The stem cell hope, p.20
The Stem Cell Hope, page 20
The stalemate, as always when it came to embryos, revolved around abortion. Pro–and antiabortion legislators tussled over how far to go with nuclear transfer. Those against abortion and stem cell research pushed for a blanket ban on all human cloning activity, while those in favor of embryo research advocated limited use of cloning, specifically to generate stem cells. These advocates felt that an outright ban on all cloning was too restrictive—while no one had successfully generated a human embryo using nuclear transfer yet, they feared that without government support of the science, no one ever would, at least not in the United States. They lobbied for a less inclusive policy that would make the distinction between reproductive and therapeutic cloning.
For the pro-life and antiabortion legislators, however, such a distinction did not go far enough to protect human life. To them, such open-ended regulation represented the first push down a steep and slick slope toward a world in which cloning people joined IVF as yet another reproductive option, and in which human life was reduced to and ultimately devalued as a laboratory process of pick-and-choose, mix-and-match genetic characteristics.
And for a while, it seemed they might be right. Two days after the NBAC announced its recommendations, and even before the commission’s chair had an opportunity to officially present the report to President Clinton, a white-robed French former race car driver sporting a topknot announced that he was launching a human cloning service. Rael, the leader of a worldwide religious cult claiming some thirty-five thousand members who believed aliens had created all human life, offered to clone members of infertile and homosexual couples for “as low as $200,000.” Within months, Richard Seed, a Chicago physicist with a degree from Harvard, joined the fray, announcing that he, too, was attempting to create a human clone—of his wife. “The less everybody knows the better,” he cryptically admitted to the Ottawa Citizen during a phone interview about his efforts. He would only acknowledge that his wife would also serve as the surrogate for her own clone and carry her to term.
By August 1998, the fever had spread overseas, and Korean infertility researchers claimed to have generated the first human clone via nuclear transfer. The presumably well-meaning scientists failed, however, to follow basic scientific protocol for such a stupendous breakthrough, and not only destroyed their embryo at the four-cell stage, but never wrote up their findings for publication in a scientific journal, making it impossible to verify.
By the spring of 2001, the cloning circus had descended upon Washington, D.C., promising to indeed be the greatest show on earth. The elements were all there, with Representative John Greenwood, a Republican, who called a hearing to debate the pros and cons of human cloning and hash out appropriate legislative regulation of the practice, serving as ringleader. The Raelians fulfilled their purported role as the clowns, since it was so difficult, if not impossible, to take seriously their claim to have both the scientific wherewithal and the funding to sustain a human cloning service. Even the Republicans who had invited them to testify did so somewhat sheepishly. Clearly, as one staffer who was working on the Hill at the time admits, they hoped that the sight of the white-robed cultists would establish, once and for all, how dangerous and ridiculous the whole idea of human cloning was.
To a certain extent, the strategy actually worked. The net result was that all efforts involving the words human and cloning were tinged with what some bioethicists were beginning to call the “yuck factor.” And that left Congress deadlocked over cloning legislation. For Melton, it meant that while he had been successful in drumming up funds for making stem cells from excess IVF embryos, doing the same to make nuclear transfer embryos was an entirely different matter, because it involved cloning.
Melton had no interest in making cloned babies. In fact, he remains opposed to using nuclear transfer solely to produce a clone of a living being. He instead was obsessed with the idea of exploiting the cloning process for its ability to yield stem cells from patients, because it would provide an unprecedented way to watch the cells as they grew, from stem cell to endoderm to pancreatic cell and eventually to an insulin-producing beta cell. It would also be the only potential way to chronicle why that cell loses its ability to produce insulin or respond to glucose.
The uneasiness over creating a life in the lab only to study and destroy it, however, remained a powerful counter to the ultimate goal of helping patients. Even the Howard Hughes Medical Institute, which had been so ready to fund Melton’s embryo-based stem cell work, drew the line at therapeutic cloning. So did the JDRF, whose board had supported Melton’s previous work because he would be using only embryos destined to be discarded.
Yet again, Melton had no other option than to create what he needed himself. As he had done in deriving new embryonic stem cell lines from IVF embryos, he would simply have to learn to clone human cells himself. Or at least recruit someone who could.
If Chad Cowan’s initial meeting with Doug Melton was reminiscent of Love Story, then Kevin Eggan’s was more like The Godfather.
A native of Illinois, Eggan still exudes a Midwestern gregariousness—he’s not averse to chatting up seatmates on plane rides—and possesses dark-haired good looks that once earned him an invitation from GQ to pose for a feature on rock stars in science (which he declined). His appearance, however, shouldn’t detract from a keen intellect that has earned him a MacArthur “genius” grant and the distinction of being one of the youngest junior faculty members accepted at Harvard.
