Books

The Death Project

Robert J. Lefkowitz
By Robert J. Lefkowitz
Dec. 2, 2020

This is an excerpt from “A Funny Thing Happened on the Way to Stockholm: The Adrenaline-Fueled Adventures of an Accidental Scientist” by Robert Lefkowitz with Randy Hall (published by Pegasus Books) due to be released Feb. 2, 2021.

The phone rang in my office, and when I answered it I received shocking news: my collaborator, the legendary Harvard structural biologist Don Wiley, was missing. Don and I had been collaborating on trying to determine the three-dimensional structure of the beta-2 adrenergic receptor. In the 1970s, my lab had pioneered the purification of the receptor, and in the 1980s we had discovered the receptor's gene sequence. Now, in the early 2000s, we were collaborating with Wiley's group to perform X-ray crystallography on purified beta-2 receptors in order to see the receptor's structure and understand precisely how molecules like adrenaline bound to it. My lab was adept at purifying receptors and Don Wiley was one of the best X-ray
crystallographers in the world, so I felt confident about our chances for success. There was only one problem: Wiley had now vanished without a trace.

Don was an amazing scientist and brilliant wit who lit up every room he entered. He could give a talk about a seemingly dry topic, like the structure of a protein, and weave a spellbinding narrative that would have an audience hanging on his every word. As a storyteller myself, I recognized Don as a kindred spirit and was thrilled to have him as a collaborator. My affection and admiration for Don made his unexplained absence all the more difficult to accept.

Wiley's disappearance became a national news story, so between reading the news and talking with colleagues who knew Don, I became aware of all the details of the case. Don had been at a meeting in Memphis at St. Jude Children's Research Hospital, where he served on a research advisory board. He'd had dinner with some colleagues, and everyone at his table said Don was his usual upbeat and jovial self. Don left the dinner in a rental car to visit his father, who lived in the area, but then never showed up at his father's house. Police found Don's car parked on the Hernando de Soto Bridge, a huge overpass spanning the Mississippi River. One obvious possibility was that Don might have stopped on the bridge and jumped to his death. However, Don had never shown the slightest hint of depression and by all accounts was in especially good spirits that evening.

Conspiracy theories

Wiley-Don-200x301.jpg
Harvard structural biologist Don Wiley
was "one of the best X-ray
crystallographers in the world"
and an expert on infectious
diseases, such as Ebola.

As weeks passed without any break in the case, conspiracy theories began to pop up. Don was one of the world's top experts on the structure of dangerous viruses, such as the Ebola virus, which led some people to speculate that he may have been kidnapped by terrorists who wanted to develop a biological weapon. This was shortly after the terrorist events of 9/11, so terrorism was very much on everyone's mind. Others speculated that maybe Don knew too much about some sort of dark secret and was murdered. Several other virus experts had died under mysterious circumstances around the same time, which only fueled speculation about Don's case.

About a month after Don's disappearance, his body was found in the Mississippi River about three hundred miles south of Memphis. FBI agents and local law enforcement officials examined his body and also performed a careful examination of his car, which had some damage on the right front end. The official theory of Don's death, put forward by the Shelby County Medical Examiner, was that his car had grazed a post on the bridge, which led him to stop his car and get out to inspect the damage. Somehow, he had then accidentally fallen off the bridge to his death. A large truck may have gone past, creating a strong surge of wind that knocked Don off the bridge. Alternatively, as Don did have an epileptic condition and was prone to the occasional seizure, he may have experienced a seizure event (perhaps related to the stress of hitting the post) and fallen over the railing.

HernandoDeSoto_Bridge_Pyramid-890x473.jpg
Trevor Birchett
Don Wiley disappeared in November 2001 after a meeting in Memphis at St. Jude Children's Research Hospital. His car was found parked on the Hernando De Soto Bridge, which spans the Mississippi River.

In whatever way Don's death actually happened, it was a jolt to the scientific community to lose a man who many thought might win a Nobel Prize in the next few years, and it was especially shocking to me, as we were actively collaborating with his lab.

A cursed project?

