September 9, 2013 - By Bruce Goldman
Thomas Südhof is being recognized for his work in understanding how nerve cells communicate with each other.
Given to wearing sporty sweaters even on hot, sunny days, he is a man whose research is as meticulous as his attire is casual. Bit by bit, his patient sleuthing has pioneered our understanding of how nerve cells, which scientists call neurons, communicate with one another. And now, Thomas Südhof, MD, has been named a winner of the 2013 Lasker Basic Medical Research Award, culminating almost three decades' worth of unrelenting, focused work.
The award, among the most respected science prizes in the world, is given annually by the New York City-based Albert and Mary Lasker Foundation to honor visionaries whose insight and perseverance have led to dramatic advances with practical medical potential.
A professor of molecular and cellular physiology at the Stanford University School of Medicine, Südhof will be honored at a Sept. 20 ceremony in New York City. He will share the prize's $250,000 honorarium with co-winner and former Stanford scientist Richard Scheller, PhD, now executive vice president for research and early development at South San Francisco-headquartered Genentech Inc. (Scheller's Lasker-winning research was performed at Stanford, where he was a faculty member from 1982 to 2001.)
"We are all proud of Dr. Südhof's contributions to science and grateful to the Lasker Foundation for recognizing the value of his work," said Lloyd Minor, MD, dean of the School of Medicine. "With his passion for basic research and drive to piece together a puzzle of unquestionable clinical importance, he exemplifies the qualities that make Stanford Medicine a leader in advancing science."
Südhof is the Avram Goldstein Professor in the School of Medicine. He is a member of the National Academy of Sciences, the Institute of Medicine and the American Academy of Arts & Sciences and is a recipient of the 2010 Kavli Prize in neuroscience. His peers' descriptions of him abound with phrases such as "integrity," "intensity," "intuition," "intellect" and "a memory so prodigious it's scary."
"I don't know how he does it," said Robert Malenka, MD, PhD, professor of psychiatry and behavioral sciences at Stanford, who has known Südhof since the early 1990s. "Tom's the scientific equivalent of a force of nature. He is the most productive scientist I have ever seen. The extent of his contribution to the field is mind-boggling. Without him, we would be at least 10 years behind."
Axel Brunger, PhD, professor and chair of molecular and cellular physiology, as well as professor of neurology and neurological sciences, has been involved in a series of joint projects with Südhof. "Tom is driven by a desire to understand things at a deep level," Brunger said. "He's a great collaborator, and very successful at motivating his graduate students and postdocs. Many people from his group have gone on to become tenured faculty at first-rate institutions."
Südhof's reaction to being named a Lasker Award winner was characteristically humble. "You wonder if it's justified," he said.
The co-author of close to 500 peer-reviewed studies, Südhof has helped to pry 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.
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 one of these presynaptic terminals, calcium from outside the neuron floods in through channels that open temporarily, and a portion of the neurotransmitter-containing vesicles fuse with the surrounding bulb'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 Scheller and several other researchers worldwide, have 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.
The proteins Südhof has 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.
"I think Tom, more than any other investigator in the world, has revolutionized our understanding of the molecular mechanisms of synaptic transmission," Malenka said. "These proteins are being studied in hundreds of labs around the world as we speak."
Südhof loves the outdoors and San Francisco Symphony concerts, but he seldom gets to enjoy them these days; his time is consumed by 10-hour workdays and parenting his two youngest children, ages 2 and 4, with his wife, Lu Chen, PhD, associate professor of psychiatry and behavioral sciences. (He also has four grown children by another marriage.) Although he wishes he didn't have to spend such a huge amount of his working time writing grant proposals, his status as a Howard Hughes Medical Institute investigator helps relieve some of the burden.
Südhof was born in 1955 in Göttingen, Germany, one of four children of two physicians. At age 19, with the intention of becoming a practicing physician himself, he attended medical school first at Aachen, then at Göttingen, where he was mentored by pre-eminent biochemist Victor Whittaker, PhD, who first isolated and biochemically purified mammalian presynaptic vesicles.
