Robert Lefkowitz and Brian Kobilka: A certain kind of magic

The 2012 Nobel Prize in Chemistry was awarded to Robert J. Lefkowitz of Duke University and Brian K. Kobilka from Stanford University for their studies of G-protein coupled receptors. Sitting in the small sofa in the Zetterwallska drawing-room of Grand Hotel in Stockholm, it is quickly clear they are two men with opposing personalities. The confident, gregarious professor Bob Lefkowitz is enjoying the lime light, whereas a decidedly more reserved, maybe even demure professor Brian Kobilka is probably happier in his lab than in the bright photo lights of this room.

However, much like a protein and its receptor, they complement each other brilliantly. The dynamic between them is mix of creativity, scientific knowledge, analytical skill – and humor! It is easy to imagine how their meeting in Lefkowitz’ lab in the 80’s fueled the cascade of research results that have brought the two to Stockholm to receive the most prestigious award in the realm of science.  

The sensor of all sensors

G-protein coupled receptors (GPCRs) have been a puzzle to medicine since the end of the 19th century. At this time, researchers discovered that adrenalin causes heart rate increase, relaxes the pupils and elevates blood pressure. Hormones administered outside the cell caused changes inside the cells without ever penetrating the cell membrane – a mystery of medicine. Since the nervous system was not involved, it was concluded that cells must have some sort of sensors for chemical substances.

Finding these receptors, however, was a much larger challenge. The receptors, now identified as GPCRs, are scarce and tend to be encapsulated within the cell wall. The trial proved so large that the first researcher on the topic – Raymond Ahlquist – began to consider his original theory of receptors an “abstract concept”. 

An accidental scientist

In the 1960’s, Lefkowitz started on the path that would solve the mystery of the unidentifiable receptors that rule our entire body.

“I was driven to a career in medicine,” says Robert Lefkowitz when asked how he ended up in research, “A research profession never even occurred to me.” A family physician in the Bronx was his inspiration. “I loved science and the idea that you could study science and then use that special knowledge to heal – to a kid, that was magical,” he says and his eyes light up at the wonder medicine was to him at that time.

No other profession was of interest, and the joy of research was a forced discovery. “When I was in my residency, there was a Vietnam war draft which I wanted to avoid at all costs. An opportunity existed to join the public health service and do research at the NIH instead of being sent overseas,” explains Lefkowitz who secured one of the highly coveted spots. Even at the NIH, in the lab, the research bug didn’t catch on.

“The first year was dreadful and I made plans to leave,” he recounts, but during the second year, he did make some notable discoveries. His findings of an active receptor were published in Science and PNAS in 1970.

“After the two years were over I went straight back to practicing medicine but I actually missed the laboratory. There was no data at the end of the day to mull over!” It drove him crazy and after six months he knew he had to get back into the lab. The rest is history – a bright career at Duke University in North Carolina, topped by the greatest prize a researcher can dream of. 

By the 1980s, the G-proteins had been discovered (leading to the Nobel Prize in Physiology or Medicine in 1994). Scientists were slowly gaining an understanding of the process where signals are sent between the outside and the inside of the cells. At this point in time, our second 2012 Nobel Prize Laureate in Chemistry enters the scene.

The baker’s son

Just like Bob Lefkowitz, Brian Kobilka wanted to be a physician. Instead of following in the footsteps of his father and grandfather – famous bakers in the small Minnesota town of Little Falls – Kobilka was inspired by knowledgeable high school science teachers, by his pediatrician – “in a small town, the physician was God” – and by his first college mentor Conrad Furling.

“Working in his lab is probably what got me interested in pursuing research,” says the mild-mannered Kobilka with a smile that nevertheless betrays his passion for science.

He admits he has learned plenty about managing teams from his father but we forget to ask if he knows how to keep a sourdough alive. Another bug definitely grew and flourished – the thirst for understanding things at the very core.

“I wanted to try something big and really understand a concept at the fundamental level,” he says, and Lefkowitz fills in, “It is interesting to hear you say that because when you were in my lab, you really gravitated toward the most challenging and difficult tasks!” 

A meeting of minds

In the early 1980’s, Brian Kobilka moved with his wife (and constant lab partner) Tong Su Thian and their two children to North Carolina to be a post-doctoral fellow in the lab of Robert Lefkowitz. Lefkowitz had just made the crucial decision that his research group should look for the gene that codes the β-adrenergic receptor. Kobilka, in turn, came out of a residency in hospital intensive care with a fascination of adrenergic receptors. He had approached Lefkowitz because he wanted to study the power of epinephrine (which binds to β-adrenergic receptors) at the fundamental, molecular level. Had the two forces not joined at that time, who knows how much of the current GPCR understanding we would have today. Lefkowitz saw potential in Kobilka and involved him in the most important project of the lab: The quest of finding the genes behind the GPCRs. 

“When I came to this lab, I was really green,” Kobilka says and continues, “From point of experience I was the lowest on the totem pole.”  Kobilka gives fellow post docs credit for patiently teaching him many of the basic steps. “My first contributions were actually some serious errors that I made that we won’t bring up again,” he says and lets out a laugh. 

But Brian has a certain magic, creativity and an ability to come up with free-thinking, out-of-the-box solutions.

