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1 PROMETHEUS Douglas Melton

There’s a natural fear of the unknown. On the

other hand, I think it’s uninteresting to live in

a society where one is so afraid of the unknown

that you won’t try new things.

—Douglas Melton

Harvard embryologist

Why did Prometheus do it? Myths about this god who gave fire to mortals against the express wishes of Zeus never explain his motive. But I’m going to make a guess. He had mortal children who were cold and tired of eating berries and gnawing on raw meat. And father Prometheus, who sat around Olympus with other gods warming his hands with glowing embers on cold nights, felt guilty. And that’s how we got fire.

Prometheus paid dearly. Zeus punished him for breaking a command to keep fire in Olympus by chaining him to a rocky crag, where his liver was eaten every morning by an eagle, only to grow back by the next morning, so the screeching bird could tear it out again.

The Harvard embryologist Doug Melton, fifty-one years old, makes no secret of his motive for pushing hard to develop a modern-day equivalent of fire—embryonic stem cells. These are special cells produced in the first days after an egg is fertilized that will develop into a heart, brain, skeleton, or any other part of the body of an organism. Melton wants to use stem cells to save his own children, fourteen-year-old Sam and eighteen-year-old Emma. They suffer from type I diabetes, which he hopes can be treated by understanding how stem cells grow into special cells called islets in the pancreas that normally produce insulin in a healthy person but shut down and stop functioning in a diabetic.

By extension, the cherub-faced Melton, with floppy, short, graying hair and round-rimmed glasses, hopes to save us all if he is successful in learning from stem cells how to cure his children, to spare them the organ failure, blindness, heart disease that eventually afflict many diabetics. If stem cells work as treatments, his work could be used to heal other illnesses, a list of maladies that afflict hundreds of millions of people around the world. That is, if Melton is allowed to continue his work by certain lawmakers in Washington, D.C., who today collectively play the role of Zeus.

1

Sitting in Melton’s office on a cool, bright spring day in Cambridge, I look at the faces of his children in photographs on his desk. Sam is lanky with short hair and a slightly awkward smile; Emma has long, dark hair and serious eyes. Now a college freshman, Emma once wrote in an essay that she wants to become an embryologist like her father. “I am also interested in becoming a member of Congress and petitioning for a cure that way,” she wrote. “I just hope she gets the chance,” says Melton. “In this, I am no different than any parent.”

Inside Sam and Emma and 1 million other in-sulin-dependent diabetics in the United States, the body’s immune system inexplicably attacks islet cells as it would a foreign invader such as a virus, an autoimmune response that destroys these cells’ ability to produce insulin. Insulin is an enzyme that helps transport sugars from the blood into cells for use as fuel. Without it, the sugars gum up in the blood vessels as sugar does in a gas tank, causing a patient with full-blown, in-sulin-dependent diabetes to go into shock and die. Most diabetics today are saved by frequent shots of synthetic insulin, though the balance between blood sugar and injected insulin is often a crude calculation. Almost all diabetics receive either too much or too little insulin at various times, a situation that can cause gradual damage to organs and muscles over the years. For Melton’s children, this imbalance may be an early death sentence, unless researchers can find a treatment or a cure for the islet dilemma. One of the most promising is for their father or another stem cell researcher to discover a stem-cell fix for pancreatic cells.

Melton’s resolve to give the embryological equivalent of fire to his children is evident from the floor plan of his office at Harvard. Unlike most senior science professors here and at other elite institutions, where offices of big shots often resemble the world headquarters of a company, or a nation, with staff, awards, and reprints of papers everywhere, Melton’s nondescript office is connected to a personal lab that is separate from his team’s main labs down the hall. His office has some of the expected awards and reprints, too, but as I sit with him at a small table near his desk, it’s clear where he would rather be. “I don’t want to waste any time,” he says, popping up to show me the small work station where he tries to tease out the mechanisms of how a stem cell makes the transformation into a pancreas.

Melton may be soft-spoken, but he has become a firebrand for his children, and for his science, openly defying the Olympians in Washington who oppose his research. Several times he has traveled to Washington to give testimony to Congress, especially after President Bush announced in August 2001 that federal funds for stem cell research would be restricted to sixty-four frozen embryonic stem cell lines already culled from existing embryos. These “lines” are special groupings of stem cells coaxed to replicate to produce more stem cells, and not to develop into other cells. These lines are critical for research, though acquiring them is controversial because the only source at the moment is to snatch them out of embryos grown in petri dishes, a process that causes the embryos to be destroyed. To some people, this is murder. To others, the embryos are simply a grouping of cells that are incapable of becoming human beings unless they are in a womb. As Melton and other scientists point out, thousands of embryos are discarded every year during in vitro fertilization procedures, though under the Bush rules, scientists using federal funds are banned from using them.

