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Scientists travel beyond
the genetic code

February 2003

by Amanda Gallagher

In 2000, scientists across the world celebrated one of the biggest breakthroughs in research history: they unraveled the genetic code, effectively creating a "roadmap" of the human body.

Now, Health Science Center scientists are heading off the beaten path and into an unexplored frontier called "proteomics." Itís an exploding field that will enable scientists to better understand disease, target proteins for drug therapy, determine the effectiveness or toxicity of pharmaceuticals and explain basic biochemical processes.

The DNA roadmap gave researchers the ability to determine which genes are involved in specific disease processes. Proteomics goes one step further. It explores the proteins that are encoded by the DNA strands, enabling scientists to determine some of the consequences of genetic alterations. "With proteomics, we can gain a wealth of information about proteins -- their identity, quantity and ways they have been modified," said Susan Weintraub, Ph.D., a professor in the department of biochemistry. "Finding a protein or groups of proteins that either increase or decrease in quantity may even lead us to the basis of a disease."

Dr. Weintraub directs the Mass Spectrometry core laboratory at the Health Science Center. It is one of only a limited number of academic proteomics labs in the nation. Mass spectrometers are powerful instruments used to study proteomics. A scientist can first separate proteins on two-dimensional gels and then stain them. By comparing changes in color spot intensity of each protein among disease states or treatment groups, the researcher can gain insights into alterations that have taken place. Mass spectrometers are used to identify the proteins that have changed.

While instrumentation and expertise in the field are not widespread, proteomics is becoming one of the hottest areas of research. In fact, two of the three recipients of this yearís Nobel Prize in Chemistry were recognized for discovering new ways to ionize peptides and proteins for mass spectrometry. Those techniques are now used in Dr. Weintraubís lab every day.

"We are now able to answer questions we couldnít even imagine before because we lacked the necessary technology," Dr. Weintraub said. "Now, someone can bring me a sample of a protein, even in a polyacrylamide gel, and if it is of human origin, there is a high probability that I can tell what it is and if it has been modified. This gives us insight into biochemical and disease processes that were not realistic to obtain by other means. The applications are limitless."

Researchers could use proteomics to understand anything from cancer to psychiatric disease. Lawrence Mandarino, Ph.D., a professor in the department of medicine, is applying it to diabetes research.

"We are studying a protein called insulin receptor substrate-1 (IRS-1)," Dr. Mandarino said. "It is one of the key proteins that allow insulin to decrease blood sugar."

A defect in IRS-1 could prevent insulin from lowering the bodyís blood sugar level, resulting in insulin resistance. This disorder is at the root of type 2 diabetes mellitus.

"We are trying to determine whether a specific modification of IRS-1, an increase in serine phosphorylation (which would reduce IRS-1ís ability to do its job), is present in individuals with type 2 diabetes mellitus," Dr. Mandarino said. "Identifying a specific protein abnormality in type 2 diabetes would give scientists a place to target new drugs that might be designed to affect that molecular step."

Martin Meltz, Ph.D., professor in the department of radiation oncology and director of the Center for Environmental Radiation Toxicology, is using the technique to study the effects of non-ionizing radiofrequency radiation.

"The frequencies of interest are similar to those found in radios, TVs, microwave ovens and cell phones," Dr. Meltz said. "However, we are not focusing on a specific appliance at a specific frequency. We are, in this project, looking at sources of electromagnetic fields where pulses are extremely short, one-one-millionth of a second, in duration. The exposure is to a broad range of frequencies all at the same time."

Published evidence overwhelmingly shows exposures to the frequencies of electromagnetic energy emitted by small appliances donít cause cancer. After having studied this problem for many years, Dr. Meltz is using proteomics to determine if pulses of low-frequency radiation can act as a tool to treat the disease. "It is possible that the rapid rise of the electromagnetic radiation pulse or its high peak field intensity could perturb the nuclear or cytoplasmic membranes of cells, or cause some other alteration that could be beneficial,"
Dr. Meltz said.

While scientists have used a number of tools to study proteins on the molecular level, Dr. Meltz said his work would not be possible without proteomics. "It is a unique tool to assess protein changes and modifications," he said.

To date, nothing has proven quite as effective. "The answers obtained by mass spectrometry are far more definitive than the results with other techniques,"
Dr. Weintraub said.

So while we revel in the unraveled genetic blueprint, researchers have quite a few more side streets to add to the human map. For now, proteomics is the best road through that new frontier and the Health Science Center is leading the way.


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