The Nobel Assembly at the Karolinska Institute announced today that Randy W. Schekman, a Howard Hughes Medical Institute (HHMI) investigator at the University of California, Berkeley, Thomas C. Südhof, an HHMI investigator at Stanford University, and James E. Rothman of Yale University are the recipients of the 2013 Nobel Prize in Physiology or Medicine for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.
According to the Nobel Assembly, this year’s Nobel Prize in Physiology or Medicine honors three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.
Schekman discovered a set of genes that were required for vesicle traffic. Rothman unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Südhof revealed how signals instruct vesicles to release their cargo with precision.
Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.
Randy W. Schekman
Traffic inside a cell is as complicated as rush hour near any metropolitan area. But drivers know how to follow the signs and roadways to reach their destinations. How do different cellular proteins “read” molecular signposts to find their way inside or outside of a cell?
For the past three decades, Randy Schekman has been characterizing the traffic drivers that shuttle cellular proteins as they move in membrane-bound sacs, or vesicles, within a cell. His detailed elucidation of cellular travel patterns has provided fundamental knowledge about cells and has enhanced understanding of diseases that arise when bottlenecks impede some of the protein flow. Schekman has been an HHMI investigator since 1991. He also serves as editor-in-chief of the open access research journal eLife.
His work earned him one of the most prestigious prizes in science, the Albert Lasker Award for Basic Medical Research, which he shared with James Rothman in 2002.
Schekman’s path to award-winning researcher began with a youthful enthusiasm for science and math, which he attributes to his father, an engineer who helped develop the first online program for real-time stock quotes. High school science fairs—and winning them—further whetted his appetite for competitive science. Biology’s power hit him more personally, though, when his teenage sister died of leukemia.
He considered pursuing medical school as an undergraduate at the University of California, Los Angeles. But after spending his junior year in a laboratory at the University of Edinburgh, his path to graduate school became set. He obtained a Ph.D. in biochemistry at Stanford in the laboratory of Arthur Kornberg, who won the Nobel Prize in 1959 for identifying a key enzyme in DNA synthesis.
Schekman first became interested in how proteins move within cells during a postdoctoral fellowship between 1974 and 1976 with John Singer, who was studying the outer membranes of mammalian cells. At the time, though, scientists couldn’t easily study the steps of vesicle movement in mammalian cells growing in culture.
So Schekman, who moved in 1976 to the University of California, Berkeleyexternal link, opens in a new tab, as an independent investigator, decided to use yeast, a one-celled microorganism, to determine how vesicles containing proteins move inside and outside the cell. Scientists can easily genetically manipulate yeast, which have membrane-bound organelles similar to those of higher organisms. Organelles, such as mitochondria or the Golgi apparatus, are structures within cells that perform specified functions.
When Schekman began his yeast studies, scientists only had a general sense of the cellular traffic patterns that proteins follow: Ribosomes manufacture proteins, which enter the endoplasmic reticulum, a membranous network inside the cell. Vesicles carrying proteins pinch off from the endoplasmic reticulum and travel to the Golgi apparatus, which further processes the proteins for internal or external use.
What Schekman, using genetic methods, and Rothman, with biochemical approaches, working independently did, was dissect in meticulous detail the molecular underpinnings behind vesicle formation, selection of cargo, and movement to the correct organelle or path outside the cell.
Ultimately, he identified 50 genes involved in vesicle movement and determined the order and role each of the different genes' protein products play, step by step, as they shuttle cargo-laden vesicles in the cell. One of the most important genes he found, Schekman says, is the SEC61 gene, which encodes a channel through which secretory proteins under construction pass into the endoplasmic reticulum lumen. When this gene is mutant, proteins fail to enter the secretion assembly line.
Another significant set of genes he discovered encode different coat proteins that allow vesicle movement from the endoplasmic reticulum and from the Golgi.
Although Schekman’s research was done in yeast, follow-up studies confirmed that higher organisms, such as humans, share the majority of the genes in the yeast secretory pathway. Such knowledge provided a foundation for understanding normal human cell biology and disease states.
In fact, as the study of the genetics of mammalian cells has become easier, Schekman has been characterizing human diseases that arise from secretory pathway problems. He has identified the structural basis of a rare craniofacial disease that disrupts the construction of a coat protein complex essential for transport vesicle formation. He also is studying whether the accumulation in the brains of Alzheimer’s disease patients of the protein amyloid is due to a secretion pathway roadblock.
While many steps in vesicular trafficking are now known, some have evaded discovery. Schekman continues to look for receptors in the endoplasmic reticulum membrane that find appropriate protein cargo for transport to the Golgi. He is also trying to identify molecules that help protein-laden vesicles move from the Golgi out of the cell. Schekman, with as much passion for science today as he has had throughout his career, is confident he can persuade Nature to reveal undiscovered routes in her traffic patterns.
