Late Start, Rigid Bureaucracy Delay Taxol Production

The National Cancer Institute (NCI) is desperately looking for alternatives to the wild yew tree to ensure a lasting supply of the promising cancer drug taxol. If only the agency had listened to an agriculture department botanist 25 years ago.

The federal government, the botanist suggested back then, should plant millions of yews in nurseries - in essence creating farms for the tree bark from which taxol is made.

Human tests show taxol slows the growth of deadly ovarian cancer and might be effective against breast, prostate and skin cancer. But the drug remains in short supply, and the only government-approved source is still the dwindling stock of wild Pacific yew.

Hence the desperate scientific search for alternatives.

Retired botanist Robert Perdue Jr. says that's what he worried about in the late 1960s when he suggested that the NCI move away from its favorite source of taxol. He figured a faster-growing ornamental variety of yew could provide a constant supply of cuttings and thus a steady flow of taxol.

Today, the cancer institute wants a yew plantation - and a lot more. The Weyerhaeuser Corp. is growing the tree in farms experimentally.

With nearly everyone involved in taxol saying today that the wild yew can't be the only source, Perdue just sighs. He says of the NCI: "If they need it today, then they are willing to do something about it. But they are prone to wait until a crisis. Then they want it yesterday."

Institute official Saul Schepartz says resources are always tight and tough decisions have to be made about which drug to pursue. That's true today, and it was true back then, he says.

"You can't afford to have a Manhattan Project for every drug," he says, referring to the crash program to develop the atomic bomb in World War II. "You have to make choices."

But the taxol decisions made by Schepartz's predecessors didn't turn out to be the best deal for dying people.

OFF TO A SLOW START

The company that's developing taxol, Bristol-Myers Squibb, harvested nearly 40,000 wild Pacific yews this year, containing enough taxol for 12,000 women who are dying of ovarian cancer.

Forestry officials predict they'll go into old-growth forest and perhaps even spotted-owl territory to get yew trees as the pressure for supply increases.

With that in mind, scientists are studying alternatives that include using needles, heartwood, lab cultures and synthesis. But the Food and Drug Administration licenses each alternative type of taxol separately, a process that can take years. Even taxol from bark isn't FDA-licensed yet.

Many critics say the drug makers dragged their feet on alternatives because bark is the cheapest and easiest way to go, since the government provides the trees.

" . . . Chemical companies furnishing the NCI with taxol have refused to refine the taxol-extracting process because it is more costly for them," wrote Jenny Dimling, a botanist for the Willamette National Forest in Oregon, in an internal newsletter.

But Bristol-Myers vice president Zola Horovitz says his company plans to spend "many, many times" more money on alternatives than on bark. The regulators and drugmakers say it's not a question of will, but of way.

"We should have started the process of trying to find a renewable resource at a much earlier date," says Kenneth Snader, head of taxol procurement for the cancer institute.

"People are doing studies and sharing information as fast as we can get them on board," said Nan Vance, a U.S. Forest Service researcher in Corvallis, Ore.

STUCK WITHOUT NEEDLES

The yew remains a mystery in many ways. No one knows, for instance, why it makes taxol. To prevent rot, insect attacks or tree diseases?

But scientists should have known some things and didn't until very recently. Tests done years ago indicated that yew needles had less taxol content than the bark, and that the taxol in needles degraded within days after picking. Researchers also thought ornamental yew trees grown in nurseries didn't produce enough taxol to make them worthwhile.

Neither is true, but the myths dictated a policy that has the NCI still killing wild trees for bark when it could take needles from nursery stock and preserve the trees. When Bristol-Myers harvested wild yews this year, the needles were for the most part left on the ground.

"I feel every time they cut down a tree, we are losing a factory," said yew bark collector Patrick Connolly. "It is like cutting down the apple tree to get the apples."

In 1986, researchers at the University of Mississippi, working with no federal funding, took another look at the myths and began exploding them. The scientists found that some needles of ornamental yews contain more taxol than bark, and that the drug could be preserved in the needles with proper drying. In addition, taxol yield is more predictable in nurseries, which cuts extraction costs.

"It took me years to convince people," said botanist Ed Croom at Mississippi. "We had an uphill battle. Nobody believed us. They said they'd looked and it wasn't there."

