Discover

Science's Worst Enemy: Corporate Funding

Cecille Isidro — Mon, 01 Oct 2007 14:14:00 -0400

In recent years there have been a number of highly visible attacks on American science, everything from the fundamentalist assault on evolution to the Bush administration’s strong-arming of government scientists. But for many people who pay close attention to research and development (R&D), the biggest threat to science has been quietly occurring under the radar, even though it may be changing the very foundation of American innovation. The threat is money -- specifically, the decline of government support for science and the growing dominance of private spending over American research.

The trend is undeniable. In 1965, the federal government financed more than 60 percent of all R&D in the United States. By 2006, the balance had flipped, with 65 percent of R&D in this country being funded by private interests. According to the American Association for the Advancement of Science, several of the nation’s science-driven agencies -- the Environmental Protection Agency (EPA), the Department of Agriculture, the Department of the Interior, and NASA -- have been losing funding, leading to more "outsourcing" of what were once governmental science functions. The EPA, for example, recently began conducting the first nationwide study on the air quality effects of large-scale animal production. Livestock producers, not taxpayers, are slated to pay for the study. "The government is clearly increasing its reliance on industry and forming ‘joint ventures’ to accomplish research that it is unable to afford on its own anymore," says Merrill Goozner, a program director at the Center for Science in the Public Interest, a consumer advocacy group.

The full text of this article can be found at: http://discovermagazine.com/2007/oct/sciences-worst-enemy-private-funding

Blast from the Vast

Cecille Isidro — Thu, 01 Jan 2004 00:00:00 -0500

Leave aside, for a moment, the question of why Ted Cranford wanted to perform a CT scan on the head of a sperm whale and consider instead how he could pull it off. First, of course, he would need a dead whale, preferably a young one that had beached itself on the coast of California near his home. Then he would need a device big enough to scan a 600-pound head. And he would have to figure out how to keep the head preserved until he could set up the scanning machinery.

Finding a whale turned out to be the easy part. One fall day, a newly dead infant sperm whale conveniently appeared on San Gregorio Beach, just south of San Francisco. Cranford was attending a scientific meeting in Bristol, England, at the time, but two friends who are marine-mammal veterinarians knew what he was looking for. They drove up Highway 1 from Santa Cruz, 30 miles to the south, cut through several feet of blubber, muscle, and bone, and scooped up the head with a front-end loader borrowed from a nearby lumber company. Cranford's friends dumped the head into the back of a pickup truck and drove it to the University of California at Santa Cruz's Long Marine Laboratory, where they stashed it in a walk-in freezer. Then they sent him an urgent message to come home.

When Cranford began looking for funding to scan his whale head, several scientific agencies politely but firmly turned him down. The data would undoubtedly be of interest, they said, but the head of a sperm whale -- even a baby sperm whale -- simply could not be scanned.

Cranford, however, is a man not easily parted from his ideas. He is also handsome, with a thatch of unruly reddish brown hair and a carefully trimmed graying beard. He has small, even teeth behind fleshy lips, one blue and one hazel eye, and a penchant for wearing sneakers, shorts, and vibrantly colored Hawaiian shirts, even at scientific meetings. Now a 47-year-old adjunct professor of biology at San Diego State University, he is known as Grizz, short for grizzly bear, to friends and close associates from his undergraduate and graduate student days in Santa Cruz. The nickname describes not so much his demeanor as his ursine size and his habit of greeting friends with bear hugs.

In graduate school Cranford first used high-tech medical imaging to probe the anatomy of a mammal -- in that case a dolphin's head. Since then he has made it his mission to find out how toothed whales and dolphins make their sounds. It is a nontrivial question, as scientists like to say, meaning the answer is both significant and hard to get. Toothed whales, a group that comprises sperm whales and killer whales along with another six dozen species of lesser whales, porpoises, and dolphins, can emit a bewildering cacophony of noises underwater. Drop a hydrophone over the side of a boat in the middle of a school and you will hear, depending upon the species, anything from birdlike trills to whistles, squeaks, squawks, oinks, blats, and Bronx cheers.

