Biochemistry 101: a glossary
Receptor A structure found on the surface of cells, or within cells, that recognizes external signals and triggers responses. Examples of these external signals include hormones, nerve chemicals and allergens. Receptors can also be stimulated by light, sound, pressure, touch and chemicals that give odors their smell and foods their taste.
Adrenergic receptor A family of receptors stimulated by adrenaline. The body has two major types of adrenergic receptors, alpha and beta. In the Lefkowitz laboratory Dr. Marc Caron purified the first adrenergic receptor and Dr. Brian Kobilka isolated the gene that carries its instructions. Kobilka then determined the atom-by-atom, 3-D structure of the receptor in his laboratory at Stanford.
G-protein coupled receptors, or GPCRs A large family of receptors that translate signals outside cells to cause responses inside cells via a G-protein. The G-protein converts the receptor signal outside the cell to an amplified signal inside the cell. Think of the G-protein part of the receptor as a loudspeaker that converts an electrical signal into sound that you then hear.
ACTH, or adrenocorticotropic hormone ACTH is released from the pituitary gland at the base of the brain and travels through the blood to stimulate the adrenal glands to release corticosteroids.
Endocrinology The medicine specialty that concerns itself with the action of hormones throughout the body and diseases or disorders of hormone regulation. For example, insulin is a hormone released from the pancreas that signals other organs (e.g., muscle or brain) to absorb sugar from the blood.
On the cloudy morning of Monday, Oct. 10, 1994, Dr. Robert J. Lefkowitz was asleep at his home in Durham while, six time zones away, a call was being readied in Sweden.
That year rumors had been swirling that the Duke University Medical Center cardiologist and researcher was a top candidate for the Nobel Prize in Medicine. Since the early 1970s, his discoveries showed how the body sends and detects signals that regulate heartbeat, breathing, vision and other essential functions.
At lunchtime in Sweden, Nobel officials placed a call to the Triangle. But it was not for Lefkowitz.
Instead, the phone rang at the Chapel Hill home of Dr. Martin Rodbell, former director of the National Institute of Environmental Health Sciences (NIEHS). Rodbell would share the prize with Dr. Alfred Gilmanhe was a year behind Lefkowitz when they were research fellows in the 1960son a topic so close to Lefkowitz’s that the Nobel Committee could easily have put the Duke doc in the remaining third slot.
“That was very tough,” Lefkowitz says.
In 2004, Lefkowitz continued to be a Nobel favorite, as he had been since the early 1990s. This time, he lost out to scientists whose work he made possible. Again, the Nobel Committee had left a potential third slot empty.
Then this past October, 18 years to the day from the first snub, the news came from Stockholm that Lefkowitz had finally won the Nobel Prize, not in medicine but in chemistry. Because he sleeps with earplugs, Lefkowitz could not hear the phone when it rang and says he was instead awakened by “the elbow” from his wife, Lynn.
Another official came on the line and told Lefkowitz that he was sharing the prize with his former Duke cardiology fellow Dr. Brian Kobilka, who joined the lab in the 1980s. He is now a professor at Stanford University.
Lefkowitz elaborated in his Nobel banquet speech, “For me one of the most poignant aspects relates to sharing this award with a former fellow of mine. This highlights an aspect of science which is very important to both Brian and methe mentoring of young trainees.”
Scientists are not known for being the best personnel managers, with most learning how not to run a laboratory group. Yet Lefkowitz is well known as a caring and motivating mentor, unlike most scientists. While training more than 200 research physicians and scientists during his 40-year Duke career, Lefkowitz led a laboratory team that revealed the molecular heart and soul of the processes most central to our existence.
As a result of Lefkowitz and his team’s research, the potential now exists to develop new drugs for human diseases that are more targeted and have fewer side effects.
