• Formation : 1975; 46 years ago

• Type : Nonprofit organization

• Headquarters : Seattle, Washington, U.S.

• Leader : Thomas Lynch Jr., M.D.

• Budget : $654.62 million (2020)^[1]

The Fred Hutchinson Cancer Research Center, also known as Fred Hutch or The Hutch, is a cancer research institute established in 1975 in Seattle, Washington.^[2][3]

History

The center grew out of the Pacific Northwest Research Foundation, founded in 1956 by Dr. William B. Hutchinson (1909–1997). The Foundation was dedicated to the study of heart surgery, cancer, and diseases of the endocrine system. Hutchinson's younger brother Fred (1919–1964), was a major league pitcher and manager who died of lung cancer at age 45. The next year, Dr. Hutchinson established the Fred Hutchinson Cancer Research Center as a division of the Pacific Northwest Research Foundation.^[2]

In 1972, with the help of Senator [Warren Grant "Maggie" Magnuson (born 1905)], PNRF received federal funding under the National Cancer Act of 1971 to create in Seattle one of the 15 new NCI-designated Cancer Centers aimed at conducting basic research^[4] called for under 1971 Act; the Fred Hutchinson Cancer Research Center became independent 1972 and its building opened three years later in 1975.^{[2][5][6][7][8]:3,5}

The center was named an NCI-designated Comprehensive Cancer Center in 1976.^[9]

In 1998, the center formed the Seattle Cancer Care Alliance (SCCA), a separate nonprofit corporation,^[10] with UW Medicine, and Seattle Children's. This solidified the center's reach into clinical care and was essential for it retaining its NCI comprehensive center designation;^[11] the designation was extended to the center's consortium including the SCCA in 2003.^[9] SCCA's outpatient clinic first opened in January 2001.^[11]

In 2001, The Seattle Times published a series of articles alleging that investigators at the center (including the Center's co-founder [Dr. Edward Donnall "Don" Thomas (born 1920)]) were conducting unethical clinical studies on cancer patients. The paper alleged that in two cancer studies conducted in the 1980s and early 1990s, patients were not informed about all the risks of the study, nor about the study doctors' financial interest in study outcome. The paper also alleged that this financial interest may have contributed to the doctors' failure to halt the studies despite evidence that patients were dying sooner and more frequently than expected.^[12] In response, the center formed a panel of independent experts to review its existing research practices, leading to adoption of "one of the nation's toughest conflict-of-interest rules."^[13]

In 2014, the center announced that D. Gary Gilliland would become president and CEO in 2015;^[14] he took over from Lawrence Corey who was appointed as the 4th President in 2010, following the retirement of Lee Hartwell.^[15]

2014 also saw the organization adopt its longtime local nickname, "Fred Hutch", as its official name as part of a rebranding.^[16]

In 2018, the center announced that it would expand into the former Lake Union steam plant, which previously housed ZymoGenetics.^[17]

Notable faculty

The center has employed three recipients of the Nobel Prize in Physiology or Medicine:

• Linda Buck, Ph.D., who received the award in 2004 for solving many details of the olfactory system;^[18] and

• [Dr. Edward Donnall "Don" Thomas (born 1920)], who received the award in 1990 for his pioneering work in bone-marrow transplantation and who died in 2012;^[19][20] and

• Lee Hartwell, Ph.D., who received the honor in 2001 for his discoveries regarding the mechanisms that control cell division.^[21] After retiring from leading the center in 2010, Hartwell left to join Arizona State University.^[22]

Commercialization

The center is active in technology transfer. In 2013, it was one of the top ten biomedical research institutions in the field (excluding universities); it made 18 new deals with companies to develop inventions made at the center, and earned $10,684,882 in income from past deals it had signed.^[23] Most notably, Juno Therapeutics, a company developing CAR-T immunotherapy for cancer and that raised $314 million in venture capital investments and had a $265 million initial public offering in 2014, was started based on inventions made at the center.^[24] As of 2015, about twenty companies had been started based on center inventions since 1975, including [Immunex Corporation] and Icos.^[24]

Campus

The institute's main campus consists of thirteen buildings on fifteen acres (6.1 ha) in the South Lake Union neighborhood of Seattle.^[25]

In 1987, the center began exploring possible new homes to replace its 9-building campus on First Hill that it was set to outgrow.^[26][27] A site in the South Lake Union neighborhood, envisioned by the city as a future high-tech and biotechnology hub,^[28] was chosen in September 1988 after a deal to move to Fremont fell through earlier that year.^[29][30] The first phase of the campus, designed by firm Zimmer Gunsul Frasca Partnership,^[31] began construction in 1991 and opened on June 1, 1993 in a ceremony that included the burying of a time capsule set to open in 2093.^[32][33]

The campus is accessible via the Mercer Street exit of Interstate 5 as well as several public transportation routes, including the South Lake Union Streetcar.^[34]

[...]

[...] In 1955, Thomas was appointed physician-in-chief at the Mary Imogene Bassett Hospital in Cooperstown, New York. Here he became fascinated by the discovery that rodents given a lethal dose of radiation could be rescued by an intravenous infusion of marrow cells from a donor. In 1957, Thomas treated a patient with leukaemia using high doses of total-body irradiation to wipe out the cancer, and then gave them an infusion of marrow cells from an identical twin. The transplant was at first successful, although the patient later died from a recurrence of the leukaemia.

Meanwhile, the medical literature was charting numerous cases of patients with blood disorders who had been treated using marrow transplantation from healthy family members. All the patients died from infections or severe immune reactions that were not predicted from studies in inbred rodents. Many investigators left the field, pronouncing it a dead end.

Thomas did not give up. In 1957 he began experimenting in dogs. Like humans, dogs have unusual phenotypic diversity, a well-mixed gene pool and can develop haematological diseases, including non-Hodgkin lymphoma. In late 1963, Thomas set up his laboratory at the United States Public Health Service (USPHS) Hospital in Seattle, which was affiliated to the University of Washington's medical school.

When I joined his small band of scientists in 1965 as a research fellow, transplantation was not a widely known concept. Indeed, the university's print shop once produced letterhead stationery for us that read “Division of Hematology and Transportation”. A remarkable thing about Thomas's leadership style was that he was happy to give people like me a free hand in innovating, as long as it helped the patients.

Under Thomas's guidance, we spent the 1960s developing high-intensity irradiation treatments to eradicate patients' cancer cells and establishing the importance of tissue matching for transplant outcome. To control and treat graft-versus-host disease, we developed drug combinations to suppress the immune system and produced antibodies against human lymphocytes — which once involved a 1.5-hour chase of an antibody-producing horse. Our total-body irradiation sources were set up in a Second World War underground bunker.

Work with patients began in 1969 at the USPHS hospital. Initial survival rates were low, and unexpected problems required going back and forth between bench and bedside — something that remained a hallmark of Thomas's work. By 1979, after performing a number of transplants, we were able to describe a phenomenon called graft-versus-tumour effects, in which donor lymphocytes help to eliminate residual malignant cells. There are patients who received transplants in 1971 still alive today.

Progress has been slow but steady. Early marrow donors were siblings. In 1979, the first patient with leukaemia was successfully treated with a transplant from an unrelated donor using new immunosuppressant drugs. This success sparked Thomas and others to set up international marrow-donor programmes. Transplant outcomes have improved, with survival rates for some diseases, such as aplastic anaemia, close to 95%.

In 1972, the US government closed the USPHS hospital. This prompted the founding of the private Fred Hutchinson Cancer Research Center (the Hutch), with close ties to the University of Washington's medical school. Thomas headed the medical oncology divisions at both.

Over the years, Thomas's team trained hundreds of young investigators. As one of them put it: “Virtually every major transplant centre in the world got its start by sending someone to train under Don Thomas.” Owing to his influence, the Hutch's clinical focus has always been the patient, and its approach, one of teamwork. After retiring in 1989, Thomas continued writing manuscripts, lecturing and serving as an ambassador for the place. [...]

AT A KITCHEN TABLE in a noisy apartment in the Flatbush neighborhood of Brooklyn, N.Y.:

David Blech, a 24-year-old songwriter and entrepreneur, sits with his brother and father. Like expectant parents choosing a baby name, they bark ideas for what to call their just-invented company: "DNA Techniques." "Hybridoma Service Center." "Genetic Systems."

"That's it!" Blech calls out, rising excitedly. "Genetic Systems Company!"

The Blechs will start with that name. They will use it, shares of stock and personal charm to recruit top cancer doctors to jobs and board positions. And, they dream, they will all get rich in the nascent biotechnology boom of the 1980s.

AT A KITCHEN TABLE in a quiet house in rural Heflin, Ala., five years later:

Becky Wright, a 36-year-old housewife and mother of three, sits with her husband, Pete, owner of the local drugstore. Their talk is not about dreams, but a nightmare: Becky has leukemia.

Pete has searched for the best place in the world to take his wife for treatment. His choice: the Fred Hutchinson Cancer Research Center in faraway Seattle.

They are hopeful. "The Hutch" is the pioneering institution in transplanting bone marrow - by then a proven treatment for the type of leukemia Becky Wright has - and she is the perfect candidate, with a donor sister whose marrow matches hers.

Doctors tell the Wrights that with a standard transplant, chances are good that Becky will live to see her youngest, a 5-year-old girl, grow up.

But when the couple travels to Seattle in 1985, Becky is not given a standard transplant.

Instead, she is thrust, unwittingly, into a world where the quest for cure gets tangled in the pursuit of fame and fortune. The world of David Blech.

At the urging of her Hutchinson Center doctors, Becky Wright joins an experiment in which eight manmade proteins are added to her sister's bone marrow before it is transplanted.

Some of those proteins belong to a Seattle biotech company - a company named Genetic Systems.

Some of Wright's doctors at The Hutch were among David Blech's recruits. The doctors - and The Hutch itself - had financial ties to the company Blech and his family had invented in their Flatbush flat.

By the time Wright was enrolled in the clinical trial, the doctors knew it wasn't working. Transplants were being rejected at alarming rates. New cancers were appearing and old ones reappearing far more than they normally would.

All were problems directly attributable to the experimental treatment.

The doctors didn't tell the Wrights any of that.

Not about the 11 patients who had already died. Not about other, less-dangerous ways of treating her disease.

Not about their own financial interests.

Becky Wright died of causes directly attributable to this experiment, as did at least 19 other people, according to evidence in medical journals and Hutchinson Center documents.

Odds are high that some of them would otherwise have survived a standard transplant and lived full lives. Many of the others likely would have lived at least a year or two longer than they did --a year or two they would have shared with their spouses, their children, their families and friends.

The story of Protocol 126, as this experiment was called, has never been told. Federal and state investigators looked into Protocol 126 for a while, then closed their investigations half-completed - leaving one investigator "saddened and alarmed" at the lack of follow-through.

During the 12-year span of the trial, several doctors at The Hutch tried to curb it. They said it was hurting rather than helping patients, and that mice or dogs rather than humans should be the test subjects. They complained that patients weren't being told about the risks, the alternatives, the researchers' financial conflicts.

As Dr. John Pesando, a member of a Hutch committee charged with protecting the rights of patients, wrote to federal officials in 1998:

"Many patients died at the Fred Hutchinson Cancer Research Center when the Institutional Review Board charged with protecting them was shamelessly used and abused by senior staff."