The sounds Cranford is most interested in, and has spent the last two decades trying to understand, are the rapid-fire clicks toothed whales use for echolocation. A single click comes as an instantaneous burst of energy that usually lasts less than 1/10,000 of a second yet contains an astonishing range of frequencies, or pitches, most of which are too high for humans to hear. These intense packets of sound emerge from the animal's forehead as a focused beam, much like the light from a miner's headlamp. Many dolphins and whales seem to be able to narrow or widen the beam at will by deforming a lump of fat in their forehead, known as the melon, the way a glass lens can shape a cone of light. The animals are able to shift the loudness of a single click in order to penetrate farther into the water in front of them. Some clicks are loud enough to temporarily deafen a person.

Sperm whales make the loudest sounds of all. One of their clicks, if heard in the open air, would be much louder than the sound of a jumbo jet taking off. "It's the biggest and loudest damn biosonar source in the world," Cranford says. Just imagine a crack that lasts 1/10,000 of a second but can be picked up by hydrophones -- and heard by other sperm whales -- at a distance of 15 miles or more.

How a flesh-and-blood animal can produce such a violent blast remains a mystery. Actually, almost everything about sperm whale anatomy is mysterious, because it is difficult to map body parts that are far bigger than the anatomist doing the mapping. The head of a big male sperm whale can be 25 feet long and take up a third of the animal's length. Much of a sperm whale's head is occupied by the spermaceti organ, a huge fibrous cask containing a milky, waxy material that was highly prized as a lubricant and lamp oil, and which to Nantucket whalers looked like nothing more than gallons and gallons of semen -- hence the name. "I've never been able to figure out how they rationalized females having spermaceti too," Cranford says.

To modern biologists, a structure as big and as odd as the spermaceti organ cries out for an evolutionary explanation, and marine mammalogists have argued for years over its function. Cranford subscribes to what marine mammalogists call the big bang theory, which argues, among other things, that a sperm whale's head is a gigantic noisemaker. The spermaceti organ, according to this school of thought, helps amplify and focus the whale's sonic emissions, which it uses to stun fast-swimming squid and fish long enough to gobble them up. The big bang theory has been difficult to demonstrate because no one knew the precise arrangement of parts inside a whale's head. "When you cut into the animal you destroy the geometry, and it's the geometry, the shape of tissues, and their consistency that are responsible for the sound beam," Cranford says. He thought if he could find a way to scan a whale's head, he could pin down the geometric relationships between its parts and decipher the purpose of the spermaceti organ.

First, though, there was the small matter of funding. Cranford's adjunct professorship at San Diego State is unpaid unless he teaches or gets a grant through the university, and marine-mammal biology is not exactly a big priority for the National Science Foundation. Some years, Cranford has had to pay for his research out of his own pocket -- or rather that of his wife, who is an invertebrate zoologist for the San Diego water department. The rest of the time, nearly all of his funding has come from the Office of Naval Research (ONR).

The Navy has very practical reasons for being interested in dolphin sounds. A blindfolded dolphin can detect an object three inches in diameter from a distance of 123 yards. That's roughly equivalent to standing at one end of a football field and spotting a tangerine in the opposite end zone. More to the point for the Navy, a dolphin is a lot better at such tasks than the sonar dome on a submarine. Trained dolphins can pinpoint underwater mines from a distance of several hundred feet with almost 100 percent accuracy. Even the best submarine sonar domes, backed by a roomful of sophisticated computers that analyze the returning echoes, routinely miss mines. That's not good enough, Cranford says: "It only takes one inexpensive little mine to blow a hole in a great big expensive ship full of sailors."

Five years ago, the federal government gave a group of engineers several million dollars to begin developing an electronic dolphin -- a self-propelled, mine-detecting underwater drone as perceptive as a cetacean. Such a device could be deployed from a ship to scan for mines even in shallow waters. If the drone found any, the ship could hightail it to safer waters without worrying about having to come back and pick up its drone. "We want to have something in a box that can do what the dolphins can do," Bob Gisiner, the marine-mammal science program manager at ONR, told me. "They can find objects buried under the mud. We don't have any sonar that can do that anywhere near as well."

