Cloned Embryos Could Help Explain Basis for Diseases

Scientists Expect to Determine Causes, Develop Therapies by Watching Progress of Illness in Cells Implanted in Mice

By Rick Weiss
Washington Post Staff Writer
Monday, February 23, 2004; Page A08

When South Korean researchers announced two weeks ago they had made the world's first cloned human embryos, they emphasized they had no intention of allowing those embryos to grow into cloned babies. Their goal -- like that of others doing similar work -- is to develop new therapies for Parkinson's disease, diabetes and other ailments.

The idea is to make a cloned embryo from a patient's healthy cells and then retrieve from the embryo stem cells that could be used to repair the patient's failing organ -- an approach known as therapeutic cloning. Because the cells would come from an embryo genetically identical to the patient, the theory goes, they would not be rejected by the patient's immune system.  or....

This potential to regenerate ailing organs has been a powerful -- though so far unsuccessful -- selling point as scientists and advocates have tried to persuade Congress and the Bush administration to loosen federal restrictions that preclude the use of federal funds for work involving cloned embryos.

In moments of candor, however, many scientists concede that therapeutic cloning is far down the list of reasons they want to clone human embryos. In the long run, the promise is real, they insist. But the technical and regulatory hurdles are so high that it could be a decade before the first proposal is ready for consideration by the Food and Drug Administration.

The agency has already said it will want answers to tough questions before it will consider allowing cloned embryo cells to be injected into patients: Will the cells go where they're supposed to go in the body? Could they turn into the wrong kinds of cells once they're in the body? Will they start multiplying uncontrollably and form cancers?

By the time those and other questions get addressed in animal studies, an entirely new approach to regenerative medicine -- one that may not depend on cloned embryos at all -- might have emerged.

But there are avenues of research that scientists do want to pursue immediately with cloned human embryos. They fall under the category of basic research and so are unlikely to get patients and politicians excited, researchers acknowledge. But they are experiments that could reveal in spectacular detail the basic causes of many diseases. And they could speed the development of new drugs through already well-established pharmaceutical pipelines, without having to break the new technical and regulatory ground that therapeutic cloning does.

Although the goals of these experiments are less sexy than the almost magical regrowing of sick organs, scientists are starting to talk about them more -- in part out of frustration that Congress remains unconvinced embryo cloning deserves federal support.

Instead of making cloned embryos as a source of healthy stem cells for transplantation into patients, scientists are proposing to make cloned embryos that explicitly bear the genetic glitch or glitches at the root of a patient's disease.

They would start with a diseased cell from a patient -- a degenerating nerve cell, for example, from a person with Lou Gehrig's disease, a neurological disorder that robs people of control over their muscles. Using cloning techniques, scientists would transform that cell into an embryo, which after a few days would produce stem cells. Each stem cell would bear the genetic roots of the disease and each would have the potential, as stem cells do, to turn into any kind of cell or tissue.

In the case of Lou Gehrig's, scientists already have found a handful of genes that appear to play a contributing role. But as with many diseases, they don't know which are most important. They also don't know what environmental influences might determine whether a person with those genes would get the disease or not.

With stem cells from a cloned Lou Gehrig's embryo, however, scientists believe they could quickly answer those questions -- and a host of others.

Here's how it would work: Researchers already know how to force stem cells to become nerve cells, so in one set of experiments they would do so with stem cells taken from a cloned Lou Gehrig's embryo and watch those cultured nerves as they degenerate in a laboratory dish. That alone would be an unprecedented opportunity to watch the disease unfold outside a person, and to test whether certain classes of chemicals or drugs might slow or prevent the process.

But even better, said Irving Weissman, director of Stanford's Institute for Cancer/Stem Cell Biology and Medicine, scientists could inject those fresh but doomed neurons into the brains of mice and watch how the cells grow, die and respond to various drugs.

"You could study them not only in a dish but in the context of the kind of organ in which they normally find themselves," Weissman said.

Studies could go much further than that, others said. Scientists already know how to "fix" broken genes in stem cells by splicing out the bad copies and replacing them with normal copies. Researchers could start doing that one at a time with the handful of genes suspected of playing a role in Lou Gehrig's. Then they could see whether fixing one gene, or another, or a combination of several, prevented the degeneration of nerves.

They could do the same with genes in muscle cells from a Lou Gehrig's embryo. After all, the disease is all about communication between brain cells and muscle cells. And although scientists suspect that muscle cell genes may contribute to the disease along with nerve cell genes, it is not known how big a role each plays.

With key genes identified, it would be much easier to design a drug or other therapy that could target the biochemical essence of the disease.

Finally, since defective genes alone often are not enough to cause a disease but do so only after a specific environmental trigger -- exposure to pollutants, stress hormones or cigarette smoke, for example -- scientists could add those influences in lab dishes or in mice and see how they contribute.

"You could study the multistep progression of the disease," said Robert Lanza of Advanced Cell Technology in Worcester, Mass., a company pursuing human embryo cloning with private money. "This use of clones has been totally missed by the public but is of extreme importance to really understand the molecular basis of disease."

Cloned embryos could also shed light on an entirely different class of diseases, said Douglas Wallace, a geneticist at the University of California at Irvine. More than 125 diseases have been linked to genes not in the central nucleus of people's cells but in the mitochondria -- tiny cellular structures inherited from the mother. Because cloning involves the transfer of nuclei from one cell to another, it would allow scientists for the first time to sort out the respective contributions of nuclear and mitochondrial genes in various diseases.

Such experiments are specifically allowed under an otherwise broad ban on cloning research in Britain, Wallace said, because of their potential to explicate and eventually treat these diseases.

In this country, all such work is off-limits to federally funded scientists, who conduct the vast majority of the nation's basic biomedical research, because of political battles over the ethics of embryo research. There is no good great enough to justify the destruction of human embryos, opponents of the research vehemently maintain.

Because private companies are almost universally unwilling to tread on such controversial turf, Weissman and others said, it is likely -- for better or worse -- that many of the advances to come in the next year will, like the South Korean announcement, highlight foreign scientists.

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