Hutch management "denied the existence of financial conflicts of interest, refused to halt the protocols, and refused to have protocols reviewed by independent outside examiners," Pesando wrote.

The researchers involved were [Edward Donnall "Don" Thomas (born 1920)], Hutch co-founder and clinical director and winner of the 1990 Nobel Prize in medicine; Dr. John A. Hansen, head of a tissue-typing lab and later clinical director; and Dr. Paul J. Martin, a young oncologist.

When the review board questioned the work of these doctors, Pesando said, board members were "lied to, intimidated, ignored and punished." Thomas argued in writing that it was the board's job to promote, not hinder, the research.

That's not what federal law says. By law, the board was to ensure that risks to patients in clinical trials were minimized in relation to potential benefits, and that patients fully understood those risks before consenting to participate.

More than 100 interviews and 10,000 pages of documents - including Becky Wright's consent form - reveal that neither occurred in Protocol 126.

Thomas refuses to discuss the trial or his financial holdings. The other doctors involved defend their actions, saying they were driven by science and that money issues didn't affect them.

Martin adds: "I don't think survival is the best measure of outcome in these studies."

Fifteen years after his late wife began her treatment at The Hutch, Pete Wright, who still runs the Wright Drug Co. in Heflin, was shocked to learn all he didn't know: That other Hutch doctors had tried to stop the experiment. That the doctors running the trial had financial interests in it. That there was an alternative treatment with a higher likelihood of success.

"To say it's disturbing is an understatement," Wright said.

"All these years I have told myself that she got the very best care possible and I swore that would be the case when she was diagnosed. It makes me want to buy a plane ticket to Seattle and beat the hell out of somebody."

The biotech boom begins

When young David Blech went recruiting for his fledgling company, he found a kindred soul in the upper-left corner of the country: Dr. Robert Nowinski of The Fred Hutchinson Cancer Research Center in Seattle.

Both hailed from New York. Both were brash and ambitious. And both saw potential riches in biotechnology.

The Bayh-Dole Act of 1980 had encouraged publicly financed scientists to patent their inventions, setting off a boom in biotech. Nowinski, who was 35 that year, wanted in, and Blech was holding the door open.

Blech asked Nowinski to head up Genetic Systems, and to bring some of his Hutch colleagues along. With their reputations, Blech knew they could create enough buzz around the company's stock that they would all get rich.

Genetic Systems incorporated on Nov. 13, 1980. In the next two months, Nowinski and Blech gave penny-a-share stocks to three key scientists at The Hutch:

• Don Thomas got 100,000 shares, a $3,000 annual stipend and a seat on the company's scientific advisory board.
• John Hansen got 250,000 shares and a job as the company's medical director. He would continue to work at The Hutch but promised to "devote such time as is necessary" to Genetic Systems for an $18,000 consulting fee.
• Paul Martin, Hansen's protégé and assistant, got 10,000 shares and a three-year exclusive consulting agreement with Genetic Systems.

Blech put together a prospectus touting the doctors and The Hutch. He raised $3 million in the first three months of Genetic Systems' existence, swelling the value of the doctors' stock holdings.

Thomas' presence on the prospectus was particularly important. At age 60, he had earned an international reputation.

An immunologist, Thomas had been involved in the world's first bone-marrow transplant, in New York in 1956. The patients, identical twins, had died, but the procedure had shown promise.

Marrow, a spongy tissue inside bones that produces blood cells, begins to die when cancer patients receive radiation and chemotherapy. The amount of damage to the marrow depends on the amount of cancer-killing material the patient receives. It limits how much treatment a person can survive.

Thomas and others believed that if marrow could be replaced through transplant, they could boost the cancer-killing treatment and then restore the patient's ability to produce new blood cells.

A bone-marrow transplant is a straightforward procedure. Marrow from a donor is infused through a catheter into a recipient's veins. If all goes well, the factory cells in the donor marrow, known as stem cells, lock in and begin forming new blood cells in the patient.

Thomas moved to Seattle in 1963. Between 1969 and 1974, he transplanted marrow into 54 patients with supposedly incurable leukemia. Most died, either from their cancer or from treatment complications such as infection. But six were cured.

In 1975, Thomas and other doctors opened the Fred Hutchinson Cancer Research Center, naming it after a former professional baseball player from Seattle who had died at age 45 from lung cancer. The Hutch specialized in cancers of the blood, and grew to perform some 450 bone-marrow transplants a year.

Worldwide, the procedure has been credited with saving more than 150,000 lives.

Meanwhile, Hutch doctors have conducted hundreds of clinical trials to advance the science. The Hutch receives more than $140 million a year in federal grants to pay for these experiments.

Controversial from the start

On Jan. 20, 1981 - two weeks after Thomas, Hansen and Martin received their founders' shares from Genetic Systems - the Human Subjects Review Committee at The Hutch met to consider a research proposal from those three doctors.

The doctors wanted to use money from the National Cancer Institute and leukemia patients from The Hutch in a new bone-marrow experiment, labeled Protocol 126.

The experiment would try to prevent an immune-system reaction known as graft-versus-host disease, or GVHD.

As many as half the recipients of marrow transplants from tissue-matched sibling donors suffered GVHD. At best, the disease was annoying, like a rash. At worst, about 5 to 10 percent of the time, it was fatal.

The researchers believed GVHD was caused by "T-cells" in the donor marrow. T-cells, so named because they mature in the thymus gland, are certain white blood cells that trigger the immune system to destroy foreign material and fight infection.

The researchers wanted to use newly manufactured drugs, known as monoclonal antibodies, to kill the T-cells. If it worked, they believed, the success rate of bone-marrow transplants would improve.

But first, they needed the approval of the Human Subjects Review Committee, which assessed the ethics of all human experiments at The Hutch. Congress had mandated that all medical research centers have such review panels.

In pushing their proposal, Hansen and Martin cited studies in which this therapy had been successful in mice. And, they said, the only known study with dogs had also been successful.

However, Dr. Rainer Storb, the Hutchinson Center's expert on GVHD, knew that at least one T-cell study on dogs had been unsuccessful, with some of the subjects dying in treatment. Although the results were not published, Storb said, they were widely known by those in the field.

Storb was not a member of the review committee, but he opposed Protocol 126. In doing so, he collided head-on with one of his fellow Hutch founders, Thomas.

Thomas, Hansen and Martin did not mention financial interests in Genetic Systems to Storb or the review committee. When Storb ultimately learned about those interests, he said, "It raised issues in my mind" and solidified his opposition to the trial.

First proposal is rejected

Most of the 11 members of the Human Subjects Review Committee were Hutch employees. Among them was Dr. Michael Kennedy, a specialist involved in the type of research proposed in Protocol 126.

In a recent interview, Kennedy recounted that he, too, had objected to many features of the proposed study. His objections in 1981 would presage the problems of the next dozen years.

The committee - whose members are identified by numbers rather than by name in these records - gave the proposal a largely negative reaction. Among their concerns:

• The lack of adequate prior research on animals. Normally, experiments of this type at The Hutch were performed extensively on mice, followed by studies of dogs before moving to humans.
"The jump from mouse to man is too great ... " said one committee member.
• Contrary to most such research, Protocol 126 proposed experimenting on the healthiest, rather than the sickest, patients. Some of them, whose leukemia was in remission, had a 60 percent chance of lifetime cancer-free survival with a standard transplant from a matched sibling donor.
• The proposed subjects for the experiment - those with siblings whose tissue type matched theirs - were the least likely to get GVHD, much less die from it.
• Some thought T-cell removal might actually prevent the bone marrow from engrafting, or taking hold in the recipient's body. Normally, graft failure is extremely rare, occurring in 1 out of every 100 marrow transplants.
Kennedy, in particular, thought T-cells were needed for new marrow to lock in and start producing healthy blood. And some thought T-cells helped prevent cancer relapse.
• The "informed-consent" form for patients minimized the risk of graft failure and made it sound as if a second transplant could be done without difficulty if the first one failed. In fact, second transplants were known to be fatal about 95 percent of the time.
• The consent form also failed to mention alternative treatments for GVHD.

Given all that, the committee voted not to approve Protocol 126. Hansen was told he could change it and reapply.

The experiment was revised to cut back the T-cell-killing power of the drugs and resubmitted. This time, the review team was headed by Dr. John Ensinck, an endocrinologist and Thomas' counterpart as head of clinical research at the University of Washington, where many Hutch doctors taught.

The committee voted on April 21 to approve the experiment. The minutes do not show why, and Ensinck couldn't recall specifically.

Ensinck, now retired, said in a recent interview: "At that point, I recall, The Hutch was doing uniquely experimental protocols at the cutting edge, so I recall we reviewed them very stringently."

Kennedy, who now has a private practice and teaches at the UW, says the committee's concerns were never addressed.

Again, committee members were not told that some of the drugs in the experiment - three of the eight antibodies ultimately used - were licensed to a company in which the researchers had a financial interest. Nor were they told that by that time, The Hutch itself had a monetary stake in the experiment.

In March, Nowinski had struck a deal with The Hutch to acquire the exclusive commercial rights to 37 specific monoclonal antibodies for 20 years. In return, Nowinski promised the center a percentage of royalties on sales of the antibodies. Simultaneously, he signed a deal with the Hutch-affiliated Pacific Northwest Research Foundation — the parent from which The Hutch was founded and, like The Hutch, headed at the time by Dr. William Hutchinson — that would give Genetic Systems the rights to new antibodies developed by Hutch doctors in exchange for 50,000 shares of stock and at least $125,000 in research funding.

Blech proceeded to raise $3.7 million from a pharmaceutical company and $2.6 million in two private stock offerings. The Hutch antibodies were the company's main assets. A written pitch to investors touted the development of antibodies to diagnose and treat infectious disease and cancer.

Genetic Systems raised an additional $6.6 million in an initial public offering. In its first quarter, the value of the stock the Hutch doctors had received was $875,000 for Hansen, $350,000 for Thomas, $35,000 for Martin, and $175,000 for the foundation.

Changes raise more concerns

Hansen began spending more and more time at Genetic Systems. He gave Martin, a postdoctoral student in his early 30s who had spent two years in the lab refining the antibodies, the title of principal investigator in Protocol 126.

This would be Martin's first experiment involving humans.

The initial results proved next to nothing. About half of the first group of subjects got GVHD - exactly as would be expected without T-cell treatment.

The antibodies alone hadn't killed T-cells in people as they had in mice. Then the researchers asked the review committee to approve major changes in the experiment. They wanted to add enzymes known to make the antibodies more lethal to T-cells. And they wanted more and healthier patients as subjects, people strong enough to survive years after a transplant so they could monitor the long-term results.

When the experiment went back to the Human Subjects Review Committee in April 1983, one member, Dr. Robert Bruce, a UW cardiologist, raised an alarm: One of the antibodies in the new proposal had been associated in another study with the emergence of unexpected new cancers.

Bruce recommended continuing Protocol 126 if and only if Martin established rigorous criteria to stop the experiment immediately if such problems occurred.

"The informed consent should at the very least indicate that some unexpected adverse effects have occurred," Bruce wrote. "The risk of fatality from an additional malignant process ... can hardly be overlooked in the statement of potential risk."

But the consent form wasn't changed. And there is no evidence the new review panel was ever told about the broader objections raised by its predecessor. The concerns Kennedy had raised about the role of T-cells in grafting and relapse were not addressed.

