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| Courtesy:nobelprize.org |
The Nobel Assembly at Karolinska Institutet has today (2013-10-07) decided to award
The 2013 Nobel Prize in Physiology or Medicine
jointly to
James E. Rothman, Randy W. Schekman
and Thomas C. Südhof
for their discoveries of machinery regulating vesicle traffic,
a major transport system in our cells.
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.
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