A study published in the International Journal of Cancer in 2009 examined the activity of chlorophyllin and found that, on a dose-by-dose basis, it was 10 times more potent at causing death of colon cancer cells than hydroxyurea, a chemotherapeutic drug commonly used in cancer treatment.

Beyond that, chlorophyllin kills cancer cells by blocking the same phase of cellular division that hydroxyurea does, but by a different mechanism. This suggests that it – and possibly other “cocktails” of natural products – might be developed to have a synergistic effect with conventional cancer drugs, helping them to work better or require less toxic dosages, researchers said.

“We conclude that chlorophyllin has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents,” the researchers wrote in their study.

The concept of combining conventional or new cancer drugs with natural compounds that have been shown to have anti-cancer properties is very promising, says Rod Dashwood, professor and director of the Cancer Chemoprotection Program in the Linus Pauling Institute.

“Most chemotherapeutic approaches to cancer try to target cancer cells specifically and do something that slows or stops their cell growth process,” Dashwood says. “We’re now identifying such mechanisms of action for natural compounds, including dietary agents. With further research we may be able to make the two approaches work together to enhance the effectiveness of cancer therapies.”

Chlorophyllin is a water-soluble derivative of chlorophyll, the green pigment found in most plants and many food products that makes possible the process of photosynthesis and plant growth from the sun’s energy. Chlorophyllin is inexpensive, and animal studies plus human clinical data suggest that it can be ingested at relatively high levels without toxicity.

In the study, researchers found that pharmacologic doses of chlorophyllin caused colon cancer cells to spend more time than normal in their “synthesis phase” in which DNA is duplicated. Timing is critical to the various phases of cell growth, researchers said, and this disruption started a process that ultimately led to cell death, the study found.

In particular, the presence of high levels of chlorophyllin caused a major reduction in the level of ribonucleotide reductase, an enzyme critical to DNA synthesis, researchers found. This is also the mechanism of action of hydroxyurea, one drug already being used for cancer chemotherapy.

“In cancer research right now there’s interest in approaches that can reduce ribonucleotide reductase,” Dashwood adds. “At the doses used in our experiments, chlorophyllin almost completely stops the activity of this enzyme.”

Further research is needed both in laboratory and animal studies, with combinations of chlorophyllin and existing cancer drugs, before it would be appropriate for human trials. Chlorophyllin, in general, is poorly absorbed from the human gastrointestinal tract, so it’s unclear what levels might be needed for therapeutic purposes or how well they would work.

Other dietary agents also might have similar potential. Work published by LPI researchers in the journals Carcinogenesis and Cancer Prevention Research explored the role of organic selenium compounds in killing human prostate and colon cancer cells. Colorectal and prostate cancers are consistently among the leading causes of cancer mortality in the United States and accounted respectively for 18 percent and 9 percent of all cancer deaths in 2009, according to estimates from the American Cancer Society.

In the recent studies, a form of organic selenium found naturally in garlic and Brazil nuts was converted in cancer cells to metabolites that acted as “HDAC inhibitors” – a promising field of research in which silenced tumor suppressor genes are re-activated, triggering cancer cell death.

“Whether it’s HDAC inhibition leading to one manner of cancer cell growth arrest, or loss of ribonucleotide reductase activity leading to another, as seen with chlorophyllin, there’s significant promise in the use of natural products for combined cancer therapies,” Dashwood says. “These are areas that merit continued research.”

These studies were supported by the National Cancer Institute and the National Institute of Environmental Health Sciences. Other collaborators included researchers from the New York Medical College and the Penn State College of Medicine. Further information on chlorophylls and selenium compounds can be found in the LPI’s Micronutrient Information Center.

Light spectra by artist Stephen Knapp illuminate a wall in the new Linus Pauling Science Center. In their research, scientists use spectra to detect and measure the abundance of chemical elements. (Photo: Theresa Hogue)

In 2011, the first Baby Boomer turned 65 — the leading edge of a wave that is going to change the country. By 2030 one in every five Americans will be older than that. People are already living longer, taking time to travel and to enjoy their families. Think gourmet cooking classes, fishing trips and art museums.

