Up on the third floor of the pharmacy school, evaporators whir, spectrometers spin. This is the kind of gear people use to make drugs—serious medicine.

But talk to the 20 medicinal chemists holed up in that bustling lab, and they’ll tell you about the mayapple plant, “thunder god vine,” or desert parsley. They’re discovering serious medicines all right. But they start with plants and herbs. They want to extract their potent parts—compounds or chemicals in the plants that are bioactive—that can, for example, kill cancer cells, viruses, or bacteria.

The plants they study are part of everyday life for people in many Asian countries. Most are ingredients in remedies that have been used in traditional Chinese medicine for centuries. K. H. Lee, professor of medicinal chemistry and director of the Natural Products Laboratory, sees traditional Chinese medicine as a head start on finding new, more effective drugs.

These remedies have been tested for centuries—not in animal assays or in clinical trials, but in centuries of experience of practitioners using them to treat people,” Lee says. In some ways, this experiential knowledge more directly applies to humans than the animal testing used to test Western drugs, he says. But many of these remedies lack quality control and have never been evaluated scientifically. And it’s often not known exactly which ingredients in a remedy are active.

Lee believes that modernizing and scientifically testing the remedies will help legitimize traditional Chinese medicine so it can benefit a greater number of people. He’s constantly pushing for interest from government agencies such as the National Institutes of Health (NIH), and every year he speaks at international conferences on traditional Chinese medicine. This year he’s cohosting one in Hong Kong and another in Taiwan.

Lee began studying Chinese medicine partly because his grandfather dabbled in it. When Lee was a boy in Taiwan, his grandfather would take him on trips to gather herbs. “He’d say, `You want to go with me, I’ll show you something.’”

Once Lee saw his grandfather treat a woman suffering from water retention. “Her belly was swollen up,” Lee says. “My grandfather picked a handful of elephantopus mollis that was growing underneath some banana trees. He suggested that she boil it with water and drink the juice. After a few hours, that water was expelled.

When I was young, the herbs were there, and I never paid attention,” Lee says. “Later I decided to go to pharmacy school and investigate the active ingredients of these herbs.”

Traditional Chinese medicine uses thousands of medicinal plants—so many it could take centuries to investigate them all. But not if Lee has anything to do with it. Since 1971, Lee’s Natural Products Lab has discovered more than 1,000 new bio-active natural products and their synthetic derivatives—leads that pharmacologists can use in drug design and development. He also has 10 patents on potential new drugs.

When a visitor walks in Lee’s door, “extremely busy” are the first words he utters. Known for his meticulous hard work, he’s a machine when it comes to turning out new research ideas. Lee received his first grant from the NIH in 1971 and hasn’t lost one since. Proudly, he shows off 32 file cabinets filled with records of the lab’s work and points out two drawers filled with new ideas.

Lee doesn’t seem to mind the long hours. “It’s a joy to work in this area because every day you discover something new,” he says. “And who knows—a compound that we find may become a drug that will treat disease.”

The Natural Products Lab gets plant samples from Brazil, China, Japan, and Taiwan as well as the U.S. Lee collaborates with more than 60 researchers worldwide. Often his collaborators send him samples, or sometimes people from his lab bring them back when they return from visits home. Most of the lab’s 20 visiting professors, postdoctoral fellows, predoctoral grad students, and research faculty are from Taiwan, China, or Japan. “We are the lab of Martians,” Lee jokes.

The lab receives at least one letter a day from a researcher wanting to join them. “Usually, we have to tell them no,” Lee says. “All of the people in our lab are the best at what they do, or have some special talents.”

Lee and his team usually start with a plant used in traditional Chinese medicine, then dissect it until they get one or more pure, active compounds. Sitting around Lee’s lab are beakers filled with shredded plants soaking in solvent to extract the active ingredients. On another bench an evaporator spins, separating the solvent from the extract. The extract might end up in any form—one beaker contains a thick, dark-brown oil, while the vial next to it holds white granules.

Once they have a plant extract, the researchers find out how many chemical compounds it contains using a procedure called liquid chromatography. In one version, the extract is put into a glass column that’s been filled with an absorbent material such as silica gel. Then a solvent is continuously poured down the column, taking the plant extract with it. Since the compounds in the extract have different properties, some will run down the column quickly, and some will stick to the silica gel. This separates the compounds so the researchers can start testing them to see which are most active.

