$4.8M stimulus grant launches feasibility study of massive endeavor to measure all human proteins

October 27, 2009

SEATTLE - An expert in cancer proteomics at Fred Hutchinson Cancer Research Center has received $4.8 million in federal stimulus funding from the National Cancer Institute to co-lead a pilot study to assess the feasibility and scalability of a project that aims to measure all of the proteins in the human body.

"If successful, this study could help to stimulate a larger international endeavor that would be comparable to the Human Genome Project," said Amanda Paulovich, M.D., Ph.D., a geneticist and oncologist in the Hutchinson Center's Clinical Research Division who is co-leading the effort with Steven Carr, Ph.D., a senior scientific leader in protein biochemistry and proteomics at the Broad Institute in Cambridge, Mass. A senior adviser on the project is N. Leigh Anderson, Ph.D., founder and chief executive officer of the Plasma Proteome Institute in Washington, D.C.

"In the same way that the Human Genome Project has had a tremendous impact on our ability to measure the expression levels of all 21,000 genes in human cells, we hope that the long-term output of this effort - the human Proteome Detection and Quantitation (hPDQ) project - will allow us to build a method to measure the products of those genes, which are the more than 100,000 proteins in the human body," Paulovich said.

Understanding the body's protein landscape is important because proteins are the workhorses of the cell that carry out genetic instructions. Changes in the structure or abundance of proteins are associated with genetic mutations that cause diseases such as cancer.

Currently there is no good way to simultaneously measure large numbers of human proteins, which presents a major obstacle to progress in both basic and applied translational research, in which fundamental scientific findings are translated into clinically useful results, from diagnostic and screening tests to drug development.

"You can't study what you can't measure," Paulovich said. "Currently the biomedical research enterprise is severely hindered by its inability to measure the vast majority of human proteins." Unlike gene signals, which can be amplified in the laboratory, protein volume cannot be dialed up. Because many proteins are present in very low quantities - like a needle in a haystack - they are below the limits of detection with current techniques.

This study is designed to change that. "This pilot has the potential of developing the first step toward making the entire human proteome clinically accessible," said Henry Rodriguez, Ph.D., director of Clinical Proteomic Technologies for Cancer in the Office of the Director at the NCI.

"If we can create ways to measure a large fraction of human proteins, particularly those in very low abundance, this will facilitate the development of new drugs and personalized medicine," Paulovich said.

Ultimately, the "holy grail" of proteomics is the discovery of protein biomarkers that could be used to create reliable and inexpensive blood tests to identify the onset and risk of a wide range of cancers and other diseases so they could be prevented or treated at the earliest possible stage, when cure rates are highest.

For the project, Paulovich and colleagues will use a highly sensitive and targeted analytical technology - multiple reaction monitoring mass spectrometry - to develop 400 assays, or tests, to measure the levels of 200 proteins found in breast-cancer cells. While the purpose of the study is to test the feasibility of scaling this technology to a much broader scale, a side benefit may be to determine whether certain proteins are associated with specific subtypes of breast cancer.

This type of mass spectrometry is not new - it has been used for years in clinical laboratories worldwide to measure drug metabolites and small molecules associated with inborn errors of metabolism. What is new is Paulovich and colleagues' pioneering use of this technology, also known as triple quadropole mass spectrometry, to measure proteins.

Unlike traditional mass spectrometry, which attempts to detect all proteins in a biological sample in a scattershot fashion, this technology is highly targeted, allowing researchers to calibrate the equipment to specifically look for peptides, or protein fragments, of interest, filtering out the rest as white noise.

The approach used in the Hutchinson Center/Broad Institute collaboration is complementary to other ongoing protein-discovery initiatives such as the Human Proteome Project of the Human Proteome Organization (HUPO) and the Swedish Human Proteome Resource. "While these other groups are identifying proteins expressed in different human cell types, we will complement their work by quantifying the expression of proteins beginning with those of potential clinical interest," Paulovich said. "We'll measure these proteins to see if their abundance changes in relation to disease."

The project also includes collaborators at Massachusetts General Hospital in Boston and the University of North Carolina at Chapel Hill, as well as a commercial partnership with Applied Biosystems of Life Technologies, whose AB Sciex triple quadrupole mass-spectrometry equipment will be used for the project.

To maximize productivity, Paulovich and colleagues also will closely coordinate activities and share their results with Robert Moritz, Ph.D., a faculty member and director of proteomics at the Institute for Systems Biology in Seattle, who recently received federal stimulus funding to lead a related human proteome project.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

Fred Hutchinson Cancer Research Center

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