But they will increasingly face the diseases that now kill most people in the developed world: heart disease, cancer, stroke, diabetes and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

They want answers and solutions. And in the future, many of those answers will come from a new research facility at Oregon State University, the Linus Pauling Science Center.

This new $62.5 million, 105,000-square-foot research and educational structure, just completed this fall, has arrived at an opportune time in American history. But its foundations were laid 94 years ago, in the fall of 1917, when a young student arrived at Oregon Agricultural College and enrolled in a chemistry course. Linus Pauling, OSU’s most accomplished alumnus, went on to win two Nobel Prizes.

“Linus Pauling revolutionized the fields of chemistry and molecular medicine, and this facility will be a working memorial to him, a great tribute,” says Balz Frei, director of the Linus Pauling Institute. “It will help further establish LPI as a national leader in the study of diet, optimal nutrition and micronutrients.

“Chronic disease prevention through diet and lifestyle is the future of medicine,” Frei adds. “And it’s for everyone, not just the elderly.”

Advances in health will come from better understanding of phytochemicals such as sulforaphane, a cancer-fighting compound in broccoli and other cruciferous vegetables. Other research focuses on vitamin D in enhancing immune function and fish oil in preventing fatty liver disease. New types of antioxidants and “anti-inflammatories” are also being investigated, such as lipoic acid, which may be key to getting the most out of life as we age.

Chemical Collaboration

The institute will share the new facility with the OSU Department of Chemistry. Specialists in analytical, materials and organic chemistry will work in close proximity to their peers in the health sciences and develop new strategies for disease diagnosis and treatment. “These new facilities house approximately $10 million in state-of-the-art transmission- and scanning-electron microscopes and nuclear magnetic resonance spectrometers that will serve the entire campus,” says Vince Remcho, chemist and associate dean in the College of Science.

The new instruments were made possible by grants from the M.J. Murdock Charitable Trust, the National Science Foundation (NSF) and partnerships between several of OSU’s colleges, the OSU Research Office and the Oregon Nanoscience and Microtechnologies Institute (ONAMI).

Chemists in the new facility bring with them “an astonishing research track record, as measured by publication count, impact, external funding and intellectual property development,” Remcho adds.

Primary support for the center, which was designed to the U.S. Green Building Council’s LEED silver standards, came from the Wayne and Gladys Valley Foundation – a $20 million gift – and another $10.6 million from Pat and Al Reser. Most of the research in the facility will be supported by grants from the National Institutes of Health and NSF.

—   Linus Pauling, 1983

Linus Pauling spent the latter years of his career at Stanford University and at the scientific institute that bears his name exploring the role of micronutrients in health, from the common cold to cancer. By the time he wrote the paragraph above, he had received two unshared Nobel Prizes and had become well known for his advocacy of vitamin C mega-doses. Today, his legacy lives on through the Ava Helen and Linus Pauling Papers Collection, the Linus Pauling Institute (LPI) and a new 105,000-square-foot science center at Oregon State University.

Two recent reports from LPI scientists demonstrate their ongoing efforts to understand the relationship between health and dietary compounds.

Green Tea for the Immune System

Green tea drinkers may be on to something. Scientists have found that a beneficial compound in the ancient beverage has a powerful ability to increase the number of “regulatory T cells” (a type of white blood cell) that play a key role in immune function and suppression of autoimmune disease. This may be one of the underlying mechanisms for the health benefits of green tea, which has attracted wide interest for its ability to help control inflammation, improve immune function and prevent cancer.

Emily Ho's research focuses on naturally occuring compounds that play a role in cell regulation. Better understanding of these processes could lead to treatments for cancer and other diseases. (Photo: Kelly James)

“This appears to be a natural, plant-derived compound that can affect the number of regulatory T cells, and in the process improve immune function,” says Emily Ho, an LPI principal investigator and associate professor in the OSU Department of Nutrition and Exercise Sciences. “When fully understood, this could provide an easy and safe way to help control autoimmune problems and address various diseases.”

The immune system performs a delicate balancing act between attacking unwanted invaders and protecting normal cells. In autoimmune diseases, which can range from simple allergies to terminal conditions such as Lou Gehrig’s disease, this process goes awry, and the body mistakenly attacks itself.