The president banned the development of further lines with federal funds, although the restriction does not affect private or statesponsored funding. Bush’s position sounded like a compromise, but it quickly became evident that the sixty-four lines did not really exist. The actual number of cell lines widely available to researchers has turned out to be far fewer, a stem gap that is hampering research paid for with U.S. money—the lion’s share of all funding for scientific research. Some of the approved lines are either in the hands of private entities, or have been tainted by mouse cells that make them unusable for human research. “There was this idea now that there are these sixty or seventy cell lines which the administration claims exist,” says Melton. “I think the number is closer to five to ten.”

Soon after President Bush announced his policy, Melton and others launched various crusades to get around the restrictions. At Harvard, Melton worked to assemble funding from the privately endowed Howard Hughes Medical Institutes, where he is a chief investigator, the Juvenile Diabetes Research Foundation, and other nonfederal sources. In March 2004 Melton announced that he had developed seventeen new embryonic stem cell lines, available to any researcher who has access to nonfederal funds. He also is director of Harvard’s new stem cell institute, which has raised $100 million for stem cell research from private donors. In California, scientists, universities, and their political supporters sidestepped the Bush rules in November 2004 when voters passed a state referendum approving $3 billion in bonds to fund stem cell research at the state level—including research using embryonic stem cells. This referendum will fund stem cell research in California at $300 million a year for ten years.

Across the sea, the British Parliament has passed regulations allowing government-funded embryonic stem-cell research, with safeguards, which went into effect in 2003. Singapore, China, South Korea, and other nations are also vigorously moving ahead with stem cell research.

Researchers are a long way from using stem cells to cure Sam and Emma, or anyone else. Stem cells may never work as treatments for many diseases, though at the very least, says Melton, they will help scientists understand the basics of how organisms develop and why mistakes occur that cause people to suffer. Yet researchers hope that someday these microscopic blobs might be tweaked to grow into healthy aortas to replace cells damaged by heart disease, or into a pristine spinal cord for someone like the late actor Christopher Reeves, who was paralyzed when his backbone was shattered in a horseback-riding accident. Nancy Reagan has also talked about her hope that stem cells can regenerate cells in the brain damaged by Alzheimer’s disease, which killed her husband, the former president Ronald Reagan.

Researchers also experiment with adult stem cells, created in each of us throughout life by specific organs such as the skin, which uses these stem cells when they grow into specialized replacement cells. However, not all organs and bodily systems have adult stem cells, and even when they do, these cells are not always as useful in repairing and regenerating as embryonic stem cells that have the potential to differentiate into anything. In the summer of 2004, Melton announced the results of an experiment that indicates there are no adult stem cells to regrow islets in those who suffer from type I diabetes.

Before his children grew ill, Doug Melton was an ambitious young researcher conducting leading-edge research in developmental biology using frogs, though he was perfectly content with a high-profile position in academia, writing exceptional scientific papers and getting kudos from his peers. His forays into politics and the media began only after he discovered Sam and Emma had diabetes, when Melton made the switch into pancreatic stem cell research. “I’m an activist now, I guess,” he says, smiling shyly. Most of his testimony and appearances are on behalf of the Juvenile Diabetes Research Foundation, which also has helped to fund his new stem cell lines.

Melton has a calm, private energy compared to other more fiery egos who appear on these pages. He has an earnestness about his work, a sense of humility that is not feigned, and less of a restlessness and a need to accomplish fantastic feats for all to see. He is not trying to rankle people with grandstanding ideas or using science as a vehicle to fame and glory. With undergraduate degrees in both philosophy and biology, and a Ph.D. in molecular biology, Melton loves nothing more than a vigorous intellectual argument. This is how he likes to present his ideas, with a passionate, long-winded, fascinating discourse.

Later, Melton will surprise me by presenting in the form of intellectual “puzzles” ideas that most of us would consider out there, such as, What might happen if scientists inject human stem cells into a monkey embryo? What would grow? A human heart, brain, or toe? “Now, this won’t happen in the next few years,” he says, “or even in the next few decades. But that, to me, is a kind of new biology that I find a million times more interesting than these specious arguments over whether life begins at fertilization.”

