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NHLBI Set to Start Third Major Proteomics Program

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With its two major proteomics programs winding down, the National Heart Lung and Blood Institute is embarking on its next major program, which calls for researchers to develop proteomics technologies and apply them to solve clinical puzzles.

In late January the institute put out an RFP for a new proteomics program, which combines the goals of two earlier programs that are set to expire in the coming months. In one, researchers were tasked with developing validation methods for proteomics research. In the other, awardees were asked to develop new proteomics technology.

In the new program, set to start early next year, awardees will be charged with "using novel technology approaches to answer a clinical [question], to try and understand the mechanisms that underpin" diseases, Pothur Srinivas, a program director at the NHLBI, told ProteoMonitor this week.

The institute expects to give out awards to seven research teams. Each team will receive an average of $1.9 million each year for up to six years in direct and indirect costs, depending on the scope of the project. The awards are expected to be made on or about Jan. 13, 2010. The deadline for submitting a proposal is May 20. A proposal intent response is due April 20.

NHLBI is leaving it completely open as to the technology that will be used and direction of the research. NHLBI said it is seeking an integrative approach, however, and each awardee is expected to put together a team with expertise in multiple disciplines "to advance proteomic applications in heart, lung, blood, and sleep diseases and disorders," it said in its solicitation. Areas of expertise include chemistry, physics, bioinformatics, and engineering, as well as proteomics.

Each team will address specific clinical areas using three approaches: proteomic technology development; "mechanistic and functional understanding of the proteome, its interactions, and dynamics;" and clinical application of the technology and discoveries.

As examples of the kind of research that could be done with the funding, the institute said they could include the development of novel approaches for measuring the proteome, subproteome, and/or post-translational modifications that will predict rejection of organ transplants; technologies and methods for the detection and diagnosis of myocardial ischemia; and development of tools and methods for the discovery of biomarkers of sleep apnea and biological timing.

'Not There Yet'

The proposed program marks the first major proteomics initiative by the NHLBI in nearly four years and comes amid growing impatience with the state of clinical proteomics. While proteomics was hyped earlier this decade as the Rosetta Stone that would elucidate the mysteries of a whole range of diseases, resulting in new diagnostic tools and therapies, more recently the community has taken a more sober view.

Leaders in the field warn that more time is needed before the science and technology can achieve meaningful results in the clinic. At last month's US Human Proteome Organization's annual conference, Reudi Aebersold, a professor of systems biology at the Swiss Federal Institute of Technology, said that trying to rush proteomics into the clinic "may do a disservice to the field." [See PM 02/26/09]

Srinivas said that while proteomics technology has made strides in recent years, there is still a schism between the technology and clinical use for them.

"The technology has developed but [it's] still not there yet, and we need to use these tools to answer a clinical question, so this is an effort at trying to do that," Srinivas said of the NHLBI's current RFP.

The institute's two earlier major proteomics initiatives were the Clinical Proteomics Program and the Proteomics Initiative. The Clinical Proteomics Program, established in July 2005 and ending this June, was created to address one of the major hurdles in trying to translate discovery into clinical utility, validation, by moving protein biomarkers that had been discovered in smaller studies along the development pipeline.

"There are quite a lot of proteins in the cardiovascular arena that have been identified as potential biomarkers, but they have not gone to the next step because [they lack] validation," Srinivas said. "The tools that we have need to be tuned to perfection before we [then] can bring it to the clinic. … If we find a marker, we have to be sure that it's really a marker of what we're looking for.

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"And then you have to take it through validation and that requires really good reagents that can reproducibly and quantitatively give us measurements of what we have been looking at. If you have a protein, you want to make sure that the reagent that you're using to measure it is really robust. All these things need to be developed," he added.

Four institutions participated in the clinical program: the University of Colorado specifically looked at biomarkers for lung disease; Mayo Clinic in Rochester, Minn., tackled biomarkers of vascular disease; Massachusetts General Hospital focused on biomarkers for myocardial injury; and the Vanderbilt University Medical Center worked on biomarkers for acute respiratory distress syndrome.

Meanwhile the NHLBI Proteomics Initiative, begun in September 2002 and expiring this September, focused on technology development and has 10 participating centers: the Boston University Cardiovascular Proteomics Center; Johns Hopkins Proteomics Center; Medical College of Wisconsin Proteomics Center; Medical University of South Carolina Proteomics Center; Seattle Proteome Center; Stanford University Proteomics Center; Uniformed Services University Medical Proteomics Center; University of Texas Medical Branch, Galveston; University of Texas Southwestern Medical Center, Dallas; and the Yale Proteomics Center.

According to Srinivas, the technology researched by the centers ranged from mass spectrometry to software to alternates to antibodies. There was also exploration of nanotechnology methods to improve throughput.

In its RFP, the NHLBI said that the participants in the Proteomics Initiative were "instrumental" in advancing proteomics "through innovation technology development, expansion of proteomic approaches, and application to biological questions." But as more information about the proteome is learned, and new methods are developed to "measure and manipulate the proteome, it is apparent that more knowledge and understanding is needed in order for the promise of personalized prediction, prevention, and treatment in clinical practice to become a reality."

Create Clinical Proteomics

Garry Nolan, an associate professor of microbiology and immunology at the Stanford School of Medicine, led the team at Stanford, which received $14.9 million over seven years to develop antibody-based technology directed at rheumatic diseases.

"So what ours was about was really … developing proteomics technologies that could address an understanding of what's going on of clinical value in the blood insofar as the immune cells and constituents of the blood are mediators of disease at disparate sites," he said.

The work done with the award led to the development of a test for rheumatoid arthritis that was eventually licensed to Roche Diagnostics. Nolan and his collaborators also developed microfluidic technology for the analysis of "all kinds of immune mediators," such as antibodies and cytokines. Other technologies developed partly under the program allowed for single-cell analysis of signaling networks, a technology that was licensed to Becton Dickson who sells it under the PhosFlow brand.

Two companies also grew out partly as a result from the research funded by the NHLBI grant: Nodality, a diagnostics development firm, and Cytobank, a flow cytometry computer analysis company. The success of the research done under the grant, Nolan said, is "a demonstration of how important these kinds of programs are in getting cutting-edge science back into the public domain to reduce health care costs."

In addition, the technologies created under the NHLBI program led to the development of the Stanford Human Immune Monitoring Core, bringing the developed science directly to an academic early-stage clinical-assay laboratory to support other investigators at Stanford who want to work with clinical samples.

"What this is doing is … supporting the efforts of many more researchers beyond simply those who participated in the original NHLBI contract … to have statisticians on board, to have pathologists, and then to know that there's a path toward homebrew and CLIA certification, to basically build a mini-diagnostics development group," he said.

Nolan said he will be applying for the new NHLBI program for research directed at how blood changes the biology of lungs and the vascular system. He did not want further details to be publicly disclosed because it involves unpublished concepts.

The importance of programs such as NHLBI's is that it can force a researcher to focus on the ultimate endpoint of any scientific research, he added.

"Too many researchers use biomarkers as a way to get funding but [don't] understand that unless you run your biomarker study on clinically annotated samples in the context of a validated clinical trial … you're really just going to publish a nice paper," he said. "You're not going to necessarily convince a clinician to do anything different with your biomarkers as regards treatment decisions."

The new program, he said, "is basically saying [to researchers] "Create clinical proteomics.'"

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