Some cells exist primarily to help control that problem and dampen or “turn off” the immune system, including regulatory T cells. The number and proper function of those regulatory T cells, in turn, are regulated by other biological processes such as transcription factors and DNA methylation.

In this study, scientists exposed laboratory mice to a compound in green tea called epigallocatechin gallate, or EGCG, which has both anti-inflammatory and anti-cancer characteristics. They found that mice with higher EGCG levels had a higher production of regulatory T cells. Its effects were not as potent as some of those produced by prescription drugs, but it also had few concerns about long-term use or toxicity.

“EGCG may have health benefits through an epigenetic mechanism, meaning we aren’t changing the underlying DNA codes, but just influencing what gets expressed, what cells get turned on,” Ho says. “And we may be able to do this with a simple, whole-food approach.”

The findings were published in Immunology Letters, a professional journal. Co-authors included scientists from OSU, the University of Connecticut and Changwon National University in South Korea. The National Institute of Environmental Health Sciences and the OSU Agricultural Experiment Station supported the work.

Tea consumption was also the focus of one of the LPI’s most frequently cited papers. In 2003, scientists Jane Higdon and Balz Frei, LPI director, published a survey of studies on tea and the incidence of cancer, coronary heart disease and other illnesses.

For the Love of Cauliflower

If you ever needed a reason to eat broccoli, Brussels sprouts or cauliflower, consider sulforaphane. Ho and other LPI scientists have shown for the first time that this phytochemical can selectively target and kill prostate cancer cells while leaving normal cells healthy and unaffected.

The findings are another important step forward for the potential use of sulforaphane in cancer prevention and treatment. Clinical prevention trials are already under way for its use in these areas, particularly prostate and breast cancer.

It appears that sulforaphane, which is found at fairly high levels in cruciferous vegetables, is an inhibitor of histone deacetylase, or HDAC enzymes. HDAC inhibition is one of the more promising fields of cancer treatment and is being targeted from both a pharmaceutical and dietary approach, scientists say.

“It’s important to demonstrate that sulforaphane is safe if we propose to use it in cancer prevention or therapies,” says Ho, lead author on the study. “Just because a phytochemical or nutrient is found in food doesn’t always mean it’s safe, and a lot can also depend on the form or levels consumed,” Ho adds. “But this does appear to be a phytochemical that can selectively kill cancer cells, and that’s always what you look for in cancer therapies.”

The findings were published in Molecular Nutrition and Food Research, a professional journal. The research was supported by the National Cancer Institute, National Institute of Environmental Health Sciences and the OSU Agricultural Experiment Station.

Previous OSU studies done with mouse models showed that prostate tumor growth was slowed by a diet containing sulforaphane.

They called him the “Iron Horse” because he was known for his durability. But even in 1938, he was feeling tired by mid-season. And for him, a season like that was considered mediocre.

Finding a way to eliminate, not repair, mutant nerve cells could lead to improvements in Lou Gehrig's disease treatment, says Joe Beckman (Photo: Karl Maasdam)

The next year started off much worse. “I think there is something wrong with him,” one sports reporter wrote. “Physically, I mean. I have seen ballplayers ‘go’ overnight, but they were simply washed up as ballplayers. It’s something deeper in this case.”

The reporter was right. Seventy years earlier, a French doctor named Jean-Martin Charcot had described a strange disease called amyotrophic lateral sclerosis (ALS), and in the seven decades since, very little had been learned about it. It was only in 1939 that ALS burst onto the world consciousness when Lou Gehrig, one of the greatest baseball players who ever lived, announced he was suffering from the disease, retired and died just two years later.

ALS would evermore be known to most people as Lou Gehrig’s disease. Unfortunately, when World War II was just starting in Europe in 1939, they didn’t know much about it.

Unfortunately, after another seven decades has passed, that’s still true.

Still No Cure

Doctors do not know for sure what causes ALS. They don’t know how to slow its progression. They certainly don’t know how to cure it. Researchers debate among themselves and trade theories in science literature. Dedicated doctors, nurses, therapists, aides and especially family members work to reduce suffering and treat symptoms, but the disease is debilitating, progressive and terminal.