I mention to him that these experiments might seem bizarre to many people, and he agrees, though he argues that they will become normal one day. “There was a time when surgery was abnormal,” he says, when it was considered a violation of the body as the sacred vessel of the soul. “I’m intrigued by this issue of what is normal and abnormal,” he tells me, indicating that his ideas of normal may be different from most people’s—and that, as many scientists do, he gets juiced up by imagining scenarios just beyond what is now possible. This is a crucial characteristic of scientists, that they need to live in a space at the leading edge of what is possible, operating within the outer boundaries of acceptable ethical norms, but also pushing these norms into potentially new territory. This is what Melton is talking about with his puzzles.

Hopefully, Melton’s work and ideas will not result in his being chained to a mountain with a daily assault on a vital organ by a giant predator bird. Indeed, his comments about human brains in monkeys were posed as Socratic suppositions about what is normal, and what is not. Yet I also think that given the chance, and if ethically it was allowed, he’d perform the experiment—out of curiosity, to save his kids, and perhaps, to usher us into a new age of fire.

2

A researcher in obstetrics and gynecology at the National University of Singapore, Ariff Bongso, first grew human stem cells in 1994. In 1998, the University of Wisconsin’s James Thompson isolated human stem cells for the first time. Yet scientists have known about stem cells in mice since the seventies. The original discovery in mice occurred when researchers were studying certain cancer cells, which they now know have many of the properties of a mouse’s embryonic stem cell that can grow into different types of cells. Melton says this promising line of research stopped, however, in the early eighties before a connection was made between what was going on in mice and humans.

“The field didn’t move forward at the time because of an historical accident,” he says, which was the discovery of recombinant DNA technology. This became all the rage and sidelined other research as scientists sought to learn about cell differentiation not through working with stem cells, but by recombining genes from different species, and also by removing, or “knocking out” genes in mice to see what impact all of this would have on a cell or organism. “It’s only now that people are going back to mouse [embryonic stem] ES cells, let alone human ES cells. And while they’re extremely useful for studying gene function in an animal, they also have their own inherent interest. Could you make body parts, tissues, ex vivo? That’s the field I’m very excited about, but we’re way behind.”

Since Bongso’s discovery in 1994, stem cells have ignited two firestorms. One is a creative fire, a breathtaking moment for Melton and other scientists, for whom a new world has been opened up for exploration that they believe will save countless Sams and Emmas. The other is political and ethical, the scorching debate that pits scientific optimists against skeptics who believe that this fledgling science may open up a Pandora’s box that could have unforeseen and catastrophic consequences.

For those who believe that life begins at conception, an experiment using embryonic stem cells is indeed a homicide. “We should not intentionally create life in order to destroy it, even for good purposes of scientific research,” says William Hurlbut, a Stanford physician and conservative bioethicist who was appointed by George W. Bush to sit on the President’s Bioethics Commission. He is not opposed to doing stem cell research, he says, just to acquiring the stem cells by destroying an embryo. “If we say that a human life in process should have a certain inviolable moral status,” he says, “then we protect ourselves against the dangers of both crossing a fundamental moral boundary and what other people call the slippery slope.” Hurlbut is closely connected to Catholic leaders and opposes abortion but says his convictions about the status of an embryo are based less on his religious convictions than on a fundamental belief that a line needs to be drawn to protect what it means to be a human.

Opposition does not arise from just the right-to-life camp. There are liberal secularists, too, who bring up Brave New World scenarios of baby farms where clones of you or me would be grown exclusively to provide spare parts—and farmed like a turnip or a chicken is now. Another fear is that stem cells will lead to designer babies engineered by using stem cells not merely to replace damaged cells in Melton’s children, but to add new cells designed to be supermemory cells, or super-muscle cells. The technoskeptic Bill McKibben frets that biotech companies and commercial interests are poised to patent stem cell discoveries, which may lead to biotech barons’ pushing stem cells and other bioenhancements on the public out of greed. “And they’ll be hard to police,” writes McKibben in his 2003 book Enough, “not only because they’ll contribute to political campaigns, but also because their work, day in and day out, won’t be dramatic enough to attract notice.” Many others who are not religious zealots or anticorporate warriors feel uneasy about the notion of creating a human embryo solely with the intention of harvesting its cells to benefit a full-grown human, though this unease may dissipate if cures are discovered.