It turned out to be a hellishly difficult problem. Most of the Navy's efforts were focused on signal processing, or detecting the echoes that come back from distant objects and computing where and what the objects are. "Everybody thought signal processing was sexy," Gisiner said. Cranford's research, by contrast, seemed to the engineers like a mere mechanical problem and not worth spending a lot of money on.

The engineers tried using piezoceramic elements, each of which emits only a single frequency or a very narrow band of frequencies. But a dolphin's broadband click required a huge array of elements, and the prototypes failed to produce sounds of the right length, frequency, and duration. "In the end, they couldn't make dolphin noises," Gisiner said. "They just could not do it."

Even so, Gisiner has had to fight to keep Cranford's funding going. Cranford says, "The only reason I've been able to stick with it is I'm really excited about the nuggets of discovery -- that moment of finding something that nobody has found before. It's like being a modern-day explorer. You've got to be a little abnormal to be willing to do absolutely anything to answer a question. Only 1 percent of the world's population has a Ph.D. You are at the tip of the tail of a bell-shaped curve if you are willing to devote yourself to getting a Ph.D. in what amounts to a backwater of science."

Cranford had no yearnings to be a scientist as a child. He grew up in a suburb of Los Angeles, the grandson of a dairy farmer who emigrated from Switzerland in 1919. He wears his grandfather's gold ring. Cranford's father was an elevator constructor. "He had to figure out how to maneuver an elevator into a little hole in the skeleton of a building," Cranford says. "I've always wondered if I got my interest in understanding how things work from my dad. He was a mechanical engineer without the training."

When Cranford enrolled in Long Beach Community College after finishing high school, no one in his family had ever gone past 12th grade. One day his zoology instructor told her students to propose a research project. "I wrote down,

Bad Science & Breast Cancer

Cecille Isidro — Thu, 01 Aug 2002 08:00:00 -0400

The patient's name was Diane. She was a 28-year-old truck driver with advanced breast cancer, and her tumor was one of the largest that her doctors had seen. It bulged from the upper right quadrant of her right breast and penetrated deep into her ribs, attaching itself to her chest wall. "It was the size of a muskmelon," oncologist William Peters recalls. "It was a terrible circumstance."

Peters was as young as his patient, but he was rising through the ranks of his profession with the unswerving trajectory of a missile. He had been studying cancer since he was 14, when he took a job as a summer intern at Roswell Park Cancer Institute, in his hometown of Buffalo, New York. He had been a triple major at Pennsylvania State University in biochemistry, biophysics, and philosophy, and had both a medical degree and a Ph.D. in human genetics from Columbia University. Now, in 1981, as a faculty member at the world-renowned Dana-Farber Cancer Institute in Boston, he was about to administer what would become one of the most controversial treatments in all of medicine.

Peters began by outlining the experiment for Diane. He wanted to give her extremely high doses of several chemotherapy drugs -- doses toxic enough, he believed, to kill her enormous tumor. Unfortunately, the drugs might also kill her. They would certainly wipe out her bone marrow, leaving her vulnerable to infection. To restore her defenses, Peters would extract some marrow from her hipbone before starting the procedure, then inject it back after the chemo treatments. If all went as planned, her marrow cells would find their way back into her bones and rebuild her immune system in a matter of weeks.

The treatment was the brainchild of Emil "Tom" Frei, director of Dana-Farber at the time and a towering figure in the field of cancer research. Like other physicians, Frei had been frustrated by limited success treating advanced breast cancer with chemotherapy. The tumors would respond -- and sometimes even disappear -- only to come creeping back once the treatment ended. Frei knew that a single dose high enough to kill every last cell might also kill the patient. But he thought that a combination of drugs might be tolerable. Each would have bad side effects -- carmustine can harm the lungs; cisplatin can damage the kidneys; both drugs, along with a third, cyclophosphamide, can wipe out the bone marrow. But together they might spread the collateral damage around. "Intuitively, it made sense," says Craig Henderson, a former colleague of Frei and Peters's at Dana-Farber. "If a little chemo is good, more is better."

