Stanford scientist Brian Kobilka wins Nobel Prize in chemistry
Kobilka received the award for his work on G-protein-coupled receptors, or GPCRs, which serve as one of the main methods of communication within the body, conveying chemical messages into the cell’s interior from outside through the membrane.
Brian Kobilka, MD, professor and chair of molecular and cellular physiology at the Stanford University School of Medicine, has won the 2012 Nobel Prize in chemistry for his work on G-protein-coupled receptors, or GPCRs.
The receptors, which snake in and out of the cell membrane, serve as one of the main methods of communication within the body — conveying chemical messages into the cell’s interior from outside through the membrane. Over the course of the last three decades, Kobilka and his colleague Robert Lefkowitz, MD, with whom Kobilka shares the prize, have played an important role in discovering and understanding GPCRs. Last year, Kobilka was the first to crystallize and analyze one of the receptors bound to its signaling molecule, which is a critical step toward understanding how to control them.
Roughly 800 different GPCRs have been identified to date, making them one of the largest families of human proteins. These proteins regulate the beating of our hearts, the workings of our brains and nearly every other physiological process. About 40 percent of all medications target these receptors, including Zyprexa, which is used to treat schizophrenia; the antihistamine Clarinex; and Zantac, which is used for stomach ulcers and gastro-esophageal reflux disease. GPCRs are also involved in some kinds of drug addictions, such as addiction to morphine and other opiates.
Ironically, one of these receptors – a starting point for Kobilka’s work – recognizes and responds to epinephrine, or adrenaline.
Kobilka, a quiet man known for his shyness and modesty, received a powerful lesson in the effect of the hormone when he received the call from the Nobel committee early this morning.
“I didn’t believe it at first, but after I spoke with about five people – they handed the phone around – with really convincing Swedish accents, I started to think it was for real,” said the jeans-clad Kobilka, who poured his coffee with shaking hands after the 2:20 a.m. call. “We didn’t make it to the phone the first time, we thought it was a wrong number. I’m glad they tried again.”
Kobilka, 57, who also holds the Helene Irwin Fagan Chair in Cardiology at Stanford, shares the $1.2 million prize with Lefkowitz, 69, his former mentor and a professor of medicine and of biochemistry at Duke University. They will officially receive the award at a ceremony in Stockholm on Dec. 10.
“Many in the scientific community thought that [Kobilka’s] work might be an unattainable goal,” said Stanford President John Hennessy, at a news conference this morning celebrating the award for Kobilka’s and Lefkowtiz’s discovery of GPCRs. “But Brian managed to achieve it through hard work diligence and many years.
“I speak for the entire Stanford community regarding the pride we have in our medical school, of course in Brian’s achievement, and in our faculty on this day,” Hennessy said.
In the 1980s, Kobilka joined Lefkowitz’s lab and they began to work together to learn more about the epinephrine receptor, also known as the beta-adrenergic receptor. Kobilka was able to isolate the gene for the receptor (no small feat at the time) to learn more about its composition. When he studied the sequence, he realized that it was very similar to that of another, seemingly unrelated receptor called rhodopsin that detects light in the retina of the eye. This research helped the scientists realize that GPCRs are a large family, with many different examples throughout the body.
In 2011, Kobilka and his team were the first to obtain a three-dimensional image of the same G-protein-coupled receptor bound to its signaling molecule – an extremely difficult technical endeavor due to the protein’s size and complexity. Knowing the structure is important to be able to design better drugs to activate or inhibit the receptors.
“It was so exciting to see this three-dimensional structure and finally know how these trans-membrane regions interact during signaling,” said Kobilka. “I hope my discovery leads to better and less-expensive drugs for patients.”
Kobilka credits the many people he’s worked with through the years, including his wife (with whom he works), Tong Sun Kobilka, MD. “I’m particularly surprised to be honored, because so many people have contributed to things that I’ve done,” he said. “It’s been a collaborative effort with researchers from around the world. I consider that this award recognizes their work as well.”
At the news conference, medical school Dean Philip Pizzo, added: “This award speaks to several things: to endurance, brilliance, dedication and commitment. To assailing the odds because you really passionately believe in something. But I think it also speaks to a person. Everyone in this room who knows Brian shares great admiration for what a wonderfully kind, generous, humble, thoughtful and courageous person he is.”
Earlier in the day Pizzo remarked on Kobilka’s training as an MD, and how he “became dedicated to solving deep and important mysteries that impact the work of hearts and minds.”
“When others felt the problem he was attempting to solve was impossible to accomplish, he focused his energies and, over the past decades, he defined the three-dimensional structure of the adrenergic receptor, along with its function and physiological relevance,” Pizzo said.
Kobilka received his MD from Yale University in 1981. In 1984 he joined the Lefkowitz laboratory. Early in his career, Lefkowitz used radioactivity to understand the receptors’ function and their shape in the cell wall. Lefkowitz said at a news conference at Duke today that his life’s work had been dedicated to defining these receptors, beginning with a fellowship at the NIH in 1968. “When I started there was a lot of skepticism about whether such receptors even existed, and there was no way to study them,” he said. Lefkowitz’s research dispelled such doubts, and he credited Kobilka with advancing the understanding to a new level. “What Kobilka has done is to carry this to atomic resolution,” he said, explaining that it was now possible to see the protein “literally atom by atom.”
Kobilka came to Stanford in 1989 from Duke to join the then-nascent Department of Molecular and Cellular Physiology. “It was probably the only place that offered me a job,” said Kobilka, who recalls himself as a “good, but not exceptional” student. He has two grown children, Jason and Megan, neither of whom are in science. He and Tong Sun have been together since he was an undergraduate student. “She’s probably more excited than I am,” said Kobilka.