In the middle of this quandary is Joe Beckman, an Oregon State University professor of biochemistry, holder of the Ava Helen Pauling Chair in the Linus Pauling Institute and director of the widely recognized OSU Environmental Health Sciences Center.

Major research programs are under way, and Beckman has been laboring in them for 15 years. The goal is a therapy or cure for ALS. But this disease is not simple. If it were, very smart scientists would have figured it out a long time ago, and that hasn’t happened.

“This is complex, and it’s not certain yet where the right answer lies,” Beckman says.

The complexity, from one perspective, is about whether to restore zinc, remove copper or stabilize “superoxide dismutase” (an enzyme that protects cells from damage). If you think that sounds complicated, consider that Beckman has a stack of scientific studies on his desk about a foot thick, at risk of toppling to the floor, that address this and a lot of other issues.

But if the OSU researchers are right — and they think they are — then at least some research programs may be on the wrong track, and their efforts to stabilize a certain biological function are misguided. Instead of helping, these approaches may lead to the death of motor neurons and progression of the disease. As it progresses, ALS causes lost motor function, paralysis and usually death within a few years.

Beckman and nine other researchers last year published what they believe is an important study that summarizes more than a decade of findings and helps make the case for their theory.

The work was funded by the National Institutes of Health, the Amyotrophic Lateral Sclerosis Association, and other agencies. And it’s been facilitated by the sophisticated mass spectrometry facilities at OSU, which allow detailed questions to be asked at levels never before possible.

Copper May Be Key

Therapies that could remove copper atoms from superoxide dismutase (SOD), the OSU team believes, would allow it to die and be naturally eliminated. In the process, they could form the basis for a treatment for ALS. Researchers say this could stop the progression of the disease, while others in the science community continue to argue that copper is irrelevant.

“With the approach we’re using, we can already remove copper atoms in cell cultures and stop the death of motor neurons,” Beckman says. “We haven’t done this yet in animals, and some researchers who disagree with us point to certain experiments that they say show this won’t work. But I think this issue is more complex than many understand and those experiments are flawed.

“The devil is in the details,” he adds.

Complexity is a word that keeps coming up in discussions about ALS. That’s the sometimes painful process of science, which rarely yields simple findings and unchallenged facts. With ALS, some things are known. The disease results from the death of nerve cells in the brain and spinal cord. It’s less clear what starts that process, how it could be slowed or stopped, and there’s no known way to detect it before it begins.

Which brings us back to copper-zinc SOD, an antioxidant that helps rid cells of harmful molecules known as free radicals. A genetic mutation in the SOD gene leads to a zinc-deficient form of this compound, and some people with this mutation are far more likely to get ALS.

“In healthy people, superoxide dismutase compounds sort of partner together, fighting back-to-back to make each other stronger and help protect other cells,” Beckman says. “In ALS patients, for genetic or other reasons that are not clear, this process breaks down. Zinc-deficient SOD proteins begin to lose their shape and function, and the end result is dead motor neurons.”

Many researchers believe that stabilizing these mutant proteins would help prevent the progression of ALS. “Some neuropathologists look through a microscope at damage from ALS, and they see the tangled globs of misfolded proteins that are hallmarks of the disease,” Beckman says. “They find SOD associated with that, and think that’s the cause of ALS, and believe preventing that damage, preventing that unfolding, is the way to a therapy.”

Beckman’s findings are just the opposite. They suggest the SOD damage is just step in the process and an early one at that.

“We believe that keeping this dysfunctional superoxide dismutase around just makes things worse, creates a situation that is even more toxic to motor neurons and leads to the disease,” Beckman says. “Our studies indicate the best thing is to just let the zinc-deficient SOD go ahead and unfold, fall apart and be naturally eliminated.”

Scientists have found that removing copper atoms from this zinc-deficient SOD allows just that. The SOD is eliminated and does not create a toxic environment. In cell cultures, this has been shown to stop the death of motor neurons.

Therapies that would do this effectively don’t yet exist, but Beckman says they could. It would probably be a drug that helps remove the right amount of copper in cells in the right places, a metabolic balancing act that may be tricky but possible. “The real cure to defective superoxide dismutase is not to try to stabilize it; it’s to get rid of it. Removing copper is a way to do this, and we believe in that direction may lie a cure for ALS.”

