The melding of diverse minds around proteomics initiative

At first glance, Dr. Amanda (Mandy) Paulovich's Clinical Research Division lab seems stocked with standard equipment one would expect to find in any scientific setting. There are the same rows of benches, the same shelves brimming with the same beakers. But upon further inspection, this is not your typical lab. In the back room, mass spectrometers the size of compact cars hum along, methodically analyzing proteins. Beyond that, in a room that looks more like an office, one encounters the most unique aspect of the lab: the people.

Finding another lab with more diversity could be difficult. "We're a little bit of everything," Paulovich said. "It's really an unusual group. It's incredibly interdisciplinary."

Working in the office next door to Paulovich is a man with a doctorate in electrical engineering and another with a doctorate in particle physics. Then there's a former nurse from Japan who decided to pursue further education and now holds a doctorate in molecular cell biology. "There are a couple of geneticists, biologists, biochemists; the point is, it's not your traditional lab," said Paulovich, who hold a medical degree and doctorate in genetics from the University of Washington.

"In a lot of labs in academics, the principal investigator could, if need be, step in and do most people's job, with a little bit of time to catch up on where things are and everything. That's the opposite model of what I have here. There's no way I could do the particle physicist's job or the engineer's job or the analytic chemist's job — the biologist's job I could do," Paulovich said. "But the whole here is really greater than the sum of its parts."

And that whole is doing impressive work. The team is one of the major contributors to a network established by the National Cancer Institute, which is funding a five-year, $104 million Clinical Proteomic Technologies Initiative for Cancer, or CPTI. The Paulovich Lab is one of five Clinical Proteomic Technology Assessment for Cancer (CPTAC) teams within the program, and is a key player for its contributions in mass spectrometry, the practice of analyzing proteins.

Putting biomarkers to the test

Much of clinical proteomics until now has been focused on the discovery of new biomarkers, which has led to large numbers of candidate biomarkers for various cancers or other disease states. But, technology limitations and problems with experimental design have led to a high rate of false discoveries. So the numbers of biomarkers needing to be verified sometimes run into the thousands — a painstaking process.

"Verifying those markers requires building individual tests to each candidate and testing them one by one. That's incredibly expensive and time-consuming and often doesn't work," Paulovich said. "Our team is focused on filling that need to have a lower-cost, higher throughput way to look at a given protein of interest and see if it's really a biomarker."

"For the past two years, my lab, in collaboration with Dr. Marty McIntosh, has been leading a proteomic consortium also funded by the NCI. The consortium was focused on developing technologies for discovering biomarkers using inbred mouse models to cancer, which were developed by Dr. Chris Kemp," Paulovich said. "That project is winding down, and this new initiative was announced to basically follow up on that early work."

Other collaborators on the new initiative include the Center's Drs. Peggy Porter, Connie Lehman and Julie Gralow on the clinical side, and statistical analysis by Pei Wang, Dr. Danny Shen, Linda Risler, and Dr. Mark Wener of the UW. Now, the collaborators are moving away from an untargeted discovery approach to verification of already discovered biomarkers.

That's where the strength of the Paulovich Lab again comes through: The biology, medicine, computation and technology are all critical to the mission of verification. "There is no other place in the NCI consortium that has the biology this intermingled in one lab with the technology and computational work. People have strengths in one or two of those areas, but not all of them. Having all of those disciplines with highly trained people in one place is a tremendous advantage," Paulovich said. "It really is team science. This is a collection of colleagues more than a structure with a figurehead. These are highly educated people who've come together to form an interdisciplinary team."

The lab is divided into two sections — one half works on risk assessment, the other on verifying biomarkers. Mass spectrometry is an important component for improving new ways to discover biomarkers as well as for verification. Like a clock's individual parts working together, the diversity of the team members is essential for meeting the lab's goals.

"I write programs, sometimes on a case-by-case basis, for particular questions that we have," said John Keane, an electrical engineer. "It's more about understanding the data-production process and helping to ensure that we're producing valid, high-quality data."

Karin Everett is a molecular microbiologist who has characterized molecular aspects of a wide range of bacterial species. "My role in the lab is to develop cost-effective, cell culture-based molecular assays for radiation exposure and human-phenotype variation."

Li-Chia Feng, who earned a master's degree in chemical engineering in Taiwan and another in bioengineering in Seattle, is working to learn more about proteomics. "Proteomics is a growing and attractive field, which is one of the things I like about this group," Feng said. "My main job in the lab is to do the sample preparation before the mass spectrometry analysis. I am also learning to operate the mass spectrometer."

"I run instrumentation, help design experiments and help analyze data," said Dr. Jeff Whiteaker, a mass spectrometrist. "It's very interesting; a lot of times, we will encounter a problem where we all have different views on it, and it's very handy to have people with different expertise."

That appreciation for problem-solving resonates throughout the lab. Richard Ivey, a molecular biologist and project manager, said that while he appreciates the intellectual diversity of the people he works with, the key to the lab's success is the teamwork. "We have such a broad level of expertise that just about any problem that crops up can be addressed in a creative and innovative fashion."

Making sure that everyone is able to communicate effectively is a big part of running the lab. Every Monday and Friday, lab members set aside time to educate one another about different aspects of projects and to brainstorm about how to troubleshoot problems.

"It's good for me, too, because I learn a lot from the engineers and chemists," Paulovich said. "But for them to understand the experiment that we're working on, I have to do some teaching, too. They're not biologists, they're not physicians, so part of my job is to enlist the engineer to think about this with me. It's my job to teach him what he needs to know about biology to be able to contribute to this process. It's fun. We all like being challenged."