COLUMN ONE : Scientific Method in Overdrive : An urgent search for a way to mass-produce an anti-cancer drug brings out the best and worst of modern science. The profit motive helps the effort, and hinders it.
On the night in question, the Florida State University building that houses Robert Holton’s lab was locked. But somehow a desperate man who had driven hundreds of miles managed to slip inside.
Despite the hour, nearly midnight, the bespectacled chemist was at work. When Holton responded to the rapid pounding on his office door, he faced a youngish-looking stranger, talking fast and loud: His mother had cancer. He needed taxol for her, needed it right away. He was “very insistent,” in Holton’s understated recollection.
It took 15 minutes to calm him. Then the man departed, empty-handed and apologetic. Still, the shock of the encounter lingered, crystallizing for Holton the urgency of the efforts in his lab, and in as many as 100 others around the world.
On a Palo Alto campus, in a San Carlos industrial park, in a Mississippi garden, on the shore of Long Island Sound, among other places, researchers are trying to develop new sources for the most promising anti-cancer drug in two decades. Administered so far only in tests, taxol has shrunk breast, ovarian and lung tumors in patients who had not responded to traditional treatments--patients who previously would have been advised of death’s certain approach.
For now, taxol comes only from the bark of the Pacific yew, a scarce tree that also provides a home for the endangered spotted owl. It takes the bark of at least three yews to provide enough taxol for one cancer patient; those yews take on average 100 years to reach the proper size. Peeling off the bark kills the trees. If harvests continue at the current rate, the large old yews will be gone within a few years, a federal forestry team has concluded, perhaps even before taxol is licensed for general use.
And so the race is on to find other ways to get the drug, a race that has brought out the best and worst of modern science. Here, theory, practice and the profit motive converge. The two-year-old taxol frenzy has been marked by long hours and inspired inventiveness on one hand, and by extreme secrecy and petty sniping on the other.
A flurry of advances on a number of fronts were announced in recent weeks. Researchers are mining taxol from materials as common as cedar oil and as exotic as leaves plucked from Himalayan peaks.
But all the work is still preliminary. “There are still concerns, no question about it,” said Saul Schepartz, an official with the new-drugs program of the National Cancer Institute. “We still don’t have a supply even for all the research we’d like to do.” Only about 2,000 patients have received taxol since 1984.
For most of the chemists and botanists involved, this is the first time their work has been so directly linked to pressing matters of life and death. They are spurred by distraught phone calls from outsiders, the thought of relatives with cancer, and in one graduate student’s case, the 50% chance that her own breast cancer will recur.
Stanford University chemist Paul Wender periodically recites cancer death statistics to the graduate students and postdoctoral fellows working with him on the taxol quest. It is a not-so-subtle reminder: The sooner they get results, the more lives they can prolong.
Submerged under those magnanimous motives are other driving forces that many are more reluctant to discuss. The far-flung scientists are by no means pulling together. “We are,” Holton said, understating again, “a very competitive bunch.”
There is the glory of being first. Already, speculation is rampant that to the victor goes a Nobel Prize. There is the jousting for grant money from pharmaceutical companies, engaged in a ferocious struggle of their own to lock up licensing rights to taxol patents. There is the prospect that scientists and their institutions will reap handsome royalties if their processes are used for mass production.
Consequently, many details are kept under wraps. Queries are often met with answers like these: “That’s part of our proprietary program,” said University of Mississippi chemist James D. McChesney. “I think I’m getting into a sensitive area now, since I took industrial money,” said Lester A. Mischer, a professor of medicinal chemistry at the University of Kansas. “I have some problems in being completely open.”
The scientists are as circumspect with each other as with the public. In what has become common procedure where money is at stake, papers are published only after patent applications are filed. And the papers tend to describe only small slices of the work under way.
Stanford graduate student Tom Mucciaro, who is part of Wender’s team, spent the last two years restraining himself when friends from other universities asked him what he was up to. “They called and said, ‘Tell us what you’re doing,’ and I have to say, ‘It’s taxol, it’s very exciting, but I can’t.’ ” Part of his work has been published; major pieces still have not.
The forced reticence “is one of the more abhorrent aspects of human nature creeping into science,” Mucciaro said. “Probably one of the most stimulating aspects of science is sharing knowledge and talking over problems, and this is the total antithesis.”
Even Schepartz at the National Cancer Institute is not sure he knows all about the taxol research under way. “I can’t guarantee that they’re telling us everything,” he said. And he, too, must be careful with what information he has. “We can’t reveal what we know to other researchers if somebody tells us something in confidence.”
If all the scientists involved disclosed their findings--both the successful processes and the routes that failed--”admittedly, there would be less duplication,” Schepartz said. “But competition can be very healthy too. That’s the system we have.”
The contest was kicked off in June, 1990, when the National Cancer Institute convened an extraordinary meeting at a Bethesda, Md., hotel. NCI invited nearly 200 researchers to hear its plea for help--the first time, according to Schepartz, that the federal health establishment had ever sent such an SOS.
The scientists heard the history: Yew bark samples had been collected in the 1960s from an Oregon forest as a routine part of an NCI program to check berries, herbs, mosses, lichens--any and all natural products for cancer-fighting ability. By 1971, taxol had been isolated and its structure identified, and by 1974, it was impressively attacking human tumors implanted in a mouse.
Researchers told of their experiments and their hopes. They had found that 30% of ovarian tumors responded to taxol in patients essentially given up for dead.
At the time of the meeting, they did not know they would soon find that the response rate for breast cancer patients at a similar stage was an astounding 50%. Or that even later, doctors would use taxol to shrink 20% of lung tumors that had withstood all other treatments.