Hope for Today

While this work goes on, 30,000 Americans have ALS at any given time, and Beckman provides what relief he can as he makes progress on the research front.

“Joe is a brilliant scientist, but he can also explain these very complicated topics in ways that others can understand,” says Lance Christian, executive director of the ALS Association of Oregon. “He regularly meets with our support groups to help explain the latest research findings. And he’s very patient, never rushed. Even though the science is so narrow and focused, Joe will answer every question, and he understands the larger issues of real people dealing with this disease.”

Beckman says that’s important, and he gets upset when he hears stories about people being told “nothing can be done.”

“There’s a lot we can do for people who are stricken with this horrible disease,” Beckman says. “We can’t cure it yet, but we can provide hope. And we can make sure that patients get all of the special help they may need to watch their nutrition, communicate, breathe, reduce their stress levels. That can improve both the quality and length of their life.”

ALS affects everything from swallowing to maintaining weight, breathing, and in some cases, cognition. Fatigue and depression are common. Most people die from respiratory failure or pneumonia within a few years of diagnosis.

“ALS is such a difficult disease that it not only can kill individuals but can destroy families, with the constant struggles and demands for 24-hour care,” Beckman says. “We have to do everything we can to help people until we can finally figure out exactly what is causing this disease.

“And when we do that, I really believe we can find a therapy for it, at least a way to slow or stop its progression. We’ll see the day when ALS is no longer a terminal illness.”
_____________________________

See more about Joe Beckman’s research.

Anneke Tucker has demonstrated the power of natural plant products to reduce glucose levels in people with Type 2 diabetes. (Photo: Frank Miller)

Last winter, judges in a national competition, The Journal of Young Investigators’ Second Annual Virtual Poster Session, recognized her sklls and ambition when they awarded her first place for a video presentation on research with scientists in OSU’s Linus Pauling Institute (LPI). It was Tucker’s second presentation to a scientific audience.

The University Honors College student grew up in a ranching community and, inspired by her participation in Future Farmers of America, came to Oregon State University to study animal science. But instead of healthy cows, it was healthy people that drew her attention, so she switched her focus in the College of Agricultural Sciences to BioResource Research. Intent on getting into a lab to satisfy the required 400 to 600 hours of laboratory experience, she searched for a mentor and applied for undergraduate research funding from OSU’s Howard Hughes Medical Institute program and from the OSU Office of Research.

Natural Remedies

Then she met Balz Frei and Meltem Musa. The LPI scientists were planning to test plant extracts — grapeseed, Japanese knotweed and white and green tea, among others — for their ability to treat Type 2 diabetes. In addition to laboratory studies, they planned to do human trials. Tucker was hooked. “Since I was the only student working with Dr. Musa and Dr. Frei on that particular project, it allowed me to have a greater understanding of the overall goal of the research,” says Tucker. She followed the project from the start, asking questions along the way. “It seemed like a perfect match,” she adds, because she was taking classes in biochemistry and nutrition at the same time.

Tucker focused on two enzymes — alpha amylase and alpha glucosidase — that play a key role in diabetes by breaking carbohydrates down into glucose molecules. Glucose is vital since it powers our cells, and most people keep blood glucose levels within a healthy range.

But in those with Type 2 diabetes, blood glucose can rise to harmful levels. The disease has an unknown cause, and its symptoms are devastating: increased risk of Alzheimer’s Disease, stroke, heart attack and high blood pressure; damage to nerves, kidneys, eyes, skin and mouth; osteoporosis. In the United States alone, 23.6 million people have been diagnosed with Type 2 diabetes, and another 54 million are thought to be pre-diabetic. The price tag: $218 billion annually, according to the American Diabetes Association.

Results Were Mixed

Working closely with Musa, Tucker compared the effectiveness of plant extracts to a prescription medication that carries a high price tag and has serious side effects. Her results were mixed. She found that several of the plant extracts are more effective than the drug in reducing the activity one of the enzymes, alpha glucosidase. For the other enzyme, alpha amylase, the drug was more effective.

Tucker is applying to medical school and intends to specialize in women’s health and nutrition. “Ultimately,” she says, “I would love to open a clinic in a rural and under-served community (which is where my fiancé and I come from) and offer medical services and education regarding women’s health and life-long nutrition and health.”

