Sunday, May 21, 2000 |

SUNDAY REPORT, Los Angeles Times

A Wonder Drug That Carried the Seeds of Death

Health: Human growth hormone held promise for thousands, but contamination of early samples has been linked to a fatal disease. A purification method was known but not used.

By EMILY GREEN, Times Staff Writer

     In 1958, an American scientist managed to do what nature had failed to. He made a dwarf grow. For the first time, man had harnessed human growth hormone.
    By 1963, while technically still an experimental drug, the hormone was being supplied free of charge by the National Institutes of Health to pediatricians across America. For the next 22 years, the drug was administered to more than 8,000 stunted children.
     It worked. The children grew--collectively, more than a mile. They went on to become soldiers, doctors, journalists and secretaries. They married and had children. But then, decades after taking the hormone, a small but steady succession of recipients began to develop strange symptoms.
     First they lost their balance. In the case of a 32-year-old foot surgeon from Brooklyn, N.Y., Dr. Stacey Crair, she suddenly started toppling over. As a child, Crair had received growth hormone treatment for 12 years.
     Nearby on Long Island, a water safety engineer named Mike Nofi remembers that his 30-year-old wife, Wendy, suddenly started feeling like "she was on a boat." She had received growth hormone for six years.
     Soon they began to stagger and drool. Their personalities changed. Within months they were in comas. Their brains were turning to sponge.
     They had Creutzfeldt-Jakob disease, or CJD, a human variant of the so-called mad cow disease. CJD is incurable. The agent that causes it is unknown. How they got it, however, was clear. They had been infected by contaminated hormone. Twenty other hormone recipients in the United States have also died from CJD, and the toll continues to rise.
     But the NIH has not apologized, or even helped with the care of victims. Having investigated the debacle, the NIH has insisted for the last 15 years that the deaths were unforeseeable.
     "It was an experimental treatment, and people signed informed consents," NIH spokeswoman Jane Demouy said recently.
     However, The Times has unearthed British court documents showing that the deaths were not only foreseeable, they were foreseen. The NIH lab called in to investigate the deaths in 1985 had been warned of the danger of contamination seven years earlier.
     Moreover, a body of research shows that a safer method for processing the drug had been available from the inception of the program. But scientists under contract to the NIH chose a cheaper, less labor-intensive method.
     Shown the documents, Demouy said the NIH involvement was limited to funding the program:
     "Physicians around the country administered the hormone. Decisions regarding the program were made more than 35 years ago, and the people involved are deceased or retired. In 1985, when it was learned that three patients who had received human growth hormone had contracted CJD, distribution of human growth hormone [from cadavers] was ended."