On May 26, 1983, the next stage of Protocol 126 was given a green light. The research doctors started looking for new patients to enroll.

Later that year, The Hutch's Board of Directors adopted a conflict-of-interest policy. It said scientists "shall not participate in any (research) involving the Center in which the member has an economic interest," including any form of ownership or any outside pay.

Hansen and Martin say they were never told about the policy. And even if they had known, they insist, their work at The Hutch had no bearing on business prospects at Genetic Systems.

The company was developing products to diagnose disease, they say, not to treat it. Given that, they say, the T-cell experiment could not possibly have benefited Genetic Systems or their stock.

Yet the company's own filings with the Securities and Exchange Commission from that period show plans to use antibodies to treat cancer. And Nowinski told The New York Times in 1983 that he expected to move from diagnosis to treatment.

The doctors' business partner, Blech - who was later convicted of securities fraud in an unrelated case - said in a recent interview that the big money was in treatment, and that was where Genetic Systems had planned to go.

Martin and Hansen insist Genetic Systems was not involved in Protocol 126. But Hansen was a full-time employee and director of Genetic Systems at the height of the trial. He is listed as a co-author of the study every step of the way; he participated in major decisions and tracked results.

Martin was working for a Genetic Systems official intimately involved with the conduct, results and funding of the experiment.

Further, the doctors' agreements with Genetic Systems obliged them to give the company the fruits of their research on company products, even if the company did not formally sponsor the research.

New panel raises questions

In September 1983, The Hutch signed up a new group of volunteers for the Human Subjects Review Committee, combining it with a similar group at Seattle's Swedish Medical Center, where Hutch doctors treated patients.

The committee was given a new title: the Institutional Review Board, or IRB.

Dr. Henry Kaplan of Swedish Medical Center, featured here on a Seattle Magazine cover, saw problems as soon as he was appointed chairman of an experiment-oversight board in 1983.

Dr. Henry Kaplan of Swedish, who would become one of the Northwest's leading oncologists, was appointed chairman. Dr. John Pesando of The Hutch was recruited to be a member. Pesando was reluctant because of the demands of his own research but agreed, hoping the volunteer work would help his chances of promotion.

Pesando says he and Kaplan "walked in and found problems everywhere we looked."

"These included unsafe ongoing protocols," Pesando said. "So we had double jeopardy of not only putting the brakes to new research, but trying to stop things that had already been approved."

The experiments that raised their eyebrows, and their concerns, the highest were the tests of new monoclonal antibodies.

Kaplan complained that antibodies were being used in "a completely uncontrolled fashion," and that animal testing had been insufficient. He wasn't told that similar objections had already been raised and ignored.

In one of his first acts as chairman, Kaplan wrote to Thomas asking about rumors that researchers had financial interests in a company that would use the findings from Protocol 126.

"What checks and balances are utilized to deal with potential conflicts of interest between academic and financial considerations of the staff?" he asked.

Thomas replied with a strongly worded letter denying any financial conflicts of interest and refusing the IRB's request to review each antibody separately for human safety.

"I think Committee members have not only an obligation to review the ethical aspects of this work, but also an obligation to assist us and not impede our research, which is directed toward solving some of those problems that are killing the children and young adults who come to us with fatal disease," he wrote.

In fact, the IRB had no such duty to assist research. Federal law gave the panel a single, pointed mission: "Protect the rights of the human subjects."

Nevertheless, Kaplan said he got a clear message from the future Nobel Prize winner who ran The Hutch. "It certainly didn't appear that we had the power to investigate anything once I got that letter from Thomas."

But what Thomas wrote was mild compared with some of what Pesando heard in the hallways. Thomas and others were enraged with the challenge to their research, Pesando said.

"[Dr. Edward Donnall "Don" Thomas (born 1920)] had a fearsome reputation," Pesando said. "You crossed him at your peril."

'Who the hell are YOU?'

IRB members felt unable to do a proper scientific assessment of Protocol 126. They felt they didn't have the information or the power to do their job.

Six weeks after Thomas' letter, Kaplan, on behalf of the IRB, asked Hutch President Dr. Robert Day to set up a new, independent body to consider the merits of all the monoclonal antibodies under study. The IRB termed them "entirely new, experimental drugs" which had not met normal safeguards.

Day refused to set up an outside panel, saying it would cost too much and reveal secrets to The Hutch's competitors.

Kaplan also contacted the National Institutes of Health for advice on how the panel could act, but got no help.

In January 1984, IRB members heard that two patients in the newest version of Protocol 126 had failed to engraft transplanted marrow. Normally, properly matched marrow was accepted 99 percent of the time, so these rejections were alarming.

They meant patients might actually die from their treatment before they would even reach the point where GVHD was a possibility.

Pesando started warning patients to stay out of the protocol. Some did; some did not.

Day summoned the senior clinical staff to a meeting with Kaplan and Pesando. Day would not curb the protocol or start an outside review. But he agreed to one demand: The lowest-risk patients, who had the most to lose from graft failures, would not be allowed to enroll in Protocol 126.

"We got something - granted, not very much, because we had no power - but we got the best patients out," Pesando says.

The research team did not appreciate those efforts. Pesando says Thomas asked him at a scientific staff meeting, "Who the hell are YOU to question what we do around here?"

Graft failures, relapses high

Death by leukemia occurs as cancer cells crowd out normal cells in the blood. Victims suffer infections, bleeding and oxygen deprivation.

Death by graft failure after a bone-marrow transplant is an accelerated but no less agonizing process. The victims, weak from Hiroshima-dose radiation and chemotherapy, fail to accept the marrow that could save their lives. They suffer all the effects of a destroyed immune system and die of infections and bleeding.

Graft failure is extraordinarily rare in normal cancer work, occurring 1 percent of the time in tissue-matched transplants between siblings.

But of the 20 people enrolled in Protocol 126 between June 1983 and March 1984, at least seven of them died from graft failure.

At least five patients suffered relapses of their cancers, which was also an unusually high rate, believed to be caused by the absence of T-cells to fight off stray cancer cells.

The dead included people who stood a good chance of being cured with standard therapy. Among them:

• Ruth Agnes Fisher, a Los Gatos, Calif., computer programmer. She was 38 years old when she learned she had leukemia.

It was a relatively mild form that could be bothersome but not fatal for many years. She also had a perfectly matched sibling donor for a bone-marrow transplant. With the standard treatment, she had a 60 percent likelihood of being cured.

But Fisher was enrolled in Protocol 126. Her bone-marrow transplant failed to engraft and she died of cardiac arrest on Jan. 27, 1984.

"The whole thing was sort of a blur," her widower, Joe Fisher, says today. "T-cells - I thought that's what makes the transplant work."

• Jacqueline Couch, 31, an attorney for the city of New York who lived in Summit, N.J. She, too, came to Seattle for a transplant with a relatively good prognosis. She, too, was signed up for Protocol 126.

She, too, died of graft failure almost certainly caused by the experiment.

Her brother, Richard Stanford Jr. of Yardley, Pa., who donated his marrow, says today, "For some reason - we were told the doctors didn't know why - it all of a sudden stopped producing cells."

No one ever told the family what went wrong. "It took me a long time to get over that," Stanford says.

• Lourdes Caridad Llera, 32, a homemaker from Tampa, Fla. She died in May 1984 after graft failure.
• Carolyn Sue Obermeyer, 37, a homemaker from Oldenburg, Ind. She died in September 1984 after graft failure.
• Lawrence Haspel, 48, a New York orthodontist. He died after graft failure and a second transplant attempt.
• Bina Bidasaria, 31, a homemaker from India. Ten months after a transplant with a brother's matched marrow failed to engraft, she tried a second, then died in Seattle a month later. Her widower, Mahavir Bidasaria, says he doesn't remember talking about T-cells and wasn't told why she had graft failure. "All those terms were not very familiar to us."
• Paul Mahler, 41, chairman of the anthropology department at Queens College of the City University of New York. He suffered graft failure, tried a second transplant after the first one failed and died in Seattle seven weeks after that.

The Seattle Times identified these people through death certificates and public records.

Fisher and Couch had been Pesando's patients for a time when he worked on the transplantation ward. Their deaths affected him deeply. He believed they could have survived a standard bone-marrow transplant.

In retrospect, Martin concedes the results of the experiment on chronic leukemias at that point were "awful."

"A lot of rejection, a lot of recurrent malignancy," he said in an interview. "And so it didn't work. It was a bad idea."

'Something's really fishy here'

The Hutch didn't have to report these patient deaths to the federal government. Experimental drugs that do not cross state lines are not regulated by the Food and Drug Administration.

The Hutch didn't alert the King County Medical Examiner, either, despite state and county requirements to report unexpected deaths associated with medical procedures.

Martin was required by federal and Hutchinson rules to report the deaths to the IRB, but he did not.

Inside the corridors of The Hutch and Swedish, however, word of the unusual deaths spread. And the drumbeat against Protocol 126 intensified.

Dr. Rainer Storb - the Hutch co-founder who had opposed the experiment from the start - says he spoke out in staff meetings time and again over the years.

"It was becoming evident on the wards that, you know, something's really fishy here," Storb recalls. "You have to have a very keen eye and bring the whole thing to a screeching halt if something goes wrong."

Storb had long been The Hutch's top expert on GVHD. In the same hallways and at the same time that patients were dying in Protocol 126, Storb was perfecting a better treatment against GVHD.

He had found that a combination of two FDA-approved drugs, methotrexate and cyclosporine, prevented GVHD and treated its effects.

Storb had started enrolling patients in his own clinical trial in August 1983, just as the most dangerous arm of Protocol 126 began.

He published his work in the New England Journal of Medicine. He had cut rates of acute GVHD from 54 percent to 33 percent and had raised the 18-month survival rate from 55 percent to 80 percent. He had had no problems with graft failures or relapse in 93 patients.

Storb came closest to a public attack on Protocol 126 when he cited it twice in passing in his New England Journal article, noting "survival rates that were poorer than those seen among patients who received untreated marrow."

Storb's regimen has stood the test of time. It remains the gold standard for treatment of GVHD to this day.

There is no evidence any Protocol 126 patient was ever told about the Storb treatment, even though its positive results had emerged. Instead, they were told there was no alternative to Protocol 126 to prevent GVHD.

It was a careful choice of words. Thomas' wife, Dottie, a program aide who helped with Protocol 126, argued in a memo that the Storb method was "treating" GVHD but only Protocol 126 was "preventing" it.

In the 1990s, The Fred Hutchinson Cancer Research Center moved to a new campus at South Lake Union, 1100 Fairview Ave N., which it built for more than $150 million.

THE FRED HUTCHINSON Cancer Research Center in Seattle has saved thousands of lives in its 25 years of existence.

The Hutch performs about 450 bone-marrow and stem-cell transplants a year on patients whose cancers were once thought to be incurable.

It is the largest bone-marrow-transplant center in the world, and, in the words of leukemia experts such as Dr. Richard Shadduck of Pittsburgh, it is "the Mecca."

"Everyone would agree the Seattle program took off not only numerically but scientifically and blazed trails in the field," he said.

The taxpayers have helped: The Hutch leads the nation in funding from the [National Cancer Institute] - a notable achievement for a place specializing in blood cancers, which account for just 10 percent of the new cancer cases in the United States each year.

The Hutch received $69 million from the NCI in fiscal 1999 (the latest figures available) - more than Johns Hopkins, Sloan-Kettering, M.D. Anderson or any other well-known cancer center.