Around 9:30 on the morning of the Nobel Prize announcement, Lefkowitz was still in his office fielding phone calls from well-wishers and reading the first of 1,500 congratulatory emails. One even came from a fellow Nobel laureate with advice on how to manage the onslaught of attention. Down the hall, the laboratory and administrative staff assembled an impromptu brunch in a conference room. On one of three cakes, the bakery had misspelled “Lefkowitz” but got “Nobel” correctly. Lefkowitz emerged around 11:30 a.m. to join his “scientific family” for the obligatory champagne toast and dozens of pictures.
“There’s no one more gracious and open,” said Dr. Marti Delahunty, a Duke oncology researcher ,at the toast. She worked with Lefkowitz from 1998 to 2006. “He’s always here and he cares. You can tell there’s a lot of love here. It’s a family.”
Lefkowitz’s closest friend is Dr. Ralph Snyderman, chancellor emeritus of Duke’s Medical Center. He had expressed the same sentiment in his presentation speech for one of Lefkowitz’s many awards: “It is hard to imagine how one individual could have possibly achieved so much while being so genuinely loved by his colleagues.”
Lefkowitz and Kobilka’s research is based on the chemical signals the body uses to regulate itself. Like boats docking to a pier, these signals touch the outside of our cells at points called receptors.
These receptors receive information from both the body and drugs. For example, the body could send signals to pump adrenaline in preparation for a sporting event. And half of the prescription and over-the-counter drugs sold today interact with receptors to perform certain tasks such as relieving pain and allevating asthma.
The Nobel Prize-winning discoveries of Lefkowitz and Kobilka brought this concept down to earth, with real-world applications. Their research involved a large family of receptors called G-protein-coupled receptors, or GPCRs (see “Biochemistry 101: a glossary” in sidebar). They exist in almost all living organisms including plants, insects, bacteria and fungi, dating back almost 1 billion years through evolution.
Lefkowitz describes GPCRs as locks that are fit by keys of particular shapes. These chemical keys occur naturally in the body or can be a drug. They open the door to one or more of the hundreds of processes that regulate almost every imaginable bodily function. Some chemical keys only fit certain locks, or receptors, like those controlling heartbeat or breathing. Others fit those that control mood or appetite. They can stimulate certain processes, block them or do something in between.
So what are real-life versions of these stimulators and blockers? Have you taken pseudoephedrine (Sudafed) for a stuffy nose? The drug works by stimulating the alpha-1 receptor on blood vessels in swollen sinuses.
How about atenolol (Tenormin) for heart conditions? You’re blocking beta-1 receptors to make your heart beat more efficiently.
Smoke medical marijuana? The chemicals partially stimulate CB1 and CB2 cannabinoid receptors in the brain.
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Before he discovered science, Lefkowitz wanted to be a baseball player. Like many boys in 1950s New York City, Lefkowitz aspired to be like Mickey Mantle. But a childhood photo showing him with the wrong bat grip for a right-handed hitter made clear that another goal might be in order.
By third grade Lefkowitz decided to become a doctor, a choice he attributes to the influence of their family physician. Lefkowitz scored high enough on New York City academic exams to qualify to attend the Bronx High School of Science. It has a rich tradition of excellence, counting among its graduates eight Nobel Prize winners, six Pulitzer Prize winners and diverse talents such as music synthesizer pioneer Robert Moog and Web visionary Dave Winer.
Lefkowitz excelled there and was offered early admission to Columbia University, where he whisked through in three years and stayed on for medical school. In 1966, he graduated at the top of his class at age 23.
He worked at NewYork-Presbyterian Hospital for his internship and medical residency. It was the height of the Vietnam War, and the dramatic escalation in troop numbers created tremendous demand for military physicians. In 1967, Congress severely restricted physician deferments and exemptions; as a result, two-thirds of graduating medical students were being drafted.
However, the Selective Service exercised its right to reactivate the “doctor draft” initiated during the Korean War. Doctors would be drafted but serve in the U.S. Public Health Service as commissioned officers. Doctors could meet their military responsibilities with two years of clinical service and basic medical research at the National Institutes of Health (NIH).
