http://www.nytimes.com/2001/12/18/science/life/18MICE.html?pagewanted=print

December 18, 2001
By GINA KOLATA

Dr. Brigid Hogan has never worked with human embryonic stem cells — her expertise is with mouse cells. But patients with virtually every sort of chronic disease have found her, and they plead for help.

"I even hear from patients whose fathers have lung cancer," said Dr. Hogan, a professor at Vanderbilt University School of Medicine. "They have a whole slew of problems they think can be treated. They think stem cells are going to cure their loved ones of everything."

If it ever happens, it will not happen soon, scientists say. In fact, although they worked with mouse embryonic stem cells for 20 years and made some progress, researchers have not yet used these cells to cure a single mouse of a disease.

Scientists say the theory behind stem cells is correct: the cells, in principle, can become any specialized cell of the body. But between theory and therapy lie a host of research obstacles. Though not often discussed in public forums, the obstacles are so serious that scientists say they foresee years, if not decades, of concerted work on basic science before they can even think of trying to treat a patient.

Yet as excitement over stem cell research built over the summer, and surged again with recent reports of experiments with human cloning, scientists and doctors became deluged with calls from desperate patients who saw salvation around the corner. Somehow this research has come to be seen as the great hope for medical science. How, scientists ask, did expectations grow so quickly?

Though some say the news media overplayed the issue, some scientists say the problem lies within themselves. The crucial questions involve basic research, the sort supported by federal funds and conducted in universities. But with calls by some politicians to ban the work, and to bar any use of tax money to pay for it, scientists say they feel obliged to stress how important the research is. And, some say, they now fear they may have promised too much.

"We're being forced into taking extreme positions by the whole need to try and convince people of the need to go ahead," Dr. Hogan said.

Dr. Gail Martin, a mouse stem cell researcher at the University of California at San Francisco, said: "The expectations have been raised a little higher than perhaps is appropriate. It became politicized and tied up in the abortion debate." But, as the exaggerations and talk of revolutionary treatments continued, few made concerted efforts to set the record straight. And some small biotechnology companies continued to promise quick cures.

One problem is simply to find a way to get stem cells to grow into the types of cells that are needed, and not a mixture of cells.

Scientists know this is a thorny problem, but their views were not widely heard when the public and politicians seemed to assume that it was easy to grow any tissue type desired from embryonic stem cells. In fact, no one has been able to do this even with mouse cells.

Using stem cells to cure diabetes, for example, would mean converting them to islet cells, specialized cells of the pancreas that secrete insulin. And then the new islet cells would have to be protected from the underlying disease process that caused the diabetes in the first place. The science is not even close.

"Do we know how to make islet cells? No. Do we know how to make kidney cells? No," said Dr. Shirley M. Tilghman, a mouse molecular geneticist, who is the president of Princeton. "You can go on and on," she said.

"In the early days there was a cottage industry of trying to get them to do different things," Dr. Tilghman said. But the stem cells would never become just one type of cell, developing instead into mixtures of specialized cell types.

Few outside the field realize the difficulty of working with stem cells, Dr. Martin and others said. When mouse stem cells grow in the laboratory, she said, some of them spontaneously change, with chunks of genetic material moving from place to place on chromosomes. She said that if such changes gave cells even a 5 percent growth advantage in the laboratory, the altered cells completely took over the stem cell population within three generations. And if such cells were put into patients, they could cause cancer.

Even if all the other problems with stem cells are solved, researchers will face another problem. The body's immune system will see the new cells as foreign tissue and reject them. The only sure way to prevent this is to take powerful immune suppression drugs for a lifetime, trading insulin injections, for example, for immune suppression.

The problem would be avoided if the stem cells were derived from an embryo that was a clone of the patient — the stem cells of such an embryo would be genetically identical to the patient's cells. But cloning has its own problems. Not only do many politicians and religious leaders find it ethically abhorrent to create a clone and then destroy it as an embryo to extract its stem cells, but no one has yet come near getting the process to work.

One company, Advanced Cell Technology, recently announced its first attempts to create human embryos by cloning. The company failed — its embryos never grew or developed anywhere near a point where they would contain stem cells.

That normally occurs after about five days, when the embryo becomes a sphere with a ball of stem cells inside. Most of the company's embryos died without dividing even once, although one made it to an amorphous clump of six cells. In animals where cloning has succeeded, it remains very inefficient, often requiring 100 or more eggs to get a single viable clone.

Finally, researchers must get replacement cells derived from stem cells to integrate into the body's complex machinery and fill in the blanks left by diseased or dying cells. That task may pose its own problems, as scientists found when they tried to supply fetal brain cells to patients with Parkinson's disease. In some patients, the fetal cells apparently grew too well. They pumped out too much of the brain chemicals, and there was no way to remove the cells or turn them off.

But these cautionary findings were seldom mentioned when advocacy groups for patients with various disease took up the cause, even though researchers expressed little optimism for cures any time soon, if ever. The task of getting stem cells to develop into specialized nerve cells and then getting those cells to repair the damage in the disease is well beyond today's science, experts say.

"I have no idea how someone expects that you will inject neuroblasts and they will run all over the brain and replace your sick and dying neurons in Alzheimer's disease," said Dr. Davor Solter, a mouse stem cell researcher who directs the Max Planck Institute in Germany.

Dr. Martin, who is a co-discoverer of mouse embryonic stem cells and the one who named them, added, "There are a gazillion issues."

That is not to say that the issues will never be resolved. Dr. Steen Willadsen, a Danish scientist and a cloning pioneer who saw the impossible happen in his field, said demand for stem cell therapies was so great that scientists would make it happen, sooner or later.

But Dr. Martin and others say they worry about the short term, concerned by how the public will react when it becomes clear that stem cells are not an immediate answer for suffering patients. She and others say they are bracing themselves for a backlash when treatments fail to materialize.

"There's almost certainly going to be a backlash," said Dr. James A. Thomson, the University of Wisconsin scientist who first isolated human embryonic stem cells. "These are novel, unproven therapies. I believe there is tremendous promise, but it's going to take years to develop therapies." He said, however, that the media, not scientists, were at fault for the exaggerated promises.

"I blame the press," Dr. Thomson said. "It is very compelling to be able to make new body parts. It captures the imagination."

But Dr. Inder Verma, a gene therapy researcher at the Salk Institute in San Diego, said scientists set off the frenzy with their own hyperbole. And, he said, he has seen this sort of process unfold once before, with disastrous consequences.

Gene therapy, Dr. Verma said, had the same sort of promise attached to it two decades ago. In that field, too, scientists predicted too much too soon. When gene therapy failed, many turned against it. Stem cell therapy is heading in the same directions, Dr. Verma said, and some scientists are beginning to worry.

"We started it," Dr. Verma said, speaking of the debate. Now, he said, "we withdraw from it because we realize it is going out of control."

Yet, he said, this time, with abortion politics entwined in the story, the public backlash may be far worse than it was with gene therapy.

"In five years, if it doesn't work out, people will turn to us and say, `You divided the nation,' " Dr. Verma said.
 

Copyright 2001 The New York Times Company