—   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.

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)