     Plundering the Pituitary Gland

     Today human growth hormone is synthetic, and safe. So it is easy to forget how crude its early forms were--or that it was an important medicine. A sign of how fast its development has been is that, at the turn of the 20th century, the word "hormone" did not even exist. Endocrinology--the study of the network of glands that produce hormones responsible for growth, sexual maturation, reproduction and digestion--was a new science.
     Early research was brutal but effective. Experimenting on animals, mainly dogs, scientists in Europe and North America deduced what endocrine glands did by surgically removing the organs and seeing what happened. Usually the dogs died.
     In 1921, a University of Toronto team found not only that removal of a dog's pancreas caused diabetes but also that injecting the dog with pancreatic extract appeared to cure the disease. The extract contained the lifesaving hormone insulin. Within a year, insulin from the pancreases of cows was being injected into diabetic children. The first American recipient went on to live to the age of 74 and came to describe the hormone as "unspeakably wonderful."
     Plundering the pituitary gland proved a good deal trickier. Located behind the bridge of the nose, the bean-size organ was difficult to remove without killing the test animal. By the 1950s, however, not only had scientists managed this, but it had also become clear that the pituitary was home to a complex cache of hormones governing growth, maturation and reproduction.
     The first pituitary hormone to receive the insulin-style extraction treatment was human growth hormone. But unlike insulin from cattle, bovine growth hormone had no effect on people. Scientists needed human pituitary glands to make people grow. They would have to look to morgues.
     In 1958, a Boston-based researcher named Maurice Raben at the Tufts University School of Medicine produced another first. A 17-year-old boy, whom Raben had experimentally injected with human growth hormone, grew 2.1 inches in 10 months.
     For parents of stunted children, this offered precious hope: Their children might be spared lives as dwarfs.
     But then they were asked to wait. Dwarfism wasn't diabetes. It wasn't life-threatening. Unlike insulin, human growth hormone was not seen by drug companies as commercially viable.
     Almost immediately, the most enterprising parents enrolled their children in small trials, very like the first Raben experiment. Even then there were not enough pituitaries for steady production of the growth hormone. Some parents turned organ scavengers, personally petitioning hospitals and morgues for pituitary glands from cadavers.
     By 1963, pressure from parents, pediatricians and endocrinologists had become so intense that the NIH stepped in. It formed the National Pituitary Agency out of Baltimore's Johns Hopkins University. The agency would organize collection and redistribution of the glands to three universities for processing into growth hormone: Emory in Atlanta, Tufts in Boston and Cornell in Ithaca, N.Y.
     Soon, the NIH was guardian of a sweeping experimental drug trial. For 22 years, from 1963 to 1985, it supplied the hormone to 8,157 children nationwide and to about 50 foreign-born children who came to America for treatment.
     For the first 14 of these years, the largest seat of hormone production was at Emory, supervised by Alfred E. Wilhelmi. A former Rhodes scholar, he was at the peak of a charmed career. He had received a doctorate from Oxford University in England and taught at Yale before moving to Emory. Soon to become president of the Endocrine Society, he was the NIH expert of choice.
     But more advanced work was going on in Sweden, at the University of Uppsala, where chemists had observed problems with the human growth hormone being extracted using Wilhelmi's method; it caused immune responses and was far from pure.
     The Swedes, by contrast, had developed a method to produce hormone that was 95% pure. It did not spark immune response and appeared to be more potent in inducing growth. The difference was part effort--the Swedes took a much more labor-intensive approach to gland collection and storage--and part technology--they filtered their drug using a process called Sephadex gel filtration.
     Wilhelmi chose not to use the filter.
     "Wilhelmi's philosophy was that the material was human protein, and human protein cannot harm human beings," said Albert Parlow, a Harvard-educated biochemist who was at Emory at the time.
     The result was that the NIH supplied thousands of American children with a drug that could have been pure, but wasn't. In 1969, Wilhelmi unveiled what he described as an "improved method" for hormone extraction. But the improvement was in yield, not purity. The resulting hormone was, Wilhelmi wrote in the Journal for Clinical Endocrinology, "clinically useful and . . . may be purified further for chemical use and immunochemical studies."
     Put more simply, this meant that Wilhelmi regarded the hormone as safe for children but in need of further refinement for use in experiments.
     Another believer in the acceptability of clinical grade hormone was Anne Stockell Hartree, an American-born biochemist then on staff at Cambridge University in England. She co-wrote the 1969 Wilhelmi paper announcing the "improved" hormone and was using the method to process the hormone being employed in an almost identical program in Britain.
     By 1973, both Wilhelmi and Hartree were facing questions. A member of the British hormone program's steering committee raised concerns about the safety of the drug.
     Wilhelmi replied: "We have been preparing hGH since 1958 in increasing quantities, and in all that time there has never been a complaint of that kind of contamination. . . . We are presently going to modify our procedure to include a step of filtration on Sephadex G-100, and this, I think, will provide further assurance of removing virus from the system."
     The Times could find no record that Wilhelmi or Hartree ever used the Swedish-style Sephadex filtering.
     The method wasn't officially adopted until after Wilhelmi's retirement in 1977. That year, the NIH put hormone production out to bid. The winner was Parlow, by then a research professor of obstetrics and gynecology at the UCLA School of Medicine. Written into his proposal was strict incorporation of Swedish-style protocols.
     The same year, British purification was moved from Hartree's lab to one that also began filtering the drug.
     Even so, for the next seven years, Wilhelmi's confidence in his method seemed justified. As he had once observed to those questioning his methods, nobody seemed to "have caught anything."

