Once seen as worthless, the Pacific Yew is the only natural source of taxol, a powerful cancer-fighting drug.
Our van snakes up a logging road between Mount St. Helens and Mount Rainier in the Gifford Pinchot National Forest, a three-and-a-half hour drive from Seattle. Though night is far off, Jim Riley, a Forest Service ranger and our guide, advises flipping on the headlights. "You want to be very careful here," he says. "These logging trucks are on top of you before you know it."
This timber highway’s one lane is paved, attesting to its high traffic. Sure enough, minutes later a loaded truck rolls toward us. We pull over to let the tons of metal and wood pass. We will repeat this maneuver several times before reaching our destination: the world’s largest Pacific yew tree.
The van carries valuable cargo. Besides Riley, there are UW scientists Arthur Kruckeberg and Heinz Floss. Kruckeberg, an emeritus professor of botany, is along to describe the flora. Floss, a chemistry professor, wants to borrow the yew’s recipe for a substance called taxol, which the National Cancer Institute considers the most important anti-cancer drug in years.
Women in clinical trials for breast and ovarian cancer are alive today only because of taxol. The wonder drug also has shown promise against lung, colon and other cancers resistant to standard treatments.
What’s more, researchers are excited about taxol’s novel way of killing tumors: It freezes the cancer cell in its final stages of division, trapping genetic information the cancer would normally pass on to deadly new cells. All anti-cancer drugs wipe out healthy cells with the bad, resulting in sickness and hair loss for most patients. Add more drugs with the same cell-killing effect, and you get stronger side effects. Combining taxol with other drugs may soften these side effects, while attacking cancer on yet another biochemical front.
It’s no wonder, then, why newspapers and TV news shows have proclaimed taxol the wonder drug of the decade. But the stories have a twist: the bark of the Pacific yew, Taxus brevifolia, from which taxol is extracted, is in short supply. “Ovarian cancer patient frustrated at lack of taxol,” one recent headline said, mildly. Since the Pacific yew grows in ancient forests, questions over harvesting its bark sound like the spotted owl vs. logging jobs debate. Only this time, you have preservationists on one side and cancer victims on the other.
One big reason for the shortage is the yew’s painfully slow growth rate—200 years for a 40-footer. The average tree yields two-thirds of a gram of taxol, which equals two dosages for an ovarian cancer patient. One report puts it another way: To meet the demand for ovarian cancer treatment alone, 36,000 60-year-old trees a year would have to be harvested.
How many yews can be logged without threatening the species? No one can say for sure. Until now, there hadn’t been a good reason to keep a census of these raggedy evergreens, found in southwest Canada and the Pacific Northwest. Yew—”the hardest wood in the woods,” Kruckeberg says—was only good for archery bows and fence posts, though the trees are a botanical curiosity. Instead of cones, they have red berries (fishermen harvest them for ersatz salmon eggs). Adding to the scarcity, once yews are logged, they are tricky to strip without wasting precious bark.
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“Look out!” Riley shouts. A logging truck grinds around a bend and blows by. We are almost there.
Thirty years ago, when this forest was logged for the first time, a lumber company forester saved the big yew tree—quite a remarkable act. In the 1960s loggers usually mowed down commercially “worthless” trees while harvesting the coveted Douglas firs, hemlocks and giant cedars. Of course, the forester had no idea that, about the same time, the U.S. government was sponsoring research that would one day raise the yew’s esteem in humans’ eyes. In labs throughout the nation, researchers were systematically testing plant extracts on cancer cells. Not surprisingly, most experiments were duds. But not the yew.
In 1971, the complex taxol molecule was isolated. (Nobody knows why yews make taxol, Chemistry Professor Floss says. A leading theory: The chemical helps the tree resist bug attacks.) Despite the early promise, only recently has the drug reached the clinic—last year in the case of ovarian cancer trials at the UW.
If taxol can be synthesized, more cancer patients could be treated while saving the yew in the forests.
Today, money for basic taxol research is pouring in to counter nature’s paucity of the drug. At year’s end, the National Cancer Institute alone was funding at least 29 research projects, including a Weyerhaeuser Co. plan to cultivate yew trees and to boost their taxol-making ability.
Many cancer victims put their hopes on synthesizing the drug. Perhaps the most publicized research belongs to Florida State University’s Robert Holton. Using simple materials available from chemical supply companies, Holton has synthesized a piece of the taxol molecule. He hopes to build the whole thing.
If taxol can be synthesized, more cancer patients could be treated while saving the yew in the forests. But the molecule’s complexity makes chemical synthesis a tall order, Floss says. Undaunted by the task, he has a two-year, $236,000 grant from the American Cancer Society to biologically synthesize taxol—to swipe, as it were, the whole taxol enchilada from nature’s oven.
Though a latecomer to taxol research, Floss’ track record in biosynthesis gives drug designers reason for optimism. During his tenure as the chemistry chair at Ohio State, Floss applied biosynthesis to painstakingly plot the course by which fungi crank out substances called ergot alkaloids. The alkaloids have powerful biological effects on humans; drug companies used the breakthrough to create a new generation of antibiotics. His pioneering work prompted the UW to offer him a huge lab in Bagley Hall. In a coup for the chemistry department, the University lured him from Columbus four years ago.
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“Turn around here, then pull over,” Riley says. “It’s not far.”
We park and hike. Riley says the Forest Service had planned to map a trail to the world-record yew, about a half-mile from the road. But the agency abandoned that idea when stories surfaced about poachers selling yew bark to the highest bidder. Floss says he can’t imagine who those buyers are—only a few companies can convert bark to the fine, white powder that is pure taxol. The impracticality of closing an illegal bark deal hasn’t discouraged at least a few yew poachers—federal agents have busted several people for stripping bark without Forest Service permits.
