It is easy to recognize the usual problems with being a scientist during the early 21st century: low pay, lack of job security and no clear path towards career advancement.  In comparison, being a medical doctor is simple and lucrative, with well-worn paths marked by certification exams and gradual pay rise.  The scientist-in-training must establish a new methodology or  open new ground - one that is rich in possibilities for medical application.  This is no longer about intelligence but, rather, a combination of luck, perseverance, and political acuity.  Luck is needed to land the right project.  No matter how skillful one is, having a project based on false assumptions that leads no where would generally result in failure.  And there is so much failure in science.  However, it is almost impossible to judge a project from the outset, so one also needs perseverance and not quit too early.  Finally, political acuity is required to take control of the project from competing hands, as well as to acquire new projects as they arise.  This many-bodied problem is impossible to solve and just like the early spanish explorers, the scientist-in-training must boldly tread with their own feet into the new world, hunting for gold on the grassy wastes and sulfurous swamps.  However, once the gold is found, more troubles arise.  The supervisor who trains the scientist suddenly becomes a competitor: he covets the new findings for himself and does not want the scientist to take it away from his laboratory.  Other scientists from around the world also rush around the finding, a violent conflict arises as they compete with each other to secure the next step.  What the scientist-in-training thought was his own discovery quickly becomes taken by everyone else and he is quickly forgotten.  And in time, he can no longer leverage his achievements to become an independent researcher with his own lab, which is the ultimate goal.  From this, it is apparent that scientific progress is the mass movement of all scientists competing with each other fueled by egotistic ambitions.  Unfortunately, these ambitions are seldom rewarded and the individuals, even the grand prize-winners, are quickly forgotten.

What then, are the rewards for being a scientist?  Earlier this year, I solved the first crystal structure of a viral protein with a novel fold.  As I stared at the untamed electron landscape, I was overcome first by the beauty of the structure and second by a deep dissatisfaction with what is there.  There was no meaning to the architecture - especially since it had been amputated from the biological assembly of the virus.  I wanted more, more, more.

I believe one of the earliest "structural scientists" was Leonardo Da Vinci. Many people today consider him to be the model "Renaissance man",  who perfected his pictorial arts while at the same time dabbled in mechanical inventions, cartography, human anatomy and siege weaponry.  It may therefore be surprising to learn that when he was young, Da Vinci showed no natural aptitude for math or languages (especially Latin during a time when Latin was essential) - and he ended up working in a painter workshop more out of necessity. It was only much later in Milan after his apprenticeship that he began to dabble in science in a non-mathematical manner.  How can one be "scientific" without mathematics?  Da Vinci believed that to understand a thing, one must see it completely without bias.  Therefore, his scientific investigations sought to describe a phenomenon without quantitative theories but instead with meticulous visual reproductions. For example, to understand water eddies, he attempted to draw every visible shifting of water as they are formed:

"What causes the eddies of water" -  Notebooks of Leonardo Da Vinci

Through this painstaking work, the complex whirlpool and foam patterns are deconstructed to individual water paths, from which a general theory may arise. This purely descriptive endeavor is at the heart of structural science.  

Some centuries later Werner Heisenberg had this to say:

"The experiments of physics and their results can be described in the language of daily life. Thus if the physicist did not demand a theory to explain his results and would be content, say, with a description of the lines appearing on photographic plates, everything would be simple and there would be no need of an epistemological discussion. Difficulties arise only in the attempt to classify and synthesize the results, to establish the relation of cause and effect between them - in short, to construct a theory." 

 - from The Physical Principles of Quantum Theory - Werner Heisenberg

However, is it really possible to construct the experimental apparatuses to generate, record and then to recognize "lines appearing on photographic plates" without having some pre-formed theory?  Did Da Vinci really draw his eddies without any notion of what he was drawing?  Or perhaps at some point during his work, a theory arose in his mind, so that as he completed his lines of water, he completed them with an intact theory?  Unfortunately, I can no longer test this on myself through structural biology: my mind quickly interprets the computer generated blobs of electron density as idealized ribbons, screws and strands - with shapes corresponding to this or that amino acid residue - fitting everything into the standard theory.  Even at the beginning, before my first encounter with electron density, I had been heavily schooled in biochemical structures so that my mind was already prepared for what I was to see.  Recently, I showed some of these blobs from my published work to my aunt who had never been brainwashed by a scientific education:

mFo-DFc electron density map of a hairpin turn from a viral protein

However, to my great surprise and consternation, she responded with enormous disgust and fear - screaming that I was a very bad nephew for scaring her with this worm-like insect and that now she will have nightmares from seeing it...

