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
"An Incredible Gift to Mankind"

Although ACT is adamant that commercial realities had not motivated the announcement, one thing was clear: last fall ACT was not far from going broke. Its scientists were tight-lipped about the situation. When I spoke with Mike West about it, he chose his words carefully. He described the state of affairs as "nerve-racking," and went on to talk about the difficulties of a situation "where you are not making any money, you are losing millions of dollars a year ... and trying to raise money when Congress is trying to criminalize your business."

ACT was running on fumes. It was making payroll at the last minute and funding its human cloning experiments with eleventh-hour investments from friends, or with money from its scientists' own pockets. By October the situation had reached crisis proportions. "The finances were such that much of our research had to be put on hold," Bob Lanza told me.

The company did have a small amount of cash trickling in from an agricultural subsidiary, however, including a round of investment that came in shortly before the November announcement. In the end the announcement did attract interest from venture-capital firms, but everything hinged on the Senate's upcoming decision, since no one was committing money to a business that might soon be outlawed.

Others in the field weren't particularly encouraging about the company's long-term prospects, even if the work remained legal. "We don't think this is a good business," William Haseltine, the chief executive officer of Human Genome Sciences, in Rockville, Maryland, told me when I asked him about ACT's viability. Haseltine is a pioneer in regenerative medicine (the field that includes human embryonic-stem-cell therapies) and also the editor in chief of The Journal of Regenerative Medicine. "I think the government should fund this work," he said. "Private companies can't do it justice ... Therapies using these cells are ten to fifteen years away, and most of these companies will probably be long gone by then. In my opinion, they can't sustain themselves for that long without sales." Tom Okarma is skeptical for a different reason. He thinks that therapeutic cloning is too inefficient and costly ever to achieve commercial success, and calls it a "nonstarter," because, among other reasons, each patient's cells would have to be put through FDA-mandated safety testing individually. (Geron is exploring several other potential solutions to the immune-rejection problem.)

All that said, when asked how the company plans to make money from therapeutic cloning, scientists at ACT are likely to give an impatient response. "I don't care about whether there's commercial value in it," Bob Lanza told me. "You know, the point is that if a mother can give her oocyte and cure her kid from a lifetime of suffering—if you can cure people, you know, screw whether it's commercially viable."

Mike West was confident, although not very specific, about the potential for profit. He told me, "I've heard the criticism, you know, that 'Mike West is just into trying to help people, he's not serious about business.' My philosophy is, cure diabetes and you'll make plenty of money. You see what I'm saying? Don't put the cart in front of the horse. Cure the disease and you'll make money."

The most frequent refrain among political opponents of therapeutic cloning, and of human embryonic-stem-cell research in general, is that adult stem cells are a better choice for the development of medical therapies. Like cells from cloned embryos, adult stem cells are a perfect genetic match for a patient. Unlike embryonic cells, however, they can be found in the tissues of the patient's own body—a fact that prompted Senator Brownback, after ACT's announcement, to insist on CNN that adult-stem-cell research is "a much better route to go." Opponents of therapeutic cloning wonder why there's a need to work with embryonic cells at all, since adult stem cells aren't rejected by the immune system, can produce a wide variety of body tissues, and do not require destroying embryos.

A report released by the NIH last July provided some answers, pointing out that most adult stem cells are rare, may be difficult or dangerous to harvest from patients, and have a limited capacity to divide in the laboratory, which means that they can't yet be grown in large enough quantities to be of therapeutic value. What's more, adult stem cells have not been found for all types of tissue.

Still, if any type of adult stem cell has proven its clinical promise, it is the HSCs in bone marrow—the same cells needed for Trevor Ross. Clinicians have been doing bone-marrow transplants involving these cells for more than thirty years, and have been able to help cancer patients, correct anemias, and even reboot the immune system to provide respite from auto-immune diseases such as systemic lupus, multiple sclerosis, and rheumatoid arthritis. Some clinicians who work with adult HSCs on a daily basis, however, think that therapeutic cloning could do even better. One of them is Malcolm Moore, a specialist in blood-cell development at the Memorial Sloan-Kettering Institute, in Manhattan. Moore is among the scientists collaborating with ACT on therapeutic-cloning experiments in animals. "We want to improve the whole strategy of bone-marrow transplantation," he told me when I visited him in his office, which overlooks East Sixty-seventh Street. If anyone knows the promise of adult hematopoietic stem cells, it's Moore, who for thirty years has been working to optimize their use in treating cancer patients whose bone marrow has been destroyed by chemotherapy. But Moore points out that giving patients back their own adult stem cells is not always an ideal therapy. In cancer patients these cells are sometimes damaged by early rounds of chemotherapy or contaminated with cancer cells that are difficult to purify away. In a patient like Trevor the cells have a genetic defect that gene-therapy techniques are still far too experimental to treat effectively. And in all cases adult stem cells suffer from a major limitation: cellular aging.