____________________

Learn more about undergraduate research opportunities at OSU.

Advertisers promote them. The American Heart Association recommends eating foods that contain them. Without antioxidants, you may be more prone to cancer and neurological or cardiovascular problems. While antioxidant science is far from settled, OSU researchers have identified sources and are learning how these micronutrients promote health by curbing “free radicals.”

Berry good sources

In 2002, a highly cited paper by an OSU research team led by Ron Wrolstad and Balz Frei documented antioxidant concentrations in 107 varieties of blackberries, red and black raspberries, blueberries and currants. Top-ranked for antioxidant pigments (anthocyanins): black raspberries (Rubus occidentalis)

First line of defense

In a paper that has become a citation classic, Balz Frei reported that vitamin C acts as a powerful antioxidant in human plasma. He showed that it quickly disarms lipid-damaging “free radicals,” thereby preventing “bad cholesterol” from going rancid and contributing to heart disease.

One-two punch

In a series of papers, Maret Traber and OSU colleagues have shown that in humans, vitamins E and C team up to pack more antioxidant punch than either does alone. They also showed that when taken as a supplement, vitamin E must be accompanied by fats to be absorbed by the body.

Gene regulator

Lipoic acid acts as a powerful antioxidant in laboratory experiments (in vitro), but it plays other roles in the human body. Tory Hagen has reported that it regulates genes that stimulate production of glutathione, one of the body’s own antioxidants, and the transport of antioxidants into cells. It thus provides a long-term means of staving off oxidative and toxic stresses.

Heavy metal

Zinc is the most abundant intracellular trace element in the body, contributing to immune function, reproduction and oxidative stress response. In 2009, a team led by Emily Ho reported that a lack of zinc induces single-strand DNA breaks and leads to oxidative stress in otherwise healthy men. The findings confirm that zinc plays a crucial role in the body’s own antioxidant defenses

For more information

See the Micronutrient Information Centerat OSU’s Linus Paul Institute. LPI, one of the nation’s first two NIH Centers of Excellence for Research on Complementary and Alternative Medicine, specializes in the study of micronutrients. Researchers above are affiliated with LPI and the colleges of Science, Agricultural Sciences and Health and Human Sciences.

Funding support

National Institutes of Health (National Center for Complementary and Alternative Medicine, National Institute of Diabetes and Digestive and Kidney Diseases, Office of Dietary Supplements, National Institute on Aging)

U.S. Department of Agriculture

Collaborators’ home institutions, including OSU

For more information, see these OSU news releases:

Study Citing Antioxidant Vitamin Risks Based on Flawed Methodology, February 27, 2007

Studies Force New View on Biology, Nutritional Action of Flavonoids, March 5, 2007

To support the Linus Pauling Institute and antioxidant research at OSU, contact theOregon State University Foundation.

Hardening of the arteries and high blood pressure may result from a breakdown in cell communications, researchers in OSU’s Linus Pauling Institute have discovered. The finding could pave the way for new dietary measures and pharmaceuticals to reduce cardiovascular diseases.

“It’s also a key to understanding the biological effects of inflammation, which increasingly seems to be implicated not only in heart disease but other chronic and neurologic diseases,” says Tory Hagen, associate professor of biochemistry and biophysics and lead author of the study.

As they age, the cells lining artery walls no longer produce chemicals that diffuse to under-lying muscle cells. As a result, vessels remain constricted, increasing blood pressure and the likelihood of cardiovascular diseases. In test tubes and animal models, the researchers identified the mechanism that impairs normal blood vessel function. The results provide new targets for therapies to prevent hardening of arteries as we age.

A diet that’s heavy in fruits and vegetables seems to slow down the loss of blood vessel function, says co-author Balz Frei, director and holder of the Linus Pauling Institute Endowed Chair. The scientists also study lipoic acid, a powerful antioxidant that may play a role as a dietary supplement to help address this problem. Their findings were published in the journal Aging Cell last fall.

