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In October 2006, former NIH Director Elias Zerhouni launched a national consortium designed to bolster clinical and translational research. One of the first institutes to be funded under this series of grants, known as the Clinical and Translational Science Awards, was the Oregon Clinical and Translational Research Institute. Based in Portland, Ore., the institute is a collaboration between the Oregon Health & Science University and Kaiser Permanente's Center for Health Research.

As a virtual institute whose investigators and collaborators are "kind of all over the place," its main goal, says Director Eric Orwoll, is to provide the infrastructure, training, and resources necessary for doing clinical and translational research at a medical center. In the initial grant application, the institute was proposed as a partnership between the university and the Kaiser Permanente center. "OHSU brings to clinical and translational research a lot of traditional basic biomedical research, whereas Kaiser brings expertise in population and community research and a very large patient population," Orwoll says. "Translational research obviously would have a very fertile ground to grow in with that partnership."

Specifically, the partnership seeks first and foremost to create and build the infrastructure for participating scientists to do clinical and translational research. The center's programs encompass a wide variety of enabling science and technologies, including biomedical informatics, biostatistics and design, and community and practice research. A second goal is to educate biologists and clinicians alike as to how to run translational research, and a final goal is to fund that work through pilot program grants. Institute leaders are also "very interested in sponsoring genetics and systems biology approaches," Orwoll says, with resources spanning a specimen processing core lab, an Illumina microarray core, and an extensive biospecimen library thanks to Kaiser.

"The Kaiser partnership was challenging because you're trying to merge two independent systems," Orwoll says, "but I think we've gotten that more under our belts now and are really supporting quite a number of new translational research projects at the interface of the two systems." Broadly speaking, some of their current projects are using genetics to discover all sorts of connections to health and disease susceptibility. One is looking at the genetic basis for the influence of vaccine responsiveness in older people, another at the genetics of tobacco cessation, and still others investigate the genetic underpinnings of hypertension and longevity. Through the alliance, the resources to gather and analyze genetic information are at scientists' fingertips, or no more than a phone call away.

Faces of OCTRI

Bill Hersh, who directs the institute's biomedical informatics program, says that what attracted him to his position was the fact that the institute actually puts a big emphasis on bioinformatics. Hersh spends 10 percent of his time in this role, and his other working hours as chair of the medical school's department of medical informatics and clinical epidemiology. "They put a high value on informatics," he says. "I view it as an opportunity for informatics to contribute to translational research and, through that, [to enhance] the field of informatics."

By combining, as Hersh puts it, "part service and part science," his informatics program helps researchers manage and analyze data, as well as better utilize the bioinformatics tools available to them. For example, his group is attempting to extend the virtual data warehouse at Kaiser beyond the HMO research network and make it accessible to OHSU researchers. "The virtual data warehouse expands the ability to get access to clinical data for everything from identifying patients for studies [to] collecting data on people," he says.

A big part of the institute's mission is to educate both basic scientists and clinicians about translational research — how to get funding, how to design studies, and how to access and analyze data. Hersh says that advancing the use of bioinformatics and genomics tools through educational programs is one of his institute's main efforts, along with acquainting informatics specialists with the science behind the clinical and translational research.

Over on the research side, Gary Thomas is a neuroscientist who works at the Vollum Institute, a privately endowed research unit of the university. Over the years, his work on the secretory pathway has led to the identification of the PACS family of sorting proteins, which control key sorting steps between secretory pathway compartments and mitochondria, "something that doesn't sound immediately obvious to be related to cancer biology," he says. What he also found is that under apoptotic regulation, the cell redirects these proteins to become cell death proteins that help drive apoptosis. "The problem is that cancer cells can become inherently resistant to apoptotic regulators," he adds, "so when they're told to die, they lack the machinery that allows them to die and they become dysregulated," causing the cells to grow uncontrollably.

In collaboration with a pathologist at Kaiser, Thomas was able to determine that expression of this protein, called PACS-2, is lost in about 50 percent of colorectal cancer cases. It's this loss of expression of PACS-2 that could be contributing to resistance to treatment, Thomas says. "So this is an idea that we have, and we want to be able to test this," he says. "Where OCTRI comes into play is it provides a mechanism for people like myself, who are outside the conventional cancer community, to actually begin to ask questions where our work has led us into a cancer biology question."

While Thomas has spread his wings into what could be scary new territory, others aren't so willing. Aside from the "difficulties of changing entrenched practices," one of the main challenges OCTRI faces is changing scientists, Orwoll says. "It's very challenging to create new science that is translational and interdisciplinary when it demands that investigators kind of step out of their box," he says. Many investigators aren't easily swayed to jump into translational projects that might be outside their area of expertise. "New collaborations and new translational research areas — for them, it's not done lightly. We've had to wrestle a lot with how to effectively incentivize that kind of research growth," he says.

OCTRI tries to encourage collaborative efforts in many ways. Its pilot programs give priority to researchers like Thomas who are trying to bridge basic research to the clinic. Additionally, the institute doesn't wait for scientists, many of whom have never done translational work, to put forth ideas. Orwoll says, "Leaders of the institute specifically go out to identify potentially exciting projects, and then we try and put our resources behind the initiation of those projects to get them off the ground, get them to the point where they're submitting grants." Institute leaders make special efforts to streamline where they can, for instance, creating a common IRB procedure so that investigators don't have to go to the university and Kaiser IRBs independently, or implementing processes to collect DNA from Kaiser patients "so that research that otherwise wouldn't be possible is made possible," Orwoll says.

Oregon Clinical and Translational Research Institute
Portland, Oregon
Director: Eric Orwoll
Established: 2006
Size: OCTRI is not housed in one central location. Instead, it's composed of researchers from the Oregon Health & Science University and Kaiser Permanente's Center for Health Research.
Staff: 150
Funding: OCTRI is one of 38 academic health centers throughout the US funded by the Clinical and Translational Science Awards program. OCTRI received $55 million over five years on the first of four RFA funding cycles.
Focus: OCTRI's programs aim to build infrastructure, educate scientists, and fund pilot projects. Key programs include: biomedical informatics, biostatistics and design, a clinical and translational research center, community and practice research, education/human investigations, evaluation and process improvement, investigator support and integration services, and translational technologies.

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