“It was extraordinarily difficult to get the assignment, so they took the best and the brightest,” Lefkowitz says.
The program was a great opportunity, but at the time, Lefkowitz had zero interest in research. Still, he ventured to NIH’s Rockville, Md., campus and interviewed with Dr. Jesse Roth, an endocrinology researcher. Roth, now a highly decorated physician-scientist who remains active in the field, remembers the date clearly: July 1, 1966, the first day of Lefkowitz’s medical internship.
Lefkowitz was very anxious to return to New York. Yet he tried to convince Roth that he was passionate about medical researcheven though he had done little at Columbiaand wanted to work on “receptaz.” (For both Lefkowitz and Roth, the New York pronunciation remains evident today.)
Roth says he knew that Lefkowitz, sporting “a crew cut and horn-rimmed glasses,” was more interested in doing his military service on home soil. But he was impressed by the fact that Lefkowitz had survived a very rigorous and highly selective medical training program, finishing at the top of his class and securing a competitive internship, and was clearly “smart and hard-working,” Roth recalls.
So in the summer of 1968, Lefkowitz drove with his wife, Arna, and their three children to Maryland to begin his two years at NIH.
Roth says he had been working with another then “not-famous guy,” Dr. Ira Pastan, to understand how hormones worked. Pastan and Roth had a project for Lefkowitz in which he would try to show the existence of hormone-receiving receptor sites on the outside of cells.
Specifically, Lefkowitz was trying to understand how the brain told the adrenal glands (one sits atop each kidney) to send adrenaline into the bloodstreamthe same adrenaline that we talk about flowing in athletes when they’re pumped up.
To appreciate how ambitious Lefkowitz’s project was, it’s important to understand the state of science at the time. The receptor concept had been proposed in 1905, but most scientists thought it was an abstract idea. Few believed that receptors were real, physical thingsplaces on cells where naturally occurring or man-made chemicals could dock and, say, cause the heart to beat faster.
“If he had been a sophisticated researcher when he came,” says Roth, “he probably wouldn’t have taken the project.”
Roth and Pastan suggested that Lefkowitz start working with ACTH, or adrenocorticotropic hormone. ACTH is made in the pituitary gland at the base of the brain and travels to the adrenal glands to prompt them to release corticosteroids when you feel stressed or threatened. At the time, ACTH was one of few hormones sold commercially. Roth knew it could be tagged with radioactive iodine, and its effect could be easily measured inside adrenal gland cells. No one had been able to get it to work in practice.
Neither could Lefkowitz. For the first time in the precocious young doctor’s career, he was an unqualified failure. “I started for 12, 18 months; nothing worked,” Lefkowitz says. “I was going nuts!”
“We had to be very encouraging,” Roth recalls. “I had to spend a lot of time with Bob every week. ‘Don’t worry, Bob. Don’t worry, kid. It’ll work out.’”
At Thanksgiving of his first year, Lefkowitz traveled home to New York and talked with his father, Max, about his difficulties. Max counseled him not to worry, that he needn’t work in the lab forever and he could always return to clinical medicine after he fulfilled his service commitment.
Lefkowitz returned to NIH, still dejected but knowing he had to tough it out. His father suffered his fourth and final heart attack a few weeks later, just before Christmas.
“There is no doubt that the combination of his death and my initial failures in research resulted in one of the bleakest, most difficult periods of my life,” Lefkowitz said in a 2010 interview for the journal Circulation Research.
Lefkowitz slowly had more success in the lab, leading to two landmark papers published in top journals in 1970. Moreover, he benefited from what was one of the most productive training environments in modern medical research, one that Roth called “an intellectual bouillabaisse.”
Four of the physician-scientists Lefkowitz trained with went on to win Nobel Prizes. “I was the schlep of the group,” he says.