A Molecule for Health

Full understanding of vitamin E’s role in human health has long eluded scientists, largely because plants make eight molecules with vitamin E antioxidant activity, but humans only require the one form shown here. OSU’s Maret Traber has found that only this form — naturally occurring alpha-tocopherol — is “vigorously retained” by the body.

Maret Traber’s experiments feature an eclectic collection of subjects: rats and tropical fish, overweight people and ultramarathon runners, apples and baked goods.

That’s because the focus of her research — vitamin E — is among the most complex and least understood of the micronutrients. So she and her graduate students study it from all sorts of angles: metabolism in rodent livers, protein transporters in zebrafish, nutrient interactions in humans stressed by obesity or grueling physical activity and blood plasma levels in muffin eaters.

Teasing out E’s elusive secrets from her laboratory at OSU’s Linus Pauling Institute has earned Traber international prominence in the world of nutrition science. Her most recent discovery proving the synergistic action of vitamins E and C in the human body has far-reaching implications. But bigger breakthroughs are ahead.

“More than 80 years after the discovery of vitamin E, we still don’t know its specific molecular functions. This is the last frontier in vitamin research,” says Traber, who is also a professor in the OSU Department of Nutrition and Exercise Sciences.

Vitamin E’s status as a nutritional conundrum stems from its many chemical forms. The term “vitamin E” is an umbrella covering a “family” of at least eight structurally related compounds that occur naturally in plants — four tocopherols and four tocotrienols. Yet the human body rejects all of these except one form of tocopherol called alpha.

The term tocopherol has its roots in an early discovery: it is essential to successful production of offspring. Hence, it takes its name from the Greek words tokos (“childbirth”) and pherein (“to bear”). It’s the alpha form whose role in the human body is best known as an antioxidant — that is, it protects normal cells that are under oxidative stress.

Sources of such stress include tobacco smoke and, on the opposite end of the lifestyle spectrum, punishing road races. These stressors can trigger the production of free radicals, which rob molecules of their electrons and damage normal cells. Antioxidants like vitamin E — sometimes called “radical scavengers” — can head off the molecular damage that leads to chronic diseases such as cancer, Alzheimer’s and heart disease.

Because of work by Traber and other scientists, we also know that vitamin E doesn’t work alone. In a report published this year in the journal Free Radical Biology and Medicine, Traber, along with Dean Tammy Bray of the College of Health and Human Sciences and then graduate student Rich Bruno (now at The Ohio State University), revealed a metabolic link between E and C. They knew from prior LPI research that smoking depletes vitamin E in plasma. They also knew that, in test tube experiments, the two vitamins work together. But whether the two nutrients “talk” to each other in the human body had not been clearly demonstrated. The study comparing 24 college-age smokers and nonsmokers found that daily vitamin C supplements of 1,000 milligrams blocked the depletion of E in the smokers by as much as 45 percent. Researchers from the University of Washington, Columbia University and Brock University also collaborated on the study.

“It’s the Mt. Everest of micronutrients.”
Maret Traber
Professor, Linus Pauling Institute

One of the surprises of this E-C synergy stems from the old adage, “oil and water don’t mix.” Vitamin E dissolves in fat, while vitamin C dissolves in water. As anyone who shakes up the vinaigrette knows, oil and water separate as soon as the shaking stops. Nevertheless, chemists have shown that E and C can get together through a series of complex chemical steps. It was Traber’s team that moved the science from the test tube to the dinner plate, demonstrating the interactions between vitamin E and the foods we eat.

But eating E-loaded foods — sunflower seeds and almonds, spinach and dandelion greens, oils pressed from canola, cottonseed, safflower or olives — isn’t sufficient to protect you against free radicals. As Traber has shown, an adequate intake of its co-antioxidant, vitamin C, is also critical. If you’re taxing your cells by smoking or by running the McDonald Forest 50-K Ultramarathon, you’ll need to bump up your C intake to compensate.

If you’re among the 95 percent of American adults who aren’t getting the 15-milligram daily requirement and decide to take an E supplement, many nutritionists recommend a full-spectrum pill — one that contains the less-understood tocotrienols as well as the tocopherols. Traber “vehemently” objects to this stance. Her studies have shown that only alpha-tocopherol is vigorously retained by the human body, while the other forms are metabolized and excreted. Her studies show, too, that synthetic alpha-tocopherol is only half as effective as natural alpha-tocopherol.