One of the most macabre aspects of Don's death was that he was actually our third collaborator on the X-ray crystallography project to die unexpectedly. Prior to collaborating with Don on this project, we had been working with Paul Sigler at Yale. Shortly after that collaboration began, the talented postdoctoral fellow who was leading the project, Serge Pares, died tragically (along with his pregnant wife) aboard TWA Flight 800, which exploded and crashed into the Atlantic Ocean shortly after takeoff in 1996. The project continued in the Sigler lab with contributions from several other postdocs. Then, in early 2000, Paul Sigler was walking near the Yale campus one day when he suddenly had a massive heart attack and dropped dead. Paul was a wonderful man and a hell of a scientist, so it was a devastating loss for all who knew him.

One of the postdocs in Paul's lab who was working on the project, Ben Spiller, then moved to the lab of Don Wiley at Harvard, and Don expressed an interest in continuing the collaboration with my lab. Thus, when Don's body was pulled out of the Mississippi River on December 20, 2001, he was our third collaborator on this project in six years to have met an untimely demise. In my lab, there was hushed talk about the X-ray crystallography studies being the "Death Project," and concerns were raised that anybody working on this project might be cursed.

Though he had every reason to feel shaken, Ben Spiller was undaunted by talk of a curse. After suffering through the deaths of two consecutive mentors, Ben moved to the lab of yet another famous structural biologist, Stephen Harrison at Harvard, and told me that he wanted to keep working on the project. Amazingly, Steve Harrison was also on board with the idea. Steve had actually taken in quite a few of the mentorless young scientists from Don Wiley's lab and was trying to help them continue their work. I called Steve and offered him the chance to decline this particular project, noting that the last two investigators who took on this collaboration were both now dead. In an act of defiance and bravery, Steve said he didn't believe in curses and was excited about the project, and he insisted on continuing the collaboration with Spiller as the point man.

Squirmy proteins

At the same time as these X-ray crystallography efforts were going on in my lab at Duke, we also had a number of other projects that were yielding interesting findings. For example, we were discovering novel G protein-independent signaling pathways emanating from the beta-2 receptor and other G protein-coupled receptors.  While these groundbreaking studies were in full swing, we also were purifying large amounts of beta-2 adrenergic receptors on a weekly basis and sending these samples to Ben Spiller in Steve Harrison's lab at Harvard. It was a tough situation for Ben, having lost two mentors in tragic fashion and now doggedly trying to carry on his attempts to solve the crystal structure of the beta-2 receptor.

Technically, the project was incredibly demanding, as by definition receptors are squirmy proteins that are prone to rapidly changing conformations. If you think about it, that's what receptors do for a living: rapidly change conformations in response to ligands. Thus, it's incredibly challenging to get a receptor to hold still for a photograph, which is basically what you have to do in order to capture an X-ray crystal structure.

After a couple years of work on the project, Ben finally threw in the towel, and my lab moved on completely from the X-ray crystallography efforts because we were so focused on other interesting lines of research. Thus, when it came to the X-ray crystallography studies, aka the "Death Project," the bad news was that we were unable to solve the crystal structure of the beta-2 receptor. The good news, though, was that no further deaths were associated with the project: Spiller, Harrison, and the folks in my lab who were pursuing these studies all survived to tell the tale.

Bob-Brian-Sheila-890x565.jpg
During a break from a scientific meeting in California in the late 1990's, Bob Lefkowitz does his best to keep up with former trainees, Brian Kobilka and Sheila Collins, who by that time were both faculty members directing their own labs.

A couple of years later, in 2006, my former trainee Brian Kobilka and I shared a visiting lectureship at the University of Illinois at Urbana–Champaign. This joint lectureship provided Brian and me with some quality time to catch up with each other. Brian had been on the Stanford faculty for about sixteen years at that point. 

At a dinner together during our visit in Illinois, Brian confided to me that he had been focusing much of his lab's efforts on solving a crystal structure for the beta-2 adrenergic receptor. I told him that we also had pursued efforts in this area for a while but dropped the project several years earlier because of concerns that success might not be possible with the current state of the technology. Brian said he also had encountered many technical difficulties and was simply hoping to get a crystal structure before he retired, perhaps at some point in the next twenty years.

When Brian said this, I patted myself on the back for having the wisdom to drop the X-ray crystallography project and focus on other research directions, because it seemed crazy to labor for twenty years trying to achieve a goal that might end up being just a pipe dream.