In all, The Hutch got $142 million in 2000 - about two-thirds of its total revenue - from the federal government. Of the remainder, about $40 million comes from patient fees, $25 million from direct public support and $12 million from other sources.

• Fred Hutchinson Cancer Research Center :

  • • Established: 1975

    • Employees: 2,300

    • Volunteers: 1,400

    • Clinical Research Division staff: 943

    • Budget: $204 million

    • National Institutes of Health grants (2000): $142 million

The center is named for a former major-league baseball player and manager from Seattle who died of cancer in 1964. Fred Hutchinson's brother, Bill, a Seattle surgeon, knew U.S. Sen. Warren Magnuson of Washington, the longtime chairman of the Senate Appropriations Committee. Magnuson pushed through a $5 million grant, and The Hutch was on its way, opening in 1975.

It is one of 38 federally designated Comprehensive Cancer Centers in the United States and the only one in the Northwest.

Over the years, The Hutch has spawned seven major biotechnology companies, including [Immunex Corporation] and Cell Therapeutics, making Seattle the nation's fifth-largest biotech center by employment.

In the 1990s, The Hutch built a new campus at Seattle's South Lake Union for more than $150 million.

In 1998, The Hutch, Children's Hospital & Regional Medical Center and the University of Washington formed the Seattle Cancer Care Alliance, described as "the new front door to comprehensive oncology services in the Pacific Northwest." The alliance's seven-story outpatient clinic was built next door to The Hutch.

The Hutch is also becoming a leading center for stem-cell transplants, a safer procedure in which immature cells that give rise to other blood cells are used instead of bone marrow to rebuild the body's immune system after massive chemotherapy and radiation.

The procedure left two-thirds of patients cancer-free after two years, compared with 45 percent of bone-marrow patients, according to a Hutch study recently published in The New England Journal of Medicine.

Dr. William Bensinger, director of the study, said stem-cell transplants could help thousands of patients worldwide who are treated for blood cancers, especially those with advanced disease.

In addition, Dr. Rainer Storb is preparing a paper about a revolutionary new "minitransplant" that activates the body's own immune reaction to attack cancer. The procedure can be done at low cost without hospitalization, and Storb is reporting remarkable preliminary results.

The center's mission is vast and simple: "eliminating cancer as a cause of human suffering and death."

FOR NEARLY two decades, Dr. John Pesando sounded the alarm over what he saw as a dangerous and unethical human experiment at Seattle's Fred Hutchinson Cancer Research Center.

In the 1980s, he complained from the inside: As a member of an oversight committee at "The Hutch," he repeatedly objected to the clinical trial in which leukemia patients were dying at unusually high rates.

In the 1990s, he complained from the outside: In letter after letter - to members of Congress, to federal and state agencies, to newspapers - he said "many good people needlessly lost their lives" in the leukemia experiment, which lasted from 1981 to 1993.

"Trusting, desperate human beings were used as laboratory rats," he wrote to state authorities in 1994. "One should not assume that these patients would have soon died anyway because they had cancer, and that it was therefore not possible to do any harm. Many of these patients were correctly told that they could expect cure rates of approximately 50 percent (with standard treatment) ...

"Real people lost their lives, and there was no way to stop it."

For the most part, Pesando was received as Hutchinson Center officials have portrayed him: a disgruntled former employee with an ax to grind. But a Seattle Times investigation supports most of his allegations and finds his concerns shared by some of the most respected cancer doctors in the Northwest.

Seventeen years passed between the time Pesando and other doctors first objected to Protocol 126, as the experiment was labeled, and yesterday's revelations in The Times of deaths, misleading assurances and potential financial conflicts surrounding the experiment.

In those years, the doctors' complaints were largely rebuffed, rejected or ignored. Finally, under incessant pressure from Pesando, they were taken up by federal and state agencies but never fully investigated.

Underlying all of this, Pesando and other doctors believe, was a reluctance to challenge an institution as respected and powerful as the Hutchinson Center. That reluctance was all the greater because one of the people behind Protocol 126 was Dr. E. Donnall Thomas, a Hutch co-founder and co-winner of the 1990 Nobel Prize in Medicine.

As Pesando puts it: "They were all afraid of taking on the 800-pound gorilla."

Experiment already under way

John Pesando came to Seattle and The Hutch in 1982 as a 36-year-old magna cum laude graduate of Harvard University with a medical degree and Ph.D. from the Albert Einstein College of Medicine in New York. Pesando was board-certified in oncology and internal medicine; his research focused on tumor immunology. He had taught at Harvard and had worked for four years as a cancer doctor and researcher at the Dana Farber Medical Center in Boston.

At Harvard, Pesando had discovered an important antibody marker in tracking and treating leukemia, and conducted the first-ever clinical trial with a monoclonal antibody, treating five leukemia patients.

He was recruited to The Hutch by one of its co-founders, Dr. Rainer Storb. Soon after joining the staff, Pesando was asked by his bosses to serve on the Center's Institutional Review Board.

That board was required by federal law to review all proposed human experiments at The Hutch. Its members were to ensure that risks to patients were minimized in relation to potential benefits, and that patients fully understood those risks before agreeing to participate in clinical trials.

Pesando was reluctant to take on the unpaid duty of policing his colleagues, some of whom were in a position to affect his future. But he believed deeply in the need for such policing, he says, so he swallowed hard and served.

Also joining the review board was a new chairman, Dr. Henry Kaplan, from Seattle's Swedish Medical Center, where some Hutch patients were treated. He is now one of the Northwest's most highly regarded oncologists.

From their first days on the board together, Pesando and Kaplan were concerned about Hutch researchers using unproven new antibody drugs.

In Protocol 126, researchers were testing antibodies to see if the elimination of certain cells in the blood, called "T-cells," would make bone-marrow transplants safer. The researchers theorized that killing off the T-cells in the marrow of donors before injecting it into patients would help stave off a troublesome complication known as graft-versus-host disease, or GVHD.

The experiment was directed by Don Thomas; Dr. John Hansen, head of a tissue-matching lab and later clinical director; and Dr. Paul Martin, a young oncologist. The trial was funded by the National Cancer Institute.

From the time the experiment was first brought to the oversight committee early in 1981, some committee members had challenged it, saying:

•The science behind the experiment was dubious. While mice benefited, some felt there had been inadequate prior research on dogs before moving on to tests in humans.
•Some thought T-cell removal might actually prevent donated bone marrow from engrafting, or taking hold in the recipient's bones, and some thought it might open the way for the return of the cancer.
•While GVHD was bothersome and uncomfortable, it was seldom fatal. And the proposed subjects of Protocol 126 - those with siblings whose tissue type matched theirs - were the least likely to get it. Besides, there were other ways to effectively treat GVHD.
•Unlike most cutting-edge medical research, Protocol 126 proposed experimenting on the healthiest, rather than the sickest, patients. Committee members saw no need to subject those patients to undue risk.
•The "informed-consent" form for the experiment - the required document outlining risks for patients - was misleading.

Despite all these concerns, the previous oversight board had approved the experiment in April 1981. By the time Pesando and Kaplan joined the board, the experiment was well under way.

Financial conflicts of interest

Within their first few months on the Institutional Review Board (IRB), the new members suspected that Protocol 126 wasn't working. Patients enrolled in the experiment were dying - including some people who otherwise would be expected to live.

Kaplan and Pesando raised many of the same questions their predecessors had on the medical and scientific aspects of the experiment. They received lots of assurances but no answers.

Meanwhile, a new concern emerged: Rumors were rampant in hospital hallways that the researchers - Thomas, Hansen and Martin - all had financial interests in Genetic Systems, the Seattle biotechnology company that owned rights to some of the drugs being tested in the experiment.

When Kaplan asked Hutch officials about the rumors, he was told the researchers had no financial conflicts. What he was not told was that not only did those researchers all hold stock in Genetic Systems, they all held advisory or actual working positions with the company. Nor was he told that The Hutch itself had stock in Genetic Systems.

"We didn't even know which investigators were connected with which companies," Kaplan recalls now. "We never got the opportunity to ask about the decision-making process. I guess the fair thing to say was John (Pesando) was absolutely convinced there was a problem, and the rest of us thought there was enough to raise questions about. They were not answered satisfactorily in the time I was on the board."

Meanwhile, the early stages of Protocol 126 were proving a failure, and patients were dying - some, apparently, as a direct result of the experiment. Among the dead were two patients Pesando himself had treated.

When their two-year terms on the Institutional Review Board ended in 1985, Kaplan and Pesando were told again by the president of The Hutch, Dr. Robert Day, that their concerns about both medical and ethical problems with Protocol 126 would soon be addressed.

They trusted that assurance, and went on to focus on their careers. Kaplan built one of the most successful private oncology practices in the Northwest; last year, he was the cover subject of a Seattle Magazine feature entitled "Top Doctors."

Career hits a snag

Pesando, meanwhile, went about trying to land a long-term position doing cancer research at The Hutch. That didn't happen. In 1987, his contract expired and was not renewed. Storb says Pesando "didn't work out. He was removed by Don (Thomas) for a number of reasons. I agreed with them. He was not an active member. He led a sheltered life. He was very paranoid about sharing data. He didn't bring in grants. He left under poor circumstances."

Pesando has another explanation: his run-ins with Thomas and the other people behind Protocol 126. He recalls Thomas confronting him after one particularly tense session, barking: "Who the hell are YOU to question what we do here?"

(Thomas refused to be interviewed by The Times for the articles running this week.)

Pesando doesn't deny that he struggled at The Hutch. He says that was because he was unable to get support from his bosses for research he proposed.

He tried unsuccessfully for a time to find a good position elsewhere in his specialty areas of leukemia and lymphoma - "They (would) go to The Hutch for recommendations" - then decided to take another path. He began working as a consultant for the Social Security Administration and for biotechnology companies.

He and his wife settled into a hundred-year-old Victorian home on Capitol Hill and raised their daughter.

Over the years, Pesando tried to put Protocol 126 out of his mind. He might have succeeded, had he not picked up a book entitled "Magic Bullets" in 1991. In it, Seattle author Grant Fjermedal describes the invention of new antibodies to seek out and destroy cancer.

Among the companies Fjermedal wrote about was Genetic Systems. He outlined the company's relationship with The Hutch and its doctors, and quoted Day, Hutch president, on why such financial interplay was a positive factor in medical research, not a negative.

Pesando was incensed to see this apparent confirmation of what he and Kaplan had suspected all along: that Protocol 126 was driven not only by science but also by money. And Day's position was a signal that nothing had changed.

Pesando contacted Fjermedal, a longtime science and medical writer, who was struck by Pesando's knowledge of the situation and by his passion.

"What you've got in this guy is a rarity," Fjermedal said in a recent interview. "You've got somebody who has the credentials. He's seen all this, he's on the inside, and he's coming forward. That's very, very rare."

Fjermedal encouraged Pesando to take his complaints to the proper authorities.

For the rest of the decade, that's precisely what this lonely warrior did - only to be repeatedly frustrated.

Federal agencies take a look

Pesando began firing off letters in various directions in 1991. He wrote to members of Congress, to federal and state agencies, even to The New York Times.

Finally, a letter to the federal Office of Protection from Research Risks (OPRR), a unit of the Department of Health and Human Services, caught someone's attention.

