Top of His Game

Top of His Game

Brian Kobilka’s path to biochemical research might have been unconventional, but it led to a Nobel Prize.
By Mike De Socio

The phone rang in the home of Brian Kobilka, MD, at around 2:30 in the morning. He figured it was a wrong number and let it go to voicemail. But when the phone rang again, Kobilka climbed out of bed and picked it up. The voice on the other end told him he had just been awarded a Nobel Prize.

Stunned, Kobilka didn’t say much at first. He thought to himself, “Am I really awake?” Then a new voice came through the phone—someone Kobilka knew from Sweden—congratulating him and making sure he believed what was happening. 

“Then after that, you don’t go back to sleep again because the phone starts ringing and the news organizations come over,” Kobilka recalls. 

That fateful morning came in 2012, a year after Kobilka had published a paper on the structure of a G protein-coupled receptor (GPCR) activating a G protein—the culmination of some 30 years of research in the lab. The Nobel Committee recognized Kobilka’s work uncovering the mechanics of cell receptors and the hormones that constitute communication between cells. He shared the Nobel Prize in chemistry with Robert J. Lefkowitz, MD, the leader of a lab at Duke University, in Durham, North Carolina, where Kobilka got his start working on this research.

The pair of scientists traveled to Sweden that year to accept the Nobel with an entourage of family members and colleagues. Kobilka remembers spending the first few days of “Nobel Week” obsessing over his speech, adjusting it endlessly. But after he delivered the talk, he relaxed into the celebrations. 

One particularly memorable part of the week for Kobilka was the “Students’ Nobel Night Cap,” the official after-party to the Nobel Banquet. In a converted classroom building, the honorees spread out into themed rooms off-limits to press and photographers. There, Kobilka and his family and colleagues mingled with other academics and students, everyone enjoying a late night fueled by free food and an open bar.

The Nobel experience was the pinnacle of a career that Kobilka never expected. “I didn’t really plan for any of this to happen” he says. “I was very fortunate to find a good lab, where I could be trained, and to have people in the lab willing to take on an extremely inexperienced MD without really any graduate training.”

Physiologists will hear more of Kobilka’s story when he delivers the opening keynote during the 2024 American Physiology Summit, April 4–7, in Long Beach, California. 

A Winding Road

Kobilka’s path into biochemical research was certainly unconventional. Growing up in a small town in Minnesota, he settled on an early ambition to become a physician, a profession shared by three of his friends’ fathers and a close neighbor. It seemed like a respectable career, and Kobilka left high school on a trajectory for medical school. 

By the time he graduated medical school, Kobilka had had several brief experiences in the lab, doing small research projects. The first was during his undergraduate years at the University of Minnesota, Duluth, where a professor brought him in to help in a biology lab. (It’s here that Kobilka met Tong Sun Thian, who would become his wife). Then during medical school at Yale University in New Haven, Connecticut, Kobilka used his required thesis project to conduct original research on the genetic diversity of rotavirus.

“I didn’t really plan for any of this to happen. I was very fortunate to find a good lab, where I could be trained.”

“I found that I enjoyed working in the lab, trying to work out technical problems,” he says. He was also fascinated by how things work on a molecular level and the opportunity to be the first person to learn or see something.

After earning his medical degree, Kobilka completed training in internal medicine, where he was drawn to intensive care medicine. It inspired him to pursue a clinical fellowship in cardiology at Duke, in the Lefkowitz lab. It was there that he started working on GPCRs, which he knew were foundational to some of the drugs he saw being used in intensive care units.

But Kobilka spent a good amount of his time at Duke playing catch-up. “I was the least-experienced person in the lab with the fewest lab skills and techniques,” he says. “My skills weren’t valuable to anybody. But nevertheless, they taught me a lot and helped me to develop a toolbox [so I could] at least start a project on my own.”

In 1986, Kobilka and colleagues in the Lefkowitz lab succeeded in cloning the gene for the β2 adrenergic receptor (β2AR), a GPCR that is the target for many asthma medications. This sparked his interest in obtaining a high-resolution structure of a GPCR. “I didn’t know at the time how overly ambitious that was with the technology available,” he says. “It was kind of a ridiculous goal because I had very little expertise in biochemistry and none in crystallography or structural biology.”

Nonetheless, he chipped away at it and carried the work over when he founded his own lab at Stanford University in California in 1990. Building on his experience with these receptors, it was here that Kobilka dug into the research that would earn him the Nobel Prize. 

He would eventually reach that “ridiculous” goal, obtaining the structures of the β2AR in the inactive state and the G protein-coupled state. The discovery, published in a 2011 paper in Nature, is what Kobilka thinks pushed him over the mark for the Nobel Prize. 

Searching for New Treatments

Today, Kobilka and his lab are still focused on this same area of research, which has broad implications for drug development and human health. The Nobel Foundation estimates that “approximately half of all medications used today” target GPCRs, though Kobilka says it’s probably closer to a third. 

Either way, understanding how the receptors work is critical. Kobilka readily admits that his 2011 discovery was not the end of the road. “It turned out that that was a really important structure, but there was a lot it didn’t tell us,” he says. There were many different types of GPCRs, and he needed confirmation that what he learned was applicable to other receptors. In the decade that followed the prize, Kobilka’s lab has obtained more receptor structures and worked to characterize them in different states.

“We’ve also become interested in some drug discovery projects, particularly for the treatment of pain,” Kobilka says, with a focus on modulators that target the cannabinoid receptor and the opiate receptor. His lab is working closely with chemists to use structural information for the design of new therapies.

Kobilka’s work is important to the worlds of physiology and health care. “The vast majority of hormones and neurotransmitters work by activating G protein-coupled receptors,” he says. “And most of the communication within the body—either from neurons to other neurons, or neurons to muscle, smooth muscle, or hormones to distant cells in the body—they rely on G protein-coupled receptors for that signal.”

Indeed, Kobilka has contributed some of the most foundational research in the understanding of hormone receptors and their potential for use in treatment. During his Summit keynote, Kobilka plans to talk more about the drug discovery process and how these receptors can be challenging targets.

“It’s not easy, even though we have so many of them and a third of drugs target them; they’re still really difficult targets,” Kobilka says. He will share examples of why these targets can be challenging and talk about approaches for surmounting those obstacles. 

For all of his expertise, Kobilka is quick to point out that he did not make any of his discoveries alone. A glance at the authorship for the 2011 paper reveals a large team of researchers—not to mention the many collaborators and mentors he’s had throughout his career and the support of his wife and family. “I’m really happy to have a Nobel Prize. But it certainly wasn’t all of my doing."

This article was originally published in the January 2024 issue of The Physiologist Magazine. Copyright © 2024 by the American Physiological Society.