Earning a medical degree in 1982, Südhof completed an internship at Gottingen before proceeding, in 1983, to a postdoctoral appointment at the University of Texas-Southwestern under Joseph Goldstein, MD, and Michael Brown, MD. The two researchers, who share a lab to this day, were already famous for their studies of cholesterol metabolism and, in particular, the LDL (low-density cholesterol) receptor, easily one of the most significant proteins in cardiovascular medicine. (The pair shared a Nobel Prize in medicine in 1985.) During his postdoctoral tenure there, Südhof succeeded in cloning the gene for the LDL receptor.
Goldstein and Brown convinced Südhof to forgo a clinical career and stick with research. In 1986, he became an assistant professor at UT-Southwestern. It was then that he moved from lipid metabolism to the question of how synapses work. "I might have been just as happy to have been a practicing primary-care doctor," he said. "But as a medical student I had interacted with patients suffering from neurodegeneration or acute clinical schizophrenia. It left an indelible mark on my memory."
Herein lay the lab bench's potential, Südhof recalled thinking. "We pretty much know how to build a bridge or an airplane. But nobody knows how to deal with mental or neuropsychiatric disorders. We're only now beginning."
It was known that presynaptic terminals are filled with tens to hundreds of small, standardized, synaptic vesicles, and that the release of these vesicles' contents were triggered by calcium. But nobody had any idea how any of it actually worked. Südhof's two decades as a UT-Southwestern faculty member, punctuated by a brief sojourn back in Gottingen in the late 1980s, helped to solve the riddle.
In 2008, the Avram Goldstein endowed professorship at Stanford opened up. Former Stanford professor of neurology and neurological sciences William Mobley, MD, PhD, who then led the medical school's neuroscience institute, wooed Südhof to the campus.
Since then, Südhof's pursuits have included a joint effort with Brunger to pinpoint the normal biological function of a protein called alpha-synuclein, far better known for its neuropathological potential than for any constructive behavior in neurons. Mutations in alpha-synuclein, and other less well-understood factors, can cause it to misfold and aggregate into clumps called Lewy bodies, the hallmark neurological feature of Parkinson's disease.
"One thing we've wanted to know," said Brunger, "is whether a mutation's effects arise due to the plaques formed by misfolded alpha-synuclein, or are due to the mutation's having compromised the protein's normal physiological function."
But until lately, nobody had any idea what the protein's putative "normal" physiological function — if any — was. In 2010, Südhof discovered that alpha-synuclein functions to maintain neurotransmitter release over the lifetime of an organism, and that a loss of alpha-synuclein leads to neuronal dysfunction. A series of studies extended these seminal findings to explore how alpha-synuclein contributes to neurodegeneration.
In a study published last April, Südhof and Brunger showed that alpha-synuclein helps regulate the orderly clustering of neurotransmitter vessels near their release sites. Their discoveries suggest that the actual loss of alpha-synuclein's healthy function plays a part in the pathology of Parkinson's. If so, drugs that restore or substitute for that activity might help.
Another push by Südhof has been the study of synaptic cell adhesion proteins that bridge the pre- and post-synaptic sides of a synapse. Understanding how synaptic cell adhesion proteins work in making synapses form and in maintaining their function or organizing their restructuring during processes such as learning and memory is now a major focus of his lab.
"I would love to know how synaptic connections are formed in the brain, both during development and throughout life," he said. "I think that is the most important question in neuroscience." Knowledge about synapse formation and restructuring will open a window of insight into understanding not only cognitive processes, but also schizophrenia and autism.
Asked to recall any defining "eureka!" moments that had catapulted his hunches forward to the status of certainty, Südhof noted that in his experience, science advances step by step, not in jumps. "I believe strongly that most work is incremental," he said. The systematic solution of highly complex problems requires a long view and plenty of patience.
He added that he'd learned a valuable lesson from Goldstein and Brown: "You shouldn't worry what journals you publish your papers in. This has become almost an obsession now. But as Joe and Mike always said, most papers are forgotten soon enough. What counts is not what journal you publish in but whether, 20 years later, these papers still matter."
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