91av

WHEN the chance for surgery came, George Doeschner seized it. Sure, there
were risks. The operation, part of a pioneering American clinical trial, would
involve drilling holes in his skull and injecting nerve cells from aborted
fetuses into his brain. But after more than a decade of Parkinson’s disease, his
tremors were getting bad. The fetal cells were never going to cure Doeschner,
but they might ease his symptoms.

And so they did. Yet as the tremors disappeared, Doeschner’s left arm began
to jerk uncontrollably. Four other patients suffered similar side effects.

Suddenly, fetal tissue transplantation—one of the most promising
avenues for treating not just Parkinson’s disease but Huntington’s, Alzheimer’s
and a host of other brain conditions—is in trouble. Ethicists are calling
for the transplants to be halted, and newspapers are talking about miracle cures
turning into catastrophes. Opponents of fetal research are having a field day.
“What’s morally bad turns out to be bad medicine too,” says Jack Scarisbrick,
chair of the British anti-abortion group Life.

But is the medicine bad? Since the news of the side effects broke, experts in
Europe have moved swiftly to limit the damage. Doeschner’s jerky left arm, they
claim, is down to a rogue transplant technique that hadn’t been tested properly
on animals. The American surgeons, meanwhile, say the problem of the side
effects has been overblown. And confusingly, Doeschner and one of the other
patients affected have defended fetal transplants, claiming their lives have
improved despite the jerky movements. So just how risky is this surgery?

Previous trials suggested fetal transplants can relieve the severity of
Parkinson’s symptoms by up to 40 per cent without side effects. But those
studies were small and uncontrolled. Not everyone benefited and even when there
was improvement it was hard to be certain it was not a placebo effect.

And while the benefits remained vague, the dangers were occasionally stark.
One 52-year-old Japanese woman living in the US had a fetal graft in 1995 that
she hoped would relieve the rigidity and shuffling gait that are typical of
Parkinson’s. Instead it grew into a cyst that killed her. The fetal tissue
appeared to have been contaminated with unwanted fluid-secreting cells.

“The fetal cell procedure is very crude,” says Robin Lovell Badge, an expert
on stem cells at the National Institute for Medical Research in Mill Hill,
London. “If you put a whole chunk of mid-brain from a fetus into a patient, who
knows what’s there.”

In future, stem cells isolated in a purer state from much younger embryos
might be the answer
(see “What are the alternatives?”).
But for now, most teams
are using grafts from fetuses. And clearly, the risks are only worth taking if
there is solid evidence of efficacy.

It was to get such evidence that the Colorado-based team at the centre of the
current storm decided to carry out the first large-scale placebo-controlled
trial. They injected 20 patients with fetal cells while 20 more,
controversially, received only sham surgery: holes were drilled in their skulls
but no cells were injected. Only after the trial were the second group offered
real transplants.

In standard coordination and speech tests, the younger patients—those
under 60—did show clear signs of improvement. Unfortunately, these
patients also included the ones who developed the worst side effects.

Curt Freed, the University of Colorado neuroscientist who led the trial,
insists the findings are broadly in line with expectations. “Over the years, we
have said that about a third of patients have remarkable benefit, about a third
some benefit and a third no benefit or are worse.”

Doeschner has been happy to put up with his jerky left arm. But others were
affected more seriously. Neurologist Paul Greene of Columbia University in New
York, who evaluated the patients, told The New York Times that one man
was so badly affected he could only eat by using a feeding tube.

What went wrong? One theory blames the surgical technique. Instead of
injecting the cells through the side of the head as is usual, the Americans
injected through the forehead. “The tissue may have spilt over into the frontal
cortex to give unpredictable results,” says Anders Björklund, an expert on
fetal cell transplants at Lund University in Sweden.

But overactive grafts could be the real problem. The American grafts may have
grown too well, churning out too much of the movement-controlling chemical
dopamine. Previous trials have used only fresh fetal tissue, finely diced or
softened with enzymes. But the Americans used strands of tissue that had been
kept in culture for up to four weeks. There’s no published evidence evaluating
this method, says Stephen Dunnett, a neuroscientist at Cardiff University.

Freed says his team is working on ways to improve transplants. Animal models
are useful, but don’t accurately mimic severe Parkinson’s symptoms. “These are
problems that must be solved in patients.”

The timing couldn’t be worse. Researchers in Britain are now testing fetal
cell transplants on patients with Huntington’s. But they say their grafts have
been tested properly on animals and they won’t be halting their operations.
“We’ll be writing to our patients to explain what has happened in the American
trial and giving them the chance to withdraw,” says Roger Barker, a
neuroscientist at the University of Cambridge.

Barker sees the latest episode as a warning of what can go wrong when teams
pursue their own pet surgical recipes using a variety of graft materials. We
need to standardise transplant methods, says Barker, before things get out of
control.