Proteomics: Uncharted Research Waters

For pharmaceutical chemist Christian Schöneich and others involved in the exploding new field of proteomics, the human genome project has provided just one more piece of the puzzle that must be solved to understand the underlying causes of disease. Proteomics carries genomics one step further. The gene is the basis of the function. It encodes the protein that eventually carries out a designated biological action. The fact that a person has a certain gene does not necessarily mean that the protein is ultimately expressed or is even present in the cell. Schöneich explained, "People learned fairly quickly that in order to completely understand pathologies, you not only have to sequence the genome, but also get an image of the whole number of proteins present at any given time in a specific tissue and which ones may cause problems. That's proteomics."

Initially proteomics became a race to identify as many of these proteins as possible. But now the field is broadening into other areas. Even though scientists are identifying more and more of these proteins every day, each protein can be present in various forms in the body. For example, a protein and its chemically modified version can have an entirely different structure and activity than a native one.

Schöneich is interested in those proteins chemically modified by oxidative stress, an inflammatory condition that accompanies diseases such as atherosclerosis, ischemia, cancer and arthritis. During oxidative stress, the body's tissues produce large amounts of reactive oxygen species (ROX), small, highly reactive chemical molecules which are also produced in response to various external stresses such as exercise, UV light, or ionizing radiation. Though normal in small amounts, ROX can increase in number in a sick or aging person's body and cause either necrotic (uncontrolled cell death) or apoptotic (programmed cell death) activity in the tissue.

Schöneich's research involves targeting which of the body's proteins are actually attacked by these ROX. Specifically, he's interested in ROX's activity during the normal aging process. As a body grows older, its tissues produce higher and higher amounts of ROX in response to environmental stresses. Ultimately these ROX may increase to such a high number that they begin to alter some of a person's cellular proteins and may result in disease. Many age-dependent pathologies are accompanied by oxidative stress. For example, beta-amyloid, a peptide which is one major player in the development of Alzheimer's disease, is believed to cause the formation of ROX.

Schöneich has identified several proteins in aging skeletal muscle, heart and brain tissue which carry ROX-dependent modifications.

"What we're doing now is using general proteomics to see if you can get a complete picture of oxidatively modified proteins in these tissues as cont. from page 1 a person ages." He has also seen damage to similar proteins in hypercholesterolemic aorta, which eventually causes some of the dysfunctions accompanying atherosclerosis.

Schöneich said he may actually be researching a fairly general protein target of ROX. "We may eventually be able to tell the physiologist that several age-dependent diseases may benefit from delivering the gene for this protein. Of course, gene therapy is still in a very experimental stage. But if you know the specific protein targets damaged during disease and then can develop the right methods to deliver the gene that expresses the protein, then cells in the affected tissue could rebound when under attack from reactive oxygen species. Such experimental approaches have already shown great results in treating several heart conditions."

Trained as a physical chemist, Schöneich first studied reactive oxygen species, commonly called free radicals, at the Hahn-Meitner Institute for Nuclear Research in Germany. He came to KU in 1992 as a post-doc. Within a year, he was hired as an assistant professor of pharmaceutical chemistry.

The embryonic field of functional proteomics carries Schöneich's and his fellow researchers' study of proteins even further, examining how these proteins interact with each other within the body. Researchers look at a network of proteins, rather than just one type in isolation. For example if one protein is expressed in the body it has a certain effect, but that protein can then bind to another target protein which, when expressed will have its own unique effect on the body. Also, researchers want to know what will happen, for example, if a protein's target is missing or if that target has been modified by ROX. "Proteomics is multifaceted, complicated, and thus difficult to describe," said Schöneich. "But that's what makes the work so exciting."

To support such investigations, scientists need sophisticated computer hardware and software technology. To level the playing field in pro-teomics research, Schöneich and colleagues at KU, KU Medical Center, and the Midwest Research Institute have submitted a proposal to the National Institute of Health, which, if funded, could initiate a proteomics center in northeast Kansas. "Even if we don't get funding for the center," Schöneich said, "we have laid the groundwork for bringing the technology to the area. It's only a matter of time."