Adrienne and Ben Ross (all names of the family members have been changed) first came to ACT late last October, ten months after their son, Trevor, and two of his cousins had received a diagnosis of X-linked adrenoleuko-dystrophy (ALD), a relatively rare and underdiagnosed genetic disorder that can abruptly ravage the white matter of the brain, with devastating and often fatal results.
The first symptoms had appeared in Trevor's cousin Andrew, a bright boy who loved baseball, competed in spelling bees, and played the violin. Shortly after starting kindergarten, Andrew had been given a diagnosis of attention deficit hyperactivity disorder, but otherwise he seemed to be thriving. Within a few years, however, his cognitive abilities seemed to have changed. He would regularly ask the same questions again and again. By the time Andrew was eight years old, it was clear that something grave was at work. His karate teacher began to notice a dramatic and progressive loss of coordination. Andrew was having increasing difficulty following instructions or participating in the classroom. In December of 2000, after an MRI, his ALD was diagnosed; soon after, with alarming swiftness, Andrew went blind and deaf, and then lost motor and bowel control. At the age of nine he was in a nearly vegetative state, unable to speak or move.
Andrew had developed what is known as childhood cerebral onset of ALD, a condition that afflicts a third of the disease's victims—who, for genetic reasons, are almost always boys. Half of boys with childhood cerebral onset are dead by the age of nine. Boys with ALD who are lucky enough to escape childhood cerebral onset are almost certain to suffer a degeneration of the spinal cord in adulthood, which can lead to such symptoms as muscle spasms in the legs, loss of bladder control, and general weakness and stiffness. Although symptoms in adults can vary a great deal in severity, a third of adults with the disease also develop brain involvement and are reduced to a vegetative state or die within three to four years of onset.
Within a week of Andrew's diagnosis the other boys in his extended family were tested for ALD, and a tragic pattern was revealed. Andrew's seven-year-old brother, Eric, had inherited the abnormal gene. So had Trevor, then barely a year old.
Currently, the best treatment for childhood cerebral onset of ALD is a bone-marrow or umbilical-cord-blood transplant from a healthy, well-matched donor. This procedure can halt or even reverse the progression of the disease, for reasons that aren't fully understood; it appears that some of the healthy transplanted cells travel to the brain, where they are able to prevent further damage. Compatible transplant donors are extraordinarily hard to find, however —and even when suitable donors are found, the transplants don't always take. Sometimes transplants don't work because a patient's immune system rejects the transplanted cells as foreign. In other cases mature immune cells in the transplanted material actually reject and attack their new host, a life-threatening condition known as graft-versus-host disease. Radiation and chemotherapy before a transplant—and immunosuppressive drugs afterward—can help to reduce the risks of rejection, but they also leave a patient vulnerable to serious infection. Overall, the odds aren't good: according to one expert, a quarter of the boys who receive a bone-marrow transplant to treat ALD die from complications related to the procedure.
In Andrew's case the diagnosis came too late for a transplant to have any effect. But for Trevor there still seemed to be time even to push experimental treatments forward, because his brain hadn't yet shown any evidence of deterioration. Only once have neurological symptoms of ALD been observed in a child under the age of three, and about half of boys with childhood cerebral onset develop normally until age seven. And it was conceivable that Trevor wouldn't develop symptoms until adulthood, so researchers might have a couple of decades to find a better cure for him.
The Rosses had sought out ACT with the radical hope that therapeutic cloning might someday allow doctors to create a transplant that would carry no risk of rejection. The work of a bone-marrow transplant is actually done by hematopoietic stem cells—cells in the marrow that restock our blood and immune systems throughout life, serving as a reservoir of new components as old ones wear out. HSCs are also the cells that have rescued patients with ALD. What the Rosses were exploring with ACT was the idea of coaxing human embryonic stem cells, taken from cloned embryos, into forming HSCs that might someday save Trevor.
When the Rosses first traveled to ACT to talk about Trevor's case, they met with Michael West, a dreamy, laid-back forty-eight-year-old with a lopsided grin. West is the company's president and chief executive officer, and a well-known figure in biotech circles. In 1990, at the age of thirty-six, with a Ph.D. in cell biology and one year of medical school completed, West founded a company in Menlo Park, California, called Geron Corporation, now the industry front-runner in human embryonic-stem-cell research. West's goal was to develop treatments for age-related disease. Five years later he launched a full-fledged effort to obtain human embryonic stem cells. "I was quite convinced of the power of these cells to do things that we've never been able to do before," he told me during one of our many recent conversations. "The whole intent was to get some new tools in the toolbox for physicians." West roamed the country, appearing on the doorsteps of top embryonic-stem-cell researchers (who were then working with animal cells) and offering them financial backing to work with human cells—money unavailable from government sources because of the federal-funding ban. These efforts paid off in 1998, when James Thomson, of the University of Wisconsin, with funding from Geron, successfully isolated the cells from human embryos for the first time. By then, however, amid growing friction with Geron's management team, West had left the company and joined ACT, in October of 1998. His intention was to apply ACT's cloning technology to human medicine.
At his meeting with the Rosses, West opened up a laptop computer and hit a key to start a video of the cloning procedure. "This is how it works," he told the Rosses. A magnified gray egg cell appeared on the screen. Adrienne and Ben leaned forward to get a better look. As they watched, a glass tool wielded by an invisible technician carefully sucked out the egg cell's chromosomes and then placed the egg in contact with a skin cell, in preparation for fusion. "This is bovine," West said—a reminder that he was showing the Rosses an example of cow cloning, not human cloning.