"Basically," Pesando wrote, "senior clinicians at the Fred Hutchinson Cancer Research Center in Seattle conducted clinical trials with high therapy-induced mortality rates while they were major stockholders in the company with commercialization rights to those therapies."

Admitting to feeling "much anger," Pesando concluded, "The seriousness of this issue and its implications for future patient care continue to make it very difficult for me to take the expedient course of doing nothing."

In May 1993, the OPRR opened an investigation of the case. Thomas Puglisi, chief of the agency's compliance department, assigned investigator Kamal Mittal.

Mittal got Pesando's permission to use his name, and three months later, sent a copy of Pesando's letter to Day, the Hutchinson Center president.

Two months after that, Day responded with a 24-page letter and 2-inch stack of attachments. In that package, he defended The Hutch and its researchers vigorously.

He insisted that a successful outcome to Protocol 126 would not have benefited Genetic Systems or its stockholders - ignoring the fact that some of the chemicals being tested were licensed to Genetic Systems, and that the very existence of the experiment had increased the company's value.

He insisted that any risks "were fully disclosed to and discussed with the patients." However, the consent form underplayed the risk of graft failure and failed to mention the likely outcome - death - if a second transplant were necessary.

He insisted that the IRB had the power to address any concerns - ignoring the fact that Pesando and Kaplan had pushed for an outside review.

And he insisted that concerns about conflicts of interest "were addressed promptly" by a policy adopted by the Hutch Board of Trustees in March 1983. That policy barred employees from participating in research in which they or a family member had an economic interest of any type. However, the policy was not enforced and resulted in no changes in Protocol 126. In fact, Hansen and Martin say they were never told about it.

(Day, who retired as Hutch president in 1997, refused to be interviewed by The Times for the articles running this week.)

The Hutch also hired the best medical-ethics defense lawyer at the then-biggest law firm in Washington, D.C.: Barbara Mishkin of Hogan & Hartson, who phoned Puglisi and met with Mittal briefly.

Pesando had no opportunity to respond to Day's claims. He called the OPRR several times to offer help and information but never heard back.

Frustrated, he went to the top, writing to Health and Human Services Secretary Donna Shalala. The result: more frustration.

Pesando did receive a response, from Wendy Baldwin, acting deputy director for extramural research at the Public Health Service. Baldwin wrote that she recognized "the very serious nature of the issues you have raised" and promised to review the case.

But that promise was an empty one, e-mail released to The Times under the Freedom of Information Act shows.

That e-mail, between Puglisi of the OPRR - the actual author of the letter signed by Baldwin - and Dr. George Galasso of the National Institutes of Health, indicates that top federal officials had already decided there was "nothing wrong" with conflict-of-interest issues in Protocol 126. An e-mail from Galasso suggests they send it to another office as "sort of CYA (cover your ass)."

Investigation is dropped

Meanwhile, other federal documents show, the primary investigator, Mittal, was far from convinced there was no problem. He had several pointed questions he wanted to ask Hutch officials:

• Did the IRB feel compromised or strong-armed?

• Was the risk/benefit ratio in favor of the patients?

• Were patients fully and correctly informed of risks?

• Did the doctors violate the conflict-of-interest policies? (Mittal added: "Answer appears to be yes!")

• Was it proper to develop products with federal funds that would profit a private company and doctors?

"To get answers to these questions, it may be necessary to arrange a site visit to speak with various individuals including the members of the IRB at the time period in question," Mittal wrote.

But then Mittal, who'd been brought in as temporary help, asked to be transferred to another job and was removed from the case.

"I left it almost in the middle," Mittal recalls.

Pesando's complaint lay untouched in Washington, D.C., for a year after that.

"It was just a matter of our workload being overwhelming at the time," Puglisi said.

The OPRR was absorbed in a fertility-clinic scandal in California. It was chronically understaffed. At one time it had about 70 open investigations being conducted by one full-time professional staff member and two or three part-timers, the House Committee on Government Reform found.

Eventually, Pesando and Day both wrote, separately, to ask for a progress report. Puglisi assigned a senior staffer, William Dommel, to write a report based on information in the file, nearly all of it provided by The Hutch.

That report, dated Sept. 5, 1995, and signed by Puglisi, concluded that the complaint was "unsubstantiated" and that The Hutch was not at fault since its own Institutional Review Board had failed to stop the activities. The OPRR blamed the Hutch IRB for not doing more to stop the study.

The federal investigators never interviewed Pesando or Kaplan, both of whom had tried to stem the study, or any other IRB members.

They never interviewed Thomas, Hansen, Martin, Day or any other Hutch officials.

They never interviewed any of the families of the trial subjects.

They never asked for a single tape of a single IRB meeting, nor ever spoke with a single outside expert on the risks of T-cell depletion and second transplants.

Pesando was stunned.

He wrote again to HHS Secretary Shalala and to Harold Varmus, director of the National Institutes of Health. Steam rose from his rhetoric.

"In late 20th century America, prominent physicians at a major cancer center knowingly risked the lives of unsuspecting patients in pursuit of financial gain, successfully bypassed regulatory bodies, and repeatedly silenced opposition. ... Yet there could hardly be less concern if laboratory rats had died instead."

He called the investigation "arrogant, chilling and totally unacceptable."

Shalala and Varmus never replied. Baldwin of the Public Health Service wrote to Pesando on their behalf.

"After careful examination of the OPRR's findings, I am convinced that the investigation was exhaustive and conducted with objectivity and due consideration for the rights and welfare of human subjects involved in research," Baldwin wrote.

A fax obtained by The Times, however, suggests there was no such "careful examination" by Baldwin. Instead, it shows that Dommel - the very person who wrote the findings about which Pesando was complaining - had drafted the response for Baldwin to sign.

Pesando wrote to Varmus again: "The NIH's handling of this matter suggests that it was afraid of finding something, and the profound apathy of those at the top to misconduct in the field helps to explain why such problems exist."

This time, Pesando got no response.

State panel takes on the case

While he was waiting for Washington, D.C., to act, Pesando took his crusade to Washington state officials.

He wrote to Dr. Larry Bryce, chairman of the state Department of Health's Medical Quality Assurance Commission, in December 1994, repeating his complaint:

"In essence, financial conflict of interest led to highly unethical human experimentation which resulted in at least two dozen patient deaths. Oversight committees were misled, lied to, and kept uninformed while in an atmosphere of fear and intimidation ...

"I have done my part, and more, to correct this problem. I would like to see someone else show some interest."

The state commission showed some interest in the complaint but decided to wait for the federal findings.

Nine months after federal officials dropped the case, the state opened its own investigation. In June 1996, a year and a half after Pesando's filing, the case was assigned to Dr. Robert Miller, physician staff member of the state commission, and investigators James Smith and Bill Crowell.

Their investigation went much further than the feds' had. They interviewed Hutch officials, Kaplan and Pesando.

Kaplan had forgotten many details of his own role by then. For instance, he said he wrote one letter of objection, rather than the three The Times has found, and received just "a one-sentence letter of reply" from Thomas, rather than the lengthy missives Thomas, Day and Dr. Frederick Appelbaum, head of The Hutch's clinical-research division, sent him in the mid-1980s.

The state investigators didn't interview the researchers involved but obtained written statements from Thomas and Hansen.

Thomas' letter, marked "CONFIDENTIAL," was his only written response since the flat denial of conflict in 1984.

"The decision as to whether or not these studies should or should not continue was not made by me," Thomas wrote.

Storb and Pesando say Thomas, though technically not a member of the review panels, was influential in continuing the studies.

"I have never exposed any patient to treatment risks for reasons which were not ethically and medically appropriate, and I did not do so in the matter into which you are inquiring," Thomas wrote.

In his letter, Hansen noted he was not the principal investigator on Protocol 126, and in fact had "no involvement" in it while working for Genetic Systems.

However, Hansen was named as the second author in several papers on the clinical trial. He was Martin's mentor and supervisor. And he received copies of all the key correspondence from The Hutch even while he was working at the private company holding commercial licenses for the antibodies.

In September 1997, with the case still unresolved, Miller left the state Medical Quality Assurance Commission and its investigating team.

With his departure, this investigation died.

The commission closed the complaint, citing "no cause for action," in January 1998, three years after Pesando's letter.

Miller says he was "saddened and alarmed" by the lack of follow through.

At a minimum, he said in an interview, the commission should have acted on ethical violations by Thomas and Hansen for influencing a study of materials licensed to the company in which they owned stock.

"To me, what Dr. Thomas did and the other doctor did was a clear conflict of interest," Miller said in an interview. "I think that's a pretty obvious, well-known ethical principle."

Dr. David Williams, an internist who chaired the state Medical Quality Assurance Commission at the time, was one of two doctors who personally reviewed the case. He says now that he, too, was not satisfied with the outcome.

"There still remained some doubt in our mind," he said. "I was never truly satisfied that the protocol had been written in a manner that was truly appropriate."

'Just trying to do our duty'

Through it all - unresponsive bureaucrats, half-baked investigations, patronizing letters - John Pesando, now age 55, persisted. He was both haunted and motivated, he says, by the memory of two of his patients who died in the experiment - Ruth Fisher, a 40-year-old computer programmer from California, and Jacqueline Couch, a 32-year-old lawyer for the city of New York.

He took it personally when people died on his watch and when he was, in his view, pushed out of The Hutch for raising his voice in favor of ethics and patient safety.

His quixotic quest both frustrated and frightened his wife, Patricia, who worried about his reputation.

But he kept pushing. Pushing until he got the attention of reporters at The Seattle Times, who took up the investigation.

Survivors of patients who died in Protocol 126 are grateful for that persistence.

Pete Wright of Heflin, Ala., whose wife, Becky, died in 1987, said: "I might slough this off to sour grapes if I didn't know Dr. Pesando. But I have nothing but respect for him."

Wright says that while caring for his wife, Pesando never talked about conflicts of interest or research misconduct, though he did try to talk them out of enrolling in the experiment on medical grounds.

"We were not looking for trouble," Pesando said. "We were just trying to do our duty and take care of patients."

Dr. John A. Hansen kept about $10 million stock and broke conflict-of-interest policy

Dr. E. Donnall Thomas took stock worth $5 million today, if he kept it, which he won't say. Donated the $350,000 for his Nobel Prize to The Hutch.

Dr. Robert Nowinski started three big biotechs. Sold one to Bristol-Myers for $295 million.

Dr. James Bianco owns $5.1 million stock after two products flopped then a third took off.

THE INTERNATIONAL reputation of Seattle's Fred Hutchinson Cancer Research Center was forged with a courageous and sometimes defiant approach to conventional medicine.

It was built by doctors empowered to try new weapons against cancer, even if it meant some patients might die sooner than they would have with conventional treatments.

The center's most respected researcher, Dr. E. Donnall Thomas, won a Nobel Prize for persevering on bone-marrow transplants despite the doubts of peers and the deaths of patients. In his seminal work between 1969 and 1974, he performed bone-marrow transplants on 54 cancer patients. Forty-eight died, but six lived.

In the quarter-century since, "The Hutch" has continued to improve those methods, which have saved thousands of lives around the world.

But now, in the wake of articles in The Seattle Times this week, some doctors, medical ethicists and patient advocates are questioning whether the swagger that put The Hutch on the map in the 1980s and '90s has created a culture that is unduly insulated from public accountability.

