A Talk with Robert Lefkowitz: A Determined Physician Who Won the Nobel Prize in Chemistry

Updated: Feb 13

In this event hosted by UCL Life Sciences Society, Robert Lefkowitz, an American physician who won the Nobel Prize in Chemistry in 2012 for his groundbreaking studies on G-protein coupled receptors, will be walking you through his magical journey in laboratory experiment and scientific research in discovering the G-protein coupled receptors.

The tale of two callings

What is calling? Calling is being destined to do something, and throughout Lefkowitz’s magical journey, he had the experience of feeling the calling from two careers: as a physician and as a scientist.

At the young age of 6, Lefkowitz felt his first calling to the practise of medicine. He greatly admired and identified with his family physician, who would come to the house with his black bag to treat his discomfort, write prescriptions, put the stethoscope to his chest, and answer his endless questions. During his childhood, Lefkowitz was determined to become a physician in the future, and thus spent hours and hours in the library, checking out the maximum number of books that he was allowed, and being a ‘bookaholic.’

Eventually, Lefkowitz ended up in the renowned and prestigious Bronx High School of Science. Putting this into perspective, Lefkowitz is the 8th Nobel Laureate to have studied at the school. From then on, Lefkowitz attended medical school at Columbia University, always keeping in mind that his final destination was to become a physician.

Turning Point

Everything was on track until the Vietnam War began in 1955.

Like most of the young physicians who graduated at that time, Lefkowitz did not support the war, but rather became politically active against it. As a medical graduate, Lefkowitz had no choice but to serve in the army for at least 2 years. The only way to avoid being involved in the war was to get drafted into the National Institutes of Health (NIH), and because he was a high achiever, Lefkowitz succeeded in doing so.


However, what came about was extremely discouraging for any young scientist— having had no significant failures in his career up until that point, the result of spending a whole year devoted to research was nothing more than a failure to him. After putting in consistent effort for 15 months, he saw no success at all, and this put him into the deepest tailspin. Up to this point, Dr. Lefkowitz viewed these two years in the NIH— in which he undertook all research training and lab work— as a way to escape from having to serve in the military, with no conception of how this would drastically impact his life in later years.


Dr. Lefkowitz did eventually make some progress in later research efforts, but after serving two years as a Clinical and Research Associate at the NIH, he decided to return to his initial passion, throwing himself back into clinical work. Ironically, during the first six months of clinical work, he felt that on some profound level, something was missing.

“As exciting as I found clinical work, I found that I missed the laboratory, I missed the day-to-day struggle of trying to understand some fundamental biological problem that I wasn’t finding in clinical work.”

After avoiding to undertake research for his whole life until then, Dr. Lefkowitz realized that he missed researching, and this realization led him back to the laboratory. He started doing research part-time again, making it a part of his ultimate career plan. He sorted out a mentor and started researching the β-adrenergic receptor, which is the one of the main cardiovascular receptors for adrenaline.

Getting obsessed with research

While Dr. Lefkowitz devoted half of his time to researching, most of his results fell short and took him nowhere. Once after a lunch chat with a senior scientist, he was struck by the sad reality that getting into research meant having to learn to live with failure.


“In research, failure is a constant companion. Rob, Do you have any idea of what percentage of things work for an average scientist?”
“No”
“Maybe 1%. Now how about the world leader? Let’s say, Nobel laureates in science.”
“I Don't know”
“Well, it could be as high as 2%.”

Indeed. Even for the smartest scientists, 98% of the work is failing.


In later years, Lefkowitz relocated to Duke University, working both as a physician and a scientist. In the first 2 years, he spent about 40% of his time in clinical works and 60% in labs, but over the next few years, the momentum of one success following the other gradually shifted his focus. He became more and more obsessed with research work within those five years, spending 80-90% of his time in the laboratory, and eventually this led to his groundbreaking discovery of the G-protein-coupled receptors. Now, in his seventies, he spends all of his time in the lab with his students, planning research, analyzing data, and writing papers.

What exactly are G protein coupled receptors?

What are receptors?

When living organisms change their behavior, a signal transduction process takes place, beginning with the recognition of the ‘signal’ by the organism. On a fundamental level, receptors are molecules that detect signaling molecules.


The idea of receptors is not new, but its existence is a controversial idea among scientists, as no one has ever proven the existence of receptors. Lefkowitz became convinced that it worked like a lock and a key, where a specific molecule on a cell is binded to a particular drug such as adrenaline and binds to it due to its complementary structure. There are two drugs that fit into that lock, one being agonist, which stimulates some action to take place, and the other being antagonist, which fits into the lock and stays there, thus blocking agonists from getting in and blocking an action from taking place.


