THE WHISTLEBLOWER

He saw the tests as a violation of 'trusting, desperate human beings'

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."

What happened

A timeline of doctors' complaints and officials' responses.

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

Harley Soltes / The Seattle Times

A snapshot of Ruth Fisher who died in January 1984 after a graft failure and second transplant

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

President Day successfully defended The Hutch, but in the end a state official said, 'There still remained some doubt in our mind.'

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." 

One day he picked up a copy of The Sciences magazine and spied an article entitled ''Immortalizing Immunity'' that dealt with monoclonal antibodies. He didn't know what in the world they were. He read on. 

Production of Antibodies

He found that antibodies are proteins produced by the human body to fight off invading organisms. They are valuable in detecting infections as well as in treating diseases. The recent development of so-called hybridoma technology, the article noted, allowed mass production of antibodies. By fusing cells that normally produce antibodies with tumor cells, hybrid cells are formed which are tantamount to little factories that continuously churn out highly defined strains known as monoclonal antibodies.

In the article, the author suggested that hybridoma technology could have an effect on medicine ''comparable to the transformation of electronics by the transistor.''

Lights flashed in David Blech's mind. ''When you've been on Wall Street for five years and you see an analogy like that,'' he recalled, ''you get excited.''

So the brothers hired the author of the magazine article, plus several other medical experts, to help them dig up a scientist as the nucleus of their company. Finding a Scientist

Robert Nowinski, an esteemed microbiologist immersed in monoclonal antibody work at the Fred Hutchinson Cancer Research Center in Seattle, drew repeated good comments. He had been mentioned in the Sciences article, since he had produced an antibody capable of curing mice of leukemia.

[ THIS IS THE RESEARCH ... It was Nowinski's.. but why was he not mentioned ??? https://special.seattletimes.com/o/uninformed_consent/whistleblower/story1.html ] 

[David Abraham Blech (born 1955)] placed a call to Seattle. Curiously, around this time Mr. Nowinski was himself mulling over starting a company. Except what did he know about raising money? Mr. Nowinski would later say, ''Literally through a phone call, Genetic Systems was started.''

The New Yorkers and the Seattle scientist hit it off and agreed that a company built around Mr. Nowinski as scientific director would be a winner. Wary that the Blechs might not be able to raise adequate money, Mr. Nowinski set milestones to test their mettle. Within six weeks, they had to have $1 million in hand. Within six months, the kitty had to be $3 million to $4 million.

A crucial fact the Blechs wanted to know was how soon a product could leave the labs. Making a guess, Mr. Nowinski said a year or two. That seemed promising, so in November 1980 the company was incorporated. ''It's fair to say,'' Mr. Nowinski comments, ''that this was started out by a group of determined novices.''

The Blechs put up about $200,000 of their own money, which represented much of their worth. The Search for Money

Hunting for more dollars, the group visited Schroders Inc., the financial services company. They found a receptive audience in John Connor, Schroders' chairman, who had once been president of Merck & Company, the giant drug concern.

''I was very much impressed by the modesty of the scientist,'' he recalled. ''All of them were aware of their limitations and thought they should hire in their bosses. They haven't tried to do everything themselves but have stuck to their own knitting.''

In February 1981, Schroders acted as the lead institution in a private placement that raised $1 million for Genetic Systems. Money kept rolling in. That May, the Syntex Corporation, a pharmaceutical company familiar with Mr. Nowinski, called and struck a $3.9 million, three-year research and marketing deal. Syva, a Syntex unit, would fund Genetic System's research into products to diagnose sexually transmitted diseases and then market the products to clinics. Genetic Systems would get a royalty on sales.

Syntex and its investment banker, Allen & Company, also chipped in $1.5 million for about a 12 percent stake in Genetic Systems. Several more deals were made with other drug makers. President Recruited

Meanwhile, a president was recruited - James Glavin, who had been vice president of sales and marketing for Oximetrix, a maker of medical devices.

Next, the Blechs met with D.H. Blair & Company in hopes of having them underwrite a public offering. Blair was at once receptive, and in June 1981 a public offering at $2 a share swiftly pulled in $6.6 million.

In January, the first product appeared, a diagnostic test for chlamydia, a sexually transmitted infection that afflicts an estimated 10 million people a year. The test can be read in two days, rather than the six required by earlier tests, and is easier to perform. Genetic Systems makes the antibodies for it and Syva assembles them into kits and sells them. Last week, a second product was introduced, a test for herpes. Longer-Range Plans

Down the road, Mr. Nowinski expects to move from diagnosing diseases to treating them. His team is also addressing respiratory and hospital-acquired infections, as well as researching the use of antibodies to type cells in connection with transfusions and organ transplantation. A long-term focus is cancer; a joint venture with Syntex is aimed at developing tests and treatments for cancer.

Revenues are just beginning to trickle in, though Genetic Systems has not yet made any money. Losses amounted to $401,000 and $1 million in its first two years. But Wall Street has heady hopes for the concern. A recent Paine Webber analysis predicted sales of perhaps $170 million by 1988.