Combination chemotherapy with a bone marrow transplant, as the technique is called, had cured leukemias and lymphomas, but no one knew if it would work on breast cancer. "We knew the treatment was going to kill some people along the way, to be quite honest, but we knew the disease killed everybody," Peters says. So the possibility of a cure seemed worth the risk. "We were going to swing and go for the ring," he says. "That drove us. You had to believe you were going to pull off something that was going to change history."

Peters scheduled the operating room at a nearby Beth Israel Hospital for a Monday morning. Diana was put under general anesthesia, and Peters began the brutal procedure of plunging a needle through the flesh of her hip into the bone and drawing out aliquots of marrow. Part way through the procedure, the needle broke, leaving its tip embedded in the bone and the rest buried in the thigh muscle. Cursing, Peters frantically searched the operating room pliers to grasp the hidden needle, but the hospital was not set up for bone marrow work, so there were no pliers to be found. A nurse was sent out of the operating room to fetch a pair.

That evening, Diane was wheeled back to Dana-Farber, where she received chemotherapy. "We were being watched like a hawk," Peters recalls. Other doctors at the hospital were dubious that a woman could withstand such punishing doses of drugs -- roughly 10 times the standard dose -- but Diane proved them wrong. The chemotherapy wiped out her bone marrow, yet she weathered the other side effects. Meanwhile, the effect on her monstrous tumor seemed nothing short of miraculous. "Within a week, this huge mass, this four- to five-inch mass, disappeared," Peters says. "I mean, you could literally come in every day and watch this thing melt away. Bingo."

Diane's tumor eventually returned, and she died several months later. But Peters and Frei went on to perform the transplant on 29 more women. Each responded well initially, and three made a full recovery. Over the next two decades, Peters would become the treatment's most tireless advocate, inspiring doctors around the country to try it on their breast cancer patients. Thousands of women would undergo its rigors before the efficacy of high-dose chemotherapy was fully tested, and the treatment would become a flash point for breast-cancer-patient advocates, insurance companies, and the National Cancer Institute. But that was all in the future. In 1981 the doctors at Dana-Farber were still reeling from the excitement of their initial results. "We really thought we were going to solve the cancer problem," Henderson recalls. "Tom Frei sat me down in his office and said, 'We’ve got a cure for cancer.'"

***

By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley, California, she had learned a thing or two about suing health insurers. Throughout the 1980s Philipson helped AIDS patients in the San Francisco Bay area get reimbursement for medical care and sue their insurers for discrimination and breach of confidentiality. Her specialty was a branch of law that few lawyers had mastered or wanted any part of. The Supreme Court had ruled that patients couldn't ask for punitive damages when suing their health insurers. "There was no pot of gold," Philipson says, "and most people don't have the money to pay you."

Ricki, her client with breast cancer, was a 48-year-old psychologist with a child still in high school. She had been diagnosed three years earlier, in 1988, and had undergone chemotherapy and a mastectomy. Now the cancer was back, and high-dose chemotherapy seemed her only hope. But her insurer, an affiliate of Health Net, one of the largest HMOs in southern California, refused to pay for it.

The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $125,000 and could easily hit $500,000. Drugs alone ran into the tens of thousands of dollars. The patients spent weeks in isolation rooms, shielded from infections and racking up charges as they waited for their bone marrow to take hold and begin churning out new blood cells. Publicly, insurers argued that the treatment was unproven and experimental. Privately, many doctors believe, insurers worried that if they agreed to pay for one experimental procedure, patients would soon be demanding others.

Philipson agreed to represent Ricki but only if she could find evidence that high-dose chemotherapy was an established therapy. Within a week Ricki came back with a stack of scientific articles, including some by William Peters. By then Peters had become something of an evangelist for high-dose chemo, crisscrossing the country to extol the procedure so often that one colleague nicknamed him Elmer Gantry. At scientific gatherings he paced to and fro across the stage, carrying a microphone in one hand and gesturing toward charts and graphs with the other. He appeared on TV shows, including Nightline and 20/20, and was quoted in dozens of newspaper articles. "This could save more lives than any form of chemotherapy," he told the New Orleans Times-Picayune in 1997.

