Wednesday, October 09, 2013

Nobel Winners Decoded How Neurons And Cells Talk To Each Other

The winners of the Nobel Prize in Physiology or Medicine all are working to better understand how cells - especially neurons - communicate. Cool stuff.

Apparently the Nobel folks gave the Physics prize to a couple of guys who (may have) discovered a simple particle at the heart of the universe. Geez.

Nobel Winners Decoded How Neurons And Cells Talk To Each Other

by Michaeleen Doucleff
October 07, 2013

From left: Randy Schekman, Thomas Suedhof and James Rothman 
shared the 2013 Nobel Prize in Physiology or Medicine. Reuters /Landov

The three scientists who shared this year's Nobel Prize in Physiology or Medicine all made discoveries that illuminate how the body's cells communicate.

The research has sweeping implications for our understanding of how nerves in the brain transmit signals, how the immune system attacks pathogens and how hormones, like insulin, get into the bloodstream.

Bioengineers have already harnessed the discoveries to manufacture new vaccines and improve the quality of insulin for diabetics.

How does insulin get into the blood? The hormone (dark blue) is carried to the cell surface in a bubble-like compartment, called a vesicle. When the vesicle binds with the cell membrane, it pops open and releases the insulin. Courtesy of the Nobel Prize
The winners include two Americans — James Rothman of Yale University and Randy Schekman of the University of California, Berkeley — and the German-born Thomas Suedhof of Stanford University. Both Schekman and Suedhof are also investigators at the Howard Hughes Medical Institute.

Their discoveries took place over the course of 30 years. The work got its start with a few simple experiments in cells of yeast – the same organism that leavens bread and brews beer.

In the 1970s, biologists already knew that cells weren't just sacks of fluid. Rather, they contain sophisticated highway systems that shuttle material from one compartment to the next. This cargo moves around cells in bubble-like compartments called vesicles.

In a healthy cell, some of these vesicles make their way to the cell's surface, where the material is released outside the cell. That's one way that cells communicate with each other and with organs in the body.

In 1976, Schekman, a new professor at the University of California, Berkeley, had recently found mutant yeast cells that had faulty transport systems. The cargo just piled up at the cell's surface, like cars stuck in a traffic jam.

By figuring out which genes were defective in these yeasts, Schekman discovered dozens of components that built and controlled the cell's transport system.

But there were still many pieces missing. In particular, it wasn't known how a cargo vesicle knows where to go on the cell's surface and then when to dump out its contents.

"Imagine hundreds of thousands of people who are traveling around hundreds of miles of streets. How are they going to find the right way? Where will the bus stop and open its doors so that people can get out?" Nobel committee secretary Goran Hansson said Monday. "There are similar problems in the cell, to find the right way ... and out to the surface of the cell." 

Take for instance two neurons in your brain. One neuron communicates with another by secreting neurotransmitters, such as dopamine and serotonin. But a neuron must release the neurotransmitter at a particular place — and at the right time. Otherwise the message will never make it to the second neuron, or the signal will get scrambled.

That's where Rothman and Suedhof's research comes in. In the 1980s and 1990s, Rothman, now 62, figured out that a signal on the vesicle's surface that helps it dock at just the right place on the cell's surface. The process works a bit like a zipper: A protein on the vesicle zips up with another one on the cell's membrane to position the cargo in the correct location.

Then a few years later, Suedhof, who is now 57, identified the trigger mechanism that dumps the neurotransmitter outside the cell at just the right time by unzipping the two proteins.

This transport system has served as the foundation of modern cell biology and neuroscience.

And breakdowns of the process is involved in a vast range of diseases, including Alzheimer's, cystic fibrosis, muscular dystrophies and some autoimmune disorders. 

Here is the press release from the Nobel Foundation:

Press Release

The Nobel Assembly at Karolinska Institutet has today 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.

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;
Hata Y, Slaughter CA, Südhof TC: Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.
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