When neuroscientist Samuel Pfaff was a postdoc at Vanderbilt University in Nashville, he and his future wife often visited her family in Pasadena, California. On one of those visits, the couple decided to take a side trip to San Diego. As they drove down Torrey Pines Road, he saw the Salk Institute for Biological Studies perched on a bluff overlooking the Pacific Ocean.

"I still have a really vivid memory," Pfaff says. "I remember thinking, "Anyone who runs a lab there has to be one of the luckiest people in the world. They must have the perfect career.' "

Today, many would say almost the exact same thing about Pfaff. The scientist doesn't just have a lab at the Salk Institute: He sits in Jonas Salk's former office--or part of it at least; the office has been subdivided--next to Salk's favorite window, which features a removable glass pane that Pfaff takes out some days to let in the sea breeze.

Pfaff's life may look charmed from the outside, but his path to the Salk Institute presented a mix of opportunities and challenges, occurring, often as not, when they were least expected. The first time he saw the building that has since become his scientific home, he was recovering from a difficult graduate experience at the University of California (UC), Berkeley: It was the late 1980s, and his graduate adviser, the renowned virologist Peter Duesberg, had become an outspoken skeptic of the then-new proposition that HIV causes AIDS. Pfaff recalls that he and Duesberg were barely on speaking terms by the time Pfaff finished his Ph.D. Pfaff was uncertain whether he would be able to find the kind of independent research position he sought.

Early promise, early challenges

Raised in Rochester, Minnesota, Pfaff discovered his affinity for science early. When he was in high school, a teacher suggested he talk to a neuroscientist at the Mayo Clinic, which led to Pfaff's first position in a biology lab. "I started as a volunteer. I'd go straight from school," he says. "For somebody my age, it was just an incredible opportunity to be involved in making discoveries."

From Rochester, Pfaff went to Carleton College in Northfield, 40 miles from home. Although research options were limited at Carleton, he confirmed his love of science there and discovered developmental biology. He was thrilled when, in 1983, UC Berkeley accepted him as a graduate student. And after a series of rotations, he settled into Duesberg's lab, where he hoped to learn microbiology.

"He was truly a hotshot at that particular stage of his career," Pfaff recalls. "He was well-funded, maybe one of the best-funded labs [at Berkeley]. His students were publishing lots of papers, going to great postdocs." When he first arrived there, Pfaff found Duesberg inspirational, devoted to science, and always at the bench. Pfaff was working in Duesberg's lab when he was elected to the National Academy of Sciences in 1986.

Then, Pfaff says, things started to change. Duesberg became more and more critical of other scientists and, particularly, of research being done on HIV and AIDS. In 1987, Duesberg published a paper arguing that HIV is harmless. He maintains that position today; it's one that's made him a scientific pariah.

Being Duesberg's student at the time the senior scientist was staking that position was a challenge. "He was losing the respect of other scientists. I wondered what that would mean for me," Pfaff recalls. "[At scientific meetings], I remember the feeling of embarrassment telling people this is the lab I work in and fearing they wouldn't come to my poster, thinking I'd talk about HIV and AIDS, when my research had nothing to do with it."

He says lab meetings became difficult to stomach and that, being both young and stubborn, he probably didn't handle his disagreements with Duesberg very gracefully. "There was, I'm sure, a lot of body language on my part that he didn't appreciate. ... I just sort of stopped talking to him. Even though we might be standing right next to each other [at the bench], we'd be trying not to acknowledge each other. Looking back, I'm not proud of my behavior," he says. "I just wanted to do enough research to finish my dissertation and get out of there."

"I think he was the least happy of my graduate students," Duesberg says. Duesberg does not recall that the two stopped speaking but concurs that it was not a successful match.