It comes down to a simple fact about cell division: skin cells, heart cells, liver cells, even adult stem cells, can divide only so many times—perhaps fifty to a hundred—before burning themselves out. It's as if some biological counter were tallying rounds of cell division with the help of structures called telomeres. Telomeres are repeated sequences of DNA that cap and protect the ends of each of our chromosomes, much like the plastic tips that protect the ends of a shoelace. The problem is that each time a cell divides, its telomeres grow shorter. Eventually they grow so short that the cells reach a state of senescence in which they simply stop dividing or die. Cells in the reproductive lineage, however, including human embryonic stem cells, escape this fate. They have high levels of the enzyme telomerase, which extends and maintains telomeres as the cells divide, making them immortal in a cellular sense. Human embryonic stem cells can go on dividing indefinitely, producing unlimited quantities of cells. Not so with adult HSCs derived from bone marrow.

A typical bone-marrow transplant, Moore told me, replaces only one or two percent of a patient's HSCs, and relies heavily on that small handful of cells to divide. The cells' telomeres have already shortened significantly, over years and years of use, and now those same cells are being asked to repopulate entire blood and immune systems. This means more-frequent cell division and, consequently, a faster shortening of telomeres. It is accelerated aging on a cellular level.

In the short term, Moore said, that's no cause for concern. But later in life there may be consequences. For example, a forty- or fifty-year-old who had received a transplant earlier in life might essentially have the immune system of a seventy- or eighty-year-old. (This and other limitations of adult stem cells may be overcome with further research.)

A patient's skin cell used for cloning has telomeres already shortened by years of cell division, but ACT's scientists have demonstrated that a cell's life-span is completely restored through cloning. In a paper published in Science in April of 2000, researchers at ACT showed that cloning can restore a senescent cell's telomeres to an embryonic length or greater. As a result, therapeutic cloning can produce cells with their whole "lives" ahead of them, thus providing "youthful" tissue that may in some cases respond better to injury or disease than adult cells would.

"When there's this ethics debate about adult versus embryonic stem cells and cloning," Mike West told me, "I don't think what's properly weighed in the balance is the amazing breakthrough that this is. I mean, the idea that you can take a person of any age—a hundred and twenty years old—and take a skin cell from them and give them back their own cells that are young! Cells of any kind, with any kind of genetic modification! That's such an incredible gift to mankind! For the U.S. Congress to spend two hours and debate this and say, 'Oh, we'll make all this illegal,' to me is unbelievable. They don't understand." He shook his head. "We've never been able to do anything like this before."

Malcolm Moore's main concern is that Congress will shut the door on this research before its full benefits are known—if they indeed exist. "Basically," he told me, "my plea is, don't close down an avenue of research that might be of value in the future in the treatment of human disease. Time, science, and medical practice will be the ultimate proofs of whether these strategies are going to benefit mankind."

Bob Lanza put things more enthusiastically. "I'd stake my life on it," he said. "If this research is allowed to proceed, by the time we grow old, this will be a routine thing." He pounded the table we were sitting at, for emphasis. "You'll just go and get a skin cell removed at the doctor's office, and they'll give you back a new organ or some new tissue—a new liver, a new kidney—and you'll be fixed. And it's not science fiction. This is very, very real."

Breaching the Zona Pellucida

On January 29, the night of the State of the Union address and a week after Jose Cibelli and I had fruitlessly traveled to the fertility clinic outside Boston, we again found ourselves sitting at the Starbucks, waiting for the results of another retrieval attempt. "I'm just hoping we get enough eggs," Cibelli said. "About ten. At least ten." A few minutes later his cell phone rang. The procedure was finished. Cibelli hung up and told me, "She didn't say how many."

Inside the clinic Cibelli waved at the embryologist, who was seated at a microscope on the other side of a glass wall. She was wearing a surgical blue-paper hat and gown, and was scanning a dish of fluid retrieved from the egg donor's ovaries, trying to locate eggs. She shook her head sadly at Cibelli and held up just two fingers. "Part of the game," he said, sinking into a chair. He leaned his head back against the wall and tapped his feet nervously. The embryologist continued her search.

