Nobel Prize in Physiology or Medicine 2013
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Press Release
2013-10-07
The Nobel Assembly at Karolinska Institutet has today decided to award
The 2013 Nobel Prize in Physiology or Medicine
The 2013 Nobel Prize in Physiology or Medicine
jointly to
James E. Rothman, Randy W. Schekman
and Thomas C. Südhof
and Thomas C. Südhof
for their discoveries of machinery regulating vesicle traffic,
a major transport system in our cells
a major transport system in our cells
Summary
The
2013 Nobel Prize honours 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.
Randy
Schekman discovered a set of genes that were required for vesicle
traffic. James Rothman unravelled protein machinery that allows
vesicles to fuse with their targets to permit transfer of cargo. Thomas
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.
How cargo is transported in the cell
In
a large and busy port, systems are required to ensure that the correct
cargo is shipped to the correct destination at the right time. The cell,
with its different compartments called organelles, faces a similar
problem: cells produce molecules such as hormones, neurotransmitters,
cytokines and enzymes that have to be delivered to other places inside
the cell, or exported out of the cell, at exactly the right moment.
Timing and location are everything. Miniature bubble-like vesicles,
surrounded by membranes, shuttle the cargo between organelles or fuse
with the outer membrane of the cell and release their cargo to the
outside. This is of major importance, as it triggers nerve activation in
the case of transmitter substances, or controls metabolism in the case
of hormones. How do these vesicles know where and when to deliver their
cargo?
Traffic congestion reveals genetic controllers
Randy Schekman was
fascinated by how the cell organizes its transport system and in the
1970s decided to study its genetic basis by using yeast as a model
system. In a genetic screen, he identified yeast cells with defective
transport machinery, giving rise to a situation resembling a poorly
planned public transport system. Vesicles piled up in certain parts of
the cell. He
found that the cause of this congestion was genetic and went on to
identify the mutated genes. Schekman identified three classes of genes
that control different facets of the cell´s transport system, thereby
providing new insights into the tightly regulated machinery that
mediates vesicle transport in the cell.
Docking with precision
James Rothman was
also intrigued by the nature of the cell´s transport system. When
studying vesicle transport in mammalian cells in the 1980s and 1990s,
Rothman discovered that a protein complex enables vesicles to dock and
fuse with their target membranes. In the fusion process, proteins on the
vesicles and target membranes bind to each other like the two sides of a
zipper. The fact that there are many such proteins and that they bind
only in specific combinations ensures that cargo is delivered to a
precise location. The same principle operates inside the cell and when a
vesicle binds to the cell´s outer membrane to release its contents.
It
turned out that some of the genes Schekman had discovered in yeast
coded for proteins corresponding to those Rothman identified in mammals,
revealing an ancient evolutionary origin of the transport system.
Collectively, they mapped critical components of the cell´s transport
machinery.
Timing is everything
Thomas Südhof was
interested in how nerve cells communicate with one another in the
brain. The signalling molecules, neurotransmitters, are released from
vesicles that fuse with the outer membrane of nerve cells by using the
machinery discovered by Rothman and Schekman. But these vesicles are
only allowed to release their contents when the nerve cell signals to
its neighbours. How is this release controlled in such a precise manner?
Calcium ions were known to be involved in this process and in the
1990s, Südhof searched for calcium sensitive proteins in nerve cells. He
identified molecular machinery that responds to an influx of calcium
ions and directs neighbour proteins rapidly to bind vesicles to the
outer membrane of the nerve cell. The zipper opens up and signal
substances are released. Südhof´s discovery explained how temporal
precision is achieved and how vesicles´ contents can be released on
command.
Vesicle transport gives insight into disease processes
The
three Nobel Laureates have discovered a fundamental process in cell
physiology. These discoveries have had a major impact on our
understanding of how cargo is delivered with timing and precision within
and outside the cell. Vesicle transport and fusion operate, with the
same general principles, in organisms as different as yeast and man. The
system is critical for a variety of physiological processes in which
vesicle fusion must be controlled, ranging from signalling in the brain
to release of hormones and immune cytokines. Defective vesicle transport
occurs in a variety of diseases including a number of neurological and
immunological disorders, as well as in diabetes. Without this
wonderfully precise organization, the cell would lapse into chaos.
