Our Program in Neurodegeneration
It is an honor for me to join the Linus Pauling Institute at Oregon State University as the endowed Ava Helen Pauling Chair. I am moving from the medical school at the University of Alabama at Birmingham (UAB) with my wife and three children. I attended the University of Colorado for my undergraduate and Masters studies, spent two years in the Medical Service Corp of the U.S. Army in Korea and Texas, and then completed my Ph.D. at Duke University on the biochemistry of plant disease resistance. In 1985, I joined the Department of Anesthesiology at UAB. While not trained as a physician or even in a medical field, spending the past 15 years at one of the leading medical schools in the country has taught me about the many challenges facing current medical science.
My research interests have focused on problems related to neurodegeneration, and I have spent considerable time working with the National Institutes of Health on the basic science and clinical studies to more effectively treat the many diseases that cripple the brain. A decade ago, there were no clues about the causes of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis or amyotrophic lateral sclerosis (ALS). Now we have important insights at the molecular level about what makes the brain susceptible to degeneration as we age. Significant advances in treatment have been made, and there is hope for more rapid progress.
The Ava Helen Pauling Chair at the LPI will help to advance our work on ALS, also known as Lou Gehrig's disease. ALS is a dreadful disease that kills 3-5,000 Americans each year. The disease is caused by the unexplained death of motor neurons in the spinal cord. These neurons control the movement of all voluntary muscles. As more and more motor neurons die, the victim's muscles progressively atrophy, resulting in paralysis. Death results in one to five years, usually from complications related to breathing. ALS appears to be a rare disease because its victims die so rapidly. Our research indicates that the loss of the mineral zinc from an essential antioxidant protein causes the motor neurons to die in ALS. The handling of micronutrients in the brain is poorly understood, but has become a major area of research in my lab and is an important aspect of the mission of the Linus Pauling Institute.
It is not difficult for most scientists to find roots of their research in concepts emanating from Linus Pauling. I first learned of Linus Pauling in high school when my mother gave me her copy of College Chemistry and have been influenced over the years by his pioneering work on quantum chemistry, protein structure, the molecular basis of diseases, as well as his work on micronutrients and health.
When Linus Pauling was a senior at OSU teaching "Chemistry for Home Economics Majors", he first met his future wife, Ava Helen Miller, by quizzing her in class about ammonium hydroxide, a complex consisting of ammonia and water. Much of my career has focused on molecules consisting only of nitrogen and oxygen, whose biological chemistry may have surprised even Linus Pauling. My group discovered a new biological oxidant called peroxynitrite (ONOO-) produced by inflammatory cells to kill parasites, viruses, bacteria, and cancerous cells. While important for defending against infection, peroxynitrite is also a component of oxidative stress that has been strongly implicated in atherosclerosis, lung disease, heart attack, stroke, trauma, organ rejection, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS. Evidence for peroxynitrite's participation in such a wide range of human diseases has been advanced by our discovery of tyrosine nitration, a protein modification by peroxynitrite similar to the nitro group in TNT and nitroglycerine. My group developed antibodies to nitrotyrosine that are widely used around the world as research tools to study oxidative stress caused by peroxynitrite.
Based upon the distribution of nitrotyrosine we have found in many different disease processes, I have become fascinated with the role of peroxynitrite and oxidative stress in wound healing. Wound healing is the complex process in which injured tissues stop bleeding, then recruit inflammatory cells to the injured site to control the spread of infectious microorganisms, and eventually allow surrounding tissues and blood vessels to grow and regenerate the damaged tissue. Taken in its broadest sense, wound healing not only affects recovery from trauma and surgery, but also is crucial in the control of infection, the spread of cancer, and even for the normal development of the fetus. The interactions between micronutrients and oxidative stress can profoundly affect the processes underlying wound healing.
The oxidant peroxynitrite is essentially a binary weapon against bacteria and viruses that is produced when cells synthesize two less toxic molecules-nitric oxide (NO.) and superoxide (O2.-). Superoxide is simply a molecule of oxygen (O2) with an extra electron. It is the major reason why the air we breathe can also be toxic. The existence of superoxide was deduced by Linus Pauling in the 1930s based upon his powerful chemical reasoning. He gave superoxide its name based upon his predictions of its propensity to be a strong oxidant.
