Monday, 09 December 2013 13:57

Of SNAREs, Baker’s Yeast, and a Shout Out to George Palade

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Schekman and Rothman in Stockholm 2013Randy Schekman (left) donating the microscope
he bought as a boy with money earned mowing lawns
and babysitting to the Nobel Foundation museum
in Stockholm on Friday. The picture was taken by
Joy C. Hirsch, wife of Schekman's co-winner
(and fellow ASCB member) Jim Rothman (right).
It is the Talk of Talks. Win the Nobel Prize in Medicine or Physiology and you get an hour in the brand new 1,000-seat Aula Medica of the Karolinska Institutet in which to explain the science that earned your airfare to Stockholm. In your Nobel lecture, you can thank your mentors, colleagues, and former labbies plus include a wave hello to family. You can also point out the philosophical implications of your work or issue a dire warning. Longtime ASCB members James Rothman of Yale and Randy Schekman of the University of California Berkeley, who with Thomas Südhof of Stanford University, shared this year's medicine prize took full advantage of their hour in the Aula on Saturday. All three hours of the lectures were live streamed but the Nobel Foundation reposted them as separate talks (Rothman here and Schekman here) this morning.

A great talk is a great talk and, as expected, Schekman and Rothman showed their polished skills at the lectern, dissecting the roots and branches of vesicle transport. Schekman started the modern story of vesicle transport with George Palade, himself a Nobel laureate in 1974 (and a founder and former president of the ASCB), who first visualized the process by which proteins were synthesized in the rough endoplasmic reticulum and sorted by the Golgi for export from the cell. But the marvelous new tool in the 1950s and 1960s of transmission electron microscopy (perfected by another ASCB founder, Keith Porter) could not resolve the question of how cell cargoes were assembled, delivered with such precision, and unpacked for secretion. That was the state of play in the mid-1970s when Schekman took on the problem using a radically different approach—yeast genetics. Over the years, that gamble paid off as the Schekman lab generated a vast library of yeast mutants with defective transport machinery and identified three classes of genes that give vesicle transport its wonderful specificity.

Rothman also paid tribute to his scientific forebearers, especially Palade, but also to the largely German biochemists called "enzymologists" at the turn of the last century who pioneered the discovery that biochemistry was, at heart, chemistry going on inside living cells, independent of any "vital" force. Biochemists such as Eduard Buchner showed that fundamental processes could be studied outside the cell, Rothman explained. In his own time, Rothman said he was heavily influenced by Leland Hartwell and Arthur Kornberg, Americans who also won the Nobel for their work in cell biology. Rothman needed support in the early 1980s when he set out to reconstitute vesicle transport in a cell-free extract system to identify the key players that could form, coat, uncoat, deliver, and open vesicles. From there, Rothman introduced the cast of characters—NEM, NSF, and SNAP, all of which led to SNARE, the SNAP receptor and the "SNARE pin," the hairpin-shaped molecule switch that drives vesicle and membrane together with speed and force.

Both Rothman and Schekman had a little fun with their lectures. Rothman started his talk with a slide of the nattily dressed secretary of the Nobel Foundation, Göran Hansson, calling him at 10:32 am, Stockholm time, with the good news, and Rothman himself, photographed by his wife Joy C. Hirsch, sitting disheveled and in his pajamas in Manhattan at 4:32 am New York time. Schekman started out by asking his 86-year-old father to stand at his seat in the Aula Medica while he recounted how his father would remind him each October, Nobel Prize announcement time, that he wasn't going to live forever. "Congratulations, Dad. You made it," Schekman said.

Schekman also gave a shout out to the American Society for Cell Biology, telling the story of hearing Palade speak, straight from getting his Nobel medal in Sweden, at the 1974 Annual Meeting in San Diego. Both Schekman and Rothman are going to follow in Palade's footsteps or at least his air miles, going from Stockholm at the end of Nobel Week to New Orleans for an address to the ASCB 2013 Annual Meeting on Monday, December 16.

It was Rothman who delivered the sober warning. He pointed out that enzymology, as biochemistry was first called, was a product of a lively German scientific culture but the rise of Nazism destroyed it, by forcing many of its leading practitioners into exile, largely in the United States. Grafted onto American entrepreneurism and a willingness to fail, that scientific culture rerooted itself and blossomed in the United States. "Now that culture stands deeply threatened by brutal cuts in support for basic research," Rothman said. That scientific culture gave the US unquestioned scientific leadership from the end of World War II until recent years. "And it can go away," said the 2013 winner of the Nobel Prize in Medicine or Physiology.

John Fleischman

John is ASCB Senior Science Writer and the author among other things of two nonfiction books for older children, "Phineas Gage: A Gruesome But True Story About Brain Science" and "Black & White Airmen," both from Houghton-Mifflin-Harcourt, Boston.

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