Late last year, the cancer institute and the agriculture department began negotiating a contract with the largest grower of ornamental yews, Zelenka Nurseries of Grand Haven, Mich., and with researchers, including Croom, and other researchers from Ohio State University. They would provide properly dried nursery-grown needles to the cancer institute for taxol extraction and study.

The deal was delayed for months, in part because officials worried that development and operational costs would make taxol from needles exorbitantly higher priced than bark taxol, but it didn't turn out to be so, says agriculture department official Dan Kugler.

Then the government complained that the project, as designed, was mixing taxol procurement with research. To follow guidelines, negotiators had to toss out things they wanted to do, like developing new machines to trim yew bushes and combing the country for other nursery sources.

"The original project included some components that really looked more like agricultural research than a commercial demonstration project," Kugler says.

This month the cancer institute is supposed to pick up its first load of dried needles.

Polysciences Inc. of Warrington, Pa., will extract the taxol from the needles. Bristol-Myers will purify it. The aim is five pounds. It'll be the first large production of needle taxol, but human trials and licensing are years off.

HOPE IN THE LABS

An even better way of getting taxol would be to grow it like yeast in a huge, burbling vat. Two agriculture department scientists, Donna Gibson and Alice Christen, began experiments with yew plant cultures back in 1987, and by 1988 they'd grown taxol in a flask.

They had no funding for their work then, but now they have a patent that's been licensed to a New York firm, which has a contract with Bristol-Myers to scale up the technique. Gibson says the work so far is very promising.

"Realistically, it will take five years to be at a pilot scale, to have a larger fermenter," Gibson said.

Dr. Koppaka Rao, a University of Florida scientist, says he's invented a method that increases the yield of taxol from bark by two to six times.

However, the taxol sample he sent to the NCI was impure. Impurities in a drug like taxol cause side effects. University officials say it was a mixup, that Rao misunderstood what the institute wanted. Now he's making a new batch for an independent lab to test.

Even if it's valid, there'll be more delays because of complex legal hurdles involved in transferring technology from a university to private industry.

"Everyone looks at the discovery somewhat cautiously because it has been dramatic," said Dr. Susan Wray, director of licensing for the university in Gainesville.

Rao has also worked on methods to partially synthesize taxol using derivatives found in the same tree.

GETTING INTO THE ACT

Companies are lining up to cash in on taxol innovations. Some say they've been frozen out by a contract the government signed with Bristol-Myers giving the drug maker a lock on government taxol research and on yew trees growing on federal lands. But the monopoly isn't air-tight.

While synthesizing taxol is very difficult because the molecule is complex, a French company is developing a taxol-like substance made by joining a derivative found in the yew with a partly synthesized molecule. Rhone-Polenc Rorer is Bristol-Myers' only large competitor, but smaller operators want in.

Portland businessman Jim Fowler and five associates want to build a taxol factory south of the city. They've lined up scientific advisers, some financing and they'd like to use bark, needles and partial synthetics.

NaPro, a company in Boulder, Colo., has been claiming since last summer that it has a fully operational process to make taxol from needles. Bristol-Myers has refused to play ball, and cancer institute officials say the firm has never produced a sample. A former company officer, chemist Danuta Schloemer, says when she was ousted from NaPro in a dispute with other owners in July, the company hadn't yet found a way to produce pure taxol from needles, even though it claimed it had.

But NaPro has the expertise and some backing, and is seeking more financing. Officials say they are producing taxol internally.

The company made headlines this summer when part owner Sterling Ainsworth publicly blasted Bristol-Myers for trying to prevent him from getting needles. The drug giant had shown no interest in the Pacific yew needles until June. Then it became apparent NaPro wanted them. In response, a Bristol-Myers contractor told startled Forest Service officials he wanted the needles after all. In the end, no one collected many of them.

"Unless NaPro can get in there and destabilize that monopoly, I think we'll burn; I think we'll go down," Ainsworth said at the time.

Forest Service officials say they'll take a second look at the clear-cutting and slash-burning practices that deplete forest diversity.

Snader promises that when a natural drug shows great promise, the cancer institute will look for alternative sources earlier in the game. And they won't wait so long in getting the drug to patients.

Clearly, says researcher Croom in Mississippi, "the cancer institute has learned from this."