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Stanley Hefta Carries Proteomics From City of Hope to Bristol-Myers

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AT A GLANCE

Name: Stanley Hefta

Position: Executive Director of Proteomics, Bristol- Myers Squibb

Prior Experience: Associate Professor, City of Hope National Medical Center, Duarte, Calif.

While studying proteins associated with granulocytes and other immune cells almost ten years ago at City of Hope National Medical Center in Duarte, Calif., Stanley Hefta started running up against a problem: Nobody in his lab could isolate the proteins using conventional Edmond sequencing and chromatography techniques.

So Hefta took matters into his own hands. With the help of a five-year, $1.7 million-a-year grant from the NIH, Hefta directed his lab to develop new approaches to multidimensional liquid chromatography and mass spectrometry that would enable him to pick out those elusive low-abundance proteins.

“We really started in the area of what we now call proteomics way back starting around ''92,” said Hefta of his work at City of Hope. “That’s when a lot of these initial concepts were developed for multidimensional liquid chromatography and for data-dependent mass acquisition.”

Despite these successes, Hefta felt he needed more resources to apply his technologies to medicine quickly. In 1997, he left City of Hope to apply his new protein analysis technologies to drug discovery and development, at Princeton, NJ-based Bristol-Myers Squibb., where he helped found the department of genomics and proteomics.

At Bristol-Myers, Hefta set about adapting the techniques he developed at City of Hope to discovering biomarkers and novel drug targets. To look for global changes between healthy and sick patients, or between those who have received a drug and those who have not, Hefta’s team looks for any identifiable change in protein expression level that might be useful for marking the progress of a specific disease. Identifying novel drug targets, on the other hand, requires that scientists take an approach more closely tied into the biology associated with the disease. In these cases, Hefta’s group studies the proteins involved in signal transduction pathways by identifying protein complexes or proteins with post-translational modifications.

“We know what the portfolio of [drug development] projects is within the different disease areas, and I’m constantly looking to see where we can integrate the technology,” he said. “We’re trying not to work in a vacuum but to integrate our technologies into the disease area biology and bring a unique perspective to them by looking at the functioning proteins themselves.”

Hefta’s group still uses 2D gel electrophoresis “as the mainstay of proteomics” at Bristol-Myers, but he added that the company is aggressively developing new techniques for separating proteins using multidimensional liquid chromatography that are faster and more broadly applicable than 2D gels.

But Bristol-Myers has made the most significant advances in proteomics by applying the mass spectrometry analysis algorithms initially developed at City of Hope, Hefta said. To analyze the mass spectra spewing from their Thermo Finnigan LCQ and Micromass QTOF mass spectrometers, Hefta’s team has written algorithms for matching peptide fragments in real time with their analogous peptide and DNA sequences, and for applying correlation and statistical analyses to the data. Hefta is even in discussions with mass spectrometry companies to commercialize the software, he said.

But Hefta thinks the biggest hurdle to isolating low-abundance proteins doesn’t involve mass spectrometry hardware — or even software for that matter — but the ability to manipulate microscopic amounts of fluid or sample material. His group at Bristol-Myers is working on techniques for miniaturizing chromatography separations, and he would like to see new microfluidics technologies for microdissection and subcellular fractionation of small numbers of cells. “Those areas are critical to being able to marry up the tremendous sensitivity that you’ve got with mass specs to the biological system,” he said.

Although Hefta would like to outsource much of the proteomics technology development, he has found that doing so is less effective than employing Bristol-Myers scientists who know how the technology must be applied. “You’ve got both the technology development but also the application and they’ve got to merge,” he said. “Because of that we’ve had to do a lot of our own technology development that is unique to the processes and science that we practice at Bristol-Myers.”

— JSM

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