Thomas Südhof wins Nobel Prize in Physiology or Medicine

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.

Steve Fisch Thomas Sudhof won the 2013 Nobel Prize in Physiology or Medicine.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.

He shared the prize with James Rothman, PhD, a former Stanford professor of biochemistry, and Randy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine.

The three were awarded the prize "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells." Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

"I'm absolutely surprised," said Südhof, 57, who was in the remote town of Baeza in Spain to attend a conference and give a lecture. "Every scientist dreams of this. I didn't realize there was chance I would be awarded the prize. I am stunned and really happy to share the prize with James Rothman and Randy Schekman."

Südhof noted that, although he hasn't directly worked with either of the other winners, their work was complementary and he called the Nobel committee "ingenious" in pairing the three of them. The researchers will share a prize that totals roughly $1.2 million, with about $413,600 going to each.

"Tom Südhof has done brilliant work that lays a molecular basis for neuroscience and brain chemistry," said Roger Kornberg, PhD, Stanford's Mrs. George A. Winzer Professor in Medicine. Kornberg was awarded the Nobel Prize in Chemistry in 2006. He is the son of Arthur Kornberg, in whose lab Schekman received his doctorate.

'Dazed and happy'

Robert Malenka, MD, Stanford's Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, is at the conference in Spain with Südhof, a close collaborator. "He's dazed, tired and happy," Malenka said by phone. "The only time I've seen him happier was when his children were born."

Südhof, the Avram Goldstein Professor in the School of Medicine, received the award for his work in exploring how neurons in the brain communicate with one another across gaps called synapses. Although his work has focused on the minutiae of how molecules interact on the cell membranes, the fundamental questions he's pursuing are large.

"The brain works by neurons communicating via synapses," Südhof said in a phone conversation this morning shortly after the announcement. "We'd like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?" In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice's synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Lloyd Minor, MD, dean of the School of Medicine, said, "Thomas Südhof is a consummate citizen of science. His unrelenting curiosity, his collaborative spirit, his drive to ascertain the minute details of cellular workings, and his skill to carefully uncover these truths — taken together it's truly awe-inspiring.

"He has patiently but relentlessly probed one of the fundamental questions of medical science — perhaps the fundamental question in neuroscience: How nerve cells communicate with each other. The answer is at the crux of human biology and of monumental importance to human health. Dr. Südhof's receipt of this prize is inordinately well-deserved, and I offer him my heartfelt congratulations. His accomplishment represents what Stanford Medicine and the biomedical revolution are all about."

Sweden calling

The Nobel committee called Südhof on his cell phone after trying his home in Menlo Park, Calif. His wife, Lu Chen, PhD, associate professor of neurosurgery and of psychiatry and behavioral sciences, then gave the committee his cell phone number to reach him in Spain.

Robert Malenka Thomas Sudhof pauses in Spain to celebrate winning a Nobel prize. Sudhof was on his way to the Sede Antonio Machado to deliver a lecture today about his work when he received the call from Sweden.

"The phone rang three times before I decided to go downstairs and pick it up," Chen said. "I thought it was one of my Chinese relatives who couldn't figure out the time zone."

Chen and Südhof have two young children, and Südhof has four adult children from a previous marriage. "I was very surprised," Chen said, "but he's more concerned about how I'll get the kids up this morning in time for school."

"I was expecting a call from a colleague about the conference I'm here to attend, so I pulled off in a parking lot," said Südhof, who was driving from Madrid to Baeza at the time he received the announcement. "I hadn't slept at all the previous night, and I certainly wasn't expecting a call from the Nobel committee."

On the day he got that call, he was scheduled to give a talk at a conference, Membrane Traffic at the Synapse: The Cell Biology of Synaptic Plasticity, being held in Baeza in a 17th-century building that now serves as a conference center.

"Professor Sudhof's contributions to the understanding of how cells operate have been of enormous importance to medicine, and to his own work in understanding how connections form within the human brain," said Stanford President John Hennessy. "The recognition by the Nobel committee is a remarkable achievement."

Südhof, who is also a Howard Hughes Medical Institute investigator, has spent the past 30 years prying loose the secrets of the synapse, the all-important junction where information, in the form of chemical messengers called neurotransmitters, is passed from one neuron to another. The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of taking a step forward, experiencing a fleeting twinge of regret, recalling an incident from the morning commute or tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and peripheral nervous system.

