Cloning Trevor

Granted rare access to the labs of Advanced Cell Technology, the only U.S. group openly pursuing human cloning research for medical purposes, our correspondent spent six months tracking highly experimental work on the cells of a young boy with a life-threatening genetic disorder

At 9:00 in the evening on January 29, just as President George W. Bush was about to begin his first State of the Union address, I gathered with three anxious scientists in a small, windowless laboratory in Worcester, Massachusetts. We were at Advanced Cell Technology—a privately owned biotechnology company that briefly made international headlines last fall by publishing the first scientific account of cloned human embryos. The significance of the achievement was debatable: the company's most successful embryo had reached only six cells before it stopped dividing (one other had reached four cells, another had reached two)—a fact that led to a widespread dismissal, in the media and the scientific community, of ACT's "breakthrough." The work was largely judged to be preliminary, inconsequential, and certainly not worthy of headlines. Many people in political and religious circles, however, had a decidedly different view. They deemed ACT's work an ethical transgression of the highest order and professed shock, indignation, and horror.

Nonetheless, ACT was pressing ahead—which was why I had come to the company's cloning lab that night in January. The door to the lab was locked; a surveillance camera mounted on the ceiling watched our every move; and the mood was at once urgent and tense. A human egg, retrieved just hours earlier from a young donor, was positioned under a microscope, its image glowing on a nearby video monitor. The egg's chromosomes would shortly be removed, and the scientists in the room would attempt to fuse what remained of the egg with a human skin cell. If the procedure succeeded, the result would be a cloned human embryo.

Skin cell to embryo—it's one of the most remarkable quick-change scenarios modern biology has to offer. It's also one of the most controversial. Since the announcement, in 1997, of the cloning of Dolly the sheep, attempts to use human cells for cloning have provoked heated debate in the United States, separating those who have faith in the promise of the new technology from those who envision its dark side and unintended consequences.

Crucial to the debate is the fact that human cloning research falls into two distinct categories: reproductive cloning, a widely frowned-on effort that aims to produce a fully formed child; and therapeutic cloning, a scientifically reputable procedure that takes place entirely at the microscopic level and is designed to advance medical therapies and cure human ailments. The two start out the same way—with a new embryo in a petri dish. But the scientists I was observing in the lab had no intention of creating a person. Instead they were embarking on an experiment that, if successful, would be a first step toward creating radical new cures for patients like the donor of the skin cell—Trevor Ross (not his real name), a two-year-old boy afflicted with a rare and devastating genetic disease.

The mood in the lab was tense in part because of the uncertain outcome of the experiment. But it was also tense because of concern over what President Bush might say about cloning in his address to the nation. A radio in one corner of the room was tuned to the broadcast as the scientists began their work, and they were listening carefully: in perhaps no other field of science are researchers as mindful of which way the political winds are blowing. The ACT scientists had good reason to be concerned—what they were doing that night might soon be made illegal.

On July 31 of last year, by a 100-vote margin, the U.S. House of Representatives passed the Human Cloning Prohibition Act of 2001, which would impose a ban on the creation of cloned human embryos for any purpose, whether reproductive or therapeutic. Both forms of cloning would be punishable by up to ten years in prison and a million-dollar fine. The House passed the measure over the objections of a long list of biomedical organizations (including the Association of American Medical Colleges and the American Society for Cell Biology) and patients' advocacy groups (including the Juvenile Diabetes Research Foundation International, the Alliance for Aging Research, the American Liver Foundation, and the Kidney Cancer Foundation). That same day House members overwhelmingly rejected an amendment, put forward by Congressmen James Greenwood, of Pennsylvania, and Peter Deutsch, of Florida, that would have preserved scientists' ability to use therapeutic-cloning techniques for medical research.