     Woman's Death Sparks a Crisis

     But in March 1984, in the English cathedral town of Winchester, that changed. What began as an off day for a 22-year-old woman quickly escalated into an international public health crisis.
     Alison Lay, a secretary at a local Barclay's bank, noticed that her balance was unsteady. "She progressed from not being able to go to work," recalls her mother, Mavis Lay, "to not being able to feed herself and not being able to walk without help."
     On Feb. 12, 1985, eight days short of her 23rd birthday, Alison Lay died from CJD.
     When she was 2, surgery to remove a brain tumor had also taken out her pituitary gland. To compensate, between the ages of 10 and 14, she had received more than 550 injections of human growth hormone.
     Unbeknown to the Lays, CJD cases were also being recognized in young people in the U.S.: a 22-year-old in Buffalo, a 34-year-old in Dallas, a 21-year-old in San Francisco. All had received human growth hormone.
     CJD is among the rarest of diseases, striking about one in a million people per year. It is rarer yet in the young. Of more than 3,000 cases recorded in international literature, before 1985 only nine were in patients younger than 30. The typical age was between 55 and 65.
     But when autopsy results from the first four hormone recipients came in, the average age was 25.
     Alarms blared. After an urgent meeting on April 20, 1985, the NIH suspended the National Pituitary Program. The anguished reaction of University of Virginia pediatrician Robert Blizzard was typical. He wrote British colleagues: "Just an hour ago I left a meeting at NIH and I am very depressed. . . . I realize full well the implications of this worldwide--both for investigators and for patients. The implications are tragic."
     By June, programs had been stopped in Belgium, Finland, Greece, the Netherlands, Sweden, Britain and Australia. An estimated 27,000 children worldwide had been given the drug. In the U.S., the Centers for Disease Control and Prevention in Atlanta was brought in to track down the 8,157 American recipients.
     Meanwhile, the NIH switched hats from overseer of the program to its own accident investigator. Sponsor of the hormone program had been the National Institute of Diabetes and Digestive and Kidney Diseases. Assessing the disaster fell to a sister institute, the National Institute of Neurological and Communicative Disorders.
     A pediatrician there, Dr. Daniel Carleton Gajdusek, had received the Nobel Prize for physiology or medicine in 1976 for his work on CJD. In 1968, he had published in Science magazine an article showing that CJD was transmissible through exposure to infected brain tissue.
     However, the man who would lead the institute's investigation was Gajdusek's colleague, Dr. Paul Brown, then establishing himself as a world-class epidemiologist on the spread of CJD.
     When the first CJD case appeared in a growth hormone recipient, Brown thought it was a coincidence. Then, as other cases rolled in, he became convinced that the hormone was the culprit. He began systematically testing remaining stocks of the drug.
     "One of the lots that was inoculated did in fact transmit disease to an animal," he told The Times.
     It took Brown six years to publish an estimate of how many glands infected with CJD might have entered the system. By 1991, the official estimate was 140.
     As shocking as this seems in retrospect, Brown takes pains to stress that, at the time, too little was known about CJD. "Before 1985, nobody had any idea it [the hormones] would be contaminated," he said.