James E. Rothman was
born 1950 in Haverhill, Massachusetts, USA. He received his PhD from
Harvard Medical School in 1976, was a postdoctoral fellow at
Massachusetts Institute of Technology, and moved in 1978 to Stanford
University in California, where he started his research on the vesicles
of the cell. Rothman has also worked at Princeton University, Memorial
Sloan-Kettering Cancer Institute and Columbia University. In 2008, he
joined the faculty of Yale University in New Haven, Connecticut, USA,
where he is currently Professor and Chairman in the Department of Cell
Biology.
Randy W. Schekman was
born 1948 in St Paul, Minnesota, USA, studied at the University of
California in Los Angeles and at Stanford University, where he obtained
his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize
1959) and in the same department that Rothman joined a few years later.
In 1976, Schekman joined the faculty of the University of California at
Berkeley, where he is currently Professor in the Department of Molecular
and Cell biology. Schekman is also an investigator of Howard Hughes
Medical Institute.
Thomas C. Südhof was
born in 1955 in Göttingen, Germany. He studied at the
Georg-August-Universität in Göttingen, where he received an MD in 1982
and a Doctorate in neurochemistry the same year. In 1983, he moved to
the University of Texas Southwestern Medical Center in Dallas, Texas,
USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein
(who shared the 1985 Nobel Prize in Physiology or Medicine). Südhof
became an investigator of Howard Hughes Medical Institute in 1991 and
was appointed Professor of Molecular and Cellular Physiology at Stanford
University in 2008.
Key publications: |
Novick
P, Schekman R: Secretion and cell-surface growth are blocked in a
temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad
Sci USA 1979; 76:1858-1862.
|
Balch
WE, Dunphy WG, Braell WA, Rothman JE: Reconstitution of the transport
of protein between successive compartments of the Golgi measured by the
coupled incorporation of N-acetylglucosamine. Cell 1984; 39:405-416.
|
Kaiser
CA, Schekman R: Distinct sets of SEC genes govern transport vesicle
formation and fusion early in the secretory pathway. Cell 1990;
61:723-733.
|
Perin
MS, Fried VA, Mignery GA, Jahn R, Südhof TC: Phospholipid binding by a
synaptic vesicle protein homologous to the regulatory region of protein
kinase C. Nature 1990; 345:260-263.
|
Sollner
T, Whiteheart W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P,
Rothman JE: SNAP receptor implicated in vesicle targeting and fusion.
Nature 1993;
362:318-324. |
Hata
Y, Slaughter CA, Südhof TC: Synaptic vesicle fusion complex contains
unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.
|
The Nobel Prize in Physiology or Medicine 2013
James E. Rothman, Randy W. Schekman, Thomas C. Südhof
James E. Rothman, Randy W. Schekman, Thomas C. Südhof
James E. Rothman - Facts
Photo: © Yale University
James E. Rothman
Born: 3 November 1950, Haverhill, MA, USA
Affiliation at the time of the award: Yale University, New Haven, CT, USA
Prize motivation: "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells"
Interview
"'Machinery'... that's exactly how I think about it"
Telephone
interview with James E. Rothman following the announcement of the 2013
Nobel Prize in Physiology or Medicine. The interviewer is
Nobelprize.org's Adam Smith.
Randy W. Schekman - Facts
Photo: H. Goren. © HHMI
Randy W. Schekman
Born: 30 December 1948, St. Paul, MN, USA
Affiliation at the time of the award: University of California, Berkeley, CA, USA
Prize motivation: "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells"
Interview
"I danced around with my wife and repeatedly said 'oh my god, oh my god'."
Telephone
interview with Randy W. Schekman following the announcement of the 2013
Nobel Prize in Physiology or Medicine. The interviewer is
Nobelprize.org's Adam Smith.
Thomas C. Südhof - Facts
Photo: © S. Fisch
Thomas C. Südhof
Born: 22 December 1955, Goettingen, Germany
Affiliation at the time of the award: Stanford University, Stanford, CA, USA
Prize motivation: "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells"
Interview
"Are you serious?"
Telephone
interview with Thomas C. Südhof following the announcement of the 2013
Nobel Prize in Physiology or Medicine. The interviewer is
Nobelprize.org's Adam Smith.
Nobel Prize in Physiology or Medicine 2013
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