A dazzling leap

About a year later, in the spring of 2007, I received a call from Brian with some surprising news. He said that his lab had achieved a number of technical breakthroughs and now had a crystal structure for the beta-2 adrenergic receptor!  Indeed, that November, Brian, Ray Stevens and their collaborators published back-to-back papers in Science describing the crystal structure of the beta-2 adrenergic receptor. These papers were a technical tour de force. Brian's lab innovated at every step of the process: improving the purification process to obtain much larger quantities of pure receptor than was previously possible, engineering the receptor to be much more stable than it normally was, and a dozen other technical twists that other scientists couldn't even dream up, much less actually attempt.

This breakthrough had an enormous impact on the field, as everyone now saw the path forward to solving the crystal structures for the hundreds of other G protein–coupled receptors encoded in the human genome. I was dazzled by this quantum leap in technical capability and absolutely thrilled for Brian, who had gambled a great deal in pursuing these structural studies and now saw his gamble pay off in the biggest way imaginable. What I didn't know at the time, however, was that an even more dramatic advance was on the way.

Several years later, in July 2011, Brian's group published a lead article in Nature reporting the crystal structure of the beta-2 adrenergic receptor in complex with a G protein. This work was done collaboratively with several other labs, including the labs of Roger Sunahara, which had provided the purified G proteins used to achieve the docked structure, and Yiorgo Skiniotis, which had performed crucial electron microscopy work. This work was even more of a tour de force than the 2007 papers reporting the first structure of the beta-2 receptor. If you think it's hard getting one squirmy protein to sit still for a photograph, try getting two hyperkinetic proteins to hold still and pose together long enough to take a perfect photo. The technical advances in Brian's 2011 paper were staggering, and the structure was absolutely beautiful. Many new insights into how receptors work could be gleaned from this structure, and Brian went on a barnstorming tour to describe his lab's latest findings.

Nobel calling?

That summer, I was speaking at a Nobel Symposium in Stockholm. Brian was not giving a talk at the meeting, but people were talking about him. He had just shown his receptor-G protein structure at a European biophysics meeting, and Gunnar von Heijne, a member of the Nobel Committee for Chemistry, had witnessed the presentation. He then returned to Stockholm for the Nobel Symposium where I was speaking, and when I chatted with him during a break in the meeting I could tell that he was over the moon about Brian's latest breakthrough. The sentiment seemed to be shared by several other members of the Nobel Chemistry Committee who were attending the meeting. Of course, I had long ago given up trying to read into comments made by Nobel Committee members, as I had received many enthusiastic comments over the years from various Nobel Committee members without ever being tapped for a Nobel Prize.

Bob_Brian_Post_Nobel_Lecture-445x295.jpg
Courtesy of Roger Sunahara
Brian Kobilka and Bob Lefkowitz shared the 2012 Nobel Prize in Chemistry. This photo was taken just a few moments after the two finished their Nobel lectures.

That October, the Nobel Prize announcements came and went, and neither Brian nor I received a call from Stockholm. As usual, numerous people asked me questions about whether I would ever win. I kept thinking about what Al Gilman said after he won his Nobel: "The best thing about winning the Nobel Prize is never again having to answer the question, 'When are you going to win the Nobel Prize?'"

Admittedly, my situation in 2011 was not as bad as it had been in 2003, when my local paper, the Durham Herald-Sun, had run a front-page, above-the-fold photograph of me with a headline that read, Nobel Calling? Alas, Not This Year.At the time, I was thinking: who else in the world makes headlines for NOT winning the Nobel Prize? In 2003, that headline had bothered me a little bit. By 2011, I was just enjoying my day-to-day work as a scientist and mentor, and was absolutely done with worrying about awards.  Little did I know it then, but my life was about to change in dramatic fashion.

This was written by Robert Lefkowitz with Randy Hall, a former Lefkowitz postdoc who is now a professor in the Emory University School of Medicine and a prize-winning educator with strong interests in science writing and public outreach about science and medicine.

 

Robert J. Lefkowitz
Robert J. Lefkowitz

Robert J. Lefkowitz is a Nobel Prize–winning scientist (Chemistry, 2012) who is best known for showing how adrenaline works via stimulation of specific receptors. He was trained at Columbia, the National Institutes of Health and Harvard before joining the faculty at Duke University and becoming an Investigator of the Howard Hughes Medical Institute. In addition to being a researcher, he is a cardiologist as well as a cardiac patient.

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