to be (mostly) the opposite of dark and dredging. My would-be advisor said he had an interesting proposal for me. They had developed a new and very interesting technique, and a radical one, that had to do not with finding the structure of unknown molecules, but for studying the molecular choreography of compounds in solution.

In a heartbeat, a molecule performs more twisting and acrobatics in solution than a ballerina would experience in her lifetime. Like the darting silverfish, molecules hold hands, turn their heads in heady fashion, exchange hands for feet, and suddenly turn inside out, all in nanoseconds or less. They put up this private performance unbeknownst to almost every organic chemist who does NMR daily. In fact even inside our bodies, at every moment, thousands of molecules are putting up this show with abandon, dictated by the confines in which they find themselves in, as well as by the elated kicks of energy that body temperature provides them with.
This performace would not only be a pleasure to witness, but it's also crucial in a practical way. Out of those millions of figurines, one snaphot in particular, corresponds to the orientation in which that molecule would like to bind to a giant molecule in the body. Make that molecule a crucial protein involved in either disease or well-being (and there are thousands), and there; you have yourself a drug. Once we are able to take a photograph of the molecules caught in that act, we can do a host of things. This includes changing the structure of the molecule so that it gets locked in that position, like a yoga expert magnificently frozen in 'Mayurasan'. Then we can force it to bind to that protein in that exclusive position. The protein itself stays stuck in its position, and sets in motion a cascade of events that prevents a disease, or gives one to bacteria.

Practically, however, getting a peek into the private motions of molecules is easier said than done. The valuable orientation of that molecule may exist for less than a microsecond in solution, and may comprise less than 1% of the total population of ballet movements that the molecule undergoes. Capturing the molecule in that elusive act would be more difficult than finding a needle in a haystack- it would be like finding a needle in a haystack of needles.
Now, my advisor told me, there was a method, newly developed, a joint application of the raw power of Gigahertz computer processing and the intricacies of NMR, that would target and weed out this elusive and exotic configuration of a molecule from solution. The basic principle of the method, surprisingly neglected by many researchers, was so simple that I could explain it to a friend over a sizzler on a cold evening. Our lab had already successfully applied it to many valuable cases, including some important anti-cancer molecules. However, every time, they had got the NMR data from another lab, sometimes one in another continent. There was nobody who could do both the NMR analysis and the computational work and make himself a comprehensive chronicler of molecular acrobatics. Not only would such knowledge be valuable in itself, but it would also make for a good and possibly unique (and quick?) PhD. The twin prospects of exclusive knowledge and harrowing past nemeses made me ambivalent. I squirmed in my seat. But this is graduate school, and you cannot really toss out options with the bravura of a wine connoiseur. There it was. Take it or leave it. I thought it would be worth a try, especially given the worthy fruits it would bequeath.

And try I have had to, possibly more frustratingly than at any other time in my life. But until now, the fruits have been worth it. Through exasperated boredom, calculated cajoling, constant struggling, and pristine glamour, NMR has, I believe, made a permanent place in my mind and heart. The trick was to observe and try to take in pieces of the vast landscape that NMR comprises, variegated in every dimension and aspect like our Indian subcontinent. At one end are the abstract equations of quantum mechanics that dictate the ground rules of NMR and their manipulation, in between is the physics and the pulse sequences that choreograph the movements of complex magnetic fields that can be manipulated the way a conductor manipulates musical notes (the right duration and number of pauses are both critical to the beauty of both Mozart and NMR), and the electronics that encompasses every advanced electronics concept that one could invoke. At the other end is the productive field of 'applications only' activities, as varied as everything else. Somewhere between these, I had to make a place for myself. It has been hard going, but for the first time, I can say that it has been worth it, and more importantly, I can see treasures of thought and understanding that await me further on, if only I would listen. In such a vast landscape, I have to learn how to be a dreamy eyed tourist. I don't need to be a crack mathematician, nor do I need to be oblivious of maths (fortunately, I think I am definitely more mathematically inclined than organic chemists in general, courtesy of former friends and a teacher who were crack mathematicians). I don't need to be an electronics engineer, but it would do me good if I know enough about Fourier transforms and 'matching filters' to make the journey smooth (The Fourier transform is, incidentally, absolutely essential for the working of modern NMR). My eyes need not be glazed over in understanding programming code, but my knowledge of UNIX is a steady tool. I need not say that I need to be a good chemist, but I am not too worried about that!

In the end, it has been an attempt to try to understand a vast body of knowledge that can easily occupy a lifetime. Modern NMR is in its entirety, a true and comprehensive combination of mathematics, physics, engineering and electronics, and of course chemistry. Biology has been the greatest field of dreams for those who wish to apply NMR (Nobel Prize, 2002). My job is to pick out pieces of the philosophy, break chunks of concepts from these various fields, and crucially, understand the logic inherent in them. Most importantly, the moments of greatest joy are those in which connections are seen, in which analogies are observed.
Edward Teller said that in science, there are brick layers and brick makers. He was talking about the greats like Bethe and Oppenheimer. But I believe the same principle applies to bottom feeders like me. NMR, I believe, is more a matter of brick laying for most of its practitioners. The object is to build a house, and maybe even make it into a home. One should combine creativity in choosing the right bricks with an eye for the intricate pattterns that they make, and choose those patterns that matter; in this instance, it means I have to choose, among many concepts from different fields and many parameters in experiments, the ones which will make it count and shine. At the heart of being a bricklayer is seeing the logic that every piece imparts to the superstructure. It's all about purpose, Mr. Anderson. Understand the reason, and you understand the value. Mundane concepts flower into ideas on the brink of realisation, ready to join with other similar companions. The superconducting magnet of the spectrometer beckons to anyone who wishes to gaze at its coils and explore its effects on inanimate matter. I don't have a lifetime to do NMR, but I do have some time to peruse its wonders and enrich my scientific thinking with its fine points to build an enduring body of knowledge.
In the business of bricklaying, I am still the floor scrubber. But only if you see the top from the bottom up can you wonder and aspire to imagine how the view would be from the top.
More mundanely, it has been a great satisfaction to turn a subject which I hated, into one which I actually enjoy, and which will hopefully become part of my intellectual armamentarium.

Today, I still am not interested in dog races. But I love NMR. And I suspect there is a girl someplace...