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Medicine Nobel goes to cellular transport research

By Tina Hesman Saey and Nathan Seppa

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Research on the machinery that guides intracellular bubbles stuffed with molecular cargo has won the 2013 Nobel Prize in physiology or medicine. The Nobel committee selected Randy Schekman of the University of California, Berkeley, James Rothman of the Yale School of Medicine, and Thomas Südhof of Stanford University to share the award.

Working independently, the researchers described components of the machinery that moves cargo around cells and gives the signal to dispatch it to its destination. The equipment is fundamental to cells' functioning; without vesicle transport, "the cell would lapse into chaos," says Juleen Zierath, a physiologist at the Karolinska Institute in Sweden who chairs the Nobel committee.

Cells are factories that constantly produce and export molecular products. The vesicle transport machinery to get these products to the right destination on time is indispensable for chemical signaling in the brain, the release of hormones and immune chemicals and other vital body processes. Before the three new Nobel laureates started their work, no one knew how cells move packets of material to their intended locations.

Cargo trafficking in cells can resemble a microscopic version of transport in cities, says Tomas Kirchhausen, a structural cell biologist at Harvard Medical School. From the street level, he says, “it looks quite chaotic.” But viewing a city from above reveals clear lines of transit and a semblance of order. Kirchhausen says the work of the three scientists has similarly helped to clarify the routes of molecular transport in cells.

Scientists in the 1960s and early 1970s had described the movement of vesicles around cells, but the new Nobel laureates identified the dispatcher molecules that direct that traffic, says Dieter Gallwitz of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany.

In 1976, Schekman began a search for the transport molecules in yeast. 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 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.

At the same time, Rothman was also trying to work out how cells transport molecular goods. 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. That protein 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.

The first protein Rothman identified was N-ethylmaleimide-sensitive factor, or NSF. “Rothman deserves credit, I always like to say, for coming up with the letter N,” says Edwin McCleskey, a senior scientist at the Howard Hughes Medical Institute. Rothman discovered that the chemical N-ethylmaleimide poisons the transport process. Many other important transport proteins that he and Schekman discovered incorporate the N from that poison in their name; SNAPs (soluble NSF-attachment proteins) and SNAREs (soluble NSF-attachment protein receptors) form complexes that help vesicles dock with membranes so they can unload their cargo.

Südhof began his work in 1986, a decade after Schekman and Rothman had started. The problem Südhof tackled was how cells, especially brain cells, know when to deliver their packages. He used mice to discover that spritzes of calcium work like a green light for cells to release packets of neurochemicals. He discovered a sensor protein, synaptotagmin, that detects calcium and tells molecular machines to discharge the vesicle’s payload of neurotransmitters.
The release of neurotransmitters has to happen quickly, within milliseconds, says McCleskey. Otherwise, the brain couldn’t carry out most of its basic tasks. “Every school kid is able to appreciate fast biology,” McCleskey says. “Every movement they’re able to make, every sensation they’re able to feel is the result of fast biology.” Südhof discovered the mechanism behind the speedy process.
The same process works in the pancreas to stimulate release of insulin. Some of the proteins Südhof discovered were also ones Schekman had identified. 

The three scientists’ work has led to a deeper understanding of diseases such as diabetes and epilepsy. Some people with epilepsy have mutations in a vesicle transport component. So do people with an immune disorder called Familial Hemophagocytic Lymphohistiocytosis, which can cause deadly levels of inflammation. Vesicle transport is also the target of some bacterial toxins such as botulinum toxin, better known as Botox, which interferes with the release of neurotransmitter chemicals and causes paralysis.

A better understanding of the process may help scientists develop new drugs that can regulate the release of neurotransmitters, Rothman suggested at a press conference. 
But all of the research was very basic science at the outset. “We started with no practical application in mind,” Schekman said at another press conference. But now companies have developed a vaccine for hepatitis B that is produced in yeast and trafficked along the pathway Schekman discovered. About one third of the world’s insulin supply is made and excreted by genetically engineered yeast, also as a result of the work, he said.
“I was so fortunate to start out at a time when young scientists could have an idea [and] take risks,” Rothman said. He acknowledged to having had “five years of failure” before getting traction with his work. 
“It’s much more difficult for young scientists to get started today,” he said. “In a relative sense, they get less money than we got.” He said he doubted that, with current funding levels, he would have been able to take those risks and make his discoveries.
To go along with the Nobel Prize, Berkeley’s chancellor awarded Schekman the university’s highest honor, a lifetime parking permit.

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