Sifting through the scientific papers, Philipson began to believe she had a case. "The way they portrayed it, bone marrow transplant was the best thing since sliced bread," Philipson says. "They were saying this is a cure." At the same time, she learned that high-dose chemotherapy came at a terrible cost. Besides the marrow-extraction process, patients had to endure drugs that destroyed the intestinal lining from mouth to anus, making both swallowing and defecating unbearably painful. Waves of nausea and vomiting alternated with uncontrollable bouts of diarrhea and terrible loneliness. Though they were put in isolation rooms for weeks on end, many picked up infections anyway. One in five women died directly from the treatment. Those who did survive could be left with permanent damage to the heart, kidneys, lungs, liver, and nerves.

Still, the alternative seemed even worse. As late as 1989, women with stage III breast cancer -- tumors larger than two inches across and cancer cells that had spread to the lymph nodes -- had a 50 to 70 percent chance of relapsing after standard chemotherapy. Those, like Ricki, who progressed to stage IV -- when the cancer invades other organs -- were almost certain to die. Given the odds, many patients weren't just willing to try a transplant, they were desperate for it.

Philipson's job was to prove that Ricki's insurer was obliged contractually to pay for the procedure. She bombarded the company with scientific papers and statements from breast cancer specialists who claimed that transplants were an accepted medical practice. She sent letters demanding proof that the company had properly reviewed Ricki's case. Ricki, meanwhile, paid to have her bone marrow harvested. "We were working against the clock," Philipson says. "If her tumors got too big, she couldn't have the treatment."

In the end the insurer agreed to pay, prompting more women to come to Philipson with the same problem. She won three more cases over the next two years. Then, in 1993, she assisted in a trial that threw open the legal floodgates. That year, a lawyer named Mark Hiepler sued Health Net on behalf of his sister, Nelene Fox, who had died of breast cancer while trying to persuade the company to cover a transplant. A loophole in the law allowed Hiepler to sue for damages. Health Net decided to fight.

Philipson told Hiepler to comb through the company's records for evidence that their decision was capricious. They soon discovered that the Health Net physician who denied Fox coverage had been promised a bonus at the end of the year if the insurer kept down costs. "It sounded terrible," Philipson recalls. "The defense attorney says: 'It's no different from John Deere or any other American company.' The jury comes back and says, 'The hell it isn't different. John Deere makes tractors, and you decide on people's lives.'" The jury awarded the Fox family $89 million in damages, a record judgment against an insurer. Health Net appealed and then settled out of court for an undisclosed sum.

***

Within a year of the Health Net judgment, women were filing suit against insurers in record numbers. The strategy was always the same. The plaintiffs argued that high-dose chemotherapy was accepted practice, and transplant doctors backed them up on the witness stand. The most persuasive evidence came from a study that Peters himself had published in 1993. In it he compared the results of his high-dose cases with those of patients who had received standard doses of chemotherapy elsewhere. Approximately 70 percent of Peters's patients were cancer-free 48 months after treatment; among women who had received standard treatment, only 35 percent were cancer-free. "That paper drove the field," Craig Henderson says. "Every transplanter, every cancer doctor, had a copy."

By then Peters had left Dana-Farber to build a transplant program at Duke University Medical Center. As more and more doctors began trying their hand at transplants, hopeful stories began to appear in the media. In nearly every case, the dying patient was cast as a victim of both her breast cancer and her greedy insurance company. Women were in a "desperate struggle to buy more time," as the Dayton Daily News put it. Soon advocacy groups like the Susan G. Komen Foundation, which sponsors the annual Race for the Cure, took up the cause. With the help of doctors like Peters, groups lobbied state and federal legislatures to mandate coverage.