"We're thrilled to see years of curiosity and persistence pay off for Tom with this terrific recognition," said Erin O'Shea, PhD, vice president and chief scientific officer at HHMI. "You know, what culminates in a Nobel Prize usually begins 20 or 30 years earlier, with a good idea and the guts to pursue it. HHMI likes to say that it supports people, not projects, and we join Stanford in toasting Tom and his collaborators for showing us the promise of basic research, fulfilled."

Outnumbering the Milky Way

Even a moment's consideration of the total number of synapses in the typical human brain adds up to instant regard for that organ's complexity. Coupling neuroscientists' ballpark estimate of 200 billion neurons in a healthy adult brain with the fact that any single neuron may share synaptic contacts with as few as one or as many as 1 million other neurons (the median is somewhere in the vicinity of 10,000) suggests that your brain holds perhaps 2 quadrillion synapses — 10,000 times the number of stars in the Milky Way.

"The computing power of a human or animal brain is much, much higher than that of any computer," said Südhof. "A synapse is not just a relay station. It is not even like a computer chip, which is an immutable element. Every synapse is like a nanocomputer all by itself. The amount of neurotransmitter released, or even whether that release occurs at all, depends on that particular synapse's previous experience."

Much of a neuron can be visualized as a long, hollow cord whose outer surface conducts electrical impulses in one direction. At various points along this cordlike extension are bulbous nozzles known as presynaptic terminals, each one housing myriad tiny, balloon-like vesicles containing neurotransmitters and each one abutting a downstream (or postsynaptic) neuron.

When an electrical impulse traveling along a neuron reaches a presynaptic terminal, calcium from outside the neuron floods in through channels that open temporarily in the terminal. A portion of the neurotransmitter-containing vesicles fuse with the terminal's outer membrane and spill their contents into the narrow gap separating the presynaptic terminal from the postsynaptic neuron's receiving end.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion: As a result, synaptic transmission is today one of the best-understood phenomena in neuroscience.

L.A. Cicero Lu Chen, right, wife of Nobel prize winner Thomas Sudhof, gathers with Sudhof's postdocs and grad students to celebrate the award today. The lab members ate pizza and toasted Sudhof, who is attending a conference in Spain.

Born in Germany

Südhof, who was born in Germany in 1955, earned an MD in 1982 from Georg-August-Universität in Göttingen. He came to Stanford in 2008 after 25 years at the University of Texas Southwestern Medical Center at Dallas, where he first worked as a postdoctoral scholar in the laboratories of Michael Brown, MD, the director of the Eric Jonsson Center for Research in Molecular Genetics and Human Disease, and Joseph Goldstein, MD, chair of the Molecular Genetics Department. Brown and Goldstein were awarded the Nobel Prize in Physiology or Medicine in 1985 for their work in understanding the regulation of cholesterol metabolism. In 1986, Südhof established his own laboratory at the university.

"Thomas Südhof is a biomedical exceptionalist — like Babe Ruth was an exceptionalist in baseball, Leonard Bernstein in music, and Steve Jobs in computers," said Goldstein. "Having done his Nobel work at UT-Southwestern in Dallas, Thomas is our sixth faculty member to win a Nobel prize. This is quite a record for a relatively 'small' medical school."

Südhof became an HHMI investigator in 1986, and moved to Stanford as a professor in molecular and cellular physiology in 2008. With this award, Stanford's Department of Molecular and Cellular Physiology now includes three Nobel laureates: Südhof; Brian Kobilka, MD, who received the Nobel Prize in Chemistry in 2012; and Steven Chu, PhD, who received the Nobel Prize in Physics in 1997. (Chu recently joined the department. He is the William R. Kenan Jr. Professor of Physics and professor of molecular and cellular physiology at Stanford. Until April, he served as U.S. Secretary of Energy.)

"This is fantastic news and greatly deserved. I'm very happy for Tom, and we are all proud to have him as a colleague in our department," said Kobilka. "We've always been an amazing department; it's just that most of the academic world didn't know it."

"I'm really thrilled and proud that we have such outstanding and amazing research going on in our department," said Axel Brunger, PhD, professor and chair of molecular and cellular physiology, as well as professor of neurology and neurological sciences, who has been involved in a series of joint projects with Sudhof.