“There were some great mentors there. But you know,” he pauses, “I’m a bit of a mystic myself and there’s some things you can’t understand. There was just something.” Another pause. “Who knows what the hell it was.”
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Lefkowitz almost didn’t make it to Duke. He had already committed to practicing medicine at the Massachusetts General Hospital of Harvard University after his service commitment. After six months there, “I really missed the lab,” Lefkowitz recalls, adding he was “like a junkie who needed a fix.”
Meanwhile, 600 miles south in Durham, the medical school at Duke University was flourishing. Dr. Andy Wallace, chief of cardiology, had seen the young Lefkowitz present his receptor studies at an American Heart Association meeting. He and Dr. Jim Wyngaarden, chairman of medicine, they tried to lure Lefkowitz to Duke. However, Harvard had already promised Lefkowitz a faculty position after his cardiology fellowship.
Lefkowitz admits he had no intention of coming to Duke and politely rejected Duke’s offer. But Wallace and Wyngaarden rejected Lefkowitz’s rejection. Their counteroffer included a $32,000 annual salarythe equivalent of $165,000 today (the initial offer was $24,000)and an open-ended request for his other needs.
Still thinking Duke wasn’t in his future, he responded with “outrageous demands” Lefkowitz says. One of those was that he start as an associate professor with academic tenure, a position that requires rigorous review at seven to 11 years of faculty service. He was just 30, straight out of his fellowship.
“That was the most outrageous demand and that was the one put in there to scotch the whole deal because I didn’t want to come,” Lefkowitz says. “The whole purpose of my request was to give me a graceful way out because I knew in my head that what I was asking was impossible.”
Wyngaarden and Wallace met every demand.
Lefkowitz was dumbfounded. “Duke was a young institution [in 1973]. But it was a decent institution, and the offer was just so non-comparable with what Harvard was offering that I said, ‘This is it. I gotta go for it.’”
“But a lot of people said, ‘How can you go to Duke?’ Even my in-laws at the time.” He reproduces the Yiddish accent: “‘Whaddaya, crazy? You’re at Hawvaad.’ But something said, ‘Go for this.’”
Lefkowitz credits Wyngaarden with making “a gutsy move.” “He had this amazing feel for people right at the beginning of their careers. He had this wonderful ability to pick talent,” Lefkowitz says. “It’s one thing to hire some famous professor and bring in the talent that way. But that’s not what they were doing. They saw a bright young man, who seemed to be starting to make a name for himself, and they placed a bet.”
Lefkowitz is so well-loved that it’s difficult to locate any detractors, personally or professionally. Snyderman estimates that he and Lefkowitz have spent 10,000 hours together running 60,000 milesa 10 minute-per-mile pacesharing their most intimate personal details.
“I cannot recall any time where Bob has said anything mean, prejudicial, ugly about anyone,” Snyderman says. “Just never.”
Lefkowitz speaks only briefly of his divorce from Arna, the mother of his five children. Asked whether he’s paid a price for his career success, Lefkowitz says: “The answer is ‘yeah!’ But I don’t think it has anything to do with science. I mean, I think if you achieve at this level, you pay a price. There are only 24 hours in a day and I don’t care whether it’s sports or a military career or a career in public service in government.”
He adds: “I have a great relationship with all my kids. I was just obsessed with the work.”
In the acknowledgement of her book for young adults, Breathing, daughter Cheryl Herbsman thanked her parents collectively, “for giving me permission and freedom to believe in my dreams and for providing me with loving support every step of the way.”
Bob remarried in 1991 to Durham native Lynn Tilley. Other than a deluge of speaking requests, Lefkowitz expects the Nobel will cause little change in their lives.
“I’m so busy that, like on a weekend, there’s nothing we like better than staying home, maybe watching a movie we’ve rented from Netflix on a Saturday night or reading.”
