Why do some cancer patients go through lengthy, unpleasant treatments that don't work? Why does the treatment that helped your best friend just make your nephew sicker?
The answers to these questions may lie in the proteins that make up your cells. Proteome analysis is the study of the proteins inside a cell—their identities, how they interact, and their structures. It involves analyzing all of the proteins found in a genome. The genome provides the pattern for the development of each cell, which is made up of proteins. The analysis involves separating, identifying, and counting most proteins in a cell simultaneously.
"Part of proteomics is identifying all human proteins—and 30 to 50 percent of them are unidentified," said John B. Barnett, PhD, chair of the Department of Microbiology, Immunology, and Cell Biology at West Virginia University's School of Medicine.
Proteomics is a complement to genomics, which is the study of genes and their functions. Recent advances in genomics, including the completion of the map of the human genome, are bringing about a revolution in understanding the molecular mechanisms of disease, such as the complex interplay of genetic and environmental factors. "Genomics is fairly stable, since it relates to the DNA blueprint in cells," said Barnett. "Everyone has different DNA, but the overall pattern is consistent—it's just the details that make the individual different. From the DNA blueprint, cells build proteins."
"A
person's DNA does not change over time," Barnett added,
"but the proteome does, based on what state the cells are
in. The changes are based on what the body and the cells need.
For example, resting cells may only produce the proteins necessary
to keep them alive. But, if the body calls on them to perform
a function, such as producing antibodies, then the cell generates
a cascade of new proteins to accomplish this function. The proteome
of the resting cell, then, is substantially different from that
of an activated cell."
The changes in the proteome are identifiable, and one day may be used to diagnose illness or to predict the body's response to treatment.
Some anticancer drugs work by attacking the DNA of tumor cells. By damaging this DNA, the drugs prevent the tumor cells from reproducing, which keeps the tumor from growing. However, some people's tumor cells produce proteins that make the cell resistant to a certain drug or class of drugs, so those drugs are not effective in treating their tumors.
"This means that a patient goes through lengthy, unpleasant treatments that don't work," Barnett said. "Valuable time is wasted by treating this person with a cancer drug that is not effective for him or her. Through proteomics, however, a future doctor may be able to check for the presence of a DNA-repair enzyme before the drug is chosen. If the person has that repair enzyme, then the doctor can select a different treatment drug."
WVU recently opened a Proteomics Core Facility, offering University faculty the opportunity to use this method in their research. The facility, under Barnett's direction, is available to study the proteins inside a cell, with an eye to playing a major role in the future treatment of cancer.
"In two patients with the same kind of tumor, the proteome of the tumors is different," he said. "This is because a variety of factors influence the proteome—genetics, physical health and condition, and a number of other things."
"For example, lung cancer is very hard to treat," he added. "But some people respond very well to treatment. Why? What is different about these people that allows them to respond to the lung cancer treatment? This dimension of proteomics research also has enormous potential." "The goal of this research is to eventually be able to target a therapy to each patient's genome," he added.
Discovering why, for some patients, the treatment can cause as many problems as the disease is the underlying question behind research being conducted by Laura F. Gibson, PhD, associate professor and vice-chair of research in the department of pediatrics.
"Physicians
in the Mary Babb Randolph Cancer Center's blood and marrow transplant
unit noticed that the immune systems of some people who were
treated with certain chemotherapeutic drugs did not recover efficiently
after bone marrow transplantation," Gibson said. "The
bone marrow is the site where white blood cells, which fight
infection in the body, are generated. If the marrow is adversely
affected by aggressive treatment, then white blood cell production
is affected, resulting in a weakened immune system. For about
six years, we have been studying damage of the bone marrow microenvironment
by specific drugs, trying to find out why some treatments may
result in persistent damage."
Before the proteomics facility, Gibson and her team of researchers had to first select an individual protein as the focus of their research. With the broad-spectrum protein analysis that proteomics offers, Gibson believes that new areas of investigation will become apparent. "Chemotherapy exposure may change expression of many proteins that have no effect on the immune system,"
Gibson added. "But we are looking for the protein changes that have biological significance; changes that influence the function of the bone marrow cell and the immune system."
Gibson and her team of researchers grow bone marrow cells in culture, and then compare "healthy" ones to those that have been exposed to chemotherapy. They're looking for changes in protein expression—the appearance or loss of specific proteins in treated cells, and then evaluating the function of these proteins. According to Gibson, this search may identify additional proteins whose activity or expression has been damaged by treatment, and provide insight about why the transplanted bone marrow is unable to efficiently rebuild the immune system in certain circumstances.
Cell proteomes can be studied at different metabolic stages, or at different disease states. Timothy Vincent, PhD, a research assistant professor in microbiology, immunology, and cell biology in the School of Medicine, is the associate director of the proteomics facility. He is using proteomics to understand the mechanisms of infection: "Proteomics allows us to look at all of the proteins in a cell in the global sense."
His
research is looking at an opportunistic pathogen—a bacteria
that causes infections in people with suppressed immune systems,
or those with cystic fibrosis. In conjunction with Joan Olson,
PhD, he is studying how the bacteria, Pseudomonas aeruginosa,
interacts with host cells.
"This bacteria injects its proteins directly into the host cell," Vincent said. "This allows the bacteria to manipulate the host cell. Proteomics helps us understand that manipulation."
This research has implications for cancer treatment, as well. When this bacteria is injected into tumor cells, it attacks them, recognizing them as being out of place. "We are in the early stages of working on an antitumor therapy based on this mechanism," Vincent added. "Proteomics can help us study how the bacteria knows the tumor cell is different, and why it attacks the tumor cells, but does not destroy normal cells."
"We are also studying how the proteins within a cell interact with one another, and working to determine the exact outline of their three-dimensional structures, finding the sites that are the most vulnerable to drugs," Barnett added.
Cancer research isn't the only work being carried out in the Proteomics Core Facility. Barnett is studying the effects of various herbicides on the human body. He wants to determine if cells develop a unique profile for specific toxins. According to Barnett, this research has the potential to significantly affect medical treatment, as well as raising some serious ethical questions.
"If you can find out that a certain profile means a person will develop cancer in the future," Barnett said, "then you can immediately take steps to limit exposure to that agent, and watch closely for signs of cancer developing. But at the same time, it is possible that profiling people to verify their exposure to toxic materials may become an issue in the future."
"The proteomics facility is a great addition to our Health Sciences Center," Gibson said. "The ability to evaluate the protein expression profile of an individual so comprehensively may help us predict the best treatment in the next generation. We will be able to have a comprehensive look at the cellular level and see what proteins are inappropriately expressed, which may provide clues about the underlying cause of the disease and direct physicians toward the best treatment."
"It's a given," she added, "that the ability to examine cells at this level will influence medicine."
It may be the future of cancer treatment,
and it's happening right here at WVU.