These concerns, however, touch on only part of the vitamin E-interaction puzzle. Popping an E supplement is futile, for instance, unless you take it with a fat-laden meal. “If you take a vitamin E with a glass of water and call it breakfast as you run out the door,” Traber says, “it doesn’t do you any good at all.”

She and researcher Yanyun Zhao of OSU’s Department of Food Science and Technology showed this E-fat dependency in a study in which Zhao coated apples with vitamin E as a preservative. The scientists then measured vitamin E absorption in subjects who ate an E-coated apple compared with those who ate a bagel and cream cheese along with their Granny Smith. Vitamin E absorption was much lower in the apple-only eaters than in those who also had the bagel and schmear.

Other common causes of oxidative stress include obesity and diabetes. Traber has launched a collaborative study with vitamin C expert Mark Levine at the National Institutes of Health to investigate how vitamin E requirements differ among obese, diabetic and normal women. Using state-of-the-art biokinetic technologies on 30 female subjects at the NIH hospital in Bethesda, Maryland, the researchers will be exploring such questions as: How is it absorbed and transported in the body? How does it interact with fat? How does it interact with C?

In yet another new NIH-funded study, Traber will look at how vitamin E interacts with therapeutic drugs. The $1.4 million, four-year investigation will focus on the metabolic pathways in rats’ livers for regulating vitamin E and pharmaceutical drugs — and on how those compounds interact.

“For all the other vitamins, we know exactly what they do and how they do it at a biochemical level,” Traber says. “But E is still a huge unknown. It’s the Mt. Everest of micronutrients.”

* Marathon Runners Deplete Vitamins, Raise Oxidative Stress (OSU press release, 2-26-02)

In the early 1980s, Orlo Williams, a lawyer in Springvale, Maine, sent a note to the institute asking about research on vitamin C and other micronutrients. Staff members answered and continued to send him the annual newsletter.

In subsequent years, Williams sent back small contributions, but the big surprise came in 1998. Williams’ estate included a $1.2 million unrestricted gift to LPI. His generosity spurred an additional $500,000 in contributions. With the Oregon State University Foundation, the institute created the Ava Helen Pauling Endowment, dedicated to the memory of the peace activist and inspiration for Linus Pauling, her husband and winner of the Nobel Peace Prize.

The fund enabled LPI to hire Joseph Beckman whose expertise complements the institute’s ongoing research on micronutrients and health. Beckman focuses on oxidative stress, neurodegeneration and dietary factors in disease prevention. In addition to holding LPI’s Ava Helen Pauling Chair, he directs OSU’s Environmental Health Sciences Center and is a professor in the Department of Biochemistry and Biophysics.

LPI Director Balz Frei (holder of the Linus Pauling Institute Endowed Chair) notes that Beckman is one of the most frequently cited scientists in the world, in the top 250 in biology and biochemistry, according to the ISI Web of Science.

One of Beckman’s goals is to understand ALS, or Lou Gehrig’s disease, a condition in which nerve cells die, slowly robbing the body of the ability to move and breathe. About 5,600 Americans are diagnosed with it annually. Average life expectancy after diagnosis is three to five years. The cause is unknown, but Beckman’s research shows that oxidative stress and micronutrients play crucial roles. “There are five or six things going wrong all at once. And we don’t understand all the players,” he says.

While no cure exists, treatments can improve quality of life and extend survival. Beckman and his colleagues are developing new therapeutic agents, but clinical trials can take ten years or more. “Our interest is in testing alternative therapies, and micronutrients are one way that potential benefits, even if small, could be achieved more rapidly,” he says.

Beckman shares his knowledge with patients and their families through the ALS Association of Oregon. At LPI, he works with Frei, Maret Traber and other scientists to understand the roles of vitamins, zinc and other dietary constituents in reducing the risks of ALS, dementia and cardiovascular disease.

Beckman has received numerous grants from the National Institutes of Health to study oxidative stress and ALS. However, those funds are subject to annual federal appropriations. The endowment provides crucial “seed money,” he explains. “It’s important for letting us have flexibility, trying new approaches that cannot yet be funded by traditional grants.”