This article from The NY Times March 8, 2001
Parkinson's Research Is Set Back by Failure of Fetal Cell Implants
By GINA KOLATA
A carefully controlled study that tried to treat Parkinson's disease
by implanting cells from aborted fetuses into patients' brains not
only failed to show an overall benefit but also revealed a
disastrous side effect, scientists report.
In about 15 percent of patients, the cells apparently grew too
well, churning out so much of a chemical that controls movement
that the patients writhed and jerked uncontrollably.
The researchers say that while some patients have similar effects
from taking too high a dose of their Parkinson's drug, in this case
the drugs did not cause the symptoms and there is no way to remove
or deactivate the transplanted cells.
On the researchers' advice, six patients who enrolled in the study
but who had not yet had the implantation operation have decided to
forgo it.
The results, reported today in The New England Journal of
Medicine, are a severe blow to what has been considered a highly
promising avenue of research for treating Parkinson's disease,
Alzheimer's disease and other neurological ailments. The study
indicates that the simple solution of injecting fetal cells into a
patient's brain may not be enough to treat complex diseases
involving nerve cells and connections that are poorly understood.
Some say it is time to go back to the laboratory and to animals
before doing any more operations on humans.
The findings may also fuel the debate over whether it is
appropriate to use tissue from aborted fetuses to treat diseases.
Despite their disappointment, some researchers said they hoped that
the results would not bring fetal cell research to an abrupt halt.
The research has been controversial because the fetal cells were
obtained from abortion clinics.
"This is still our one great hope for a cure," said Dr. J. William
Langston, who is scientific director and chief executive officer at
The Parkinson's Institute in Sunnyvale, Calif.
Parkinson's disease occurs when cells of the substantia nigra
region in the base of the brain die, for unknown reasons. The hope
was that fetal substantia nigra cells might take over for them.
But, the study showed, in older patients the operation had no
benefit and in some younger patients, the transplants brought on
nightmarish side effects.
Although the paper depicts the patients with the side effects in
impassive clinical terms, doctors who have seen them paint a very
different picture.
Dr. Paul E. Greene, a neurologist at the Columbia University
College of Physicians and Surgeons and a researcher in the study,
said the uncontrollable movements some patients suffered were
"absolutely devastating."
"They chew constantly, their fingers go up and down, their wrists
flex and distend," Dr. Greene said. And the patients writhe and
twist, jerk their heads, fling their arms about.
"It was tragic, catastrophic," he said. "It's a real nightmare.
And we can't selectively turn it off."
One man was so badly affected that he could no longer eat and had
to use a feeding tube, Dr. Greene said. In another, the condition
came and went unpredictably throughout the day, and when it
occurred, the man's speech was unintelligible.
For now, Dr. Greene said, his position is clear: `No more fetal
transplants. We are absolutely and adamantly convinced that this
should be considered for research only. And whether it should be
research in people is an open question."
Dr. Gerald D. Fischbach, who was director of the National
Institute of Neurological Disorders and Stroke, which sponsored the
study, said that while the operation had been promoted by some
neurosurgeons as miraculous, this was the first time it was
rigorously evaluated. It used sham surgery as a comparison, a
controversial and rarely used strategy but one that researchers
felt was necessary to understand the true effects of the operation.
Dr. Fischbach, who is now dean of the faculty of medicine at the
Columbia University College of Physicians and Surgeons, was the
director of the institute only at the end of the study.
"Ad hoc reports of spectacular results can always occur," Dr.
Fischbach said. "But if you do these studies systematically, this
is the result you get."
The surgery, he added, "is not the final solution that people
would have hoped going into it."
In the study, researchers, led by Dr. Curt R. Freed of the
University of Colorado Health Sciences Center in Denver and Dr.
Stanley Fahn of the Columbia University College of Physicians and
Surgeons, recruited 40 patients, ages 34 to 75, who had had
Parkinson's disease for an average of 14 years. The patients were
randomly assigned to have substantia nigra cells from four fetuses
implanted in their brains or to have sham surgery, for comparison.
The surgery took place in Colorado and the patients were evaluated
in New York. The fetal cell surgery involved drilling four small
holes in the patient's forehead and then inserting long needles
through the holes into the brain and injecting fetal cells. The
sham surgery involved drilling the holes but not injecting needles
into the brain. After a year, the patients were told whether they
had the fetal cell surgery and, if not, they were offered it if
they wanted it.