In 1993 Peters spoke to members of Congress at a luncheon. Paul Goldberg, editor of The Cancer Letter, later described the scene: "Peters said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' " Then he asked the 70 or so breast cancer patients he had brought to the lunch to stand up. Turning back to his audience, Peters announced that at least half of the women would be dead had they not undergone his lifesaving treatment. "'As you look at a woman across the table from you,' he said, 'ask yourself: Is the price of this woman's life worth the price of a luxury car?'"

***

The real question was not the worth of a woman's life but whether or not high-dose chemotherapy was saving lives. But the answer no longer seemed to matter once the insurance money began to flow. In the mid-1980s, fewer than 100 bone marrow transplants a year were performed on breast cancer patients. By 1994 the number had jumped to around 4,000. The treatment was a rare source of profit for hospitals in the 1990s, when they were being squeezed financially by HMOs.

Then the business got better. New drugs, called growth factors, came on the market in 1991, making transplants a little less risky and shortening a woman's stay in the isolation ward. They stimulated the growth of bone marrow to the point at which marrow stem cells could be harvested from the blood rather than extracted from the hip. Better yet, they helped the marrow regrow once the cells were returned to the woman's body. By 1995 less than 10 percent of patients were dying outright from the treatment, and a typical transplant, billed at $80,000 to $100,000, cost a hospital less than $60,000. Under Peters, Duke University Hospital's breast cancer transplant program took in as much as $14 million a year in revenue. It wasn't long before hospitals large and small were converting entire wards into transplant units. Many turned to Response Oncology, a company based in Memphis, Tennessee, that franchised bone marrow transplants. Company trainers would arrive at a hospital and, in two days, teach nurses and oncologists how to do the procedure. The company also helped hospitals build transplant wings and handle their insurance claims.

As procedures became more sophisticated, Henderson says, "Transplanters became gods at hospitals." They took a patient to the brink of death and then snatched her back at the last moment. Some began treating ovarian cancer with high-dose chemotherapy, too, although there was no evidence that it improved a patient's odds. Others subjected women with smaller, less-advanced breast tumors to high-dose chemo. Even Peters told colleagues that he was going to begin transplanting in patients with advanced prostate cancer. The doctors were silent until one pointed out that advanced prostate cancer rarely responds to chemotherapy, no matter how high the dose.

By then Philipson had taken a hard look at her clients' longevity. First, Ricki died in 1993, after winning her lawsuit, surviving the transplant, and keeping her cancer at bay for nearly two years. Then another former client died, and another. Philipson had helped five women receive bone marrow transplants over the years, and she was familiar with a dozen more. Every single one of them was dead.

Philipson wasn't the only one to notice a problem. Craig Henderson had long insisted that more testing was necessary. He knew that Peters's seminal 1993 paper, which compared high-dose chemotherapy with standard treatment, wasn't proof that the new treatment saved more lives. Peters's subjects were carefully selected to withstand the treatment. Because they were healthier than most breast cancer patients to begin with, they might have done just as well on conventional therapy.

But most doctors had little training in statistics or the design of clinical trials. They took Peters's paper as proof that his treatment worked. When Henderson warned them against accepting it as an article of faith, they mostly ignored him.

Ironically, one of the few to recognize the need for more testing was Peters. He knew that only a controlled, randomized clinical trial could provide definitive proof that the treatment worked. He persuaded the National Cancer Institute to fund a lengthy trial that would eventually involve more than 1,000 women. Patients would be eligible if their breast cancer had not yet metastasized but was likely to recur after surgery. Each woman would be assigned randomly to one of two treatments: Half would receive a moderately high dose of chemotherapy and no more. The other half would get an additional, even higher dose of chemotherapy and then a stem-cell transplant.

The trouble was, by the time Peters had organized his trial, few women wanted to participate. Joining the trial meant running the risk of not getting high-dose chemo, and many had read newspaper accounts that convinced them that the treatment was their only chance for survival. Their doctors often agreed. At the University of California at San Francisco, where Henderson would become head of oncology, one transplanter pulled out a copy of Peters's 1993 paper. "I don't see how with these data it's even ethical to do a randomized trial," he said.

