Web of Life

In a Laboratory near Harvard Square, Massachusets, USA, batches of stem cells harvested from human embryos steadily multiply inside glass incubators and petri dishes filled with pink-red fluid.

The cells result from almost five years of work by a team of Harvard scientists led by 50-year-old Douglas Melton, a self-assured former frog biologist. Dr. Melton’s two teenage children have type-1 diabetes, and he is dedicating his career to using stem cells to cure it. Over time the disease, which affects about one million Americans, can ravage its victims, causing blindness, kidney failure and limb amputation.

Driven by personal anguish as well as scientific expertise, Dr. Melton has become one of the most influential scientists in a debate that is a campaign issue in the U.S. presidential race. Along the way, he has skirted U.S. government rules restricting the use of human embryos and helped raise $5 million from private donors to create a stem-cell institute at Harvard University. While a relentless advocate of stem-cell research, he also has crossed scientists in his field, criticizing stemcell research he thinks is headed in the wrong direction.

Stem cells literally form the foundation for human life as they divide into cells that eventually become every human tissue and organ. In the laboratory, when stem cells are plucked from embryos, the cells haven’t yet formed into a specific type. The trick is to get them to grow into specialized cells—insulin-making cells to treat diabetes, brain neurons to treat Parkinson’s disease or motor nerves to cure spinal-cord paralysis.

This is what Dr. Melton and a few dozen other laboratories around the world are struggling to do. Yet, despite all his efforts, Dr. Melton has yet to accomplish his goal of producing insulin - making cells in the lab. "We are convinced we can do it," he says. "We just don’t know how."

Some groups oppose stem-cell research because it involves the destruction of human embryos. In a much-debated compromise, the White House three years ago permitted federal funding for embryonic cell research but only for cells created on or before Aug. 9, 2001. The idea was to prohibit the use of federal money from encouraging the destruction of more embryos. The cells available for study come from embryos that were donated by couples for whom extra embryos were created during in-vitro fertility treatments.

Many scientists complain that the restrictions on stem-cell research are impeding progress. But Dr. Melton’s efforts show that some of the greatest barriers to turning the cells into promising new therapies remain those that scientists encounter in the lab.

"Anyone who says new therapy is around the corner, or even a few years away, is just wrong," says Ronald McKay, a leading researcher at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

With some conditions, such as Alzheimer’s disease, science has yet to understand what goes wrong. Simply replacing damaged brain cells with new ones grown in the lab from stem cells isn’t yet feasible and may not be for decades, researchers say.

But in diabetes, doctors are reporting early success with an experimental cell-replacement therapy. The treatment involves taking insulin-producing cells, called islets, from the pancreas of cadavers and transplanting them into diabetics. Since 2000, when the first successful islet transplants were performed at the University of Alberta in Edmonton, Canada, about 300 of these procedures have been done.

Stem-cell proponents say the main obstacle to making the diabetes treatment more widely available is the shortage of transplantable islets.

"Cadavers will never provide enough islets to meet the need," says Robert Goldstein, director of research at the Juvenile Diabetes Research Foundation, one of several groups lobbying against the federal funding restrictions. Last month, in testimony before Congress, Dr. Goldstein said: "We have good reason to believe that embryonic stem cells will one day be able to grow large amounts of insulin-producing cells for transplant."

Until the late 1990s, Dr. Melton wasn’t well known outside academia. As an embryologist interested in understanding how organisms develop, he centered his career on the Xenopus species of frog. The frog’s embryos develop outside the womb. Because the embryos are translucent, scientists can watch organs develop and see which biochemical signals are responsible for turning cells into specific tissues.

In November 1998, everything changed. Scientists at the University of Wisconsin reported they had isolated stem cells from human embryos. Suddenly, scientists who had been studying organ development in embryos of mice, frogs and chickens could examine human development.

Dr. Melton decided to try techniques used in studying frog embryos to investigate how the pancreas is formed. He hoped the research might reveal a way to regenerate islets—the insulin- making cells inside the pancreas that are destroyed in type-1 diabetes—as a way to find a cure for his son’s disease.

In 1999, Dr. Melton entered the public arena with testimony before a Senate hearing on whether to provide federal funding for stem-cell research. He said the need to constantly check his seven-year-old son Sam’s blood sugar was taking "a heavy toll on the rest of the family." He noted that his wife was regularly up late checking Sam’s blood, worried that if the sugar level dropped too low, the child might slip into a coma.

"I can’t recall a night since Sam was diagnosed when we slept peacefully," Dr. Melton said.

He also displayed his sharp elbows. When the University of Wisconsin demanded that those who wanted to work with its new cells agree to commercial and scientific restrictions, Dr. Melton attacked the conditions as "unacceptable and ridiculous," saying the cells should be made available without interference.

When Wisconsin refused to budge, Dr. Melton obtained cells from a research team in Israel that had participated in the original project but was now also feuding with the university.

Collaborating with researchers in Israel, Dr. Melton tested the effects of various growth factors on the cells. He found these chemical signals would push the stem cells in one direction or another. Some became immature nerves, others resembled muscle. But the Israeli-American team soon recognized that its ability to control the direction the cells took was limited. Stem cells proved extraordinarily difficult to manipulate. Rather than respond to the scientists’ commands, Dr. Melton said, they often behaved like "popcorn," Spontaneously morphing into a variety of cell types.

The next year, the Meltons’ daughter, Emma, then 12, also developed type-1 diabetes. Spurred by the plight of his children, he decided he could get faster results by isolating his own set of stem cells from human embryos, even though that was sure to generate more controversy. Over the next two years, in a collaboration with Boston IVF, a fertility clinic, his lab was sent liquid-nitrogen packed, stainless-steel bottles containing 344 frozen embryos donated from couples who had given permission for their unused embryos to be used in research. The embryos otherwise would be discarded.

In August 2001, with conservatives pressing for a ban on any funding of embryo stem-cell research, U.S. President George W. Bush struck a compromise. He ruled federal grants could be used to study only stem cells already taken from embryos. No U.S. money could be used to create new stem cells or to study new ones, which Dr. Melton was already set on doing. Dr: Melton immediately joined other scientists protesting the policy, saying the existing cell supplies identified by the administration were too few for research.

Although the administration initially disputed that, earlier this year, government scientists conceded that of the 78 batches of stem cells approved for study in 2001, only about 20 of the so-called cell lines are actually available or useful.

In March, Dr. Melton announced that his lab had created 17 new populations of embryo stem cells. He used money from the Howard

Hughes Medical Institute, which funded much of his earlier animal research, and from Harvard, the Juvenile Diabetes Research Foundation and private donors he says wish to remain anonymous. He says he has since used private money to create five more lines of embryo stem cells.

In a conference call to reporters across the U.S. and overseas, Dr. Melton described the logistics dictated by the government rules. In order not to violate the law, Dr. Melton had to create a separate lab that didn’t contain equipment acquired with federal funds. Lab tools bought with nongovernment money were segregated into boxes with red stickers.

"It was like making four dishes for dinner and making one of these with its own salt, pepper and other ingredients," he said. Noting he planned to provide the cells for a minimal fee to others who might want to use them for growing nerves or muscle cells, he said his lab was focused solely on turning the cells into islets.

Islets belong to a family of cells called endoderm, which make up organs such as the liver, stomach and pancreas. Researchers have yet to uncover the genetic signals that turn stem cells into endoderm