Puzzling it out

Scientific research is undergoing significant restructuring. New fields are emerging, once-separate fields are merging, and many of us are trying to figure out how to combine tools and thinking from different areas of science. Nearly a year into my second post-doc, I search for the best metaphor to describe my ongoing metamorphosis from chemist to chemical biologist.In graduate school, I learned and practiced the art of organic synthesis. Four years of my life were dedicated to the construction of a single molecule. In search of a more tangible connection to the world of biology, I spent my first post-doc thinking about drug design and building libraries of small organic molecules. Now, I am in a molecular biology and yeast genetics lab, thinking about peptide libraries and genetic selections.And this brings me to my metaphor. Coming into the world of biology from chemistry was a bit like starting a 1000-piece jigsaw puzzle without knowing what picture the pieces were going to create. For the first few months, each new protocol was like one of those knobby puzzle pieces — I could find nothing to connect them together in my mind and was getting truly desperate to find a few simple straight-edged pieces. My mounting frustration did not help. Only months before, I’d been an ‘expert’ in synthesizing molecules. Graduate students and post-docs came to me for advice. But in this brave new environment, where hallway chit-chat is not of palladium-mediated couplings but of gene deletions and transformation efficiency, my molecular expertise did not seem like much of a resource. I grew used to having to ask questions: ‘Is this cut or uncut DNA?’; ‘When do yeast reach stationary phase?’; ‘What's a revertant?’In my struggle to understand how biologists think about biology, I attended seminars and asked other scientists about their work, but it was always the same dilemma. I’d grasp a few familiar words and phrases from the foreign language of genetic acronyms and previously unencountered molecular biology protocols, but I’d have no framework into which to fit them. Finally, those disorienting first months were behind me and, like getting a few edge pieces of my puzzle hooked up, I began to see differences between the way chemists and biologists think and approach problems.Chemists, who are really just molecular architects, build things, be it natural products like taxol or new superconducting materials. And just like constructing a house, the process of molecule building must be linear and tool-oriented. Solving problems linearly is both a positive and negative consequence of chemical training. Although perfectly suited to the needs of the pharmaceutical industry, a goal-oriented approach can be more of a hindrance than a help in academic biology, where the first question is usually not, ‘how will I do it?’ but ‘how does this work?’Given that the biologist's ultimate quest is no less than to understand how life works, it makes sense that my biologist friends seem much less constrained by the unknown than I and my chemistry buddies. In fact, my own apprehension of unwieldy biological systems fades with every new protocol I perform, and with an accumulating sense of how larger questions can be dissected into smaller more manageable ones that I, as a chemist, am more comfortable with.An important difference between biology and chemistry is that chemistry is the more mature science. Given enough time and pairs of hands, chemists can often outdo Nature, preparing gram quantities of rare natural products. The art and challenge of molecule building is mostly about precision and control. An isomer of the molecule in question just won’t do. Beyond natural product total synthesis, there is the even larger adventure of applying the power of synthetic chemistry to the building of tools that might answer questions in other areas of science. Such an adventure has two prerequisites: the other area of science must be sufficiently developed that it would benefit from molecular tools, and the chemist must either have a collaborator who understands chemistry or must have enough insight into that other area to know what questions are worth asking.Which explains why I have coffee these days with yeast geneticists and oncologists. Biology seems ripe for chemical tools precise enough to fill in the gaps left by the limitations of molecular biology and genetics. Biologists are already using very chemical approaches in their experimental design: the ultimate proof for understanding how a kinetochore works will be its reconstitution in a test-tube, a chemically-based experiment very much like those being done by my chemistry friends to build self-replicating systems from scratch.My puzzle is far from complete, but the edges are all connected. Now begins the larger challenge of filling in the middle.