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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
* * *
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
* * * 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
* * * 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.