     Veterinary Geneticist Raises the Alarm

     That is where American knowledge stood for the next 15 years. It was regrettable, but unavoidable. Nobody could have known.
     Except, it emerges, someone did.
     In reviewing the documents generated during the 1996 British human growth hormone trial, The Times found a paper trail between the British government and the NIH. Its existence had remained unknown in America and its significance unrecognized in Britain.
     The man who raised the alarm was not a Nobel laureate, not a neurologist, but a specialist in an obscure disease of sheep: veterinary geneticist Alan Dickinson, founder of the Neuropathogenesis Unit at the University of Edinburgh in Scotland.
     Dickinson specialized in the sheep form of CJD, called scrapie. In decades of experimentally infecting mice with scrapie, he had observed that the pituitary glands became both infected and infectious.
     On Oct. 5, 1976, nine years before the first cases of CJD appeared, Dickinson called to warn the British Medical Research Council of the danger posed by its growth hormone program.
     "My intrusion came after the sudden realization that they were using human pituitaries," he said.
     But it was only four months later, after Gajdusek reported that CJD could be spread by surgical instruments, that curiosity among the British officials was roused. Even so, a member of the British pituitary program took more than a year to write Gajdusek, seeking his opinion about Dickinson's warning. By then Gajdusek was traveling abroad.
     On May 8, 1978, a visiting Australian pathologist named Colin Masters answered on his behalf. Masters echoed Dickinson's warning: "It would be reasonable to expect that the pituitary gland and/or surrounding tissue taken from a case of CJD disease would be contaminated with the virus."
     At Masters' invitation, the British then forwarded the purification protocols to the NIH for review. But there is no record that Masters ever made good on his offer to evaluate either the Swedish or Wilhelmi methods for their ability to remove CJD contamination.
     And in spite of the now-acknowledged danger, neither the British nor the Americans moved to exclude the use of glands from organ donors who had died of CJD. Nor did Masters warn the NIH's National Pituitary Program.
     Masters subsequently returned to Australia, where he is now head of the Australian National CJD Surveillance Unit at Melbourne University. Asked why he did not relay the warning, he responded, "Presumably the people who were running the pituitary programs should have been aware of the warnings that were being sounded in the medical press."
     Both Brown and Masters were in Gajdusek's lab at the NIH. But, while Brown insists that the danger of CJD contamination was unforeseeable before 1985, to the mind of Masters, it was too obvious to mention.
     By 1979, the British were worried enough to give Dickinson money to test the Swedish protocol for its ability to eliminate CJD. Pituitaries were deliberately infected, then purified and injected into test mice. The Wilhelmi-Hartree method, however, was not tested. In 1982, Dickinson had his answer: The Swedish method appeared to be safe.
     The results were not published for three years. Both Dickinson and the British hormone program sponsors were sensitive to the potential for a scare. But in the wake of Alison Lay's death in 1985, the results showing the Swedish method's safety were seen to have a calming effect. They were published in the same issue of the Lancet as her case history.
     The drug appeared safe for children, including 4,000 Americans, who had received the drug after 1977, the year Parlow took over production and insisted on the filtration.
     The other roughly 4,000 American children treated before 1977 with hormone from Emory, Tufts and Cornell no longer needed Dickinson to test the drug on mice. They were the mice, and it was official: The drug was potentially deadly.
     After the Lancet report, in September 1985, Brown reported on the three American deaths in the New England Journal of Medicine. America faced, Brown wrote, the "ominous possibility of a burgeoning epidemic" of CJD.

     Survivors Mired in Legal Battles

     Public displays of concern about a potential epidemic of CJD were one thing. Doing something to help the victims proved to be another. When Wendy Nofi first descended into madness between July and November 1995, her husband, Mike, sought assistance from the NIH. "I was in contact with the NIH when she first got sick," he said. "I told them I wanted to keep apprised. I haven't received one thing."
     The Crairs say they too were rebuffed. "We called the NIH to seek help, but we received no counseling, no support whatsoever," said Stacey's sister, Lisa Crair. "At first we couldn't even get a doctor who would take Stacey on."
     By 1996, Gajdusek's lab was in turmoil. In March, as the laureate addressed a scientific meeting in Europe, the mad cow crisis erupted in the Britain. The next month, Gajdusek was arrested in Maryland on charges of child molestation. Found guilty in April 1997, he served a year of an 18-month sentence and then left for France.
     Mike Nofi had his wife placed on a feeding tube in a rest home. It took her 2 1/2 years to die. The Crairs nursed Stacey at home for four years.
     Both Lisa Crair and Mike Nofi are now lost in legal battles that they say they neither relish nor understand. Crair's lawsuit has been thrown out of court over legal technicalities in three states where the hormone was processed. Nofi has been given leave in New York state courts to sue numerous doctors, technicians and every university that handled the hormone--even Parlow's UCLA lab, the very place that in 1977 cleaned up the hormone.
     But Nofi is not suing the NIH. According to Pamela Liapakis, former president of the Assn. of Trial Lawyers of America, the agency enjoys what the legal profession calls "sovereign privilege" and is exceedingly difficult to sue under federal tort law.
     In Britain, however, outraged families did sue the government. In 1990, an English lawyer named David Body tracked Dickinson down in a drafty stone house outside Edinburgh, where he had been living in retirement for three years. Body then represented three of what are now 34 families of British hormone victims. He was going to try something nobody had ever done successfully in Britain: sue the Department of Health in a personal injury case.
     He needed an expert witness. After interviewing Dickinson, Body realized that he could "never put him on the stand."
     The scientist was frail and prone to severe migraines. But he typed out a statement that both outlined the state of knowledge about CJD 25 years ago and recounted his 1976 warning about the risk of contamination. In July 1996, the court decided against the British government to the tune of more than $7.5 million. Anyone treated with the potentially contaminated hormone after Dickinson's warning was issued would be compensated. Damages are now even going to the "worried well."
     Although Alison Lay's death sparked the 1985 crisis in Britain, her parents were excluded from the settlement, because their daughter was treated before Dickinson sounded the warning.
     "At least in this country we did have the trial," said Mavis Lay. "And the government admitted that it was at fault and caused the deaths.'
     By the time of the trial, Hartree had returned home to Nashville. She refuses all contacts with the media, lawyers and hormone recipients. In her absence, the British judge concluded that Hartree's failure to use Sephadex was, by analogy, "a commercial decision: quantity before quality."
     The court stopped short of finding the government negligent in the preparation of the hormone. "In the English claims, the issue of purification became secondary to the policy failures," said Body. "I'd like to see purification explored further in the United States."
     The more time that passes, the more difficult this will be. In 1994, at the age of 84, Wilhelmi died at his home in Atlanta.
     However, Parlow, his former colleague who upgraded the purity of the NIH hormone, said clear "warning bells" were ignored. Describing the early hormone, he said, "It was painful on injection. This signaled impurities."
     That was confirmed by a second side effect. "Ten to 15% of the kids treated developed antibody formation," said Parlow. "Though this is not life-threatening, it is not a good thing, and it means that there is something wrong with the product."
     In addition to the 22 Americans who have died from Wilhelmi-era hormone, CJD has killed five New Zealanders and one Brazilian who received pre-1977 American hormone. In Britain, 34 people have died, and the global toll stands at more than 125. The Centers for Disease Control says the rate of CJD cases among hormone recipients worldwide is increasing.