Creating cloned cow embryos had become routine at ACT, and the company's scientists were regularly nurturing them into blastocysts—balls of about 100 to 150 cells. The blastocyst stage of development is the point at which stem cells can be isolated. What West didn't mention to the Rosses is that despite months of effort, his scientists had not yet had any luck creating a human blastocyst. "We're working hard," he told them simply. "I'm not showing you the human data yet on purpose, because we haven't published it yet and we don't talk about human data." He wanted to emphasize the technology's promise, of course—an unlimited supply of tissue that matches a patient perfectly.
But Trevor needed something more: cloned cells in which the debilitating ALD mutation had been corrected. A leading experimental approach to correcting this kind of defect is a procedure known as gene therapy, which uses a modified virus to shuttle new genes into a patient's body cells. The virus infects a cell, carries a therapeutic gene to the nucleus, and inserts it into the DNA at a random location. Someday the procedure might be used to add a functional ALD gene to cells from Trevor's own bone marrow. This was another approach the Rosses were pursuing, but it's very experimental, and scientists are having difficulty modifying all the cells that need therapy in a patient, and difficulty ensuring reliable long-term expression of the new genes.
What therapeutic cloning should allow scientists to do, West explained, is provide a pure population of genetically modified cells. Use one modified cell for cloning, and the entire cloned embryo will then carry that modification. So will embryonic stem cells derived from it, and any therapeutic tissues they produce. Alternatively, scientists could do the modification in embryonic stem cells after cloning, and then grow a limitless supply of tissue from one properly modified cell. "We can give the patient cells that all have the same precise targeted modification," West said. "One hundred percent. We won't do that with gene therapy in our lifetime."
A therapy for Trevor isn't the only thing at stake. The stem cells derived from cloned embryos bearing an ALD mutation could be powerful research tools. In fact, scientists consider creating cloned embryos that match patients with a genetic predisposition to disease to be one of the most important therapeutic applications of the technology, because, for one thing, it would allow diseased tissues of all kinds to be created and studied in the lab. But such work is rarely discussed in the political debate about cloning.
As she listened to West spin out optimistic future scenarios, Adrienne began to wonder if they would be able to proceed—or if using Trevor's cells for cloning would be pushing the bounds of the law as well as of science. "Can you clarify for me?" she asked, interrupting West. "On the cloning side, if you're not using federal funds, can you do what you want?"
It's understandable that she would wonder. The House's anti-cloning legislation was designed to make everything Mike West and the Rosses were discussing that day illegal. If the Senate were to pass the bill, not only could ACT's scientists be prosecuted for attempting therapeutic cloning for Trevor but Adrienne and Ben could be prosecuted for participating in such an attempt. One provision of the legislation would make it illegal even to "import" a life-saving medical therapy developed elsewhere in the world through cloning.
Adrienne's question was a sore point for West. "Yeah, we're free to do what we want," he answered simply.
"But now they're looking to try to ban that?" Adrienne asked.
West hesitated. "Well, I don't know," he said. "The Senate at some point will take this up, and my honest, best read is, I don't believe the Senate will pass it." Still, he admitted, anything could happen. "We could lose," he said, "and that would be tragic."
For the moment, however, therapeutic-cloning research was legal—and the Rosses were ready to get started. "So," Ben said over lunch, pulling a ball-point pen and a scrap of paper from his pocket. "What's the checklist?" Scheduling Trevor's skin-punch biopsy went to the top. So did a reminder to send ACT the sequence of the ALD gene mutation afflicting the Ross family—and a healthy sequence that could be used to correct it.
"And are you just as happy with the eggs you have, or do you need eggs from us?" Adrienne asked.
"I could mention to our ethics board that you're interested in donating egg cells," West answered. "We should set ourselves up for as much success as we can."
West was referring to a potential complication with therapeutic cloning. The procedure involves the transfer of a patient's cell nucleus into an egg from which the nuclear chromosomes have been removed. But those chromosomes are not the sum total of an egg's DNA. A small amount of DNA is located outside the nucleus, in energy-producing structures called mitochondria. The amount of genetic information they contain is tiny, involving only a few dozen functioning genes, as opposed to the tens of thousands found in a cell nucleus. Still, studies in mice and rats have shown that unfamiliar mitochondrial proteins can provoke an immune rejection response. If the differences in mitochondrial DNA between egg donor and patient are too great, the patient's body may reject the cloned tissue as foreign.
"If you took mitochondria from the maternal lineage of the patient," West told the Rosses, "then there's no conflict. You're home free." Mitochondria are passed exclusively from mother to child, so all relatives with the same maternal lineage have the same mitochondrial DNA. This meant that many women in Adrienne's family could donate eggs that would be a perfect mitochondrial match for Trevor's body tissues.
The science, however, still had a considerable way to go. Even if ACT were able to create cloned embryos and isolate stem cells, turning those cells into hematopoietic stem cells suitable for transplant could be difficult—at the time, scientists had yet to produce HSCs, even in animals, that could migrate to the bone marrow, take up residence there, and produce useful blood and immune-system cells over the long term.
Nevertheless, West was upbeat. "You guys should take encouragement," he told the Rosses. "This is doable. It's only a question of can we mobilize the people. It won't happen unless people work on it."
Ben nodded his head. "Well, you let us know what we can do to help."