“I’m very proud of Brian,” said Tong Sun. “This is well-deserved.”
The early years of Kobilka’s lab and life at Stanford were marked by financial struggles. The couple had purchased a house, and Tong Sun enrolled in medical school. For a time, Kobilka supported his family by working on weekends as an emergency room physician to pay his mortgage and the medical school tuition. Kobilka was raised in the small, rural town of Little Falls, Minn. His father, Franklyn, ran a bakery that employed about 20 people and his mother, Betty, decorated the cakes.
“I learned a lot about running a lab from watching my father run a bakery,” said Kobilka.
“Owning a business, he had to do everything, including washing pans. It taught me how to manage students, and people with a variety of skills.”
He credits his interest in science to his high school science teachers. “I liked all my science teachers: biology, chemistry, physics. They were great teachers.”
Kobilka went on to attend the University of Minnesota-Duluth as an undergraduate in 1974. His advisor at the time, Conrad Firling, now professor emeritus of biology, remembers first meeting the freshman Kobilka as a student in his very large, introductory biology class. “After the conclusion of the quarter, in December, he came up to me and said, ‘I’d like to try some of that stuff called research.’ I said, ‘Everyone does the same thing, they start off washing glassware,’ and he said, ‘I’ll do it.'”
Firling said that Kobilka started as a freshman working on gene expression in very special kind of cell. “He obviously had the knack for it and certainly had the intelligence,” he said. “At the time it was very, very unusual to have an undergraduate working in the lab.”
Firling remembers Kobilka’s creative determination. “I was a young faculty member, and we didn’t have much equipment,” he said. “I came into the lab one morning and in the corner was the ugliest thing you could imagine. Brian had gone to lumberyard, and gotten plastic from his father’s bakery, and constructed the sterile hood that we needed to do his experiments. That’s the type of guy he was. He was so much fun in the lab.”
Proteins are linear strings of amino acids that fold into complex and dynamic shapes. G-protein-coupled receptors are also known as seven-trans-membrane receptors because they usually snake in and out of the cell membrane seven times, ending with one end outside the cell and the other inside. As such, they sit embedded in the cell membrane, with a portion sticking out on each side of the membrane. On the exterior side, the receptor forms a small trench in the membrane that can bind to a specific signal, such as a hormone or neurotransmitter.
The interior side of each of these receptors is like a small factory. When a signaling molecule binds the outside of the receptor, the whole receptor changes shape and activates a class of molecules called G proteins. The G proteins activate many other molecules within the cell to amplify the original signal, beginning a biological cascade that culminates with a physiological response like an increased heart rate, an awareness of light or the cementing of a long-term memory of the lyrics of your favorite song.
“Brian’s work stands at the crossroads between chemistry, structural biology and molecular medicine,” said Pizzo. “His commitment to staying focused on a problem of extraordinary complexity and to find the techniques and technologies to solve the protein’s structure and function is also a testament to the value of investigator-initiated, basic science research.
“In a day when big teams and massive labs have become the common mediator of modern science, Brian Kobilka represents [how] a small group of committed scientists can illuminate deep mysteries and open doors to new solutions that will ultimately improve human life,” Pizzo said.
Kobilka’s peers, including Roger Sunahara, an associate professor of pharmacology at the University of Michigan in Ann Arbor, a competitor-turned-collaborator who specializes in the study of G proteins, were also thrilled to hear about the award.
“Brian has always commanded a tremendous amount of respect from other scientists – both for his science and his integrity,” said Sunahara. “He’s a fantastic mentor who is engaged with and cares about the people in his lab. In addition to being fearless, he’s extremely creative scientifically, which is really the reason why he’s been able to demonstrate these novel receptor combinations. He’s like an artist.”
Despite his newfound fame, Kobilka has no plans to take it easy and is eager to build on his team’s success in 2011 crystallizing one of the GPCRs in tandem with its signaling molecule. “The discovery last year was a big step, but there are still a lot of questions left unanswered,” he said. “We now have a template for computational drug screening – using the three-dimensional structure to find new drugs that bind the receptor. We can also look for drugs that bind not just where the receptor interacts with its hormone, but at other sites on its surface.”
“It holds out the hope of developing more specific therapeutics than we’ve known before,” said Lefkowitz.
Kobilka struggled to get funding for his laboratory during its early, difficult years. Asked about the state of scientific funding today, he paused. “It’s not good,” he said. “There are very bright people with very good ideas who are not getting funded. Even those of us who have been fortunate enough to receive grants have seen our budgets cut to the point where we won’t be able to accomplish all of what we’ve proposed.
“It’s short-sighted, because – although it can be hard to understand and explain to the lay person – basic research like this ultimately leads to pharmaceutical products and other innovations from which we all benefit,” he said.
Asked for advice for young scientists by a reporter at the news conference, Kobilka said: “This is a fantastic way to spend your life. It’s hard, but if you’re interested and persevere, you can be successful. Every day is a challenge and exciting.” He cited his “irrational optimism” when asked why he continued his work in the face of seemingly insurmountable difficulty. “When something didn’t work, you’d be a little down, then at end of the day at home, you’ll think, ‘Oh, maybe this will work’. You always think something is going to work.”
Pizzo agreed that dogged determination is necessary to advance basic science. “His work is a testament to the importance of supporting basic science research – whose payoff can take many years or decades to reach fruition but, when it does, it changes the direction of medicine and science,” he said.
As of today, it’s also irrevocably changed Kobilka’s life.
“I’m not used to this sort of thing,” said Kobilka, standing in the dining room of his Palo Alto home and fielding calls from well wishers and media from around the globe. “I didn’t know it was this big.”