“Brian was working on the project in our lab which was ultimately the most important, so the question is, why did I entrust this to this green guy who was learning how to pipette from the other guys at the bench?,” continues Lefkowitz when they two have stopped smirking over unnamed mishaps. “But Brian has a certain magic, creativity and an ability to come up with free-thinking, out-of-the-box solutions. That was obvious to me from the start, even though at that time he didn’t actually KNOW anything,” smiles Lefkowitz. Kobilka thought outside the box. By isolating the gene and noting that it coded for seven helices he opened the door to a breakthrough. The seven helices indicated that the receptor winds in and out of the cell wall seven times. It was the same structure which had already been found in other places in the body – among them, the light receptor rhodopsin in the eye. An idea was born: What if the beta receptor and the light receptor are related in spite of the widely varying functions? They were thinking outside the box and it set them on the right path. “This is the point: knowledge takes you up to a point, but it is imagination that leads to discoveries,” exclaims Lefkowitz. The eureka moment lead them to formulate a theory that there had to be a complete family of receptors with similar structure and function coupling with the G-proteins.

As they do many times during the interview, the laureates’ curiosity takes over and instead of waiting for interview questions they start asking each other about their experiences and how they remember the situation. “I don’t think you understood just how challenging what we were trying to do was,” Lefkowitz says turned to Kobilka. “Neither did I for that matter,” he laughs and turns back to the interview to expand the train of thought.

Knowledge as a stumbling block

“Out of the people I’ve worked with, the three people who knew the most have all had nice, average careers, nothing outstanding. None were the least bit creative. But they knew the most facts,” says Lefkowitz and with the precision of a stand-up comedian, the otherwise shy Kobilka quickly leans toward the recorder and clarifies, “I was NOT one of those who knew the most.” At this even the official attachés in the back let out a laughter. Well, his career can hardly be considered “average” either.

For both you and me, part of the key to our success is just how little we know.

Robert Lefkowitz continues the discussion with his fellow laureate. “For both you and me, part of the key to our success is just how little we know. Sometimes it’s not good to know too much,” he ponders, clearly finding the subject of what makes a successful researcher one worth dissecting. Analytical skills and a certain amount of knowledge are of course the foundations, but in a room of really bright, knowledgeable scientists, what is it that leads one on the breakthrough path which identifies a Nobel Laureate?

Creativity, challenges and a dose of luck

Creativity and taking chances perhaps? “I think Brian’s whole career is about just taking on outlandish challenges” says Lefkowitz. With few exceptions he has ultimately succeeded in those challenges. The greatest one proved to be Kobilka’s quest to crystalize the β2-adrenergic receptor. He moved west, to Stanford University to work on the task with X-ray crystallography. To use X-rays to visualize protein structure, you first have to produce a crystal of tightly packed proteins. This was easier said than done because of their lipid (not water) solubility and the changing nature of the receptor structure. It would take until 2011 for Kobilka to reach his goal and get an image of the β2-adrenergic receptor at the moment when it transfers the signal from the hormone on the outside of the cell to a G-protein on the inside of the cell. 

Kobilka agrees that taking on challenges is part of his success, as is creativity, but he sees an additional factor. “We obviously both know a lot about our field but there is just so much to know,” he says. The additional player is Lady Luck. “There are scientists who are as creative as I am and certainly more knowledgeable,” says Kobilka, “but I also think there is an element of luck – putting you in the right place at the right time with the right people.” The tall, blue-eyed Kobilka is a humble recipient of success and continues, “I have had a certain amount of luck. For one, starting in Bob’s lab. I could have ended up in another lab where I would not have done as well at all. It was really a great place for me, my personality and my skills.”

To date, nearly a thousand genes that code for GPCRs have been identified. Of these, half are part of the olfactory system and a third are receptors for hormones and signaling substances such as dopamine, serotonin and histamine. Several receptors have been found to be multifunctional. Though over a hundred receptors are still challenging scientists (as their functionality is yet to be understood), the discoveries which have come out of Lefkowitz’ and Kobilka’s labs are revolutionary to our understanding of these supremely important receptors. The applications in drug development are broad and the pharmaceutical industry is keeping close watch.

Mentor, not boss

So what happened when these two now hugely successful researchers started working in tandem? We ask Kobilka how Lefkowitz was as a boss, at which the subject takes on an expression of fear which would have, had it not been humorously faked, caused a release of adrenalin which would couple to different GPCRs around the body. 

Being a good researcher is all artistry.

Kobilka ponders for a moment and then turns to Lefkowitz, “I guess I never really thought of you as my boss and I didn’t really think of this as a job; it was just a really fantastic experience,” he says and Lefkowitz nods in agreement. Kobilka decides that “mentor” is a better description. Lefkowitz fills in, “I don’t know what I see myself as; more like a gadfly or cheerleader.” They agree that mentoring talent is an important factor in bringing research forward. “I think most people look at both Brian and me as excellent mentors,” says Lefkowitz, “but our personalities could not be more diametrically different.” What it tells us is that there is not one way to do this. “If there is one secret, it is to do it your way. You have to play your own strengths and work with what you’ve got.”

Playing your strengths goes for more than mentoring – it goes for the research itself. “Being a good researcher is all artistry,” concludes Lefkowitz and expounds, “To me, artistry means you can’t write it down in a book. I often tell people, when I am mentoring: if it’s truly important, I can’t write it down. You just have to find it out for yourself.”