The Hutch's approach to ties with industry, its policies on financial disclosure and its stance on public access to its activities, while not unique, differ significantly from those at some other respected institutions.

The result: a system in which patients pondering whether to enter a clinical trial may have little information - and little choice but to trust the center, even when financial connections might raise legitimate questions about the experiments on which they're betting their lives.

"The issues that are raised in this (series), whether they occurred 10 years ago or today, are of critical importance in our system of human research," said Dr. Greg Koski, director of the federal Office for Human Research Protections.

Nowhere is the combined success and secrecy of The Hutch so plain as in its partnerships with biotechnology companies.

As The Times has outlined, the center and many of its doctors, including Thomas, have linked their research to the for-profit business world of biotech, spinning off private companies worth more than $18 billion today and producing some $100 million in personal wealth.

Those financial relationships create the potential for conflicts of interest in the conducting of human experiments. But patients and the public have had little opportunity to even ask such questions, let alone to have them answered.

The lack of openness has been highlighted this week in The Times' investigation of two failed clinical trials in which patients died prematurely. In both experiments, The Hutch and its doctors had financial connections to some of the drugs being tested. Patients were not told of those ties, nor were they fully informed of the experiments' risks.

In one of the experiments, at least 20 patients died from causes attributable to their treatment; some of them would have likely lived a full life with conventional treatment. In the other, at least four died from their treatment.

The newspaper was led to one of these clinical trials by a doctor who had been on the inside as a member of a Hutch internal review board, and to the other by the son of a woman who died from treatment.

Whether other clinical trials at The Hutch - including those that are ongoing - have had similar issues is unknown. The Hutch operates in extraordinary secrecy - justified in the name of commercial confidentiality, grown from its maverick roots.

Dr. Howard Shulman, a pathologist in the clinical division at The Hutch, says he and others have questioned whether the center should have such close ties to companies. But Shulman said he was told by Dr. C. Dean Buckner, an original member of The Hutch: "We lost our virginity a long time ago."

Partnerships with business

Supporters say partnerships with business provide incentive, reward and seed money for innovative medical research. But numerous academic studies show that medical research may be impacted, at least subconsciously, by private financial incentives.

In a 1986 article in The New England Journal of Medicine, Dr. Richard Davidson analyzed reports on drug trials in five leading medical journals. He found that when drug companies sponsored the trials, researchers were significantly more likely to favor the drugs being tested.

Dr. Marcia Angell, editor of the prestigious journal, warned last year of "a Faustian bargain" when research centers "make available their precious resources of talent and prestige to carry out research that serves primarily the interests of the companies."

Angell asked, "How can they justify rigorous conflict-of-interest policies for individual researchers when their own ties are so extensive?"

The Hutch won't disclose financial connections of its research doctors or of the center itself. It won't say what stock it owns. It won't say what experiments it is performing for the companies whose stock it owns. It won't say what inventions and patents it is licensing to those companies, or for what prices.

To do so, Hutch President Dr. Lee Hartwell says, could violate confidentiality agreements with private companies.

Several clinical researchers at The Hutch who hold patents have written about their discoveries without disclosing their financial interest in print, a Times review of more than 1,000 medical journal articles has found.

Some journals require such disclosure, and Johns Hopkins University, among others, requires all of its researchers with financial interest to publicly disclose them.

The Hutch does have a policy regulating conflicts of interest, but that policy has been weakened over the years.

In 1983, during Protocol 126 - one of the experiments described in The Times earlier this week - the policy said no Hutch scientist could participate in any study or patient care in which he or she had any outside interest.

That policy was not enforced in the case of Protocol 126, as all three of the researchers had ties to a company that owned licensing rights to some of the drugs being tested.

Today, the policy says only the "principal" investigator must avoid financial holdings that can be affected by the experiment.

Other researchers involved in studies and patient care can hold interests in private companies whose products they are testing as long as they report them to Dr. Fred Appelbaum, the director of clinical research. There is no limit on the amounts they may own - and no required disclosure to the subjects of their experiments.

Appelbaum says fewer than 10 percent of the clinical doctors at The Hutch have had conflicts. He says he has had to "manage" three or four situations. Citing privacy, he won't talk about details.

Some have stricter rules

The Hutch's current policy matches a 1994 guideline by the National Institutes of Health, and many research centers nationally have similarly loose restrictions.

But some major centers - among them Harvard University, Johns Hopkins University, UCLA, the University of Minnesota, the University of Kentucky, the University of Nebraska and even a Hutch partner, the University of Washington - are tougher.

To begin with, a few of them require research doctors to tell patients when they have private financial interests.

"It's the appropriate thing to do," said Steve Peckman, associate director for human-subjects research at UCLA. "If an investigator has an interest in the product or the company sponsoring the study, any reasonable subject would probably want that information."

A typical disclosure might say, "Dr. Smith received payment from Jones Company, sponsor of the study, for giving presentations."

Hartwell, Hutch president, says, "It's such a complicated issue that I'm not sure it makes sense to ask a patient to decide whether that's relevant or not. I don't think that's the way to handle it. I think the way to handle it is for the institution to be sure that no financial interest has an opportunity to have an influence on the outcome of the study."

The University of Washington Medical School, which works closely with The Hutch, doesn't give such information directly to patients. But unlike The Hutch, the UW does make its corporate sponsors, licensing deals and medical professors' reports of outside income available as public records, available on request.

Harvard Medical School flatly prohibits faculty from owning more than $20,000 in stock in companies whose products they are testing. Harvard reaffirmed the strict policy last year despite warnings it could lose some star faculty who wanted to make more money.

New York's renowned comprehensive cancer center, Memorial Sloan-Kettering, has far fewer spinoffs and potential conflicts of interest than The Hutch, despite having a faculty five times larger.

"Our board is very conservative," Senior Vice President James Quirk explained. "They're still concerned about what (private work) does to the faculty, meaning does it divert their attention from the work they do here."

While The Hutch has spawned more than a dozen private biotech companies, only one has spun out of Sloan-Kettering. Quirk said it was started because no vendor stepped forward to market a vaccine the hospital needed.

Sloan-Kettering requires all scientists to report potential or actual conflicts of interest internally. Quirk says only two scientists in 18 years have exceeded the limit of $10,000 or a 5 percent interest, and neither was in the clinical division, where human experiments are conducted.

Sloan-Kettering hasn't had institutional conflicts of interest with owning biotech stock, Quirk says, because it rarely asks for stock and always sells it fast.

"We feel it's cleaner," he said. "It's much easier for somebody who would ask you, `Do you have stock in that company?' We say, `Absolutely not.' "

Hartwell, meanwhile, says The Hutch should get more, not less, stock from biotech companies with which it is involved.

The Hutch sold $50 million in stock between July 1998 and July 1999, taking $3.6 million in profits, an IRS report shows. The center apparently acquired other stock and was left with about $40 million in corporate securities. It has repeatedly refused to discuss its stock dealings.

Rosetta Inpharmatics, a $250 million company co-founded by Hartwell and Dr. Stephen Friend, gave The Hutch 352,000 shares of stock for a licensing and research deal. Hartwell, hearing grumbles in the hall, gave The Hutch his own 283,200 founder's shares to avoid a personal conflict of interest.

The role of the review board

Hutchinson doctors today give two levels of scientific review to clinical trials and say they spend at least two hours with each prospective patient. But the primary safeguard against ethical and medical problems at The Hutch remains its Institutional Review Board.

The IRB, as it is known, is required by law for federal funding of any medical experiment involving humans.

Each month, two groups of about 10 people gather around tables in the E. Donnall Thomas Building on the Hutch campus.

Before each of the members is an imposing packet of papers stamped "confidential." The packets can't leave the room. They are carefully collected at the end of each meeting.

Inside are the details of 25 or so medical experiments on human beings. Five or six are new; the rest are ongoing.

The IRB's job is to ensure that subjects of medical experiments are treated in an ethical and humane manner, are fully informed, and that the potential benefits of the experiment outweigh the risks. It's a daunting task.

Waiting to speak to them are the center's most respected doctors - the ones who bring in millions of dollars in grants.

Down the hall is Dr. Thomas, a living legend who at 80 still works part time in an office in the building named in his honor.

The IRB members are all unpaid volunteers. The Hutch keeps their identities secret, but they include a housewife with a science background, a human-resources consultant, an attorney, a finance officer at a research institute and a risk-management expert. The others are doctors, nurses and pharmacists.

One former IRB chairman said the board was tough when going over patient informed-consent forms. For instance, "We made sure not to have polysyllabic words when a monosyllabic would do." But he refused to be quoted by name or to answer further questions unless, he said, The Times got a court order.

Center spokeswoman Susan Edmonds has for months refused to say who sits on the IRB. "We have nothing to hide," she said, asserting that members want to keep their identities secret to avoid being bothered by reporters' calls.

The Times did learn that two board members designated as "nonaffiliated community members" - which the federal government requires - were, in fact, being paid by The Hutch to perform legal work.

Suzanne Kelly Michael sat on the IRB from 1994 to 1998. Court records show Michael represented The Hutch in a major lawsuit in 1997 and 1998, while she was on the IRB.

Asked about that, Michael said that when she joined the board, she didn't personally work for The Hutch, though her firm, Lane Powell Spears Lubersky, did. The Hutch refuses to say how much Michael or the firm was paid during the time she sat on the IRB.

Paul Nordsletten replaced Michael in July 1998 as the "nonaffiliated" member. He works for The Hutch as an attorney on employment cases.

"At least in my own mind it's never made a difference because the two things are so different," he said, adding, "My work for them is sometimes very substantial and other times is not." Nordsletten lists The Hutch first among his clients in a lawyer directory.

After The Times raised questions about these lawyers' work as "nonaffiliated" members of the key review board, IRB administrator Karen Hansen said she asked all members of the IRB to study the statement of nonaffiliation and to report any problems. Hansen said the two lawyers then did so. She said some other people were "close" but not disqualified.

Helen McGough, IRB administrator for University of Washington research, where names of IRB members are public, said the UW "would not consider a person who has any financial relationship to be a nonaffiliated member." The purpose is to be "an outsider to the institution,'' she said.

At The Hutch, not only are the IRB's meetings closed, but also the meetings of the center's Board of Trustees. Although 68 percent of the center's funding - $140 million last year - comes from taxpayers, Hutch officials say they feel no legal or ethical obligation to open the meetings.

That attitude, and The Hutch's insulated approach, should be reassessed by its leaders, said Mary Faith Marshall, director of the program in bioethics at the University of Kansas Medical Center.

"I hope that approach will change," said Marshall, who is chairing the National Human Research Protections Advisory Committee, a blue-ribbon panel looking at such issues at research centers across the country.

"The model should be one of transparency. There should be no secrets."

IT'S BEEN MORE than a half-century since horrifying human experiments by the Nazis prompted the first code of ethics for medical research. Yet enforcement of ethics today remains largely an honor system.

On the agenda

Here's what's on the agenda in the national effort for reform of medical research:

• Sunday through Tuesday: Medical Research Summit, a privately sponsored forum in Washington, D.C., for industry and regulators, on the regulation and ethics of medical research in the U.S.

• April 9-10: Second meeting of the National Human Research Protection Advisory Committee, a panel appointed by then-Secretary of Health and Human Services Donna Shalala.

• Late April or early May: one or two days of hearings on human research and financial conflicts of interest, by a subcommittee of the U.S. Senate Commerce Committee.