The market price for yew bark, dried and ground, is about $6 a pound, Floss says. That’s what he pays for it, anyway, unless he can get it free. The Boeing Co., for instance, had to clear some yews to build a parking lot and donated the trees to Floss.
In his lab, Floss assumes the role of a master chef, sampling Taxus brevifolia, the most exotic and complex entree at the world’s most sophisticated restaurant. Others who have eaten there before have supplied Floss with a list of potential ingredients. They have even described the ingredients’ configuration (taxol is a cup-shaped molecule) and their effect (the active portions seem to be the cup sides). Floss’ task: to confirm the ingredients and to divine a recipe so that other chefs—that is, pharmaceutical company scientists—can copy the meal. “I’m not interested in manufacturing drugs,” Floss says. “I want to understand the underlying chemistry.”
Floss has enlisted a variety of techniques to piece together how the trees whip up a batch of taxol. In one experiment he soaked a yew branch in radioactive benzoic acid. Later, when he extracted and analyzed the taxol from the branch, he found the radioactivity. “This proved that the solution is taken into the plant and that enzymes in the plant will incorporate this piece into the taxol molecule,” Floss says.
“This tells us that, one, this part of the tree is indeed one nature uses to make taxol and, two, we do have a valid experimental system for learning about the building blocks of taxol.”
In another test, Floss discovered what he calls the “first unequivocal proof” that taxol has been produced from yew cell cultures—in this case a brew from fermented yew stems. The amount of drug is so minute as to be commercially insignificant, Floss says, but it proves the theory that yew cells can be made to produce taxol in the lab.
“Others have had indirect indications of taxol from cultures, and I have little doubt that they had taxol, too,” Floss says. “But they had never proved it—at least not to the mind of a chemist. It took measurements from a sophisticated mass spectrometer (a device that weighs molecules) the UW acquired last year to prove that there was actually taxol.”
Floss’ results are as yet unpublished. He wants to repeat the experiments. “I’d rather publish a good paper than a first paper,” he says. Next, Floss will combine the experiments—to learn whether benzoic acid can become incorporated in taxol made from yew brew. And he will see how other chemical components of taxol are sopped up by the plant. If and when these steps might lead to complete synthesis of the wonder drug is anybody’s guess.
* * *
We reach the tree.
The king of yews is stunning, its trunk covered with reddish flaking bark that looks like the skin of some funky Star Trek alien. It stands 54 feet and is 15 feet around at the base, not big for an evergreen but impressive for a species that usually spends its life in the shade. One can’t but wonder how many animals live within its thick, protective branches, which span 30 feet at their widest point. It looks ancient, but because it is ringless, one can only guess its age.
“Even that little one there”—Riley points to a knee-high yew—”could be 50 years old.”
Floss darts down a hill and disappears into a cavernous hollow on the far side of the contorted trunk, then emerges on the other side and snips a few needles—which also contain taxol, but much less than the bark. He will return them to his lab to assay whether larger and presumably older yew trees contain higher concentrations of taxol than smaller, younger trees. He is also curious whether taxol concentrations vary from forest to forest.
“How many cancer cures are there here?” Kruckeberg asks.
“I don’t know,” Riley answers. “But this tree’s bark would go for $1,000.”
Kruckeberg stares long at the tree. “I suppose it should just live forever.”
Two years of unsuccessful chemotherapy treatment for her ovrian cancer left Marcia Weedman prepared to die. “They didn’t have another thing for me,” she says. “I had just told my boss that he had to find somebody to replace me and one week after he started advertising for my position, we found out about taxol.”
Now Weedman reports, “I’m working full-time and I feel wonderful.”
Particularly insidious because few symptoms accompany its early stages, ovarian cancer is diagnosed in more than 19,000 women in the U.S. each year. It kills 12,000 women annually. “Over 70 percent of the patients develop advanced stage ovarian cancer before the diagnosis is made,” says Dr. Benjamin Greer, director of the UW Division of Gynecologic Oncology.
Weedman, a 49-year-old Poulsbo nurse, is one of a select group of women receiving taxol in a “compassionate use” program at the UW. The program began in September, when the Fred Hutchinson Cancer Research Center named the UW School of Medicine as a center for treating women whose ovarian cancer had not responded to at least three courses of chemotherapy. By the end of 1991, 34 women had received taxol.
The UW’s program hasn’t treated patients long enough to show conclusive results, but to date, taxol appears an effective agent against ovarian cancer, as earlier clinical research had suggested. “We have seen some remarkable responses to taxol,” Greer states.
He is particularly encouraged by the preliminary results because this is at least the fourth treatment these women have tried. Usually if the initial treatment fails, ovarian cancer doesn’t respond to further treatments.
Women participating in the program come from Washington, Alaska, Idaho, Montana and Oregon. Every three weeks they travel to the UW and receive a 24-hour intravenous infusion of taxol. During their infusion, patients are free to walk about the medical center, pushing their IV stand along.
Patients are warned to expect total hair loss, but Wendy Brown, the registered nurse who follows their progress, reports that in many cases this side effect has not been as severe as expected. Nausea, a common side effect with many other chemotherapy agents, is rare with taxol.
After two treatments, the rapid decrease in the size of her tumors leaves Weedman optimistic. While not all the patients in the program have shown response as dramatic as Weedman’s, Greer sees great promise in. taxol. “I think the critical issue revolves around the availability of the drug,” he says. Greer eagerly awaits the day it can be synthesized, “rather than have to be extracted from a natural product.”