In human embryology timing is everything. By the time an egg is collected, it has already started to age; it will lose its viability in the lab within a few hours. The older the egg, the harder fusing it with a skin cell becomes, and the shorter the likely development of any embryo it forms. Since the cloning procedure itself can take several hours, Cibelli had started asking the clinic for "younger" eggs, collected closer to the time of a donor's last hormone injection. Go in too soon, however, and an egg is too immature to be retrieved. It won't yet have entered the fluid-filled space of its ovarian follicle and will stay behind when the surgical team collects the fluid. This day's egg retrieval had been an experiment—collection had been attempted three hours earlier than usual.

"Well, I'm all done doing experiments," the embryologist said with good-natured exasperation, removing a white mask from over her nose and mouth as she came to talk to Cibelli. She and her team had taken fluid from more than a dozen follicles, but had found only two mature eggs. They'd gone in too early.

Two eggs weren't much to work with. Mice are the only animals with which scientists have reported doing therapeutic cloning from start to finish—and so far the numbers are pretty grim. A group at Rockefeller University, in New York, made 1,016 cloning attempts but got only 398 blastocysts, which yielded only thirty-five stem-cell lines. That's one stem-cell line for every twenty-nine eggs. For a team at the Whitehead Institute for Biomedical Research, in Massachusetts, the process was even more inefficient. They started with 202 eggs and produced only one cloned stem-cell line. A team at Monash University, in Australia, consumed 926 eggs to produce a stem-cell line. To get one from just two eggs would require a minor miracle.

If it were up to Cibelli, he would be doing cloning procedures every week, lining up two or three donors for each collection day in case one dropped out or an egg collection failed. ACT had no money in the bank, however, and it was unclear when he was going to be able to schedule the next donor. "And the logistics," Cibelli said to me in frustration. "You have no idea how difficult it is to do this whole thing. We need to find an alternative to human eggs." Still, he was trying to remain optimistic. "I keep thinking about Bob Edwards," he said, referring to the physician who created the first test-tube baby. "He got Louise Brown with only one embryo. He only got one embryo that day."

Cibelli winced. "Two!" he said.

When we arrived back at ACT that night, the only sound was the whir of a vacuum cleaner as the cleaning crew finished up in a hallway. The technician, whom I'll call Kate, was waiting for us in the lab. She was wearing a baseball cap and a white lab coat over jeans with rolled-up cuffs. Cibelli handed her a small vial containing the two eggs; each was going to get its full share of attention. "We can name them," Cibelli said jokingly. Kate moved the eggs to a drop of culture medium at the bottom of a clear plastic dish, and then covered the drop with a layer of oil, to maintain the pH of the medium and prevent evaporation. She examined the eggs through the microscope. "They look good," she said. She flipped on a video monitor so that we could see what she saw.

Magnified many times over, a human egg is perfectly round, and as luminous and mesmerizing as the moon. This one glowed slightly golden and slightly grainy in the light from the microscope. Surrounding the egg is a thick capsule called the zona pellucida—the closest thing a human egg has to a shell. Unlike a chicken-egg shell, for instance, the zona is flexible, and not attached to the egg itself. Instead the egg floats free within it on a thin cushion of fluid. In two dimensions on the video screen, the zona played moon ring to the egg's glowing moon. Although this is among the largest cells in a human body, it is still smaller than a grain of sand.

Kate's first step was to remove each egg's chromosomes. To anchor the first egg in place during the procedure, she had gently applied suction to it with a blunt glass tube called a holding pipette, which we could see on the left-hand side of the video screen. It was about as wide as the egg itself and was firmly suctioned onto the zona. Using a high-tech joystick mounted at the right of her microscope, she moved a much thinner glass tool (officially known as a micropipette, but called a "needle" by ACT's scientists) toward the egg in minuscule increments. The needle is hollow and somewhat like a drinking straw—by changing the vacuum pressure at its end, one can draw things up into it or spit them back out.

The zona of a human egg is rubbery and resilient. Kate would use a machine called a piezo device to make the glass needle vibrate at a high frequency, so that it could tunnel through the zona. Moments earlier she had practiced a few times on a cow egg, withdrawing the needle and spitting out the plug of zona with each pass.

"I suppose while my luck is good I should give it a shot," she said nervously. "Lights, please." Cibelli flipped off the overhead lights so that she could see the field under the microscope more clearly. The rest of us watched the monitor. Keeping the lights low also protects the eggs—the culture medium responds badly to fluorescents and can change in a way that starts to damage the cells it contains.

To make it easier to locate the egg's chromosomes, Kate had soaked each egg in a dye that binds to DNA and shows up blue under ultraviolet light. She stepped briefly on what looked like a small sewing-machine pedal on the floor, and a UV light popped on under the microscope. On the monitor the egg's chromosomes winked into view, standing out like a blue neon sign in a diner's window. They were fat and compact, lined up in "metaphase II"—the state in which an egg sits patiently and waits for the entry of a sperm cell.