In this country, government regulators leave it to research centers to police themselves. And even when regulators learn that rules have been broken, they rarely mete out stiff punishments.

This has led to inconsistent, lax standards - and, sometimes, patients dying in questionable experiments.

Birth defects caused by the drug thalidomide, prescribed without patients always being told it was experimental, led in 1962 to the first U.S. law requiring informed consent for medical research. A decade later, news that 399 black men in Tuskegee, Ala., had been deceptively denied treatment for syphilis as part of a government experiment ultimately led to major reforms.

Yet the system still has serious flaws.

"Unfortunately, because the current system of protections has, in large measure, been cobbled together in the wake of abuses, it is both more cumbersome and less effective than it must be both to support research and protect participants," the National Bioethics Advisory Commission, appointed by then-President Clinton, said in a recent report.

But critics fear that pharmaceutical and biotechnology companies, which pay for much medical research these days, will be able to thwart major reforms. Abbey Meyers, president of the National Organization for Rare Disorders, expected few results from the myriad commissions and studies calling for changes.

"I think we're probably headed toward another catastrophic event like a Tuskegee experiment" before that will happen, Meyers said.

'The science has been lost'

Of particular concern these days is the relationship of physician-researchers and their medical centers to for-profit companies.

Since Congress in 1980 made it much easier for universities and researchers to cash in on their discoveries, "the science has been lost in the rush for money," said Dr. Thomas Bodenheimer of the University of California, San Francisco, who decried this trend in The New England Journal of Medicine.

Momentum to reform conflict-of-interest rules has grown since the highly publicized death of a young man in a clinical trial at the University of Pennsylvania.

Eighteen-year-old Jesse Gelsinger agreed to participate in a gene-therapy trial even though it offered him no benefits. He slipped into a coma after being infused with a gene-therapy substance and died four days later on Sept. 17, 1999.

Unknown to Gelsinger, the researcher, Dr. James Wilson, owned 30 percent of Genovo, whose gene-therapy substance he was testing. Wilson reportedly made $13.5 million when the company was later sold to Targeted Genetics of Seattle.

Gelsinger's death has prompted many universities and medical-research centers to rethink their financial-conflict policies. Most follow federal rules requiring researchers to disclose financial conflicts to someone in administration, but none ban such conflicts outright.

Critics worry, too, that financial conflicts are compromising the validity of medical research.

"Teaching hospitals and medical schools are becoming increasingly compromised in that they are behaving like research outposts for the pharmaceutical industry," said Marcia Angell, former editor in chief of The New England Journal of Medicine.

A report in The New England Journal said 96 percent of studies in medical journals advocating the use of heart and blood-pressure drugs called calcium-channel blockers were funded by the drug manufacturers. Only 37 percent of the studies critical of those drugs had financial ties.

Another study said that in medical journals, only 5 percent of studies sponsored by the makers of six oncology drugs were critical of the drugs, vs. 38 percent of independent studies.

Review boards are pressured

The burden of protecting patients falls to so-called institutional review boards, or IRBs. But these local boards, appointed by the institution they police, are often overwhelmed and lack expertise.

And even if an IRB wants to get tough, its members may lack the time to do it. Studies by the federal General Accounting Office and the Department of Health and Human Services (DHHS) have found IRBs to be severely overworked.

"In some cases, the sheer number of studies necessitates that IRBs spend only one or two minutes of review per study," said a 1996 GAO report. For continuing studies, "these reviews are typically either superficial or not done at all."

An IRB member at one institution explained to federal investigators that for continuing studies, he usually just checks to see if there have been any deaths.

"If no patient has died, then he generally will not raise questions," said a 1998 DHHS report.

There are also financial pressures to approve research because delays could cost an institution grants or commercial partnerships. One federal report described the process used by some pharmaceutical companies as "IRB shopping." A drug company shops around for an IRB that will give it quick approval on proposed research.

Two years ago at the University of Illinois at Chicago, 10 members of the IRB quit, complaining that they felt pressure from the school not to interfere with lucrative studies. One said, "They thought we were overly scrupulous, nitpicking obstructionists who were spoiling the research-enterprise system."

The federal Office for Protection from Research Risks (OPRR), under fire for rarely inspecting research centers, signaled a new get-tough attitude in May 1999 when it temporarily shut down federally funded research at Duke University because the school wasn't adequately tracking experiments to ensure the safety of patients. It later suspended research at several other universities, including the University of Illinois at Chicago.

Dr. Greg Koski, director of the revamped Office for Human Research Protections, the federal successor to the OPRR, said that shutting down Duke and other universities caught the attention of academic centers and led to better compliance.

When the National Institutes of Health recently reminded grant recipients they were required by contract to report any deaths or other "adverse events" in gene-therapy trials, more than 500 previously undisclosed problems were reported.

However, no such reports are made public in the many clinical trials that don't involve gene therapy. The Food and Drug Administration treats those as confidential "trade secrets."

Efforts toward reform

Many of the reforms being proposed nationally focus on educating and certifying anyone involved in research and on accreditation for research centers. There's also a push to reduce paperwork.

"The mindless way to try to protect from any injury to subjects is to build a wall that's higher and thicker that makes it more difficult to do research," said Koski.

"By and large, most human research is done by very well-intentioned individuals according to high standards. The institutional review boards by and large take their responsibilities very seriously."

A U.S. Senate subcommittee is expected to hold hearings on human-research protection this spring.

Previous efforts to reform the system have fallen short. There have been several stinging reports about the failure of IRBs in recent years, including one by the DHHS in 1998.

Last year, that office issued another report, saying that virtually none of the changes it had recommended had been made.

Said Dr. Sydney Wolfe of the consumer group Public Citizen, "They are almost begging for deaths and serious injuries as the prerequisite to making further changes."

NEW YORK - The father of Seattle's biotechnology industry has a probation officer. He lives in a modest, cluttered apartment in Manhattan's Chelsea neighborhood, 3,000 miles from the glass-and-steel temples of the companies he helped create. A continent away from the houses of doctors who, with his help, turned their positions with the Fred Hutchinson Cancer Research Center into personal fortunes.

And only two miles but a world away from the $3 million penthouse where he lived in 1992, when he was on Forbes magazine's list of the 400 richest Americans. Meeting with a Seattle newspaper reporter, [David Abraham Blech (born 1955)] wears sweat pants, a sleeveless T-shirt and beat-up white tennis shoes with loose laces. He looks like a disheveled Billy Crystal, curly hair cut close, jaw unshaven.

He takes lithium for manic depression and has spent time in a mental hospital. But things could be worse: At least the federal judge who sentenced him for securities fraud in 1999 allowed him to stay out of prison.

[David Abraham Blech (born 1955)]'s precipitous fall from grace is no more fascinating than his ascension as a brash 24-year-old who turned a family dream into reality. He helped build an industry whose products have saved lives and made lots of money. And, as a Seattle Times investigation being published this week has revealed, Blech helped create a situation at the Hutchinson Center in which the care of cancer patients might be compromised by business relationships.

The get-rich-quick dream of 1980 - after plastics, before the Internet - was biotechnology. With talk of the potential of a cure for cancer, the industry's economic possibilities seemed unlimited.

Blech, a songwriter and fledgling stockbroker, watched Genentech, a company with no profits and no products, sell shares for $35 apiece and double the price to $70 by the end of its first day on the market. "I can do that," Blech told his father, a rabbi and stockbroker, and his brother, a public-relations man. The three started with a name: [Genetic Systems Corporation].

"The ideal catch-all but say-nothing name for our new biotechnology company," Blech recalls. Next, they needed to find a scientist brash and respected enough to head the company.

Among their candidates: [Dr. Robert Charles Nowinski (born 1945)], a young, rising star at the Fred Hutchinson Cancer Research Center in Seattle. They had just read about him in an article entitled "Immunizing Immortality."

• [ NOTE - We have searched the internet and found no evidence of such an article ever existing. We think they quoted the article title incorrectly.}

They called him, and for some reason - perhaps because he, like the Blechs, was from New York - Nowinski listened.

In fact, he told them, he had already been talking about setting up a company. He'd been in discussions with Bob Johnston, chief executive of Cytogen, and investor Charlie Allen of Allen & Co. Blech says Nowinski told him, "I'm going into the monoclonal antibody business." "So am I!" Blech responded. He persuaded Nowinski to fly to New York for a meeting.

• [ NOTE : No mention of Nowinski in "Monoclonal_antibody" - https://en.wikipedia.org/wiki/Monoclonal_antibody ]

Blech's father picked up the Seattle scientist at JFK International Airport and took such a roundabout way from Queens to Manhattan that, Blech recalls, Nowinski was sorry he'd ever come. Blech concedes that Nowinski thought he'd been taken in by "a bunch of amateurs." Blech didn't even have a credit card. He was a kid - wiry, fast-talking, high-strung, super-ambitious. In some ways, a lot like the 35-year-old Nowinski.

Blech won Nowinski from Johnston and Allen with the promise the scientist could do good work, get rich and stay close to "The Hutch" in Seattle.

Allen had wanted Nowinski and 11 other Seattle scientists to move to New Brunswick, N.J. Blech told Nowinski that was crazy.

"That was the best observation of my career," Blech said. "It's unusual that two kids from Brooklyn and their rabbi-stockbroker father could get a company away from Bob Johnston and Allen & Co., but we did. We used to call the company `Genetic Balls.' "

The Blechs had $10,000 apiece. Blech says they told Nowinski they'd borrow to put $200,000 in escrow for him to keep if they didn't raise $3 million within a year.

They raised $40 million. Nowinski was given 1.2 million shares of stock at a penny a share. Under Blech's tutelage, Nowinski sprinkled shares around The Hutch like manna from heaven. His brilliance and the penny stocks helped Nowinski recruit his boss, Dr. John Hansen, as medical adviser for Genetic Systems and his boss' boss, [Dr. Edward Donnall "Don" Thomas (born 1920)], as a key member of the company's scientific advisory board.

• [ NOTE: Dr. John Hansen - No wikipedia page. Use NY TImes - https://www.nytimes.com/2019/08/13/health/dr-john-hansen-dead.html#:~:text=Dr.-,John%20A.,He%20was%2076. ]

• [ Useful - http://authors.fhcrc.org/624/1/FHCRCHistoryProject.pdf ... local copy saved...

• [ Paul Neiman ... worked with Dr. Donny thomas ... https://www.fredhutch.org/en/news/center-news/2017/10/paul-neiman-hutch-founding-member-dies-78.html ]

Then Genetic Systems struck a deal with Hutch officials for commercial rights to 37 drugs.

Three of those drugs were antibodies that were to be used in a Hutch experiment called Protocol 126, an experiment in which Hansen and Thomas were involved. As described in The Times earlier this week, that experiment was controversial within The Hutch, with some doctors complaining that the welfare of patients was compromised by the researchers' ties with Genetic Systems.

In 1982, when Genetic Systems went public at $1.25 a share, the Blechs, Nowinski, Hansen and Thomas all made lots of money. Three years later, the company was bought by Bristol-Myers for $10.50 a share.

Bristol-Myers hurried in to buy Genetic Systems for $294 million in stock two weeks after Eli Lilly, its rival, had bought Hybritech, another monoclonal-antibody company, for $350 million. Blech liked to brag that Genetic Systems sold for 15 times its original public-stock value, while Hybritech merely doubled its value.