* * *

     Tracing the Growth Hormone

     1901-05: The word "hormone" coined
* * *
     1921: Creutzfeldt-Jakob disease (CJD) discovered in Germany.
* * *
     1925-45: Growth and reproductive hormones found in the pituitary glands in the brains of animals
* * *
     1958: Maurice Raben at Tufts University School of Medicine in Boston spurs 2.1 inches of growth in a dwarf by injecting him with human growth hormone extracted from pituitary glands taken from the brains of cadavers
* * *
     1963: The National Institutes of Health takes up sponsorship of the National Pituitary Program.
     The largest seat of production is the lab of Alfred E. Wilhelmi, head of the biochemistry department at Emory University in Atlanta. Swedish scientists notice that American growth hormone causes immune reactions and publish an alternative method for making the drug.
* * *
     1968: NIH doctor Daniel C. Gajdusek writes in Science magazine that CJD is transmissible via infected brain tissue. *
* * *
     1976: Edinburgh-based veterinary geneticist Alan Dickinson warns the British government that its pituitary program might spread CJD.
* * *
     1977: Wilhelmi retires. The NIH moves production of human growth hormone to the UCLA lab of Albert Parlow, who begins filtering the drug. The British hormone program also switches from the Wilhelmi protocol to the Swedish extraction method.
* * *
     1978: Dickinson's fears of CJD contamination in the hormone are passed to Gajdusek's lab at the NIH. In May, a visiting Australian pathologist replies on NIH letterhead that pituitary glands could be contaminated with CJD. But he does not pass the warning to the NIH's own pituitary program. *
* * *
     1985: Alison Lay, a hormone recipient, dies in Britain. Three unidentified American recipients also die. The NIH suspends the human growth hormone program. Paul Brown of Gajdusek's lab is called in to investigate. He warns of a potential "epidemic" of CJD.
* * *
     1991: Brown and others report in the Journal of the American Medical Assn. that 8,157 American children received the drug and that as many as 140 glands infected with CJD may have entered the system.
* * *
     1996: A class-action lawsuit on behalf of hormone recipients is brought against the British government. A London high court awards the plaintiffs
     $7.5 million.
* * *
     2000: The CJD death toll among American recipients of pre-1977 unfiltered hormone stands at 22. The Centers for Disease Control and Prevention in Atlanta reports that the incidence of CJD in hormone recipients is rising from one case a year to two.
_ _ _

     Robin Mayper in the Times library contributed to this story