The study's primary measure of success was whether the patients
themselves noticed that they were better, as determined by a survey
that they mailed in a year later but before they knew whether they
had had fetal cell implants or a sham operation. The study found no
difference between the two groups — neither those who had had the
fetal cell operation nor those who had had the sham surgery noticed
an improvement in their symptoms.
Other tests, like neurologists' assessments of the patients while
they were taking their medication and the patients' assessments of
their condition in diaries they kept also showed no effect of the
surgery. And there was no difference between the two groups in the
doses of drugs needed to control the disease.
The one glimmer of hope came from assessments by neurologists
before the patients had had their first dose of medication in the
morning. By that measure, the 10 patients under age 60 who had had
the fetal cell implants seemed better than those who had had sham
surgery, with less rigidity, although their tremor was just as bad.
Dr. Freed hailed that result, saying, "It was a clear-cut
improvement."
And, he added, the fetal cells survived in most patients' brains.
"I would be disappointed if people used a strict clinical trial
approach," Dr. Freed said. "This study is about multiple
phenomena."
Others were less enthusiastic, pointing out that finding subgroups
after the fact who may have benefited suggests a hypothesis for
future studies, not evidence of an effect.
"We try to teach everybody that you have to identify beforehand
what's the primary outcome," said Dr. William Weiner, the director
of the Maryland Parkinson's Disease and Movement Disorder Center
and a professor of neurology at the University of Maryland School
of Medicine in Baltimore, referring to the measure of success
determined before the study began. "In this case, they picked a
subjective assessment by the patients themselves, which I think is
a very good one."
And so, Dr. Weiner said, when the patients noticed no improvement,
"the study was negative."
In addition, Dr. Langston said, even if a subsequent study
confirmed that the surgery had an effect on the condition in
younger patients before they took their medicine in the morning,
and even if there was a way of preventing the terrible side effect,
the operation would still hardly be a breakthrough. Parkinson's
disease is almost always a disease of the elderly, he noted, adding
that well under 10 percent of patients who would be candidates for
the surgery are younger than 60.
The wiggling and writhing movements first emerged a year after the
operation, showing up in five of the younger patients who had at
first appeared to benefit from fetal cell surgery — three who had
the operation in the initial phase of the study and two who had it
a year later, when they learned that they had originally had a sham
surgery. While doctors sometimes see such effects in Parkinson's
patients, it is caused by giving too much of drugs that act like
dopamine in the brain. And it can be controlled by reducing the
drugs.
In this case, however, drugs were not the culprit. Even when
doctors took away the drugs, the symptoms persisted.
The fetal implant study had been controversial from the start,
both because it included sham surgery and because it used fetal
tissue from abortions. But many Parkinson's disease experts said it
had to be done because doctors were already offering the surgery to
patients, and charging them for it, at costs of $40,000 or more,
with no evidence that they were helping them. Yet patients, facing
a disease in which brain cells slowly and inexorably die and in
which even the drugs that once controlled their symptoms of tremor
and rigidity would inevitably fail, took their chances with the
operation, thinking they had little to lose.
Dr. Freed said he was the first in the United States to offer the
treatment, starting in 1988 with a 52-year- old man, who is still
alive although, of course, he also still has Parkinson's disease.
Dr. Freed continued to offer it to paying patients while he was
treating those who were part of the federal study and whose
procedures were paid for by the study. He said he considered these
other operations research because he experimented with different
amounts and placements of fetal cells. He has given fetal cell
implants to 27 patients, he said, with the most recent operation
last October.
Dr. Freed said his group was now implanting less fetal tissue and
putting the tissue in a different area of the brain, hoping to
avoid the devastating side effects. But, he said it would be a
mistake to stop doing the surgery altogether.
"To say that you can't do or shouldn't do human research because
the research has uncertain outcome, I think would be a bad
decision," Dr. Freed said.
Meanwhile, a second federally financed study of the operation is
winding to a close, and some researchers say it is time to go back
to animal studies and learn more about the complex roles of the
brain cells involved in Parkinson's disease.
Dr. Weiner said that if a patient came to him today seeking
advice, he would say: "The bottom line for patients is that human
fetal cell transplants are not currently the best way to go. If you
are willing to pay for them, you can still have them done. But my
advice is you ought not to do this."