That’s often where Ken Bastow, associate professor of medicinal chemistry, comes in. He collaborates with Lee’s lab to test compounds for antitumor ability. Researchers in Bastow’s lab grow cells from different kinds of cancer, including drug-resistant varieties, in small tissue-culture plates, then add a compound to each plate. After two to three days, they process the plates to see how many cancer cells the compound has destroyed.

When Bastow’s lab finds a compound that’s particularly good at getting rid of the cancer cells, scientists in Lee’s lab use tools such as mass spectrometers and nuclear magnetic resonance spectrometers to find out the compound’s chemical structure—how many carbons, hydrogens, or nitrogens it contains, and its molecular weight. “It’s like a puzzle,” says Susan Morris-Natschke, research assistant professor of medicinal chemistry. “You get information from each different particular piece of instrumentation and put them all together to solve the whole structure.”

Once the researchers know what nature has put into the compound, they can try to improve it. “The lab might find that a certain compound is very active against cancer cells, but also will harm normal cells. So they can alter its structure to try to correct that,” Morris-Natschke says. “Or they might want to make it even more active.” With the help, for example, of a computer modeling lab that’s next door to Lee’s lab, the researchers can create analogs—compounds that are based on the original but that have slightly different structures.

One analog created by Lee’s lab, an antitumor compound, is now in the second phase of human clinical trials. This analog is based on a compound called etoposide that was synthesized years ago from an active ingredient in the American Mandrake or Mayapple plant, which grows under trees in moist open woods. Now used in humans, etoposide is one of the most useful anticancer drugs, Lee says. In 1988 Lee’s lab started making etoposide analogs. They made hundreds of them before they came up with the new compound.

Lee’s compound improves on etoposide in three ways—it’s more potent, less toxic, and it’s active against drug-resistant cancer cells, which can be a big problem with chemotherapy. Because of the modifications that Lee’s lab has made, the new compound is not recognized by a protein often found in drug-resistant cells. Since the drug-resistance protein can’t recognize the compound, it can’t pump it out of the cell.

The compound has been licensed and patented by Genelabs Technologies, Inc. From initial studies, it looks like it may be effective against lung, colon, and stomach cancers. Lee’s lab has created many other anticancer compounds, and the National Cancer Institute has chosen about 100 of them to evaluate as potential anticancer drugs.

The lab also develops leads for drugs to fight HIV. One promising lead is a synthetic compound that in lab tests inhibits replication of the HIV virus better than AZT, a drug commonly used for treating HIV. Lee’s lab created this compound by modifying the structure of an extract of the fruits of Lomatium suksdorfi, also known as Suksdorf’s Desert-parsley, a plant that grows on the U.S. West Coast. This new compound and its analogs are in active studies as anti-AIDS drug candidates.

Another potential anti-HIV drug is neotripterifordin, a compound the lab recently extracted from the roots of a vine that grows in southern China. The root bark of Tripterygium wilfordii hook, also called “thunder god vine,” is poisonous and is touted as an insecticide in Chinese folklore. After the roots are removed from the bark, they’re used in Chinese medicine preparations to treat dermatitis and rheumatoid arthritis. In tissue culture tests, neotriptrifordin shows potent anti-HIV activity.

But “thunder god vine” must go through many more tests before we’ll know whether it will make a good anti-HIV treatment. It takes a lot of work to find a compound that may actually result in a drug.

There are many compounds that may look useful in tissue culture, but end up not working,” Bastow says. The compound may be effective in animals but not in humans, or it might not be processed well by the body.

That’s why Lee’s lab is continually sifting through more remedies or tinkering with compounds already discovered. “We provide the lead, a structure that pharmacologists can use as a model,” Lee says. Then he gets a licensee or collaborator to take over further testing, while he moves on to find the next possible new drug.

Demand for drugs and other products derived from plants and herbs has increased, Lee says, especially since 1994, when Congress passed an act that relaxed restrictions on herbal health products. U.S. sales of food supplements or medicines containing such herbs as Ginseng, Dong Gwei, and Gingko reach several billion dollars each year. And Lee regularly hears from people at other universities who want to visit his lab or collaborate with him.

As interest in alternative medicine grows, Lee and the other researchers in the Natural Products Lab keep plugging away.

They recently signed an agreement with the National Cancer Institute to investigate active plants collected from rain forest areas in many parts of the world. Lee continues to try to increase knowledge of traditional Chinese medicine. And of course, there’s always herbs to soak, active compounds to extract and synthesize. As Lee says, “People keep sending us plants.”

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