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Caution needed in Parkinson's trials

Thirty years ago, one of my favorite uncles noticed that his hands trembled even when they were at rest. He was in his 60s, still robust and proud of his prowess as a champion handball player in the Bronx. The trembling was the first sign of Parkinson's disease.

My uncle's course was typical. Although drugs helped for a while, the disease proved unrelenting as cells in his brain died and he was deprived of dopamine, an essential chemical. His warm smile was replaced by the blank mask of largely immobile facial muscles. His trembling hands spilled food. Walking was a struggle of shuffling and the terror of falling.

It is no wonder that desperate patients with Parkinson's would take great risks in search of a cure. One novel approach that has gripped the public imagination is therapy aiming to regenerate healthy brain tissue using immature brain cells from embryos and fetuses.

Over the past decade researchers conducted experiments of cellular therapy in small numbers of patients, and the anecdotal results were said to be promising.

Last week, physicians at the University of Colorado in Boulder and at New York's Columbia University reported the first controlled study on the risks and benefits of this therapy. Analyzing the same results, the researchers appear to have split sharply over the wisdom of continuing human experiments. The Colorado team plans to proceed, testing different fetal-cell preparations implanted more selectively in the brain. One of the Columbia researchers has called for a halt to these transplants.

Can we ethically give license to human experiments that appear to have done little good and caused devastating and possibly permanent harm? Yet can we deny desperate patients the procedure if they are informed of new data on risk and choose to take it?

The pivotal study randomly assigned 20 patients to receive the transplant and 20 to undergo sham surgery. Neither the patients nor the neurologists evaluating them knew which patients had received which treatment.

After one year, there was no significant difference in the condition of the two groups. But later five patients who had received transplants began experiencing severe side effects: uncontrollable movements, with swinging and writhing of their arms and jerking of their heads. It appears that the new brain tissue from the fetal cells overgrew and poured out too much dopamine.

This is not the first time that a highly innovative approach to a severe disease has caused catastrophe. The initial patients undergoing bone-marrow transplantation in the 1950s all died in short order. In 1999 a gene-therapy experiment at the University of Pennsylvania caused the death of a young man. Severe side effects are not uncommon in opening new frontiers of medical therapy.

It is often emotionally and logistically difficult to apply the brakes abruptly to a treatment hailed as having extraordinary promise. But workable cellular therapy for severe Parkinson's is unlikely to be discovered without more research in the laboratory.

Something instructive happened with bone-marrow transplants: The initial ones failed because of blanket rejection, and researchers suspended clinical trials until critical knowledge was gained from the test tube and from animals. Only then were humans again subjected to this harsh procedure, and now, after decades of incremental research, many are cured of illnesses such as leukemia and lymphoma.

In retrospect, after the outcome of the Parkinson's-disease trial, it seems almost naive to count on fragments of fetal tissue _ fragments that are not standardized with regard to their cellular and molecular contents _ to grow, mature, migrate and function with the exquisite equipoise of an organ like the brain.

While physicians engaged in experimental medicine can justify taking great leaps forward on behalf of desperate patients with incurable diseases, it is rare that clinical success is achieved in the absence of an understanding of the fundamental science.

As so often occurs with apparently revolutionary treatments, the first blush of anecdotal achievements pales in the setting of prospective studies that include a control group. One of the most painful moments for a research physician is to accept experimental failure.

Judgments about suspending further treatments are never perfect and can always be second-guessed. But researchers who suspend clinical trials need not relinquish the dream of curing patients. Their work in the laboratory is only made more urgent.

Before we have more confidence that we can do good for people suffering from Parkinson's disease and other degenerative conditions, we must rely on an ancient dictum of the physician: First, do no harm.

Jerome Groopman, the author of Second Opinions: Stories of Intuition and Choice in a Changing World of Medicine, is a professor of medicine at Harvard University in Cambridge, Mass.

New York Times