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COVER STORY
NOBEL PRIZE 2013 Medicine
BIJU DHARMAPALAN
J
UST like a traffic failure in a city leads
to chaos, malfunctioning of the body’s
internal transport system could also
create problems.
A living cell is like a factory
with
different
membrane-bound
compartments known as organelles. The
factory constantly produces and exports
molecular products 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 the right moment. Miniature bubblelike vesicles, surrounded by membranes,
shuttle the cargo between organelles or
fuse with the outer membrane of the cell
and release their cargo outside. This is
similar to a post man delivering letters
to specific addresses. If the cargo system
malfunctions, the substance does not
reach its destination. This can lead to
illness. But how do these vesicles know
where and when to deliver their cargo?
This year’s Nobel Prize was awarded
to three U.S. based scientists who solved
the mystery behind the cellular postal
service. James E. Rothman (62) of Yale
University, Randy W. Schekman (64) of
the University of California, Berkeley,
and Dr. Thomas C. Südhof (57) of
Stanford University, who explained
the inner workings of a ‘cellular postal
service’ shared this year’s Nobel Prize in
Physiology or Medicine announced on 7
October 2013 by the Karolinska Institute
in Stockholm.
Their basic research solved the
mystery of how cells organize a system
to transport the molecules within cells
and export them outside. Working
independently,
these
researchers
elucidated the various components
of the cellular machinery that
transports cargo around cells and
gives the signal to dispatch it to
its destination. This transport
mechanism is essential for the
functioning of cells. Before the
three new Nobel laureates started
their work, no one knew how cells
moved packets of material to their
intended locations.
Dr. Randy Wayne Schekman
began a search for the transport
molecules in yeast in 1976.
Baker’s
yeast,
Saccharomyces
cerevisiae, consists of single-celled
organisms that carry out many
cellular functions, just as human
cells do. Schekman created yeast
cells that have mutations in any
one of 23 genes, all of which
produce proteins involved in
Randy W. Schekman
(Photo credit: https://plus.google.com)
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vesicle transport. When the mutations
disabled the proteins, vesicles backed
up in cells like cars in a traffic jam. By
noting where within the cell the pileups
happened, Schekman teased out where
each transport protein works.
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.
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. Schekman used genetic
methods to 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 the different
genes’ protein products play, step by step,
Vesicle
COVER STORY
James E. Rothman (Photo credit:
http://newsroom.cumc.columbia.edu)
Thomas C. Südhof (Photo credit:
http://www.dw.de)
Südhof studied how neurons
communicate with one another
(Courtesy: http://www.dw.de )
A
LIVING CELL IS LIKE A FACTORY
WITH
DIFFERENT
MEMBRANEBOUND
COMPARTMENTS
KNOWN
AS ORGANELLES. THE FACTORY
CONSTANTLY
PRODUCES
AND
EXPORTS MOLECULAR PRODUCTS.
as they shuttle cargo-laden vesicles in the
cell. One of the most important genes he
found 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 likes Alzheimer’s. His work earned
him the Albert Lasker Award for Basic
Medical Research, which he shared with
James Rothman in 2002.
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.
Dr. James E. Rothman studied
vesicle transport in mammalian cells in
the 1980s and ’90s. He took a biochemical
approach to the problem, breaking open
hamster ovary cells and reconstructing
vesicle transport in a test tube. Rothman
studied how cells move a viral protein
called VSV-G, which builds up in infected
cells, and gets tagged with a sugar,
providing a convenient tracking device
for the scientist to follow. He purified
particular proteins that were part of the
machinery for moving VSV-G and other
proteins.
He discovered that a protein
complex allows vesicles to dock and fuse
with their target membranes. Professor
Rothman’s discovery of the key molecular
machinery responsible for transfer of
materials among compartments within
cells provided the conceptual framework
for understanding various processes
like the release of insulin into the blood,
communication between nerve cells in the
brain, and the entry of viruses to infect
cells.
Numerous kinds of tiny membraneenveloped vesicles ferry packets of
enclosed cargo. Each type of vesicle
must deliver its specialized cargo to the
correct destination among the maze of
distinct compartments that populate
the cytoplasm of a complex animal cell.
The delivery process, termed membrane
fusion, is fundamental for physiology and
medicine, as pathology in this process can
cause metabolic, neuropsychiatric and
other diseases.
Rothman
reconstituted
vesicle
budding and fusion in a cell-free system
(1984) and discovered the complex of
SNARE proteins (1993) which mediates
membrane fusion and affords it specificity.
He also uncovered the GTPase-switch
mechanism which controls coated vesicle
budding in the cell (1991).
Rothman’s current research concerns
the biophysics of membrane fusion and its
regulation in exocytosis; the dynamics of
the Golgi apparatus at super-resolution;
and the use of bio-inspired design in
nanotechnology.
Thomas C. Südhof mainly focused on
how nerve cells in the brain communicate
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without any errors in an ultrafast manner.
Here, neurotransmitters play a decisive
role. They 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.
Südhof has even created a genetically
altered mice having impaired transport
mechanism. These animals have epileptic
seizures or act in a way typical for human
autistic or schizophrenic patients.
The work of the three scientists has
helped to clarify the routes of molecular
transport in cells. This will further help
scientists to find effective treatments for
various disease processes like diabetes,
epilepsy, autism, Alzheimer’s etc.
Mr. Biju Dharmapalan is Assistant Professor,
School of Biosciences, MACFAST (Mar Athanasios
College for Advanced Studies Tiruvalla),
Kerala-689101; E-mail: [email protected]/biju_
[email protected]
SCIENCE REPORTER, DECEMBER 2013