I first began to consider structural biology seriously during the summer before my final academic year in college. The fatal moment occurred when I was reading a description of enzymes used in detergents: there was a brief passage about how a group of biochemists modified the enzymes based on their structures to greatly improve their activity in the harsh conditions of a washing machine.  To my impressionable undergraduate brain, this was an epiphany: a sudden realization that scientists can have complete engineering control over these nanometer sized organic devices as long as their structures are known. Fantasies of designing Maxwell's Demon-like protein complexes to perform alchemic impossibilities flooded my fevered imagination.  The entire enterprise opened before me like certain medieval triptychs filled with spiritual grandeur, precious craftsmanship bound in an artificed world complete unto itself with its own symbolic language, bizarre logic and rules of beauty.   Prior to this, I had only the briefest and most indirect experiences with the subject: a few smeary ribbon diagrams from biochemistry texts that I skipped over and a large bronze ball-and-stick representation of polymerase in front of the department that reminded me of an ugly sponge. There was also that passage in A Clockwork Orange which had given me an awful impression of crystallography as something hugely esoteric, weak, unmanly, useless and perhaps a sorry metaphor for being conventional:

"There was a doddery starry schoolmaster type veck, glasses on and his rot open to the cold nochy air. He had books under his arm and a crappy umbrella and was coming round the corner from the Public Biblio, which not many lewdies used these days. You never really saw many of the older bourgeois type out after nightfall those days...And then Pete skvatted these three books from him and handed them round real skorry...The one I had was called 'Elementary Crystallography', so I opened it up and said: "Excellent, really first-class," keeping turning the pages. Then I said in a very shocked type goloss: "But what is this here? What is this filthy slovo? I blush to look at this word. You disappoint me, brother, you do really... 'The Rhombohedral System'. The starry prof type began to creech..."

However, in a few moments of dreaming and fantasy, I came to see that roughed up "starry schoolmaster" as a hero of our times.

Another event that pushed me towards structural biology was a poster presentation I had to give about my undergraduate research to a panel of professors from the department.  One of them was a much celebrated biochemist whose husband and partner in science won the Nobel prize a few years later.  I mention her because while the other professors gave my work much deserved perfunctory glances, she latched onto my poster and questioned me relentlessly about something that felt very trivial: she wanted to know how I knew the protein on the cell I was studying was really that protein.  Iteratively, she dismissed the usual explanations from monoclonal antibody binding to molecular weight determination.  Feeling lost, I ended up concluding that short of a structure, I really would never know for certain since the protein's identity is wrapped up in its three dimensional conformation.  Her reply was a simple: "Yes".

When all this happened, I was living in the cramped attic of a dilapidated clapboard house near the university.  It was about a fifteen minute walk to the laboratory where I spent most of my time performing cell motility assays and doomed protein interaction fishing experiments. Work was a quiet affair as the laboratory was mostly empty.  The PI was rarely there and the only person who I saw daily was my immediate supervisor, a post-doc from South America. Money was a huge issue as the PI was not able to secure any funding.  It was only a matter of time (a year) before the lab was finally shut down after a long and somewhat illustrious history going back to the 70s. In retrospect, finishing my undergraduate training in a lab that dies just weeks after graduation ceremony seems like a bad omen. Instead of a happy, secure pathway, a largely uncertain and stormy ocean confronted me. However, I was very idealistic about research and instead of pursuing a much more practical profession (physician), I decided to enter graduate school to become a "scientist".  My parents, especially my father, were dismayed. To them, this was comparable to me running away to join the circus.  Indeed, from then on, they have always given me this sadly amused look as if I were the most lugubrious clown; more sad than amused because it is their own son who is doomed to walk this pathless direction.