Thomas C. Südhof
For people to have ideas, to experience happiness, or to remember the lyrics of a song, the neurons in their brains must communicate. This communication occurs in a manner similar to a relay racer passing a baton from one runner to the next.
When stimulated, a presynaptic neuron releases a “baton” in the form of a chemical messenger—called a neurotransmitter—across a synapseexternal link, opens in a new tab, a small gap between the cells in the brain. Then, a postsynaptic neuron absorbs the message and conveys it to subsequent neurons.
For decades, the majority of neuroscientists focused their research on postsynaptic neurons and their role in learning and memory. But throughout his career, Thomas Südhof has studied the presynaptic neuron. His collective findings have contributed to much of our current understanding of how a presynaptic neuron releases neurotransmitters and, more recently, how synapses form. His work also has revealed the role of presynaptic neurons in psychiatric illnesses, such as autism. Südhof has been an HHMI investigator since 1986.
Born in Germany, Südhof obtained a medical degree from the University of Göttingen in 1982. He got a taste for neuroscience when he performed research for his doctoral degree at the Max-Planck-Institute for Biophysical Sciences under Victor P. Whittaker, a pioneer in neurochemistry. To expand his knowledge of biochemistry and molecular biology, Südhof then started to work in 1983 as a postdoctoral fellow at the laboratories of Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center at Dallas.
There, Südhof cloned the gene for the receptor of LDL (the low-density lipoprotein), a particle in the blood that transports cholesterol. Moreover, his work identified the sequence that mediates the regulation of the LDL receptor gene expression by cholesterol. While Südhof was in their laboratories, Brown and Goldstein won the Nobel Prize in Physiology or Medicine in 1985 for their discoveries related to the regulation of cholesterol metabolism.
Soon after, in 1986, UT Southwestern offered Südhof the opportunity to start his own laboratory. He began his inquiry into the presynaptic neuron. At the time, what scientists mainly knew about the presynaptic neuron is that calcium ions stimulate the release of neurotransmitters from membrane-bound sacs called vesicles into the synapse, in a process that takes less than a millisecond. This release involved fusion of the vesicles with the plasma membrane, but how such fusion occurs, and how it is triggered by calcium was unknown.
Südhof decided to try to answer these questions. His work revealed that fusion of the synaptic vesicles, the small sacs filled with neurotransmitters, involves an obligatory catalytic protein called Munc18-1 that acts in conjunction with a protein machine made up of so-called SNARE proteins that were described by others and provide the muscle to the brawn of Munc18-1. Strikingly, the function of Munc18-like and SNARE-type proteins generally applies to most fusion reactions in biology, not only to synapses.
More importantly, Südhof’s work shows how calcium controls fusion at the synapse: He showed that calcium binds to synaptotagmin proteins, thereby stimulating synaptotagmins to trigger rapid neurotransmitter release. Again, Südhof’s work revealed that synaptotagmins also act as universal calcium sensors in non-neuronal cells, for example for release of hormones in non-neuronal cells.
Furthermore, his work described how a complex of organizing proteins, containing RIM and Munc13 proteins as central coomponents, embed the fusion machinery into the presynaptic nerve terminal. The RIM/Munc13 complex recruits and prepares vesicles for fusion, and tethers calcium channels in the plasma membrane next to the release sites to allow rapid coupling of neuronal excitation to neurotransmitter release.
In more recent studies that intensified after Südhof moved to Stanfordexternal link, opens in a new tab in 2008, Südhof’s work examined how pre- and postsynaptic proteins form physical connections during synapse formation. Specifically, he identified proteins on presynaptic neurons called neurexins, and proteins on the postsynaptic neuron called neuroligins and LRRTMs, that come together and bind to each other across the synaptic cleft. There are many types of neurexins and neuroligins, and the pairing of any two helps create the properties of a synapse and the wide variability in the types of connections in the brain, Südhof says.
The coming together of neurexin and neuroligin at the synapse is very important for normal brain function. Alterations in these proteins impairs the brain’s chemistry, as uncovered in recent human genetics studies showing that mutations in neurexin or neuroligin genes can cause schizophrenia or autism. Südhof has shown that these mutations, when introduced into mice, change the properties of synapses and impair neurotransmission. His current studies aim to clarify how neurexins, neuroligins, and other proteins control synapse formation and synapse function, and how they mediate synapse remodeling during learning or other adaptive changes of the brain. Progress in such studies will help our understanding on how the brain is wired normally, and how such wiring becomes impaired in neuropsychiatric diseases.