In April, Merrill Lynch was the lead underwriter on an offering of 2.2 million shares that attracted an added $21.7 million of working capital. The company's stock, traded over-the-counter, is currently selling at about $15, putting the company's market value at a cool $270 million. Each of the Blechs owns close to one million shares. David concentrates on the company's strategic planning, while Isaac focuses on promotion.

The brothers, who work out of New York, have had such a grand time starting a company that they have since spawned three others - DNA Plant Technology, an agricultural genetics company; Laser Technics, which makes laser systems, and Nova Pharmaceutical, which is aimed at devising drugs to test compounds for their appropriate usage.

A biotechnology research company says it has produced the first commercial levels of human monoclonal antibodies for the treatment of disease.

Leading experts yesterday described the discovery by the Genetic Systems Company as very significant. Monoclonal antibodies are produced in a laboratory to seek out the substances that cannot be overcome by the body's own antibodies or on which vaccines cannot be used.

Fighting Disease

Until now, only small amounts of human antibodies could be produced in the laboratory. The antibodies, which specify disease organisms in the body for destruction, are products of the recent biotechnology revolution. They are thought to hold the key to an eventual cure of diseases such as cancer.

The commercial breakthrough was made by a team under the direction of Dr. Robert C. Nowinski, a respected microbiologist who is president of Genetic Systems and a pioneer in the development of human monoclonal antibodies. In a series of interviews, Dr. Nowinski said he had produced human monoclonal antibodies at concentrations of more than 100 micrograms per milliliter - 20 to 100 times greater than previous laboratory production. He said he had used a proprietary process for which the company received a patent last week.

Dr. Nowinski said the process enables the production of a range of human antibodies a thousand times broader than with previous processes. That means that researchers would have a much better chance of finding specific antibodies that cure diseases, he said.

''The significance here is that we now have a practical method to make human antibodies for therapy,'' he said. ''It is no longer on a laboratory scale, but on a commercial scale.''

The company, which is based in Seattle, was founded in 1980. It had a 1983 loss of $1.5 million on sales of $6 million. Nelson M. Schneider, who follows biotechnology at E. F. Hutton & Company, said Genetic Systems is regarded as a company that ''combines good science with good commerce.'' He added that the company is in the developmental stage and well financed and that it has good prospects.

The company's stock, traded over- the-counter, was bid yesterday at $6.50, down from $17.75 at one point last year but up from $4.75 about a month ago.

Genetic Systems has helped develop very rapid tests using monoclonal antibodies to detect major venereal diseases and it is developing diagnostic tests for other ailments.

So far, Genetic Systems has isolated one antibody for commercial production. It is a serum to fight bacteria called pseudomonas, which cause infections that are the major killer of burn victims. The bacteria also infect people with chronic diseases such as cystic fibrosis and cancer. Dr. Nowinski said that small amounts of the antibody had cured pseudomonas infections in mice and that clinical trials were expected soon by the Cutter Group of Miles Laboratories, a subsidiary of Bayer A.G. of West Germany. Cutter collaborated on the research.

'If True, Impressive'

Dr. Jeffrey Schlom, chief of the tumor immunology laboratory at the National Cancer Institute and also a pioner in human monoclonal antibody research, yesterday called the innovation ''very important.'' But he cautioned that he had not seen the research and that the discovery would have to pass clinical trials. Dr. Carlo M. Croce, a geneticist at the Wistar Institute in Philadelphia and another respected antibody researcher, said the innovation, ''if it is true, would be very impressive.'' But he said it is hard to make a firm judgment without seeing the research results.

Antibodies find and attack substances foreign to the body, such as viruses and bacteria. Until now, research has concentrated on monoclonal antibodies produced from mice for use in disease diagnosis. It has been shown that mouse antibodies, which can be produced in large quantities, have limited use in the treatment of humans.

Genetic Systems Corp., a Seattle biotechnology company best known for its research on testing for the Acquired Immune Deficiency Syndrome (AIDS), is being sold by Bristol-Meyers Squibb Co. to a unit of Sanofi of France.

Sanofi is 25-year-old conglomerate that specializes in pharmaceuticals and diagnostics, ingredients for the food industry, agricultural and animal health products, and perfume and beauty products. Its stock is half owned by the Societe Nationale Elf Aquitaine Group and half publicly traded.

The purchase of Genetics System brings to 17 the number of Sanofi's affiliates in diagnostics. Terms of the cash sale were not disclosed.

Genetic Systems was founded here in 1980 and sold to Bristol-Meyers in 1986. Its relationship with Sanofi goes back to 1984, when the two companies formed a joint venture, Blood Virus Diagnostics, to help develop specialized tests for viruses.

The Seattle company is not yet profitable, although Sanofi executives said it has annual sales of about $10 million now and may increase that to about $18 million next year. Sanofi estimated that its diagnostics division, of which Genetic Systems will be a part, will have $175 million in sales this year.

