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Myriad Proteomics Putting Technology In Place to Map Protein Interactions

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Almost a year after announcing plans to “map the human proteome” by 2004, Myriad Proteomics is now officially on its own. As of the end of January, the joint venture between Myriad Genetics, Hitachi, and Oracle moved into its own 36,000 square foot facility, and has boosted its payroll to 60 full-time employees.

The proteomics initiative, launched last April, will use Myriad’s customized yeast two-hybrid technology for detecting binary protein interactions, in addition to the mass spectrometry-based protein complex “pull-down” technique popularized by two competing papers from MDS Proteomics and Cellzome published in Nature earlier this year. Last spring, Myriad said its ultimate goal was to sell access to a comprehensive database of protein interactions.

But the company still has a ways to go before it starts collecting its protein interaction data at full speed. Although its technology for protein expression, based on ligation-independent high-throughput cloning “is basically already developed,” said Jay Boniface, senior director of protein science and proteomics at Myriad Proteomics, the company must still boost the capacity of its technology for baiting and purifying protein complexes — based on a 96-well format — by at least a factor of 30.

In other words, said Boniface, the company is currently processing one 96-well plate every one to three months, but when automated that rate should jump to one 96-well plate every day.

With respect to its yeast two-hybrid technology, Myriad Proteomics has made progress in boosting the capacity of the system it inherited from Myriad Genetics, called ProNet. The proteomics venture is currently running 800 screens per day, Boniface said, compared with ProNet’s 500 screens per week. Ultimately, however, Myriad Proteomics hopes to reach a capacity of 3,000 to 10,000 screens per day. Boniface predicted the company would reach 3,000 per day by the summer.

Boniface, who is responsible for the mass spectrometry-based protein complex analysis side of Myriad Proteomics’ business, said the company is currently looking for a scientist to oversee the yeast two-hybrid experiments. Paul Bartel, who developed ProNet, will stay on at Myriad Genetics, he said. Boniface currently reports to Myriad Proteomics chief scientific officer Sudhir Sahasrabudhe, formerly vice president for research at Myriad Genetics.

On the protein complex analysis side of the company’s technology, Myriad Proteomics is in the midst of developing a prototype system for its automated gel-based separations technology. “What we mean by that is that the process is in place, [and] the automation is in place,” Boniface said. “We haven’t yet scaled it to the ultimate [throughput], but all the pieces are there.” The company is still developing its multidimensional liquid chromatography (MDLC) approach for separating digested proteins, Boniface added. “That’ll be coming out of development this summer into the prototyping phase.”

In addition to studying protein interactions using yeast two-hybrid and mass spectrometry technology, Boniface said Myriad Proteomics could potentially develop protein or antibody arrays as part of its platform technology. Boniface, who joined Myriad in February 2001, had previously led a proteomics group at EOS Biotechnology, where he worked on surface chemistries and mechanisms for attaching proteins to solid surfaces. “Taking advantage of that technical background could be something we could leverage at Myriad Proteomics,” he said.

Although the company has yet to make public its choice of vendor for its mass spectrometry equipment, Boniface said he currently has “representative” MALDI and electrospray ionization instruments in his lab from several vendors. One of the reasons for delaying the development of the MDLC platform, Boniface added, was to do a “bit more thorough of a job of distinguishing between a Q-TOF style instrument and an ion trap.” Once the mass spectrometry platform is in place, Myriad will be able to analyze 10 to 30 multi-protein complexes per day “by the summer or fall.”

Boniface said his group had not collected enough interaction data to determine how well it matched up with the MDS and Cellzome data in the literature, but he said he wasn’t surprised that the MDS and Cellzome groups’ interaction data overlapped so poorly. “Everybody knows that how you construct the baits, how you express them, and which cell types you use will impact [how well different data sets match up],” he said.

Rather than follow MDS’ lead and overexpress proteins in cell cultures, Myriad Proteomics is leaning towards Cellzome’s approach to expressing its proteins in cell cultures at normal expression levels, Boniface said, to avoid detecting “aberrant” interactions. “I like that philosophy, but I haven’t yet seen the data convincing me one way or the other,” he said. “I just haven’t seen the data yet to be sure whether the pain that you go through in [expressing the proteins at normal levels] is absolutely necessary.”

— JSM

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