The toxicity of superoxide to cells is greatly limited by the presence of powerful antioxidant proteins called superoxide dismutases, first discovered by Joe McCord and Irwin Fridovich in 1969. The most abundant form of superoxide dismutase contains one atom each of copper and zinc. The copper atom acts much like the copper wiring in electrical circuits to facilitate the shuttling of electrons. The role of zinc is more subtle and has been less studied. My group used superoxide dismutase to treat stroke and head trauma in the 1980s. However, we found that superoxide dismutase could catalyze several damaging reactions under certain conditions. Strong evidence that superoxide dismutase could be damaging came in 1993 when geneticists found mutations to superoxide dismutase in a small percentage (2-3%) of ALS patients. The mutations provide an important, but mysterious clue. A major goal in my laboratory has been to characterize what makes superoxide dismutase toxic, specifically for motor neurons that die in ALS.
In the late 1940s, Linus Pauling described the basis for the first molecular disease by showing sickle-cell anemia was caused by mutations affecting the protein hemoglobin. With his initial description of the alpha-helix, Linus Pauling showed that proteins have extremely specific three-dimensional structures rather than being random globs. He further showed that the structural changes induced by a subtle change in one part of the hemoglobin protein caused major structural changes that ultimately caused the sickle shape of red blood cells. At least 7,000 different disease-causing genes have since been identified, but our understanding of the molecular basis of these diseases is still primitive compared to the molecular detail known about hemoglobin in sickle-cell disease.
Every patient with sickle-cell anemia has a genetic mutation to one specific region of their hemoglobin gene, whereas over 70 different mutations scattered over the entire superoxide dismutase gene have been linked to ALS. Our problem with ALS is to explain the common denominator between these 70 different mutations. Even more crucial is discovering what clues superoxide dismutase mutations provide for the vast majority of ALS victims with no genetic predisposition. ALS can strike any of us.
Our work suggests a simple but controversial answer. The mutations slightly weaken the ability of superoxide dismutase to hold onto the zinc atom in its active site. When superoxide dismutase loses its zinc atom, the protein visibly changes in color from green to blue and becomes toxic to motor neurons by producing peroxynitrite. If our hypothesis is correct, part of the secret to ALS is to understand how zinc is handled by motor neurons in the spinal cord. Unfortunately, taking zinc supplements does not affect the course of the disease. However, people are often chronically deficient in zinc, which might be a contributing factor to the onset of ALS. An increased intake of zinc might help prevent ALS from developing in people carrying a mutant superoxide dismutase gene who have not yet developed the disease.
Although our zinc hypothesis is controversial with essential elements still unproven, zinc-deficient superoxide dismutase gives us a molecular target to attack ALS. OSU has a strong program in structural biology and biophysics, and faculty expertise will help us understand the toxic properties of zinc-deficient superoxide dismutase. We have begun developing drugs to inactivate zinc-deficient superoxide dismutase, and some compounds are already being clinically tested. Other compounds are being modified to reduce their toxicity.
About the time when Linus Pauling became interested in the therapeutic effects of vitamin C, I became interested as a graduate student in how plants use vitamin C as part of their defense system against bacterial and fungal infections. While the work of Linus Pauling on vitamin C was highly controversial, the diverse roles of diet as well as vitamins and micronutrients in maintaining optimal health were generally ignored by the medical establishment. My grandfather died of cardiovascular disease at 48. In the 1960s, our next door neighbor died from heart disease at the age of 34 years, leaving two small children. When my dad asked his family doctor whether he should give up smoking or change his diet, the doctor replied that there was no conclusive evidence that these factors affected heart disease. Even as late as the early 1980s, medical studies could not show that exercise affected the death rate from cardiovascular disease, though more sophisticated studies later established the importance of diet, exercise, and smoking cessation in heart disease.
Now, we clearly recognize
that exercise and diet have profound effects upon health and well-being.
The effects of micronutrients and vitamins on optimal health are obviously
important, but remain fiendishly difficult to approach on a scientific
basis. The quality of science is governed by its ability to quantify.
Advances come from the ability to approach questions from different directions
made possible by new methodologies. The classical approach of depleting
animals of a particular vitamin or mineral provides little insight in
the role of micronutrients in promoting optimal health. In the past decade,
new scientific advances in analytical methods as well as sequencing the
human genome have created new opportunities to measure the impact of micronutrients
on biological function at a molecular level. Micronutrients play an important
role in maintaining the balance between defense against infectious diseases
and oxidative damage. This balance can affect the development of cancer,
stroke, heart attacks, and neurodegeneration. I look forward to the opportunity
to participate with the other outstanding scientists in the Linus Pauling
Institute in tackling these important but challenging issues.
Last updated May, 2001
Honoring a Scientific Giant with Nutritional Research Toward Longer, Better Lives
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