"Dr. Sudhof's work has set the stage for a deep understanding of the complexities of neuronal communication."He's a great collaborator. We had really great interactions with him and his group. He's willing to help and to share data results."

The proteins Südhof and his lab have focused on for close to three decades are disciplined specialists. They recruit vesicles, bring them into "docked" positions near the terminals, herd calcium channels to the terminal membrane, and, cued by calcium, interweave like two sides of a zipper and force the vesicles into such close contact with terminal membranes that they fuse with them and release neurotransmitters into the synaptic gap. Although these specialists perform defined roles at the synapses, similar proteins, discovered later by Südhof and others, play comparable roles in other biological processes ranging from hormone secretion to fertilization of an egg during conception to immune cells' defense against foreign invaders.

"We've made so many major advances during the past 50 years in this field, but there's still much more to learn," said Südhof, who in a 2010 interview with The Lancet credited his bassoon instructor as his most influential teacher for helping him to learn the discipline to practice for hours on end. "Understanding how the brain works is one of the most fundamental problems in neuroscience."

He elaborated in the press call a few hours after the announcement. "There is a gap, a tremendous gap, between the need to understand diseases that affect the brain and the understanding that we have. Not because of lack of effort, but because the problem is so daunting. I do think that our work will contribute a little to the task, which is enormous. I am convinced that will eventually lead to therapies." In addition to schizophrenia and autism, Südhof cited the role of synapse dysfunction in Parkinson's disease and a rare but devastating childhood seizure disease called Ohtahara syndrome.

Südhof's accomplishments also earned him the 2013 Lasker Basic Medical Research Award. He is a member of the National Academy of Sciences, the Institute of Medicine and the American Academy of Arts & Sciences. He also is a recipient of the 2010 Kavli Prize in neuroscience.

The value of basic science

In the Lancet interview, Südhof defined basic research as an approach often neglected in the pursuit of medicine. "This 'solid descriptive science,' like neuroanatomy or biochemistry, [are] disciplines that cannot claim to immediately understand functions or provide cures, but which form the basis for everything we do."

"I think that in general the value of science is being heavily discussed in the U.S., and it worries me tremendously," said Südhof said during the press call in response to a question about declining levels of funding for this type of research. "In my personal view, Western civilization is based in part on science; it is part of our Greco-Roman heritage, this search for truth. But it seems to me that there is a significant, increasingly vocal population that thinks we shouldn't go after truth, and that truth is not important. That worries the hell out of me."

Calling the value of unbiased information the "core of my personal beliefs," Südhof said he feels funding for his type of award-winning research is in danger. "Many people say, 'We've spent so much money on research, and we should get something out of it.'" Südhof argued that, in fact, there has been enormous progress, and enormous benefit, from research spending, the amount of which pales when compared to that spent on medical treatment.

"We need to make sure that research funding is awarded based on merit, and not based on location or political connections," said Südhof . "It should be based on what someone actually does."

Asked what advice he would give to a new college graduate, Südhof replied, "More than anything, follow your passions. What are you actually interested in? What work satisfies you? I have met so many unhappy rich people. I think that, in order for a person to reach his or her potential and to be happy is to work in an area that they enjoy, can support and feel good about. I have given the same advice to my adult children."

Südhof said this morning he is excited to speak with his family about the prize, although it may be too much for his youngest children, ages 3 and 4, to grasp. "I will try to explain it to them," he said. "It will be a wonderful occasion." He noted that he has already received congratulatory calls from two of his older children. For them, the news may have come as less of a surprise.

"The Nobel prize became an inevitable topic of conversation when Tom won the Lasker award," Chen said. "But the two of us share a feeling that one should never work for prizes." Asked if she was tempted to tell her husband herself, rather than letting the Nobel committee do the honors, Chen, who said her first two loves are "neuroscience and Tom," answered, "No, I wanted him to hear it from them because the thrill is different. I didn't want to deprive him of that."

"Everyone has pegged him as a potential Nobel prize winner for many years," said Malenka. "It was just a matter of time."

Although he plans to return to the United States later this week, Südhof has no plans to let the award slow his research — or even his plans for the day. He responded to an inquiry with a characteristically low-key reply. "Well, I think I'll go ahead and give my talk."