The randomized trial ended up taking nearly a decade to complete -- twice as long as it should have. In 1999, when the results were presented at the annual meeting of the American Society of Clinical Oncology, along with those from four other, smaller clinical trials, they were inconclusive at best. Three found no significant benefit in high-dose chemotherapy and transplant over conventional treatment. Peters's trial showed that women who received a transplant were a little more likely to stay free of cancer than women who received conventional therapy. But any survival advantage was wiped out by the fact that they were also more likely to die from the treatment.

"It's too early to draw conclusions," Peters told colleagues and reporters. The data were preliminary, he pointed out, and the fifth trial, by the South African oncologist Werner Bezwoda, had proved very encouraging. Bezwoda's experiment was small -- only 154 patients -- but the results were spectacular: Of 75 women who received high-dose chemo and a transplant, only 19 relapsed and eight died. Of 79 women who received conventional treatment, 52 suffered relapses and 28 died.

Perhaps doctors should keep transplanting after all.

At least one member of the audience was skeptical. Raymond Weiss, an oncologist in Washington, D.C., had been to South Africa on vacation earlier that year and had met some of Bezwoda's colleagues. What he heard was troubling. "We don't think he has follow-up on his patients," they said. "A lot of them go back to rural areas and die, and nobody knows it."

Soon after Bezwoda's results were announced at the meeting, Weiss and fellow oncologist Roy Beberidge helped organize an audit of the South African's research. At first, Bezwoda agreed to cooperate, provided only four people came and only for two days. The audit was set for January 2000, but as the date approached, Bezwoda changed his mind. Then he relented, and Weiss's team flew to Johannesburg.

Bezwoda now said that only 151 patients had participated in the trial, not 154, yet he had charts for only 62. The other 89 charts were in a room jumbled together with those of thousands of other patients, the team was told. The records on hand contained only sketchy information: Stacked one on top of the other, all 62 of them were only seven inches tall. "I got out a ruler and measured it," Weiss says. "That's about the thickness of the chart of one U.S. transplant patient."

In the morning the Americans sat down and read through the charts -- twice. Many of the records bore unsigned, handwritten entries -- a breach of standards in a clinical trial. There was no evidence that Bezwoda had randomly assigned patients to receive either high-dose or standard chemotherapy. In fact, there were no records showing that any patients had received the standard treatment.

Weiss and the other Americans were stunned. When they confronted Bezwoda the next day, he denied any wrongdoing. Uncertain what to do next, the Americans returned home. But three days later he sent a letter to his department at the university, admitting he had a committed a "serious breach of scientific honesty and integrity." The results of the study, he wrote, had been "a misrepresentation." The letter was forwarded to the American Society of Clinical Oncology, which sent out an advisory to members and a press release announcing the fraud. Bezwoda now claims that his work wasn't fraudulent after all. But after Weiss led an audit of another Bezwoda trial, the society issued a statement declaring that the South African's results "should not be used as the basis for the treatment of any patient."

The warning came too late for four women in Seattle. In 1998 two researchers at the University of Washington had begun a trial to test Bezwoda's special high-dose regimen for women with metastatic breast cancer. They had copied Bezwoda's published formula faithfully, administering it to six patients, all under the age of 50. Two of the four died of congestive heart failure a few months after their treatment. One patient lived with acute cardiac damage until she succumbed to breast cancer. The fourth patient is still alive; she has heart problems brought on by the chemotherapy. The researchers stopped the study.

***

Most oncologists now agree that high-dose chemotherapy is simply the wrong treatment for breast cancer. Chemotherapy works by killing cells when they're dividing, so the faster cancer cells divide, the harder they're hit. Blood cancers -- some leukemias and lymphomas -- grow rapidly and so are acutely vulnerable. But breast cancer cells reproduce more slowly and tend to be far more resistant to cancer drugs. No matter how many breast cancer cells are killed, at least a few survive, and they keep dividing after the chemotherapy ends.

