In conversation Brian Kobilka is shy, self-effacing, modest and mild-mannered. In his work he is a tour de force of science who has chipped away at an unyielding problem for more than twenty years until it gave way and got him the Nobel Prize.
Kobilka and his fellow prizewinner Robert Lefkowitz were honored for their work on G-Protein Coupled Receptors, Kobilka more specifically for determining the crystal structures of several crucial forms of the proteins using x-ray crystallography. I have previously compared crystallography of proteins to mountain climbing. GPCRs represent some of the most lucrative peaks in the landscape of medical research, promising both unprecedented insights into the mechanisms which living organisms use to communicate with their environment as well as critical data for designing new drugs against a variety of disorders. In performing their tasks GPCRs constitute a singular part of the exquisite signaling networks that allow our bodies to react, think, seek and explore.
Kobilka is happiest when talking about his science. Unlike many other laureates at the meeting, his status as the world’s newest Nobel Prize winner means that he is still adjusting to the adulation and the publicity, a particularly challenging endeavor for a man who would rather spend his time at the bench looking at crystals. He finds it amusing to have a car waiting for him whenever he steps out of the building at Lindau; as he put it, they – including his wife at home – treat him very well at Stanford, but there he is one among at least a handful of Nobel Laureates, and he has to bike to and from work. His amiable personality makes it harder for him to deal with the deluge of emails that has flooded his inbox since last October. While the generic ones simply asking him for a spot in his lab can be dismissed without further thought, he makes it a point to try to answer the more detailed ones whose writers seem to be genuinely looking for an interesting project.
Just like in mountain climbing both perseverance and luck play a crucial role in attaining your goals when it comes to protein crystallization. In case of Kobilka the perseverance was there since the beginning, from the time that he started as a postdoc in his fellow Nobel Laureate Robert Lefkowitz’s lab at Duke. It took a little more time to get lucky. Crystallizing proteins and especially membrane proteins is as much of an art as a science, and much depends on employing countless rounds of trial and error to find the right combination of conditions that would coax crystals to assemble in an orderly periodic lattice. Kobilka’s early years were spent trying to find antibodies that would stabilize the especially jittery parts of the the beta-adrenergic receptor, a workhorse of GPCR structure and function that is both the target of numerous important drugs for hypertension and a “model organism” for other GPCRs. Indeed, it is largely Kobilka’s work that has turned the beta-adrenergic receptor into a microcosm of all that is good and interesting about GPCRs. In zeroing in on a specific example whose details provide insights into the general problem, Kobilka is following in the footsteps of distinguished scientists like Max Perutz (hemoglobin), Hartmut Michel (photosynthetic reaction center) and Roderick McKinnon (potassium ion channel) who have also used a single instance of a protein to shed light on more general features of a family.
After years of trying antibodies from several different organisms to try and stabilize his chosen protein, it was a chance encounter with a fellow researcher at a Gordon Research Conference that gave Kobilka the idea of using llama antibodies to lock on to the receptor and rigidify it. Kobilka got lucky, but his mind was primed to recognize the lucky moment through years of patient and dogged pursuit. Other strategies included using lipidic phases to simulate the nurturing environment of the membrane proteins and finding very high-affinity drug molecules to both stimulate antibody production in llamas and further constraint the unruly parts of the protein.
Convincing funding and grant committees that this kind of work is valuable can be a challenge, especially in the context of crystallizing a protein which can sound too much like a fishing expedition, and Kobilka’s thoughts on NIH funding were some of the most valuable in the conversation. Even working on potentially Nobel Prize winning projects does not ensure seamless funding in the world of biased human beings, and at one point the Howard Hughes Institute stopped supporting Kobilka’s projects. The trick, it seems, is to get your funding proposal to the right study section. Like many other funding bodies the NIH has study sections composed of various experts. In Kobilka’s case it was actually getting his proposal to the wrong study section, so to speak, that ensured funding, and there’s a valuable lesson in his story.
Instead of the proposal going to crystallographers who would ideally have been most qualified to judge the benefits of crystallizing GPCRs, the proposal went to biologists interested in signaling pathways. Here you see the pitfalls of having too much expertise in a field. If the proposal had gone to the crystallographers, being experts they would have probably foreseen all the great difficulties inherent in crystallizing membrane proteins and rejected the idea. Biologists, however, tend to take a broader view of things and they probably realized the far-reaching implications for signaling networks that a successful structure of a GPCR would have. Not being experts in the field they did not feel intimidated by the crystallization challenges, and the proposal was funded. Kobilka’s story says something crucial about the merits of not relying on experts who know all the mistakes that can be made in the field and in fact about stepping out of your experts’ shoes yourself. Sometimes a little bit of naiveté and gung-ho attitude is the right way ahead.
The rest is history. In a series of pioneering publications Kobilka’s group revealed increasingly stunning details about beta-adrenergic receptor structure and function. Starting with a structure of the protein alone, they proceeded to solve structures bound to different agonists and antagonists. Their magnificent efforts culminated in 2010 in the structure of the receptor bound to its G-protein, the first structure that provided a link between the outside and inside world on a molecular level and sealed Kobilka’s fate as a Nobel Laureate.
Being a scientist’s scientist Kobilka’s research continues unabated and his work, lab and family still get the highest priority. He continues to drill down deep into the innards of the beta-adrenergic receptor but has also expanded his studies to other GPCRs. At the meeting he unveiled a particularly important structure of a GPCR bound to an allosteric ligand, a molecule that binds to a site other than the regular binding site and controls GPCR activity through more subtle and interesting ways. There is little doubt that Kobilka’s work has opened up new horizons in the structure and function of these crucial molecular messengers.
After all that GPCR crystallization one undoubtedly deserves a break. Kobilka’s lanky figure is a testament to the fact that he reenergizes by bicycling, swimming and running, activities that are made pleasing and regular by Stanford’s all-round sunny weather. Kobilka’s own beta-adrenergic receptors probably work overtime during these intense bouts of exercise, and it must surely be a satisfying thought to him that he now understands them better than almost anyone else on the planet.
Akshat Rathi also has an account of our interview with Kobilka.