By 2002, with a Ph.D. in molecular biology, Eggan was establishing himself as one of the country’s leading experts in the nuclear transfer technique—and just the eager, talented, up-and-coming researcher Melton was seeking. Eggan’s education as a scientist had occurred in the formidable shadow of cloning, and he, like many of his colleagues earning their doctorates at the time, could not help but be swept away by its scientific possibilities. As he was completing his Ph.D. at MIT in 1996, Wilmut cloned Dolly, and in the following year, using the same procedure, a group at the University of Hawai’i cloned a mouse, Cumulina, for the first time. And while Cumulina hardly received the same media attention that Dolly did, for students of science like Eggan, the mouse’s birth was potentially more momentous because, as he says, “sheep and cows as cloning model organisms were not exactly convenient as molecular genetic models.”
Like Melton, Eggan appreciated the power that Cumulina would have for studying what was still the black box of development. Unlike his diabetes-focused professor, the young scientist had yet to fully appreciate the power that cloning could have on studying human disease. But he was sharp enough to sense a once-in-a-lifetime chance not only to witness but to shape an emerging field of science. “This seemed like an incredible new development in developmental biology, and I didn’t want to miss out on this opportunity,” he says. “So I jumped to Rudolph’s lab.”
And that’s where Melton found him. Rudolph Jaenisch was by then quite familiar with mouse embryonic stem cells, having worked with them for the almost two decades that they had been around. Jaenisch was making a specialty of understanding the details of how cloning worked, and was trying to recapitulate the steps that an adult cell would have to take in order to reprogram itself as an entirely new animal. As part of those studies, he assigned Eggan the task of learning and perfecting nuclear transfer in mice—which he did, and with such skill that he was ultimately brought to Melton’s attention.
An entertaining storyteller, Eggan recounts how Melton, whom he had never met and knew only by reputation, recruited him from MIT to Harvard. It’s hardly the traditional tale of nerve-wracking interviews and probing reviews. In fact, he says, it unfolded more like his own personal Godfather saga.
“I was walking around the lab one day, and this Israeli postdoc in Rudolph’s lab walks up to me and says, ‘Hey Kevin, my Israeli friend in Doug’s lab says Doug wants to meet you,” he begins. “I barely even knew who [he] was. Remember that Doug is pretty reclusive—you almost have to seek him out. Scientifically, I always imagined him sitting in the back of an Italian restaurant, if you know what I mean,” he says, a smile spreading across his face. “So I say to my friend, ‘Well, you tell your friend in Doug’s lab that I’d like to meet Doug.’
“It goes on like this, and a week later, this guy comes up to me and says, ‘My friend in Doug’s lab says that Doug wants you to come to give a seminar.’ I’m like, ‘Okay, you tell your friend in Doug’s lab—and this is getting weird—that I’ll come and give a seminar.’ So the whole thing got arranged through this Israeli arbitration without any direct contact between Doug and me.”
It was late fall in 2002, and a couple of months later, Eggan hopped on his bike for the chilly fifteen-minute ride along the Charles River from MIT’s Kendall Square to Melton’s lab, just off of Harvard Square. After making his presentation, the two moved to Melton’s office. “That was the first time I ever heard this simple idea articulated. He said, ‘Why not use what you do, and what I can do now with human embryonic stem cells, to make a limitless supply of cells that get sick in people? And surely we could figure out what was going on with diseases like diabetes if we could do that.’ ” Eggan pauses to emphasize the impact this idea, so familiar now but still only a seed in Melton’s mind in 2002, had on his thought processes. Until then, he says, the nuclear transfer technique he was learning was to him just that—a technique and a means to better understand how cells reprogram themselves back to the embryonic state. Cloning was merely a tool to answer scientific questions for science’s sake. But with his first exposure to Melton’s singular focus on finding a cure for diabetes, he suddenly saw the potential for applying therapeutic cloning to treat and cure disease. “Put the details aside, and think about that for a second,” he says. “I was sold. I drank the Kool-Aid immediately.”
And for Eggan, it was a powerful elixir. After spending nearly four years perfecting the cloning technique with mouse cells, he was itching to try it with human cells.
But based on his trial run with the mice, he knew it was going to be far from easy.
When Jaenisch presented Eggan with the task of learning and setting up nuclear transfer in his lab at MIT, Eggan’s only credentials for performing the delicate micromanipulation work it required were, he freely admits, rather unscientific. “Super Mario Brothers,” he says simply about the extent of his skills in manipulating microscopes and handling embryos. So it wasn’t a total surprise that the first year and a half of attempts to clone mice, he concedes, “were not wonderful. It was actually quite traumatic.”
Aware of the difficulties, Jaenisch dispatched Eggan to Hawaii to learn nuances of the technique that only those who have tried it could teach. By this time, the island scientists had succeeded in breeding several generations of cloned mice pups after Cumulina’s birth.