The slow pace of most breast cancers also helps explain why transplanters were so optimistic. Breast tumors can take years to reappear after treatment, but the transplanters were used to leukemia, which tends to come roaring back in a matter of months. If they found no evidence of breast cancer after a year and a half -- the usual waiting period for blood cancers -- they assumed a patient was cured, or at least in long-term remission. Yet the cancer was often lurking in the background, gathering its forces for another, more devastating appearance.

From the moment Peters first administered high-dose chemotherapy until the first clinical trials were concluded, nearly 20 years passed. During that time, hundreds of physicians practiced the unproven treatment. An estimated 30,000 breast cancer patients suffered through high-dose chemotherapy, only a fraction of them as part of a clinical trial. All told, the nation spent around $3 billion paying for it, while an estimated 4,000 to 9,000 women died not from their cancer but from the treatment.

"Nobody got cured," Philipson says of her clients. "I put them through litigation when they were dying. Then if I won, they got to have a bone marrow transplant. You can't raise your head, you are so sick, and it's so horrible and so hard, and you don't have time to say good-bye to the people you love. I had to decide for myself whether I was going to take these cases anymore, and I decided not to. It was a cure that didn't work."

***

William Peters rarely visits the oncology ward anymore. Now in his early fifties, he recently stepped down as CEO of the Barbara Ann Karmanos Cancer Institute in Detroit to become an administrator and staff oncologist. But he still has his sunny corner office in a brand new building. "I designed the interiors myself," he says, gesturing at the bright, abstract pattern of the carpet. Short and dapper, with small, soft hands, a quick wit, and a manner that veers between Marcus Welby and a salesman, Peters can fill a room with energy. When asked if he deserves some of the blame for how events turned out, he seems genuinely baffled. "My interest was to get patients on the randomized trials," he says. Besides, he adds, "transplants may still work."

Pulling a fountain pen from his shirt pocket, Peters flips over a scientific paper and quickly sketches out a series of graphs. One axis represents time, the other the number of women surviving cancer. He has reanalyzed the results of his clinical trial, he says, and found what seem to be positive results for women under 50. "It's incredible data," he says. "I still believe [transplanting] is of great value. It is a stepping-stone to finding cures for people who have not been cured before."

One gets the sense that Peters has delivered a version of this polished and heartfelt speech before -- perhaps to donors, reporters, and prospective patients. There are several die-hard transplanters around the country who still believe, as Peters does, and who are still giving transplants to breast cancer patients. But most of their colleagues are no longer swayed by the transplanters' arguments. Jeffrey Abrams, an oncologist and senior investigator at the National Cancer Institute, says Peters's new interpretation "doesn't prove anything." High doses of chemotherapy put young women into early menopause, and that alone reduces the chances that their breast cancer will return. There are ways to trigger early menopause without nearly killing the patient.

High-dose chemotherapy arrived at a pivotal moment in the history of breast cancer, when breast-cancer-patient advocates had recently learned to flex their political muscle. Yet 20th-century American medicine often values innovation at the expense of caution, and its history is littered with other poorly proven treatments -- from frontal lobotomy to radical mastectomy. "The system should have insisted on sound medical evidence before it became a widespread therapy," Abrams says. "We should have relied on the science and proved to ourselves that this really was a better way to treat women. It is more toxic [than standard therapy]; it is more expensive. If it's only going to be as good as standard therapy, then it's not an advance. The system failed."

These days, with earlier diagnosis and new drugs such as tamoxifen, the hopelessness that breast cancer brought in the 1970s and 1980s seems a distant memory. But patients and doctors are still swayed by the ancient medical dictum that says desperate diseases may require desperate cures. Patients with no other hope will always be willing to try a miracle cure -- no matter how barbaric the costs and uncertain the odds. "A lot of it had to do with psychology," says Marilyn McGregor, a breast cancer survivor and activist in San Francisco. "Women, especially younger women with children, will do anything to save their lives, so they did not hear the statistics. Or they made their bargains with God that they would go through this treatment if only they could be allowed to live. They just wanted to believe."

-- Additional reporting by Sheila Kaplan