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Reading the Leaves "All new! All natural! All herbal!" The ads for the fat-burning, energy-enhancing, sex-drive-improving pills just scream from the page. You can now find dietary supplements that claim to help with everything from remembering where you left your car keys to reducing the size of your prostate. Some even claim to cure cancer. But do they really? Researchers at MU's Center for Phytonutrient and Phytochemical Studies are working to help consumers, and other scientists, make sense of supplements. Using a five year, $1.3 million annual grant from the National Institutes of Health, the center is bringing together MU scientists and researchers from the Missouri Botanical Garden in St. Louis to learn more about which plants may help cure disease, and why. The center is coming at the question from all sides. There are, for example, scientists who tramp through jungles and swamps looking for samples of the plants companies use to make their pills. There are bench researchers teasing apart the 10,000 components that make up any given plant. And there are additional scientists using those extracts in experiments with cells, mice and even men to see if they work, and if so, how. It's about time, too. Botanical products have been used for centuries to treat everything from conjunctivitis to constipation. They fell out of vogue in the United States as pharmaceuticals become more dependable and widely available. But today botanicals are back. According to the U.S. Food and Drug Administration, 16 million Americans are spending billions each year on botanical dietary supplements that promise to enhance their health. "When you go to a health food store, you can get 15 products that say 'ginseng.' Five will have barely any, five will have some and five will have the right amount," says Dennis Lubahn, an associate professor of biochemistry and director of the center. "The labeling can be kind of flaky. In the U.S. we strictly regulate drugs for safety and efficacy, but we only regulate food for safety. In the middle is a dietary supplement, and that includes medicinal herbs." That's why the National Institutes of Health is trying to bring some order to the chaos, or at least some science to the claims. MU was one of the first universities to receive a grant through an NIH program intended to establish 10 centers across the country to study nutraceuticals, as such botanical supplements are called. The University was awarded the center grant because it could combine expertise from all over campus, including the School of Medicine, the College of Veterinary Medicine, and the College of Agriculture, Food and Natural Resources. Add to that biochemists, pharmacologists and plant taxonomists, and you've got a powerful team. "We're trying to integrate the growing conditions of a soy plant with whether someone gets cured of prostate cancer, all on one campus," says Lubahn. "Being able to tie in the plant side with the animal side with the general background of life sciences on this campus is extraordinary. Then add in that we're tied into the strongest botanical garden in the country in St. Louis, and it's a tremendous strength for us." Jim Miller, curator and head of the applied research department at the Missouri Botanical Garden, travels all over the world identifying and digging up the plants that are ground up, distilled and extracted to create the dietary supplements available at pharmacies and health-food stores all over the country. He even uses Global Positioning System technology to pinpoint exactly where he found a plant, so he can go back and get more later. His goal is to make sure the plants being used are correctly identified. "The thing that complicates things in the herbal products industry is that many of the raw ingredients are grown in the wild," Miller says. "The acquisition process includes buying from people who wandered around in the woods or on prairies and dug these things up, and you're relying on them to deliver what they say they are delivering. Many of the products are roots, and if you're paying X-number of dollars for a pound of roots and the person digging them up realizes there are three species out there that look somewhat alike, they may be inclined to dig up all three." Miller's goal is to develop a reference manual that will describe what plant material should look like and what it shouldn't look like, so people in the industry will know exactly what they're getting. Eventually, he hopes to provide identified, standardized plant material to MU researchers, so there can be greater repeatability in their science. In addition, Miller will work with University researchers Tim Holtsford and Gary Johnson to develop advanced DNA fingerprinting techniques that can precisely identify plants - even when these are mixed up within the complex herbal mixtures. Such mixtures, typical of dietary supplements, challenge the ability of scientists to recognize all of the ingredients in a particular herbal product. The study of botanicals, in fact, is rife with problems: No. 1 is making sure you have the right plant. Problem No. 2 is breaking the plant down to its component parts, and No. 3 is figuring out which component has which effect. "You've got 10,000 compounds within a given plant. You pick one and purify it and put it in and see if you get the effect, then you compare to when you had all 10,000 together," Lubahn says. "What is really needed now are ways to systematically and quickly assay all of the compounds, but right now we don't even know what all of them are." They're getting closer, though, at least with a few plants. At MU, the primary interest is in the role of phytoestrogens - plant chemicals that resemble estrogen in either structure or action - and their roles in cancer, stroke and the immune system. As it happens, a great source of phytoestrogens is soybeans, Missouri's biggest cash crop. Researchers have long recognized that the high concentration of soy in Asian diets seems to correspond to a lower incidence of certain types of cancer, cardiovascular disease and some forms of dementia, says William Folk, a professor of biochemistry in the College of Agriculture, Food and Natural Resources who is associate director of the Center. "There really is very little scientific evidence for this right now, so we're testing whether there's an effect." What they're finding is that soy may help reduce prostate and breast cancer, but individual components within the soy plant might also promote it. "People need not go out and stock up on soy products right now," Folk says. "If soy is beneficial, it may require much more tofu than you or I could ever stand to eat. The fact