Nobel Laureate Ready To Head Back to Lab

Nobel laureate Günter Blobel. When Günter Blobel and David Sabatini first proposed the signal hypothesis in 1971, the whole thing was simply ignored. There was not a shred of evidence to support it. Since then Blobel, a professor at Rockefeller University, has proven the theory that explains how newly synthesized proteins are dispatched to a target in the cell and transported across the membrane of the target organelle. This year Blobel won the Nobel Prize in physiology or medicine for his research. "It was not just one eureka experiment, but a series of experiments done over a period of more than 25 years to obtain more and more evidence," explains Blobel. Along the way he faced skepticism, resistance to change, and sometimes lost funding because he was creating a new way to look at cell biology. If criticisms did not get to the core of the scientific issues, then they did not sway him. Blobel and Sabatini, a professor at the New York University School of Medicine, hypothesized that an amino acid sequence in the first part of a growing protein chain contains the information that determines where the protein ends up in the cell. They added this information must be cleaved off with an enzyme to yield the mature form of the protein that cells use.1 Günter Blobel surrounded by members of his lab. The following year three laboratories independently found that the light chain of immunoglobulin was made as a larger form with an amino terminus extension.2,3,4 Though there was no evidence that this had anything to do with translocation of proteins, Blobel was fascinated with the results and quickly reproduced them in a cell-free system. He then tried to add membranes to see if he could convert the larger form of the protein to a truncated end product. Adding membranes after protein translation was complete had no results, and adding membranes during translation stopped the synthesis of the protein. For another year Blobel hunted for a membrane preparation that would not wipe out translation. He looked at every tissue from every laboratory animal available until one day somebody at Rockefeller studying dog hearts gave him access to dog pancreas. He recalls going into the lab on Christmas morning 1974 just to see if the experiment had worked. "To my greatest surprise I found the pancreas membranes had not inhibited translation. I saw the mature form instead of the larger form of the light chain," recalls Blobel. Blobel did several more experiments to verify that the truncated form of the light chain had indeed crossed the membrane into the vesicles. He concludes, "So I felt confident that the entire first step of the secretory pathway was faithfully reproduced in the cell-free system, and the rest really is history." He was the first person to fractionate and then reconstitute membrane transport in vitro, which opened up the realm of cell biology. These results are summarized in a two-part 1975 Journal of Cell Biology paper.5,6 Part one has been cited over 2,300 times.7 Blobel added one more concept in the paper that made a lot of people cringe: Translocation occurs through a protein-conducting channel. Most researchers believed a protein chain could partition into the lipid bilayer to cross a membrane. They did not accept that a pore large enough to accommodate proteins would not compromise the integrity of the cell. In 1991 Sanford Simon, a postdoc in the Blobel lab at the time, did electrophysiology experiments that provided direct evidence for the existence of a channel involved in protein transport.8 The following year Blobel and Simon showed that the signal sequence functions as a key to open up the normally closed channel. "Nobody drew chains going through the lipid bilayer anymore. They started drawing channels in red, green, blue, all different colors," says Blobel with a chuckle. A few years ago the world finally visualized the protein channel when the lab produced an electromicrograph of the funnel-shaped structure.9 The Blobel lab is now tackling the traffic of proteins between the nucleus and the cytoplasm. The traffic goes through a large organelle called the nuclear pore complex, which is 20-25 times the size of the ribosome. "At any stage of Günter's career there is exciting work going on in his lab," comments Simon, now an associate professor at Rockefeller University. He is driven by a passion to find out how the cell works. Only a week after the Nobel Prize announcement, Blobel was ready for the celebratory phase to be over so he could focus on research. As for the tremendous number of invitations to travel for dinners and keynote speeches: "I am very excited about science. I also have a responsibility to the people working in my lab, so I can't just suddenly disappear." As with other Nobel laureates, Günter Blobel's future holds many more discoveries that are at least as beautiful as the original. Nadia S. Halim can be contacted at nhalim@the-scientist.com. References 1. G. Blobel, D.D. Sabatini, "Ribosome membrane interaction in eukaryotic cells," Biomembranes, 2:193-5, 1971. 2. C. Milstein et al., "A possible precursor of immunoglobulin light chains," Nature New Biology, 239:117-20, 1972. 3. D. Swan, "Purification and properties of biologically active messenger RNA for a myeloma light chain," Proceedings of the National Academy of Sciences, 69:1967-71, 1972. 4. I. Schechter, "Biologically and chemically pure mRNA coding for mouse immunoglobulin L-chain prepared with the aid of antibodies and immobilized oligothymidine," Proceedings of the National Academy of Sciences, 70:2256-60, 1973. 5. G. Blobel, B. Dobberstein, "Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light-chains on membrane-bound ribosomes of murine myeloma," Journal of Cell Biology, 67:835-51, 1975. 6. G. Blobel, B. Dobberstein, "Transfer of proteins across membranes. II. Reconstitution of functional rough microsomes from heterologous components," Journal of Cell Biology, 67: 852-62, 1975. 7. G. Blobel, "This week's citation classic," Current Contents, 28[11]:18, 1985. 8. S.M. Simon, G. Blobel, "A protein-conducting channel in the endoplasmic reticulum," Cell, 65:371-80, 1991. 9. R. Beckmann et al., "Alignment of conduits for the nascent polypeptide chain in the ribosome-Sec61 complex," Science, 278:2123-6, December 1997.

Nobel Laureate Ready To Head Back to Lab

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