Kate released the egg from the holding pipette and, using the needle, rotated it, trying to find the most direct path to its chromosomes. After anchoring the egg again, she gently nudged the tip of the needle up to the zona pellucida. The sound of the piezo device filled the room—a tinny, mechanical buzzing. On the monitor we watched the needle advance, drilling a plug out of the zona. Kate hit the UV pedal intermittently, checking for the position of the chromosomes while also trying to minimize the egg's exposure to potentially damaging UV rays. Soon the needle was through the zona and poised at the surface of the egg itself, just across the outer membrane from the chromosomes. She applied a little suction. We all held our breath. It was a moment when things could go terribly wrong.

In theory, at this point in the procedure the suction draws a small portion of the egg up into the needle, bringing the chromosomes along with it. That small portion then buds off, leaving the egg's outer membrane (greasy and fluid, like all cell membranes) to flow together and repair the hole. With cow eggs the bud pinches off rather cleanly. But human eggs are trickier. Their membranes stretch, trailing a thin thread behind. ("It's like a string of mozzarella on a pizza that doesn't break and doesn't break," Cibelli told me.) A tiny mistake with the joystick, and the needle will leave a gaping tear in the egg.

It was one of those moments that drive scientists to wear amulets and recite superstitious incantations. Cibelli was so anxious that he was now sitting on the floor, his head leaning back against the door to the room and his knees pulled up in front of him.

Kate began to coax the egg's cytoplasm into the needle. But the chromosomes didn't budge. She applied a little more suction, but they still didn't move. "Come on," she muttered. Finally the chromosomes wavered and then slid slowly into the needle. Using the UV pedal as she retracted the needle carefully from the egg, she checked to make sure that the chromosomes were still in the tube. "Slowly," Cibelli warned. On the monitor the egg cell's membrane, stretching between the body of the egg and the small portion in the needle, looked like a strand of spider's silk studded with dew. The bud pinched off, and Cibelli shouted, "You got it!"

The eviscerated egg was now ready for its unusual cargo: one of Trevor Ross's skin cells.

If and when Trevor's skin cell fused with the empty egg, what exactly was going to be created? "You are creating people," Sam Brownback has insisted. "You're creating humans." Opponents of therapeutic cloning believe that embryos deserve governmental protection before they have even divided from one cell into two (although not even the world's major religions agree on when a human life begins).

Positions like Senator Brownback's frustrate Mike West. "I'm just very disappointed," he said to me. "I'm sad, because even the critics admit that millions of human beings and their fate in the hospital may be contingent on this research." As a young man, West was an evangelical Christian and a creationist. He protested outside abortion clinics. But swayed by the scientific evidence for evolution, he eventually abandoned the biblical view of creation. Science now dictates his view of the earliest human embryos as well. "You can be as pro-life as you can get," he told me, "but you can't say that making and destroying a pre-implantation embryo is the destruction of a human. Because it isn't. If it was a human life, I wouldn't touch it. Absolutely not." He went on, "A human individual does not begin at conception. It begins at primitive-streak formation."

The "primitive streak" appears after fourteen days of embryonic development in utero. It's like an arrow drawn on the embryo, one that delineates head and tail, front and back. Until then how many individuals, if any, that tiny ball of tissue will produce is entirely unclear. During the first two weeks of development one embryo can still split into two, a process that produces identical twins. Remarkably, two embryos can also fuse into one, eventually resulting in a single person whose body is a patchwork of two genotypes (with each eye a different color, perhaps, or mottled, two-tone skin). Not until the appearance of the primitive streak are the beginnings of a human individual sketched out. At that point, according to West, "There is no brain, no sensation, no pain, no memory, nothing of that. But it is an individualized human in a very early stage, and I advocate we don't touch that. But before then—they're wrong. It is just cells. It is a kind of raw material for life: the cellular life out of which human life arises."

West's line of thinking is fully consistent with the conclusions laid out by the NIH Human Embryo Research Panel in 1994. "If the President and members of Congress really understood what these little balls of cells were," West went on, "they would have a completely different view."

Adrienne Ross has a blunter assessment. "To me," she told me, "it's like, how dare they tell me that I cannot save my son's life? It's as simple as that. You know, if you want to practice your religion, practice your religion. But not when it interferes with other people's lives." She continued, "They're telling me, 'Let your child die, because my religious belief is more important than your child's life.' They can make their choices for their own embryos and they can make their choices for their own children. But they have no right to stop me from saving my son's life."

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