With the broader public stage afforded as a Nobel laureate, Lefkowitz intimates that he’ll be outspoken about anti-scientific influences in U.S. politics.
“One of the fault lines in the [U.S. presidential] campaign was the role that science plays in shaping public policy decisions,” he said during his Nobel Prize acceptance speech, “A clear anti-science bias was apparent in many who sought the presidential nomination of one of our major political parties. This was manifest as a refusal to accept, for example, the theory of evolution, the existence of global warming, much less of the role of humans in this process, the value of vaccines or of embryonic stem cell research. Each of us laureates aspires in our own small way to do what we can to counter these pernicious anti-scientific trends.”
The awarding of the Nobel Prize in Chemistry ruffled the feathers of some traditional chemists who suggested that the collective work of Lefkowitz and Kobilka was better suited for the medicine prize. Although Lefkowitz wasn’t personally synthesizing chemicals for his research, he had to use extensive chemical insight for his earlier work. Moreover, Kobilka showed the first atom-by-atom 3-D structure of an adrenergic receptor with its G-protein complex, a chemical milestone using a time-honored technique.
Dr. Derek Lowe, a well-known medicinal chemist and blogger, addressed this issue on the day of the Nobel Prize announcement. “Biology isn’t invading chemistrybiology is turning into chemistry,” wrote Lowe. “So, my fellow chemists, cheer the hell up already.”
In fact, Lefkowitz says he couldn’t have won the chemistry prize without Kobilka. “I gotta believe I could’ve won it in medicine years ago. If I had, Brian never would’ve shared it. On the other hand, at this point, I don’t think I would’ve gotten it in chemistry if he hadn’t gotten the [atom-by-atom] structures.”
This interdependence characterizes Lefkowitz’s reputation as a dedicated mentor. “When’s the last time Bob shook a test tube?” Snyderman asks rhetorically. “He’ll joke that he doesn’t have a clue about how to do this stuff.”
Snyderman calls this relationship “a blessed transaction” between professor and lab members. “These people give him everything they’ve got. To have trained with Bob in a laboratory, and now to train in a lab with a Nobel laureate, is just fantastic.”
Lefkowitz’s advice for mentoring extends beyond science. “You can’t say to somebody, ‘To be successful in science, you have to be able to absorb failure after failure after failure. You have to be persistent. You have to believe in your goals.’ Yeah, it’s fine to say that. What does it mean? They gotta work with you for three years, they gotta watch you suck it upfailure after failure after failurethey gotta watch you. I mean, that’s how you teach. And that’s why the training is very much an apprenticeship.”
Colleagues and trainees have watched Lefkowitz suck it up for 20 years knowing he was Nobel Prize material, nominated but never selected.
“My best assessment was that I had some enemies somewhere, colleagues, whothey confer broadly about the prizeand I think if somebody damned me, you know, some evaluator who maybe I had crossed swords with at some point …” he pauses. “Who knows?”
He reflects on being snubbed for the 1994 prize, “I would love to know the story someday.”
But Nobel Foundation statutes require that all nominations and committee deliberations remain secret for 50 years.
“I already told my granddaughter, ‘When they publish that, I want you to read all the documents and send me an email or a text.’”
Dr. David Kroll is a contributor to the Forbes.com Pharma & Healthcare section and a pharmaceutical chemistry writer at Terra Sigillata, a blog on the Chemical & Engineering News network CENtral Science.
A 20-year academic cancer pharmacology researcher, Kroll is currently director of science communications at the Nature Research Center of the North Carolina Museum of Natural Sciences and a science writing professor at North Carolina State University.
Correction: This article has been corrected to replace the word ‘adrenaline’ with ‘corticosteroids’ in the following paragraph: “ACTH is made in the pituitary gland at the base of the brain and travels to the adrenal glands to prompt them to release corticosteroids when you feel stressed or threatened.”
This article appeared in print with the headline “At last, nice guys finish first.”
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