Politics and religion, it seemed, were trumping science. Therapeutic-cloning research was already ineligible for federal funding in the United States. In 1995 Congress had passed legislation barring the use of federal funds for any experiment in which a human embryo is either created or destroyed, thus making official a de facto ban that had been in existence since 1975. (Congress has renewed the federal-funding ban annually since 1995 as a provision of the Department of Health and Human Services appropriations bill.) As a result, the burden of moving many areas of important medical research forward has fallen on the private sector, a situation that by many accounts has severely hobbled research into treatments for infertility—and even disorders such as childhood cancer and birth defects. These research areas, like therapeutic-cloning research, demand the kind of long-term study and financial commitment that only the federal government can provide. This past summer human therapeutic cloning already fell squarely under the federal-funding ban, yet Congress was now going further, considering making that research illegal.

In the debate preceding the House vote in July, opponents of therapeutic cloning had warned against the "industrial exploitation of human life" and had conjured up images of "cloned human embryo farms" at which "human beings" would be manufactured as a source of raw material and then "killed" for parts—this despite the fact that researchers envisioned working with five-day-old embryos, balls of undifferentiated cells that could fit on the point of a pin. Congressman James Sensenbrenner, of Wisconsin, insisted that "those who are interested in values" should vote to ban therapeutic cloning. Tom DeLay, of Texas, the House majority whip, called the practice "monstrous science that lacks any reasonable consideration for the sanctity of human life." Congressman Chris Smith, of New Jersey, stated plainly, "Creating human embryos for research purposes is unethical, it is wrong, and it ought to be made illegal." The mood was summed up the following November by Congressman Dennis Kucinich, of Ohio, in the debate that followed ACT's announcement. Kucinich said, "The Creator that our founders referred to was not ACT."

During the debate about the House bill, a handful of speakers had risen to protest what one of them called "this papal event that we are having here today." Congresswoman Zoe Lofgren, of California, argued, "Our job in Congress is not to pick the most restrictive religious view of science and then impose that view upon federal law." Greenwood, who co-sponsored the amendment to keep therapeutic-cloning research legal, said, "I am not prepared as a politician to stand on the floor of the House and say, '... You cannot go there, Science, because it violates my religious belief.'" He added, "I think it violates the Constitution to take that position."

In August, President Bush made clear that he agreed with the restrictive position. He characterized therapeutic-cloning research as an attempt "essentially to grow another you, to be available in case you need another heart or lung or liver." He continued, "We recoil at the idea of growing human beings for spare body parts, or creating life for our convenience." The President's wording did nothing to clear up widespread ignorance of the difference between reproductive and therapeutic cloning. ("What's going to happen to those clones?" a caller to NPR asked last fall, with typical confusion. "I mean, do they just live in a closet for their whole life?")

Ever since the passage of the House bill, ACT had been waiting for the Senate to act. A vote had been expected in the fall, but the events of September 11 overshadowed the matter. As the winter recess approached, Tom Daschle, of South Dakota, the Senate's Democratic majority leader, signaled his intention to bring the cloning issue to a vote by the end of March. "We need to bring some scientific light on this subject," said Senator Arlen Specter, of Pennsylvania, a supporter of therapeutic-cloning research and the ranking Republican on a subcommittee hosting cloning hearings. "The scientific community is ready to put forward a very strong case, and I think that case will be persuasive to the Congress." In mid-January the prestigious National Academy of Sciences, created to advise Congress, reiterated its support for therapeutic-cloning research, a move that proponents of the technology were hoping would sway opinion in the Senate. The word on the Hill at the time, however, was that the vote on a ban could go either way.

Last fall, with the prospect of a Senate vote looming, I decided to take a considered look at cloning research. The time seemed right: it was a unique moment in what could be the development of a major new medical technology, an odd period of legislative limbo in which the first halting steps were being taken toward creating cloned human embryos just as such efforts were in imminent danger of being outlawed.

In particular, I wanted to investigate the work being done by ACT—the only group in the country openly pursuing human therapeutic-cloning research. I wanted to know what motivated ACT's scientists. I wanted to observe firsthand what was happening in their cloning lab. I wanted to meet ordinary people afflicted with illnesses for which therapeutic cloning represented a potential cure. And, perhaps most important, I wanted to understand what happens to scientific progress when the burdens of research and development in an ethically sensitive area like cloning fall on the private sector rather than on the government. My motives were very much in the spirit of a remark made by Senator Daschle last November, when he helped to prevent a hasty Senate vote on cloning. "Let's take a deep breath," he said. "Let's think about this."

