Guiding neurons, and guiding scientists

Marc Tessier-Lavigne’s career has straddled academia and industry, and blurred traditional boundaries between basic and translational science

by ZACH VEILLEUX

Marc Tessier-Lavigne’s journey into neuroscience began a few hundred miles off the coast of Newfoundland, aboard the Queen Elizabeth II. It was 1980, and Dr. Tessier-Lavigne, then 20 years old, was headed to Oxford University with plans to pursue a Ph.D. in physics.

Physics wasn’t quite what he’d envisioned doing as a child, but it was close. Growing up, Dr. Tessier-Lavigne was certain he would become a mathematician, something he loved and excelled at in the French schools he attended while his father, a member of the Canadian Armed Forces, was posted to Europe. In college, at McGill University, he became focused on physics, and wrote his undergraduate thesis on the biophysics of blood flow.

But it was the five-day crossing to the U.K. — the Rhodes Scholarship he had secured to attend Oxford came with a free transatlantic cruise — that caused him to rethink those plans.
“During those restful days of contemplation on the ocean, I began to realize there was much I still wanted to explore before locking myself in to a specialty,” Dr. Tessier-Lavigne recalls. “While leafing through the thick book of Oxford’s courses of study, I decided to put my plans for an advanced degree on hold and instead pursue a second bachelor’s.” The Rhodes Scholarships do not put any restrictions on field of study, and so by the time the ship docked in Southampton, his new course was set.

The program he chose to pursue was called Philosophy, Psychology and Physiology. Normally, students study all three in their first year, then select two to specialize in for their final two years. Dr. Tessier-Lavigne, whose previous undergrad credits allowed him to skip the first year, immediately chose philosophy and physiology — by far the least popular of the permutations.

“It was an odd combination, but it turned out to be the perfect course of study for me,” he says. “It taught me logic and constructive skepticism and gave me my first exposure to neuroscience, which I immediately fell in love with. The brain is the most complex and fascinating organ in the body, and the thought that one could deconstruct and resolve that complexity was thrilling. My career was set.”

In 1983, Dr. Tessier-Lavigne moved down the road to London, where he would spend the next four years, his Ph.D. training, at a University College London lab bench performing electrical recordings from neural cells in slices of retinal tissue from the back of the eye. His training in physics proved useful in his work to understand how neural circuits processed information, but his curiosity soon led him to wonder how such circuits develop and form connections and, ultimately, how they alter those connections throughout life as a result of experience.

It was these fundamental questions of neuroscience that would drive Dr. Tessier-Lavigne’s work for the next three decades. Moving to the States for postdoctoral work at Columbia University, he sought to understand the molecular cues that are involved in guiding a developing neuron’s tendril-like axons through the body to connect with an appropriate target cell. He and his colleagues developed simple models of specific path-finding events in a Petri dish, and used the preparations to demonstrate the existence of chemoattractive activity for axon tips in the spinal cord.

A few years later, as a junior faculty member at the University of California at San Francisco, he made a name for himself by discovering the molecular identity of this chemoattractive factor, now called netrin. It was a high-risk project involving brute-force biochemistry and the brains of more than 25,000 chicken embryos, but it answered a question that had stumped neurobiologists for over a century, and it launched a new era of discovery in the neurosciences. Techniques and knowledge developed during the search for netrin have since been used — by Dr. Tessier-Lavigne and other labs around the world — to determine the identities of other guidance factors and better understand the neural wiring code that underlies the structure of the human brain and nervous system. The work also had potentially ground-breaking medical applications.

“Insights into axon growth and guidance during development have important implications for attempts to stimulate axon regeneration following injury in the adult nervous system,” Dr. Tessier-Lavigne says. “The development of drugs based on guidance factors like netrin has the potential to stimulate regeneration of nerve fibers following paralyzing spinal cord injuries.”

The possibility of creating such drugs was tantalizing, and so starting in the late ’90s, while still at UCSF, Dr. Tessier-Lavigne also became involved in a number of biotech ventures focused on bringing neurologic therapeutics to market. He served on several scientific advisory boards and cofounded a company, Renovis, Inc., devoted to treatments for neuroprotection, pain and neurodegenerative diseases. Moonlighting in the private sector turned out to suit him well.

“I was quite excited about what could be accomplished in industry, which has different strengths than academia,” he says. “It’s a team-oriented environment where people are working towards a defined goal — the development of medicines — and you can get to see the fruits of your work make their way through the clinic.”