Lefkowitz’s work was able to prove the existence of receptors using the beta-adrenergic receptor.

In the mid 1980s, he and his team were able to develop technologies that allowed them to study the receptors. They did this by first solubilizing and removing receptors from the plasma membrane, then purifying and isolating them, and lastly, determining the amino acid sequence of the receptor by cloning the genes. The amino sequence weaves back and forth through the plasma surface 7 times—this was a striking discovery, as at the time, there was only one protein known to have such an arrangement, which is rhodopsin, a light receptor that allows us to see. All these similarities led to the realization that all G coupled receptors - the several dozen known hormones and neurotransmitters that work by stimulating an intermediate G protein— might look alike. Indeed, more and more alike receptors with these structures were discovered, and the field expanded dramatically.


As a result, more effective drugs were developed, ones that could bind to receptors more quickly. Nowadays, the G protein is the largest family of drug targets.


Interestingly, at no point in his research career did Lefkowitz set out to develop a drug; however, just by following his scientist’s curiosity, he found that the solutions to the problems that one chose could often yield important therapeutic implementations and developments, which is one of the most fascinating elements of pursuing a research career.

Funny things happened along the way…

Sports

Being a big fan of the Duke basketball team since the 1970s, Dr. Lefkowitz received a phone call from the team’s coach Mike Krzyzewski, inviting him to be honored at the Cameron Indoor Stadium during a special event called “Countdown to Craziness.” Thousands of students were pointing at him and chanting something, and after overcoming his shock, he realized that they were chanting,

“HE’S SO SMART! HE’S SO SMART!”

Another sport related highlight is being invited to throw out the first pitch at the Durham Bulls game in 2013:

Robert Lefkowitz throws out first pitch at Durham Bulls Game ( source: https://www.youtube.com/watch?v=PiRoICrVxKA)

Nobel laureate and chocolate consumption?


If you’re a statistics student, you have definitely seen this plot and have been skeptical about spurious correlation. In the summer before Lefkowitz won the Nobel Prize, he decided to increase his restricted chocolate intake to one square of dark chocolate every night.

What conclusions can we draw from this? 1. There is a certain threshold that you need to exceed for it to take effect ( he suggested 70% dark chocolate, 10 grams every night)

2. Dark chocolate acts quickly; only 2 months after increasing the dosage, he won the Nobel Prize.

Nobel laureate and chocolate consumption, Source: New England Journal of Medicine

Suggestions to students

1. Choose your mentors very carefully.

Only mentors can show you how to do something and how to solve specific problems in the laboratory. You will spend much time with your mentor in the laboratory and will gradually start to share their values. Getting a taste of the different practical solutions to scientific problems are very important.



How do you choose mentors?

  • Look at their train records

  • Read their publications and identify their achievements in their field

  • Speak to people from the laboratory


2. 4 keys to succeed in the field of research

  1. Focus

  2. Focus

  3. Focus

  4. Figure it out for yourself


3. How can scientists stay motivated under the pandemic?


The pandemic has had a widespread psychological effect on everyone. . One thing that kept me motivated was meeting with all the young scientists, but now all that has to be done remotely, and this has been dispiriting. The best recommendation I could give is to try to stay as connected as you can, with students, lab mates, and mentors. We need to trust that scientists are heroes and the pandemic won’t last forever, but until then, we have to keep supporting each other, and there’s no better way to keep your own spirit up than sharing, the spirit of altruism.



4. What advice would you give to someone studying chemistry but doesn’t know exactly what they’d like to do after that?


The only advice I would give is: don’t worry about that. I started as a determined physician but ended up here— none of us ever know what we will end up doing, even if you think you know certainly what it’s going to be like. Sample as many opportunities as possible, and the destination will become clear over time.



UCL Life Sciences Society is a student run society specifically for students studying modules in UCL's Division of Life Sciences. This covers a wide range of degree programmes including, but not limited to, Biomedical Sciences, Neuroscience, Pharmacology, Biochemistry and Human Sciences.

Our aim is to keep the interest in life sciences alive with scientific talks, bring students together with our social events and provide academic support.

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References:

  1. Messerli, Franz H., and Author AffiliationsFrom St. Luke's–Roosevelt Hospital and Columbia University. “Chocolate Consumption, Cognitive Function, and Nobel Laureates: NEJM.” New England Journal of Medicine, www.nejm.org/doi/full/10.1056/NEJMon1211064.

  2. “The Nobel Prize in Chemistry 2012.” NobelPrize.org, www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/.

  3. Visweswariah, Sandhya S. “Receptor Biology.” The Indian Journal of Medical Research, Medknow Publications & Media Pvt Ltd, Apr. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6057257/.



 
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