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As a Child of Hunt, Yates Grows Up to Be Father of Shotgun Proteomics

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AT A GLANCE

Name: John Yates, III

Age: 43

Position: Associate Professor of Cell Biology, Scripps Research Institute, and Director of Proteomics and Metabolomics, Torrey Mesa Research Institute

Prior Experience: Developed SEQUEST and MultiDimensional Protein Identification Technology (MudPIT)

While researching graduate programs as an undergraduate zoology major at the University of Maine, it didn’t take long for John Yates to figure out which program he wanted to join. He had heard about Don Hunt, a professor of chemistry at the University of Virginia through a class on instrumental analysis, and knew that his group’s formidable expertise in mass spectrometry offered an ideal environment for applying mass spec to biological problems.

Yates joined Hunt’s lab in 1983, and immediately began to tackle peptide sequencing using mass spectrometry, a task made more difficult at the time because no database of peptide mass spectra yet existed. Hunt had published earlier data showing the potential application of tandem mass spectrometry for peptide sequencing, but “I was one of [Hunt’s] first students [doing de novo peptide sequencing],” Yates said. “I’ve been there since its beginning.”

At U.Va., Yates honed his skills in mass spectrometry, and began writing code to interpret mass spectra taken from peptides. After completing his thesis on protein sequencing using tandem mass spectrometry, he left U.Va. to take a postdoc position in Lee Hood’s lab at CalTech.

In 1992, Yates joined Hood’s new department of molecular biotechnology at the University of Washington as an assistant professor. There, he began looking into protein separation techniques, particularly liquid chromatography, as a way to circumvent the slow and labor-intensive process of separating proteins with 2D gels. “I realized it made sense to reduce the proteins to a peptide mixture” that would have uniform chemistry and eliminate problems with insoluble proteins, Yates said.

But all of this was just a prelude to Yates’ real claim to fame. In 1993, while trying to sequence a MHC class 2 peptide “by hand,” that is, by manually running a BLAST search with a partial peptide sequence derived by mass spectrometry, Yates wondered if there wasn’t a better way:

“I’m sitting there waiting for our BLAST results to come back, and I said, ëGeez why can’t I just send a tandem mass spectrum off to a database and search it?’ I took a mental health day, sat down at the computer and wrote an algorithm to show that I could in fact do that.” That algorithm became SEQUEST, which Thermo Finnigan now distributes under license from the University of Washington.

Getting the results of his initial SEQUEST experiments published, however, was not so straightforward. First PNAS roundly rejected the paper, and then reviewers for Protein Science rejected it twice before the Journal of the American Society for Mass Spectrometry published the paper in November of 1994. The issue, Yates said, was defensive posturing on the part of reviewers, and their reluctance to accept new ideas. “It slowed me down getting the paper published by about nine months,” he said. The paper showed how to identify proteins directly from proteolytically digested whole cell lysates, Yates said. “This is shotgun proteomics.”

After eight years at the University of Washington, Yates left for San Diego in 2000, where he now splits his time between the Scripps Research Institute as an associate professor of cell biology, and the Torrey Mesa Research Institute, an agricultural genomics lab owned by Syngenta, where Yates is director of proteomics.

At Scripps, the 15 members of Yates’ academic lab study protein complexes, mass spectrometry bioinformatics, and are developing new technologies to study protein expression in a range of organisms, including yeast, malaria, and anthrax. Yates’ work at Torrey Mesa revolves around rice proteomics, plant pathogens, and new technology development, he said.

Most recently, Yates has begun focusing on new approaches to studying posttranslationally-modified proteins with tandem mass spectrometry. In fact, he has recently submitted a paper to Nature Biotechnology describing a new approach to studying modifications in protein complexes. “It’s really exciting for identifying modifications and it seems to have really simplified [the experiment],” he said. “Mass spectrometry technology tends to evolve at a fairly linear rate, so it’s the application of that technology that will grow the fastest, and where you’ll get the most startling changes.”

— JSM

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