Progress Measured in Eggs

"That's Trevor's cells," Jose Cibelli told me in the ACT cloning lab on January 23. Cibelli is the vice-president of research at ACT, and the scientist in charge of its therapeutic-cloning attempts. He's a gentle, compact man with dark hair, a trim moustache and goatee, and a vaguely worried expression. A native of Argentina, he speaks quietly and with a thick accent.

It was the first time I had been in the cloning lab, which had the distinct feel of a walk-in closet. Inside the room were a refrigerator, an incubator, a sink, a sterile lab hood, and three microscopes lined up on a black lab bench. Cibelli had just placed a small plastic dish on a microscope platform. Stuck to the bottom of the dish, below a few liquid millimeters of red culture medium, were millions of fibroblasts—living skin cells taken from Trevor Ross.

"The smaller ones just finished dividing," Cibelli explained as we peered at Trevor's cells. "So they're just in G1." G1 is a rest phase that cells enter before preparing to divide again. It's also the stage that ACT has found best for cloning. Through the microscope I looked at the smaller cells. In each of them a large round nucleus—the compartment housing a full copy of Trevor's forty-six chromosomes—was clearly visible. With this payload of DNA, each cell had all the genetic know-how it needed to build a cloned human embryo.

The cells had come from a round plug of Trevor's skin, three millimeters across, and had arrived at ACT just five days before. The Rosses' dermatologist had chosen a crease between Trevor's buttock and thigh, where a scar would not be likely to show, and had punched down with a circular razor blade—past the dead cells of the epidermis and into the dermis, where fibroblasts grow and thrive. The dermatologist had closed the biopsy site with a single stitch. "I was very brave," Trevor told his mother afterward. During the next several days the Rosses treated Trevor's wound with dabs of antibiotic ointment and covered it with tiny Winnie-the-Pooh Band-Aids.

Cibelli now had fibroblasts for potential therapeutic-cloning experiments stored away at ACT from five patients: one with a spinal-cord injury, one with diabetes, two with healthy but aging bodies, and Trevor. But skin cells are the easy part—they're plentiful, hardy, easy to obtain and work with. Eggs are much trickier, and Cibelli had thus started measuring the likelihood of progress not in years but in eggs. "When do I think we'll get this to work?" he asked me rhetorically. "About two hundred eggs from now."

"We've gotten a handful of eggs so far," he had earlier explained. "It's a whole different game when you're talking about animal embryology versus human embryology." In the cow-cloning lab next door, for example, ACT receives 1,400 eggs on a typical day. But whereas cow eggs are available in abundance from slaughterhouses, human eggs must be obtained from young women who have undergone two weeks of hormone injections, regular visits to a doctor, and a nontrivial surgical procedure. All told, it costs ACT about $22,000 to take an egg-donation procedure from start to finish. "And the number is so small," Cibelli added. "I mean, you get ten eggs! Instead of working with a hundred embryos, I'm working with one." From July to October of last year, ACT collected a total of seventy-one eggs from seven donors—of which only nineteen were designated for cloning. That didn't leave much room for error, or much chance to tinker with conditions that might improve the chances of success.

To make matters worse, the company hadn't had any luck cloning from fibroblasts, which it was hoping to use routinely. In three failed rounds of experiments from July to September not a single egg vested with the DNA of a fibroblast so much as divided from one cell into two. ACT's six-cell embryo, created in October, had been produced not with a skin cell but with an ovarian "cumulus" cell—a type of cell regularly used to clone mice. Unlike skin cells, however, human ovarian cumulus cells are rather difficult to obtain and, obviously, are not available for men.

Given the situation, I asked Cibelli what he would say to critics who might accuse ACT of promising the moon to desperate families like the Rosses long before the technology is ready for the clinic. "I'm not promising anyone anything," he responded, looking surprised. "I am saying that this has the potential to cure all these diseases. There are gaps in the research, but the gaps are getting smaller and smaller." One gap would start to close, of course, when a viable human embryo was created.