is that people in the Orient are raised on soy products. They have much higher intakes of soy products from even before birth than we have. Many of these phytonutrients are probably transmitted to the fetus, and the effect might not be recognized until 40 to 50 years later." One hypothesis to explain why populations that consume a lot of soy have a lower incidence of prostate and breast cancer is that soy provides estrogen-like components that may affect tumor growth. To study this hypothesis, Folk, Lubahn, nutritional biochemist Ruth MacDonald and others are working with mice that are genetically altered to develop spontaneous prostate cancer, as well as mice that lack estrogen receptors. They feed the mice a uniform diet designed by MacDonald, then add individual components of soy and observe the effect on tumor development. Preliminary findings suggest that feeding mice the estrogenic components in soy, specifically the isoflavones, may stimulate tumor growth. "Our current thinking is that consuming whole soy foods may provide a protective effect against cancer, however there may be a risk of promoting cancer when high amounts of the bioactive compounds in soy are consumed alone," MacDonald says. "That's important to know, because you can go to the store today and buy supplemental pills off the shelf that contain high concentrations of these isolated isoflavones. Based on our research, the supplements aren't recommended." Phytoestrogens also might have an effect on the immune system, which is what pathobiologists Mark Estes, Ed Curran and Craig Franklin are studying. They're inducing inflammation in mice - which is a natural immune system response to an onslaught from bacteria or other pathogens - and then monitoring whether estrogen-like components from plants help the mice recover more rapidly and effectively. They're focusing heavily on what is called the NK - natural killer - cell, and if they find that estrogen plays a role in kicking the NK cell into gear, their research could have tremendous implications for resistance to infection and breast cancer therapy, where anti-estrogen drugs are a common form of treatment. Meanwhile, Grace Sun, a professor of biochemistry, and her husband, Albert, a professor of pharmacology, are looking at antioxidants - those compounds that help cells survive the onslaught of free radicals thought to cause neurodegenerative problems like Parkinson's and Alzheimer's diseases. Free radicals are unstable molecules or atoms that can cause damage to lipids, proteins and nucleic acids. The Suns are working at the cellular level to find out how those free radicals are created and how they kill cells. Since four out of every 10 people over the age of 85 may suffer from Alzheimer's disease, it's an important question to try to answer. Their goal is to find an effective molecule that will protect cells from damage by free radicals. Their research also involves working with animal models, to see if what works in a petri dish will also work in a living animal. Over in the College of Agriculture, Food and Natural Resources, biochemist Gary Weisman is also looking at the problem from the cellular level. Weisman wants to know how these phytoestrogens affect receptor proteins within a cell. Receptor proteins are the switches that tell a cell exactly what it's supposed to do by turning on precise cell pathways. "The availability of a wide range of compounds that could be tested against these pathways, especially if the compounds are pure and underinvestigated, has great potential for identifying novel treatments for disease," he says. While it's already evident that certain botanicals have health benefits, it's not known whether the benefits are due to single compounds or combinations thereof. "Only by purifying individual ones and then looking at them alone and in combinations can we explain the health benefits that are predicted for the impure botanical product," Weisman says. "We hope to give people who are using these products a better understanding of what the compounds are doing and move the use of botanicals into the field of pharmacology where things tend to be more precise." The collaborative effort is perfect for Weisman's lab, he says, because scientists there are already researching how various compounds affect cellular processes. "It's fairly easy to substitute a new botanical product for the pharmacological compounds that [other researchers] are already using in their experiments." Of course, another problem with working with botanicals is that even if you've got the right species, crops grown under different conditions can have different concentrations of active ingredients. That's where George Rottinghaus comes in. Rottinghaus, a chemist in the toxicology section of the Veterinary Medical Diagnostic Laboratory in the College of Veterinary Medicine, can isolate compounds, measure quantities of active ingredients, or measure the residue level of a compound in blood. In this project, that means measuring the phytoestrogen content in soy that goes into the experimental animals' diets. Meanwhile, Weisman's colleagues are trying to establish optimal growing conditions for soy and other herbal products. These include echinacea, which is a plant native to this part of the country that is believed to help alleviate cold symptoms."There are seven species, and it's not obvious that all of them are important for the botanical industry," Folk says. Andrew Thomas, a research associate in horticulture at the Southwest Research Center in Mount Vernon, Mo., is studying black cohosh, a shade-loving herb that is native to southwest Missouri. Like soy, it's valued for its estrogen-like effects. Unlike soy, it's hard to come by. "There's a lot of research suggesting
this herb has tremendous potential, and people are buying it like crazy,"
Thomas says. "But it's very expensive, and there may be a problem
with it being poached and overharvested from the wild. It's not yet
considered endangered, but it's certainly not common, so that's all
the more reason to bring it into cultivation to help take the pressure
off wild populations." It would, moreover, give farmers who have
orchards something to grow in the shady area underneath trees, thus
increasing their per-acre income. From the lab bench to the farm field
- indeed, to jungles and swamps all over the world - researchers say
MU's new phytonutrient and phytochemical center is answering questions
about how, why and whether botanical products work. Says Folk: "One
of our real strengths is the diversity of expertise that can be brought
to bear on a problem. It's a wonderful collaboration of effort."
— Illumination,
Spring 2001
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