Terrance Bieker, president of Kallestad Diagnostics in Chaska, Minn., Sanofi's American affiliate, is a former Genetic Systems manager who left Seattle in 1988. ``We intend to manage Genetic Systems as it is now,'' he said.

Mark Fieczkarek, who has been vice president of operations and finance at Genetic Systems, has been named general manager here. Tim Ellis, who has been general manager, will remain with Bristol-Meyers Squibb, Bieker said.

Genetic Systems, which has about 150 employees, is hiring now because it is anticipating approval soon from the Food and Drug Administration to market a new AIDS virus test.

Bieker said he expects some additional manufacturing work also will be assigned here through the parent company. Whether that means additional hiring is not yet known, he said.

His company specializes in different health tests.

``There is no overlap or duplication of products with Genetic Systems. It's a good fit,'' he said.

Two Seattle biotechnology companies, both quite young, are working to unlock the genetic secrets of growing old. 

Lifespan Bioscience Inc. and Aeiveos Sciences Group each have raised several million dollars with the ultimate goal of giving people additional years of disease-free living. 

But that's where the similarities between the two end: Lifespan and Aeiveos seem opposites in corporate spirit and in scientific direction. 

At Lifespan, the top executives have previous biotechnology experience and stress a practical, short-term agenda of partnering with bigger drug companies to bring in revenue. 

"What we're good at is gene discovery; what they're good at is drug discovery and development," said Lifespan president and CEO Joseph Brown. 

The more enigmatic Aeiveos is led by former software executive Robert Bradbury, who argues that the human genome is no more complex than Microsoft's Windows NT operating system. 

"Within the next 20 years, the limit on maximum human lifespan will be eliminated," he optimistically proclaims on the company's elaborate Web site. 

Its business strategy seems less well-developed, or perhaps more long-term. Vice president Tyrone Mowatt said Aeiveos -- a name coined from the Greek words for "forever" and "young" -- currently is focused on research, not revenue. 

"We're still looking at expanding our basic research, understanding more about aging, and from there understanding the potential therapeutics for this market," he said. 

The two have disparate scientific approaches, as well. 

One of Lifespan's chief assets is a library of 100,000 samples of diseased human tissue -- a reference library "of basically all the aging diseases man can get," said chief scientific officer Glenna Burmer. 

Lifespan's researchers will use these to explore which genes contribute to aging-related afflictions, ranging from Alzheimer's to osteoporosis and cancer. 

At Aeiveos, on the other hand, "We are not looking at any pathologies, we are looking at `normal' aging," said chief scientist Rajinder Kaul. 

Aeiveos aims to study the genetic codes of centenarians -- people who live to the ripe age of 100 -- to learn how they ward off the diseases that strike down most people much earlier. 

Many other companies are also in the hunt. Locally, Darwin Molecular Corp. last year identified two genes implicated in aging diseases, one for early-onset Alzheimer's disease and another for Werner's syndrome. Darwin merged with Chiroscience Group plc of England late last year, giving it access to drug-development expertise. 

The Human Genome Project -- a national effort to decipher all 100,000 genes in human DNA -- is the springboard for much of the work these genomics companies hope to do. 

The resulting database has been likened to the white pages of a city telephone directory -- a lot of data, but little help if you don't know who you're looking for. 

Extending the phone-book analogy, Lifespan's Brown said that when drug companies search for the genetic perpetrator of a disease, Lifespan will tell them more than "the culprit's in here. ... What we'd like to do is give them the name, address and occupation of everyone seen at the scene of the crime." 

That's crucial, because there may be hundreds or thousands of genes that are turned on or off by a disease, but discovering a treatment hinges on determining which ones are actually responsible for the problem. 

Lifespan has invented or licensed screening techniques that can reduce the list of suspects down to "a handful," said Brown. 

Of the entire genome, "it's the top 1 percent -- there's probably 1,000 -- that will prove excellent targets" for drugs, Brown said. "Remarkably, to date, only about 50 genes are targeted by pharmaceuticals." 

Lifespan, which now employs 15, can grow to 50 or 60 people in the 12,000 square feet it recently leased in the Denny Regrade area, company officials said. 

Unlike some rival companies studying the genetics of aging, Lifespan won't be studying the simpler creatures -- flatworms, mice, fruit flies or yeast -- favored by many genetics researchers. "We believe very firmly in working with humans" -- meaning human cells, said Brown. 

Although the initial strategy calls for Lifespan to do research under contract for big drug companies, Brown said "we insist on retaining some intellectual property" from each deal -- perhaps the rights to apply the results to diseases the partner isn't pursuing. Simultaneously, Lifespan will pursue its own longer-term research on basic mechanisms of cell aging, he said. 

Brown, previously at Bristol-Myers Squibb in Seattle, in 1992 became PathoGenesis Corp.'s first employee after founder [Dr. Robert Charles Nowinski (born 1945)]. Burmer was the first program director at PathoGenesis, and managed its pathogen discovery program. 

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