At five days of development a human embryo is smaller than a grain of sand. It's a perfectly round ball with a fluid-filled core. The internal architecture of the ball, however, is somewhat lopsided. Huddled against one wall of its interior is a group of cells known as the inner cell mass. The outside of the ball is destined to become the placenta and associated membranes; the inner cell mass is what forms a baby. But after only five days of development no cell's fate has yet been determined—it's impossible to tell which cells will become blood or muscle, skin or brain, gut or liver. All that is present is the simple raw material from which the more than 200 cell types in a human body will eventually be built.

If the inner cell mass of an embryo is removed at this early stage, it can yield cells known as human embryonic stem cells—which retain the ability to form any cell or tissue in the body. In a sense they are immortal, in that they can divide indefinitely in the lab, producing large quantities of cells. With the right coaxing those cells can theoretically be converted into an unlimited supply of tissue for transplant: new heart muscle for heart-attack survivors; insulin-secreting cells for diabetics; neurons to treat those suffering from spinal-cord injuries, the effects of stroke, or Parkinson's disease. Tissue engineers hope someday to build even more complex structures from these stem cells: new blood vessels for bypass surgery, new liver tissue, even new kidneys—all from what began as a loose collection of cells in a lab dish. They dream of a future in which all kinds of organs and tissues can be custom made to replace those ravaged by disease, injury, or a lifetime of hard use.

Since 1998 human embryonic stem cells have been isolated dozens of times—most often from embryos left over after infertility treatments. Each of these embryos, however, had a unique genetic makeup, and the stem cells derived from it will not be a perfect match for anyone on earth. When transplanted into a patient, therapies created from these stem cells—like donated organs in a traditional transplant—run the risk of being rejected by the immune system.

ACT hopes to use cloning to get around the problem of rejection, by tailoring embryonic stem cells to the patient. The procedure would be as follows: Take a patient's skin cell and create a cloned embryo in the laboratory. Five days later derive stem cells from that embryo and grow them in the lab. Then turn those cells, en masse, into the cellular therapy a patient needs. These would be the patient's "own" cells—a perfect genetic match. Of course, before putting cells into a patient, ACT would need to satisfy the FDA.

The first goal was to prove that the procedure could be done—before the Senate vote, if at all possible. "There are senators who are willing to support this," Cibelli told me. "But we'll really make their work a lot easier if we can show that this is feasible."

So far, it had been slow going. Since ACT's October "success," experiments planned for November, December, and early January had all fallen through—pushed back when an egg donor's hormone regimen failed, when the surgical team slated to collect the eggs had scheduling conflicts, and when ACT was running so low on cash that it couldn't afford to proceed.

After showing me Trevor's cells, Cibelli checked the clock. "We're going to have to get going," he said. It was 5:00 P.M.—time to drive to a fertility clinic just outside of Boston, where the eggs for ACT's experiment that day were being retrieved. We left the lab and headed for Cibelli's car, carrying a portable thermoslike incubator that would be used to transport the eggs. Cibelli plugged the incubator into his car's cigarette lighter, and a row of lights on the incubator began to turn on, registering that it was warming up to body temperature inside.

An hour later, when we arrived at the clinic, the egg-retrieval procedure was still under way, so we went for a cup of coffee at the neighborhood Starbucks. Cibelli placed his cell phone in the middle of our table, and we waited anxiously, fully aware that the number of eggs obtained can vary widely. When the phone finally rang, Cibelli checked his caller ID and said, "This is it." He answered the phone and listened for a few seconds. Then his face fell.

The procedure had failed utterly. Three big follicles in one of the donor's ovaries weren't mature enough to yield usable eggs, and the other ovary was positioned behind her uterus, where it couldn't safely be reached.

"Zero," Cibelli said when he hung up the phone, looking crushed. "We've gotten as low as five, but never zero." On the long ride back to Worcester with his empty incubator, Cibelli called to let his team know what had happened. Everyone could go home, he said. They'd try again the following week.

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