He maintained relationships with several biotech firms as he climbed the ranks in academia. He was promoted to associate professor with tenure in 1995 and to professor in 1997, and he became a Howard Hughes Medical Institute investigator beginning in 1994. In 2001 he moved down the road to Stanford University, where he was named Susan B. Ford Professor in the School of Humanities and Sciences. But two years later, the draw of helping manage the scientific portfolio of one of the biggest names in biotechnology — Genentech — proved too powerful to resist.

Genentech was the original biotechnology firm, a company established in 1976 to harness the power of recombinant DNA technology. Its founders, a venture capitalist and a biochemist, joined forces at a time when neither academia nor industry had much interest in one another. Structured much like an academic institution, with semi-independent labs run by investigators and staffed with postdocs and technicians, Genentech proved to be an enormous success. Its first product, synthetic insulin, was the first genetically engineered human medicine to be approved by the FDA. Today, Genentech is owned by Hoffmann-La Roche and employs more than 11,000 people.

In 2003, Dr. Tessier-Lavigne took a leave of absence from Stanford and set up shop at Genentech. The firm had just had a string of commercial successes, and Dr. Tessier-Lavigne’s job was to help invest the new revenue into the next generation of therapeutics. Leading an enormous research organization — he started out directing about two-thirds of Genentech’s scientific personnel and eventually ran all of it — gave Dr. Tessier-Lavigne the chance to impact not just the sliver of neuroscience he had staked out as an academic, but also to influence how resources are allocated across many areas of bioscience. What’s more, although he could continue his basic research (Genentech, like Rockefeller, has a tradition of executives maintaining active labs), he could also be involved with translational work. He soon decided that biotech suited him well, and made a long-term commitment to Genentech.

“Over the course of my career, my initial interest in basic biological processes has grown into an equally strong interest in disease processes and in the medical applications of basic science,” Dr. Tessier-Lavigne says. “Genentech was appealing because of its deep commitment to innovative research that has the potential to create breakthrough therapies for unmet medical needs. It also has a vibrant and exciting scientific culture that fosters intellectual freedom.”

In fact, in many ways it’s a lot like Rockefeller. And since Dr. Tessier-Lavigne has made a career out of straddling the fence between basic and translational science, and has moved easily between the lab bench and executive suite, coming to Rockefeller feels like a natural progression. Rockefeller, after all, was founded to focus on translational medicine, pioneered the concept of a clinical research hospital and has a long history of encouraging scientists to straddle as many fences as they can.

“Basic and translational research depend on one another, and in many areas I believe we still don’t have the basic insights on which clinical work can build — that’s why places like Rockefeller are so important to our ability to tackle disease,” Dr. Tessier-Lavigne says.

Dr. Tessier-Lavigne’s own field, neuroscience, is a fitting example. Although he has continued to chip away at the mysteries of neuronal guidance over the past decade, and has made several important discoveries about the processes of neuronal degeneration such as those that underlie Alzheimer’s and Parkinson’s diseases, there are still no cures or reliable treatments. “Even now our understanding of what goes wrong in the brain is limited, and it’s holding up our ability to develop therapies,” he explains.

“Beyond disease, I remain as fascinated as ever by what initially drew me to biology: the functioning of complex biological systems, from the operation of molecular machines, to the morphogenesis of tissues and organs, to the ability of the brain to perceive and store memories. Rockefeller scientists remain at the forefront of research into these fundamental processes — another reason I am so excited to join this community.”

Dr. Tessier-Lavigne starts at Rockefeller on March 16. Several members of his existing Genentech research program will move with him over the next few months, and he plans to ultimately staff his lab with a total of a dozen or so members — postdocs, grad students and technical staff. It’s a size he feels is both manageable and productive and will allow him to keep his feet firmly planted in the process of making discoveries, his greatest joy. His family will move to New York once the school year ends. In coming months, he plans to familiarize himself with the institution, tap into its diverse community for counsel, and ultimately work with them to craft a strategy for guiding Rockefeller through the coming years.

He sees his roles at Rockefeller, as at Genentech, as those of leader and supportive player. “In both jobs, my primary responsibility is to help recruit great people and enable them to do great science,” says Dr. Tessier-Lavigne. “In that regard, the skills I have developed in eight years at Genentech are directly relevant to how I will operate as president of Rockefeller. Together we will chart the course for the university in the next five, ten, twenty years. Within that framework, my aim will be to enable the university’s faculty, students and research staff to be all that they can be, to serve as mentor, colleague and problem-solver and to make sure people have the resources they need to focus on producing transformative science with a minimum of distractions. Just as important, I will focus on making the university a great place to work for all its members — scientists, administrators and support staff.

“That’s the formula that has led to the university’s sustained success over its long history, and it’s what will allow it to remain an international pioneer in fundamental bioscience, in its application to human health and in training future scientific leaders.”