While it was not a panacea, not a cure, researchers suspected that if they gave taxol to patients in the early stages of disease, they could slow some cancers. Taxol cannot help all cancers, they, said, but can shrink several common types to the point where the body’s own immune system could engage the enemy. They thought that eventually they could use taxol to prevent recurrences in patients who had had such tumors surgically removed.
And they knew they needed more of the drug.
It was a tough order to fill. Previous efforts to extract taxol from leaves or branches--which would spare the tree and so provide a continuing source--had failed. And for nearly a decade, researchers intrigued by the molecule’s complex chains of atoms had tried in vain to duplicate taxol in the lab. Carbon, hydrogen, oxygen and nitrogen are arranged in a structure resembling a strange sort of scorpion--a four-ring skeleton with an assortment of leg-like appendages, a long stinger tail with odd outcroppings.
But as word of taxol’s promise spread, the pace of the research quickened.
Jeffrey Winkler, a University of Pennsylvania chemist, had been using solar energy to make chemical structures that perhaps could be fragmented into taxol-like substances. It was an interesting intellectual exercise, though it would be very costly to make great quantities.
Then Winkler’s wife, a dermatologist, told him she had been reading in medical journals about his pet molecule. It looked to be an important cancer-fighting agent. He’d had no idea.
He immediately switched tactics. It was time to be practical. He decided to see if he could make taxol, or at least part of it, from cedar oil.
Likewise, Wender at Stanford, tried pinene, the main ingredient in turpentine. Pinene, he said, might not be as cheap as dirt, but it is at least “as cheap as potting soil.”
Nine miles away, in a San Carlos industrial park, a small company called ESCAgenetics Corp. ( esca is Latin for food) was cloning vanilla in petri dishes to make an inexpensive natural extract. The firm’s officers wondered if they could adapt their technique to grow taxol.
Les Mitscher, who had been working with another chemotherapy agent, had read about the odd molecule in his spare time. The NCI meeting made him realize “it’s not a hobby anymore.” Back in Kansas, he talked the situation over with a senior postdoctoral fellow, Rao Gollapudi. Gollapudi recalled that another sort of yew tree grew in his native India, in remote parts of the world’s highest mountain range.
Within weeks, Gollapudi flew to his homeland, contacted friends in that country’s forestry service, climbed to an elevation of 10,000 feet and returned to the United States with a few pounds of clippings.
“It was a shot in the dark,” Mitscher said.
Since these eclectic beginnings, all have reported great progress. Winkler and Wender have forged links of the four-ring skeleton chain, though they are not able to get the right “legs” in the right places. Mitscher has distilled the skeleton chain, with legs, from Himalayan yew clippings. Holton can attach the tail to the skeleton. ESCAgenetics last month delivered a small quantity of its fermented taxol to NCI--but a small quantity is all the firm can make. (“I can’t be more specific on our yield,” said Walter E. Goldstein, the company’s vice president for research and development.)
All of them predict they are a year away from the capability to make taxol on a commercial scale.
The researchers labor day and night. And even their sleeplessness has become a matter for one-upmanship.
At a press conference at the American Chemical Society meeting in San Francisco last month, Wender said he often wakes in the wee hours, brimming with taxol ideas. Once, he got so excited that he rushed into the lab, where he found a note on a co-worker’s desk: “That note read: Gone for breakfast, will be back soon. It’s clear that this person had spent the entire night working in the laboratory and was taking off enough time to get some food so he could start the next day’s work.”
Next came Holton’s turn at the microphone. “As a matter of fact,” he told reporters, “just last Friday morning, as I came into the laboratory at 4 a.m., I found one of my colleagues had left a similar note.”
Pierre Potier, however, thinks all that effort is wasted. He has found a drug that is, he says, better than taxol. “Yes. Yes,” said Potier, who heads the Institut de Chemie des Substances Naturelles in France. “There is absolutely no reason to continue.”
He offers instead a related compound, which he has christened taxotere. Potier isolated a precursor of taxol, the four-ring skeleton, from the leaves of the European yew and added a slightly different tail chain. One patient’s dose of taxotere is half the amount of taxol that would be necessary. And taxotere is more soluble than taxol.
“It’s absolutely sure that taxotere is the best,” Potier said.
Such pronouncements have not endeared him to others on the taxol track. “Did he also tell you that in the pre-clinical trials (taxotere) was three times as toxic in dogs?” Mucciaro asked, anger seeping into his voice. “ . . . That adds up to a less good drug.
“It’s hard,” Mucciaro added, “for somebody who’s worked as hard as I have, and actually feels very good about the work that I’ve done, to sit and listen to some blowhard out there essentially saying that my work is worthless . . . for non-scientific reasons.”
Potier is working with a French pharmaceutical company, Rhone-Poulenc Rorer, to produce taxotere. But he is far from alone in seeking patents or forming an alliance with the corporate world.
Drug manufacturers are intensely courting the taxol scientists. Rhone-Poulenc contacted chemist Iwao Ojima after he published a taxol-related paper; the firm flew him from New York to Paris. Ojima returned to his office at the State University of New York at Stony Brook with a deal: He got a $113,000 grant. Rhone-Poulenc got the right to license any patents he receives.
Bristol-Myers Squibb is supplying yew-bark taxol to NCI for tests in exchange for exclusive information on results. The pharmaceutical giant has spent “in the nine figures” on grants to researchers that lock up licensing rights, said Zola Horovitz, a company vice president.
Scientists report that at least half a dozen other firms are in more preliminary stages of negotiations. Of course, they won’t identify the companies.
“I have very mixed feelings actually,” Mitscher said. “As an academic, I want everybody to be able to make taxol. But the point is if you tell everybody, there’s no chance for anybody to make any kind of profit. And then it might not get followed through. I want these things to become available to the public.”