Finding his way

Given that he was trying not to speak to his adviser, Pfaff moved forward on his own. Eventually, he managed to finish his Ph.D. research and publish two papers on different oncogenes, but he was not particularly proud of the work. (He says his committee members commented that the dissertation seemed average, and he didn't disagree.) The experience left him drained. He wasn't ready to give up on a career in science, but he felt certain he wasn't qualified to apply for postdocs at major research institutions.

"I didn't feel I would even be considered by some of the better laboratories in the country. Maybe I had low self-esteem. I wasn't getting any career advice," he says. At that point, he and his girlfriend (now his wife) had been maintaining a long-distance relationship for 3 years while she pursued a Ph.D. at Vanderbilt University. Unsure what to do next, Pfaff decided to see if he could find a position in a lab at the school. William Taylor, a scientist there, was starting to do molecular biology in frog embryos, a system that had fascinated Pfaff as an undergrad.

Taylor recalls that he asked about Pfaff's graduate experience, but he was more interested in the young scientist's abilities than his mentor's views. "I asked and he implied that those were Peter's ideas, not his," says Taylor, now director of the Molecular Resource Center at the University of Tennessee Health Science Center in Memphis. He offered Pfaff a postdoc position. "Sam was by far the brightest person in the lab," Taylor says. "It was like having another PI [principal investigator] in the lab; it was amazing."

For Pfaff, the time in Taylor's lab was a chance to work with a mentor who took an interest in his research and his career. "It gave me a chance to reestablish myself in science," he explains. By the time his wife finished her Ph.D., Pfaff's project was wrapping up, but he still felt unable to compete for the kind of position he dreamed of. "I thought I could probably be considered for positions where my primary position would be teaching and I could maybe dabble in science," he recalls.

At about that time, a mutual friend introduced Pfaff to Thomas Jessell, a neuroscientist at Columbia University. Jessell says he felt Pfaff had picked up useful virology skills in Duesberg's lab regardless of Duesberg's position on AIDS. Pfaff's work in Taylor's lab showed that the young scientist "could work on problems in a rigorous way," says Jessell, now Claire Tow Professor of neuroscience, biochemistry and molecular biophysics and co-director of Columbia's Kavli Institute for Brain Science. "I think I just got the idea that Sam was very competent." It didn't hurt that Pfaff brought microbiology skills that Jessell needed at the time. He offered Pfaff a postdoc.

"When I went to Jessell's lab, I knew it was just an incredible opportunity, and I also knew it was my last chance if I was going to stay in research science," Pfaff recalls. Pfaff again switched systems, helping Jessell's lab start doing mouse genetics. His work on how the selective expression of LIM homeobox genes regulates the development of neurons in the embryonic spinal cord helped set the stage for future research in Jessell's lab and, later, Pfaff's own. "It was our first real foray into gene targeting," Jessell says. "I think it made it clear that [the problem] was approachable."

Independence

As that project came to an end, Pfaff finally felt ready to apply for the kind of research positions he'd been thinking about since high school. He received offers from "about a half-dozen institutions," he says.

The Salk Institute didn't offer the biggest financial package, but it did offer the La Jolla bluffs. Even more important, it offered a collegial environment and colleagues Pfaff could envision as future collaborators. He accepted the offer, and in 2005 he cleared the last hurdle, becoming full professor there. In 2008, he was named a Howard Hughes Medical Institute Investigator. He continues to study the fetal development of the spinal cord.

Pfaff says he hasn't spoken with Duesberg since he left Berkeley, and Duesberg says he hasn't had any new graduate students in his lab since he began arguing against the link between HIV and AIDS. Pfaff says his experience in the lab at Berkeley has shaped how he runs his own lab today: He considers mentoring a key component of his job.

"I tell students, 'There will be some point in your career where things will not be optimal.

You'll have to deal with some aspect of disappointment,' " he says, noting that it's easy to do good work when everything's going well. "You're defined by what you do when you encounter challenges."

Robin Mejia is a science writer in Santa Cruz, California.

is a science writer in Santa Cruz, California.
10.1126/science.caredit.a0900122