Blech made $30 million on the Genetic Systems deal. Nowinski's stock at that point was worth more than $10 million and Hansen's $1.8 million. Assuming Thomas had kept his original stake, which is unknown, his share - in Bristol-Myers stock - was worth $1 million. "I always took great comfort how the scientists made a million dollars each," Blech said.

As Rose Beer, then a company official, recalled, "We had a very high profile at Genetic Systems. Without any due diligence, Bristol Myers came in and bought us for about $300 million. And then did their due diligence. And what Bob (Nowinski) sold was his dream of what this company would be. Oh, man, if they only knew!"

They found out soon enough that the dream was brighter than the financial reality. In 1991, Bristol-Myers resold part of the former Genetic Systems for $20 million and closed the other part, taking a $274 million bath.

Despite that, Bristol-Myers has gone up six fold since then, increasing even further the value of the doctors' stock.

Selling vision and credentials

Blech became known as the nation's most aggressive biotech financier. He took high fees and a lot of stock for seed money, and he took the companies public fast.

While most biotechs had one or more products in Food and Drug Administration-sanctioned trials before they took their stock public, most of Blech's did not. That made the scientific studies and credibility of medical doctors on board all the more important.

The Hutch's Thomas, who won a share of the 1990 Nobel Prize for his work on bone-marrow transplants, was recruited by Blech for the advisory boards of three other companies.

And Blech helped two other Hutch scientists, Drs. James Bianco and Jack Singer, start Cell Therapeutics Inc.

"Bianco came to us," Blech recalls. "He told us this story about these amazing clinical results he was seeing."

Some scientists doubted the research, which touted unbelievably good results with a little-known drug shielding vital organs from harm during cancer chemotherapy. Blech says he knew the research was thin but he sold the vision and the credentials of the company's supporters, especially Thomas.

"Ultimately, the drug failed," Blech said. "I don't know why." But Cell Therapeutics tried another drug, then another. Recently the company rose from near-death to huge gains with an arsenic drug to fight blood cancers.

"They were constantly reinventing themselves," Blech said. "That's the wonderful part of dealing with (stock in) life and its frailties."

Major deal-maker in biotech

In 1989, the Blechs helped create Icos Corp., joining Nowinski and Dr. Chris Henney, who had left The Hutch to co-found [Immunex Corporation].

The Blechs put up $1 million of borrowed money. They wanted PaineWebber to sell the stock; PaineWebber wanted the Blechs to recruit George Rathmann, founder and chairman of the largest biotech company in the nation, Amgen, of Thousand Oaks, Calif.

Rathmann had taken Amgen from $4 a share to $60 and sold $190 million in products in 1989.

Ken Lee of Ernst & Young said Rathmann, 65, was "one of the most important guys in biotech in the country." Landing him was a coup for Blech and Nowinski.

"George had a fantastic career at Amgen, you know; he was the king of biotech," Blech said. "Luckily, he had one more deal in him."

The board of Icos was amazing for a start-up company. It included the former chairmen of Citibank (Walter Wriston), IBM (Frank Cary) and General Foods (James Ferguson), a former secretary of commerce (Alexander Trowbridge), and David Blech and his brother, Isaac.

Icos had the largest start-up financing in biotech history, $33 million. The Bothell-based company went public at $8 a share in 1991. David Blech owned 7 percent, and made a quick $10 million.

Rathmann described Blech as a "pure-greed" venture capitalist, and one who was very important to Seattle biotech. "It's because of his very venturesome personality. You have that kind of mindset," he said.

In the next few years, Blech helped set up about 20 other companies, mostly outside the Seattle area, including Celgene of Warren, N.J., with Nowinski, and Incyte Pharmaceuticals of Palo Alto, Calif.

He was a master salesman, whipping out lists of investors and trust funds, spinning academic cachet into cash. He sold hope: You could find a cure and make a mint.

Picking up `fallen angels'

At the height of his power, Blech estimated his personal fortune in 1992 at $310 million.

But Genetic Systems never did make a product to help cure cancer. Neither did Cell Therapeutics.

"I made a lot of money in the companies in Seattle but the products didn't quite get there," Blech said. "So I guess I entered the '90s feeling a little guilty about all that. So I started putting money into `fallen angels.' "

That's how he referred to young biotech companies that had spent at least $100 million on research but didn't have a product ready by the time they were out of money.

Blech picked them up when nobody else would.

"People get tired, you know," he said. "A lot of bright stars become fallen angels before they shine again."

He saved NeoRx of Bothell with $10 million cash, helping it raise $31 million in licensing deals.

He saved Microprobe (now Epoch Pharmaceuticals) of Bothell, personally financing operations for 16 months. He wrote monthly checks and guaranteed the salaries for six executive officers.

He bailed out another dozen companies across the nation. He was sure his name would mean gold.

"I'm not telling you there wasn't an element of greed in it for myself," Blech said. "I'm sure that played a role in it. But my doors were open to everybody - whether it was an Icos with golden management or a NeoRx that was on its ass and needed $10 million to keep the company open. I tried to save both sectors."

When Blech himself fell, though, many looked away.

Things fall apart

The biotech market soured in 1993. Blech, obsessed with buying undervalued biotech stocks, bought more and more on credit. He shifted funds to hide his mounting losses.

Blech stopped taking lithium. "As a manic-depressive, I'd get real high and low, so I'd buy when prices were high and sell when prices were low, the exact opposite what you should," he said.

The Securities and Exchange Commission investigated whether Blech broke the law by giving cheap stock to money managers and others prior to public offerings. That would inflate the price. Blech denied any impropriety.

For a time, Blech-backed companies held up under the collapse. Then he ran out of cash and the short-sellers pounced.

The first sign of deep trouble was in April 1994, when Blech had to sell his 24 percent stake in NeoRx to avoid a margin call by Citibank on $40 million in loans.

Afterwards, Blech bragged about the money he'd made on NeoRx anyway and the $150 million he claimed was held in trusts nobody could touch no matter what happened to the market, the financial newspaper Barron's reported.

Falling deeper and deeper in debt, Blech admits, he executed sham and unauthorized stock sales. It was outright criminal activity and he knew it, but he said he couldn't stop.

D. Blech and Co. failed to open its doors on Sept. 22, 1994 - referred to on Wall Street as "Blech Thursday." At least 13 stocks for which Blech was the underwriter declined by 23 percent or more that day. One fell 64 percent. The whole biotech sector sagged.

More than 300 brokers lost their jobs when the firm collapsed, and Blech stood sobbing in his trading room at the end of the day.

"A few days after D. Blech & Co. closed its doors on September 22, 1994, Blech entered the hospital due to an emotional breakdown. He never returned to the firm's offices. Within days of the firm's collapse, Blech's wife filed for divorce," according to a National Association of Securities Dealers report. Blech hadn't told his wife he was forging her signature on documents.

The SEC said investors and broker-dealers took $22.5 million in losses because of Blech's stock manipulations.

As the SEC developed criminal charges against Blech, he turned informant. Lloyd Schwed, a Florida attorney for four brokers who sued Blech, was arrested in August 1996 and charged with shaking down Blech by offering to withhold tapes subpoenaed in the SEC investigation. Schwed told Blech he would destroy two especially damaging tapes if Blech settled the suit with a big payment. Blech had worn a wire for the feds.

In April 1998, Blech was charged with the illegal security actions that led to "Blech Thursday." He pleaded guilty to two counts of criminal fraud. He faced up to 97 months in prison.

He refused to seek an insanity plea, though, even after a court-appointed psychiatrist said manic depression had contributed to his crimes.

Federal prosecutors suggested leniency because Blech had helped them. In October 1999, U.S. District Judge Kevin Duffy sentenced Blech to five years' probation and community service.

The National Association of Securities Dealers fined Blech $20,000, censured him and barred him from associating with NASD members in the future. In addition, the SEC, four former brokers and a class of investors all filed lawsuits against Blech.

Blech had never been well-known in Seattle, and none of this was even reported in the daily newspapers in the city where he'd set up several biotechs and manipulated stocks in others. Blech has not been mentioned in The Seattle Times since 1996, and in the Seattle Post-Intelligencer since 1994.

Hoping for a comeback

Today, Blech is supported by his second wife, Margie, a graphic designer and aspiring actress.

He is trying to sell a manuscript of his life story - "Million Dollar Dreamer" - but publishers aren't buying.

Sally Richardson, president of St. Martin's Press, wrote to him recently: "People don't like David Blech, they don't root for him, and we don't think they would buy his book."

Blech says he thinks about his rise and fall every day. His early times with Nowinski were the best, he says: so young, so easy.

But it's been a long time since Blech has heard from Nowinski, who lives north of Seattle and recently left Vax Gen, a company trying to develop an AIDS vaccine.

Rathmann is about the only one who calls Blech from Seattle anymore. Rathmann and Bianco wrote letters of support to the judge in Blech's federal trial.

Blech hopes to make a comeback someday. Not now, but soon. He's restless. He has a part-time secretary in his home office, a desk in the corner off the living room. He promises to never borrow money again, but watches the market closely.

"I believe I have learned from my mistakes," Blech wrote recently. "I feel good about my legacy. I have helped create over $15 billion in biotech market value, and have been associated with several products which are currently being used in the treatment of AIDS and cancer.

"But, at 44, I am still too young to retire. I may have one more go at it in me. This time, I would try to do it in a more measured way, with only one or two biotech companies. I would not try to save the world."

Since the Fred Hutchinson Cancer Research Center was founded as a tax-supported nonprofit a quarter-century ago, it has spawned private companies worth more than $18 billion and an estimated $100 million in personal wealth for its doctors.

At least 20 physician-researchers have left The Hutch to start private ventures based on the government-funded work they did there. Others, particularly senior managers, stayed at The Hutch but supplemented their salaries with private consulting, stock deals and drug-development rights. Whether they left, stayed or straddled the fence between business and academic research, the scientists say they were motivated not by the money but by the promise of better science and medicine.

That was the argument that prevailed in Congress in 1980 when the Bayh-Dole Act gave academic centers the right to patent and profit from their discoveries. Supporters thought this would spur innovation and discovery, and it has.

More and more, though, the financial benefits are ending up with individual scientists and their investor backers. And some experts worry that the motive for profit could compromise the free exchange of ideas for scientific progress.

They question the wisdom of joint ventures between publicly funded academic research and corporations. And they cite the importance of maintaining public trust in the integrity of medical research unmotivated by profit concerns, particularly when the research is performed on human volunteers.

Dr. Rainer Storb, an orignal member of The Hutch and current head of transplantation biology, said he is thankful for public funding of biotech research, and proud to be working for scientific progress rather than profit. Storb said he has never believed government-financed scientists should take money from private companies. The late Dr. Bill Hutchinson - founder of The Hutch and brother of the man for whom the center is named - reportedly felt much the same way. Clearly, though, many doctors at The Hutch feel differently. Over the years, the center's conflict-of-interest policy has been weakened and walls between taxpayer-funded science and for-profit science have crumbled.

"Actually a lot of people in the community call us `Mother Hutch,' " said Rose Beer, who moved from a Hutch lab to private industry - 18 years at Genetic Systems, Icos and Targeted Genetics - before returning to The Hutch in 1998.

Beer now works at the center's Office of Technology Transfer, its bridge with companies.

"When I came back, everyone went, `You're going back to the Mother.' The womb."