A greater source of discomfort surrounds the use of cloning to create embryonic stem cells. Scientists believe that stem cells made from cloned DNA will work best to reconstruct spinal cords and liver cells in a specific person because the cloned cells are an identical genetic match and won’t be rejected by the body’s immune system. Rejection is currently a major drawback in transplanting hearts, kidneys, and other organs. Cloning also allows researchers to study how diseased cells develop in specific patients. To clone stem cells from, say, Sam Melton, a researcher would take Sam’s own DNA and implant it into a denucleated egg, which would hopefully grow into an embryo that contains Sam-specific stem cells capable of developing into pancreatic cells. These stem cells would be harvested and the embryo destroyed, although the embryo up until then could be placed inside a womb and theoretically taken to term, creating a full-scale clone of Sam.

Melton and other stem cell scientists insist that they have no intention of creating cloned human beings. But mistrust and fear of scientists and their motives lingers in a society that wants treatments and gizmos from science but fears its potential dangers and excesses. “I’ve had to face up to the fact that most of our society thinks of scientists as people who are likely to do something bad,” sighs Melton. “Either bad to make money for themselves, or to cause trouble in the Frankensteinian sense. And the fact is, scientists that I know are trying to do good for people.”

Rogue scientists and quacks have fed into the fear. In early 2003, a company called Clonaid claimed to have created a cloned human on behalf of a New Age sect called the Raelians, founded by a former race car journalist named Claude Vorilhon, a.k.a. Rael, who says that humans were cloned and brought to Earth long ago by aliens. When the baby failed to show up, and Clonaid refused to allow independent verification, their announcement was declared a hoax. More legitimate is the Italian embryologist Severino Antinori, who has claimed to be working to create a human clone in an undisclosed location. In February 2004, the cloning issue heated up when a South Korean research team led by Hwang Woo Suk of Seoul National University cloned thirty embryos of about one hundred cells each—by far the largest number grown to date. They then successfully extracted embryonic stem cells from one of the embryos. Stem cell advocates were ecstatic, while their critics pointed out that the Koreans could have planted their cloned embryos into a womb and attempted to grow a Xeroxed person. Also in 2004, the British government for the first time issued a permit under the Human Fertilization Authority for a team of scientists at the Center for Life in Newcastle to clone embryos to create stem cells.

Geneticists insist that reproductive cloning does not work well for animals, and that clones are prone to illness and a short life span. The clones also don’t look like replicates of the parent. They are genetically identical, but environmental factors in the womb cause the clones to develop different features. For instance, a company in California recently cloned a calico cat that was born with a different calico pattern from its genetic “parent.” “So little Bobby’s clone won’t look like the original Bobby,” the pioneering molecular biologist Sydney Brenner told me. “Besides,” he said in his dry South African – British accent, “I can find much more pleasant ways of reproducing children that do not involve cloning.” Yet someone will one day most likely clone a human being, if no one has already. The scientists say that the technology is difficult, possibly impossible, though they used to say cloning a sheep would be impossible—and then came Dolly in 1997. “That will be a disaster,” says Melton, “first for the child, but also for science, if the child ends up getting sick and dying, or becomes an object of revulsion and ridicule.”

The controversy over embryonic stem cells being a force of good or evil is as old as fire. The Promethean myth is not just about a sympathetic god who gives mortals fire. A cautionary tale about the dangers of delving too much into the mysteries of the gods, it also underscores the dual nature of scientific discovery—that fire is a potent tool for improving life but can also be a force of destruction. Cro-Magnon scientists undoubtedly pointed to fire and realized the possibilities: Charbroiled mammoth steak! Torchlight to paint bison on cave walls! Cro-Magnon skeptics agreed that mammoth kabobs were better barbequed than raw, but what if the flames leapt up in a gust of wind and razed the village, burning people alive? For aeons, the profire and antifire forces have seesawed back and forth as the prevailing viewpoint when new technologies and discoveries appeared. Fire is still rightly feared in certain forms, and we have strict laws about arsonists and others who abuse it. Yet humans long ago decided the basics about what’s useful and dangerous about fire. We have imposed sensible regulations on its use, striking a balance that we can only hope will one day prevail for the work of Doug Melton and his fellow fire-bringers.