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.

Source:
Kristen Woodward

Fred Hutchinson Cancer Research Center

President Obama has announced that two Fred Hutchinson Cancer Research Center investigators have been awarded the nation’s highest honor for scientists at the beginning of their independent research careers. Basic scientist Harmit Singh Malik, Ph.D., and cancer-prevention researcher Ulrike “Riki” Peters, Ph.D., are among 100 researchers to receive the prestigious 2008 Presidential Early Career Award for Scientists and Engineers (PECASE). Each will be honored in a ceremony this fall at the White House.

Since 1996 the annual PECASE awards have honored the most promising young researchers in the United States whose early accomplishments show the greatest promise for strengthening America’s leadership in science. The awards are coordinated by the Office of Science and Technology Policy within the Executive Office of the President. Nine federal departments and agencies join together annually to nominate the candidates. Selection for the award is based on two criteria: innovative research at the frontiers of sciences and technology that is relevant to the mission of the sponsoring organization or agency, and community service demonstrated through scientific leadership, education or community outreach.

An evolutionary biologist, Malik is an associate member of the Hutchinson Center’s Basic Sciences Division and an affiliate assistant professor of genome sciences at the University of Washington School of Medicine. He was nominated for the honor by the National Science Foundation, which supports his work. Earlier this year he also was appointed a Howard Hughes Medical Institute Early Career Scientist.

Malik studies genetic conflict. He sees battles raging within a cell’s nucleus as genes jockey for evolutionary dominance. These clashes can have a long-term impact on organisms, as they sometimes alter the function of essential genes. Malik uses biochemistry and genomics to study the causes and consequences of these genetic conflicts in yeast, fruit flies and other model organisms. His work has offered novel explanations for host-pathogen interactions and for the evolution of structural DNA elements (centromeres) that are critical for proper cell division.

Recently, Malik and colleagues have turned their attention to the phenomenon of “viral mimicry,” in which viral proteins can resemble host proteins to hijack important cellular functions. His lab showed that host proteins can evolve to defeat viral mimicry, providing yet another nuance to a never-ending “arms race” between hosts and viruses. The National Science Foundation funded a project of Malik’s that will study and identify cases of “reverse mimicry,” in which host genomes hijack viral proteins to protect themselves against viral infections. In particular he will focus on such a gene that he discovered while a postdoctoral fellow in the laboratory of Hutchinson Center basic scientist Steven Henikoff, Ph.D.

“Harmit thinks creatively and fearlessly about his research,” said colleague Mark T. Groudine, M.D., Ph.D., deputy director of the Hutchinson Center and former director of the Center’s Basic Sciences Division. “His thinking really pushes the envelope, and his ideas have had an enormous impact on the field.”

In addition to his research, Malik is dedicated to educating the general public about the role that evolutionary biology plays in the current understanding and practice of medicine. To this end, he and his colleagues make presentations to the Seattle community. His lab is also in the initial stages of developing a course in bioinformatics to be used by high-school science teachers.

Malik, a native of India, received his undergraduate degree in chemical engineering from the Indian Institute of Technology in Mumbai. He completed his doctoral work in molecular evolutionary biology at the University of Rochester in Rochester, N.Y., where, under the mentorship of Tom Eickbush, Ph.D., he first became intrigued by the study of genetic conflict. Malik joined the Hutchinson Center faculty in 2003.

Peters, who was nominated for the PECASE by the National Institutes of Health, which supports her work, is an associate member of the Cancer Prevention Program within the Hutchinson Center’s Public Health Sciences Division. She is also a research associate professor of epidemiology at the UW School of Public Health and Community Medicine.

A nutritional and genetic epidemiologist, Peters studies the link between nutrition and cancer prevention - particularly how the interplay of genetics and nutrition can impact cancer risk. Analyzing blood, DNA and tissue samples from large study populations, her work focuses on integrating genetic and molecular methods to better understand the role selenium, vitamin D, calcium and other dietary components may play in preventing prostate and colorectal cancer.

Selenium, for example, found in grains, bread, eggs, meat and fish, plays a key role in activating a small number of enzymes called selenoenzymes, which can protect cells against DNA damage that can lead to cancer. Peters and colleagues are studying whether genetic variations in selenoenzymes are associated with risk for prostate cancer, and whether such genetic variations alter the association between selenium intake and prostate-cancer risk.

Selenium represents only one aspect of Peters’ research. Incorporating molecular and genetic approaches, she also studies vitamin D and calcium in the prevention of colon cancer, the second leading cause of cancer death in the United States.

Peters also studies genetic variants across the entire genome and is currently conducting genomewide association studies for colon and breast cancer. The goal is to identify new genetic markers that can be used to develop better ways to detect, treat and prevent these diseases. As part of this work, she leads a large international consortium for genomewide association studies of colorectal cancer that combines data from several well-characterized population-based studies. The consortium aims to determine whether genetic variants affect colorectal cancer and whether environmental factors, including diet, drug use and smoking, modify the impact of genetic variations associated with colorectal cancer.

“This award is richly deserved. We at the Hutchinson Center are gratified, but not surprised, that Riki has been recognized for both her extraordinary accomplishments to date and the potential for her significant scientific contributions yet to come,” said Polly Newcomb, Ph.D., M.P.H., head of the Center’s Cancer Prevention Program.

Prior to joining the Hutchinson Center faculty in 2004, she worked at the National Cancer Institute on the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. This experience provided Peters with a wealth of collaborative projects, giving her broad-based experience in nutritional and genetic epidemiology.

A native of Germany, Peters received her master’s and doctoral degrees in nutrition at the University of Kiel, and she received her master’s in public health in epidemiology from the University of Carolina at Chapel Hill.

In addition to Peters and Malik, the Hutchinson Center is home to three other Presidential Early Career Award recipients: basic scientist Cecilia Moens, Ph.D., who studies the zebrafish as a model of vertebrate developmental biology; clinical researcher William Grady, M.D., who studies the mechanisms of colorectal-cancer development; and human immunogenetics researcher Effie Wang Petersdorf, M.D., whose work has helped refine the tissue-typing process, which enables bone-marrow or stem-cell transplant patients to find suitably matched donors.

Source:
Kristen Lidke Woodward

Fred Hutchinson Cancer Research Center