Arriving in Honolulu, however, Eggan wasn’t prepared for what he saw. The laboratory, such as it was, was nothing like the modern, well-stocked hubs of high technology he was accustomed to back at MIT. It occupied an unused part of a windowless cinder-block building that served as the loading dock for the university’s food services. The researchers kept their mice in an old walk-in freezer that had been shut off. And since the facility had not been built with high-level science in mind, it lacked the vibration-buffering lab benches that are the staple of any science department in any university. Instead, students conducted experiments on sturdy, 1950s-era desks, whose legs were cushioned by tennis balls that had been split open and slipped onto the ends—a trick borrowed from the elderly who do the same to stabilize their walkers. The balls were an attempt to keep the desks from moving too much when anyone performed delicate procedures such as puncturing tiny mouse eggs and squirting them with sperm from a pipette under a high-powered microscope.
“I was like, ‘Whoa,’ ” Eggan recalls about his initial impressions of the Aloha lab. “I thought, ‘I’m going to do tissue culture, and embryonic stem cell culture, just on a desk basically.’ ” He pauses, shaking his head. “Which worked remarkably well.”
As primitive as the conditions seemed to Eggan, they were certainly good enough to lead the lab, run by an energetic and engaging Japanese scientist named Ryuzo Yanagimachi, to some important biological firsts. Yanagimachi, or Yana, as he is known, is credited with improving the success rate of pregnancy with IVF by injecting the swimmers into eggs with a more refined and targeted piezo pipette.
It turned out that same technique would set the team up for success in cloning as well. Although, truth be told, it wasn’t exactly a project that Yana had initially wanted his lab to pursue. The milestone experiment that became Cumulina actually came about because Yana’s star postdoctoral student couldn’t swim.
When he arrived in Honolulu from Japan, Teruhito Wakayama, a shy, serious man, never imagined he would gain such fame in cloning. During our first meeting in New York, shortly after his cloning breakthrough in 1998, he is apologetic about his English, although it is perfectly acceptable, and reluctant to make too much of his work. In Yana’s lab, his first project was to break down the act of fertilization on a molecular level to figure out how sperm excites the egg enough to prompt it to divide and grow into an embryo. It turns out that the mystery factor is conserved across disparate species—you can inject sea urchin sperm into a mouse egg and the egg will start to divide as if it had been fertilized by a mouse sperm. The embryo will eventually die, but for a few days, it will act as if it were on its way to becoming a mouse pup.
So that’s exactly where Wakayama focused his attention—on sea urchin sperm. The lab’s location off some of the richest coastal waters in the islands had one distinct advantage. “The cost was free,” he tells me of his urchin resource during a recent talk in his office in Kobe, Japan, where he now heads a lab at the RIKEN Center for Developmental Biology. The only problem was that he had to collect the spiny creatures himself, several times a week. To anyone enamored of the sun and surf and sea, it would have been the perfect scenario—visit the beach almost daily, go for a swim to collect sea urchins, and spend the remainder of the day back in the lab doing experiments. Ideal, that is, if you don’t mind the swim. Wakayama did. So instead of a welcome respite from the tedium of lab work, collecting the sea creatures became a bit of a chore. “I must go to the ocean from the university, and I cannot swim,” he explains.
Just next door to the lab, in that converted freezer, however, lived another species that was much more accessible—mice. So he decided to switch. They were more expensive to work with, but at least collecting them didn’t require a chilling and intimidating dip in the ocean.
Having read about Ian Wilmut’s success with Dolly, Wakayama was inspired one day to try something similar with his mice. In collecting the eggs from females that had ovulated, he often also swiped up something called cumulus cells, which, as their name implies, surround oocytes like a cloud of nourishing tissue. Unlike the egg and sperm, which contain only half the full complement of chromosomes, cumulus cells are fully developed adult cells with two copies of every chromosome. Following Wilmut’s lead with Dolly, Wakayama decided to squeeze out the nucleus of one of his mouse eggs and replace it with the nucleus of a cumulus cell from another female donor—just to see what would happen. To his surprise, the experiment worked and in eighteen days, he saw a litter of mouse pups.
“I was very surprised,” he tells me. “I believed mouse cloning was impossible because many papers said mouse was one of the most difficult species to clone. I believed the papers and the textbooks.”
If he was surprised, Yana was even more so when he learned of the experiment and its success at the same time. “I did the experiment without telling him,” admits Wakayama with a laugh. “He didn’t know until the success.”
It’s not the best way for a postdoc to endear himself to his mentor, but in Wakayama’s case, it worked. And it put Yana’s lab on the short list of “it” laboratories in the hot new field of stem cell research.
Eggan is still amused when he recalls his first days in Honolulu and the incongruity of seeing highly sophisticated work performed in a laboratory that was a throwback to a more primitive time. “The building was ambient to the outside, so it was eighty degrees in the lab,” he says. “It was just a bunch of Japanese and American guys micromanipulating with no shirts on. It was a really weird environment.”
The collaboration, though, was a mutually beneficial one. As Yana’s group continued to clone more litters of mice, they began noticing differences, beginning with the pregnancies, between the pups born via the nuclear transfer process and those gestated via the conventional IVF technique. The cloning procedure produced a high abortion rate, and if the pregnancies went to term, the pups tended to be large and overweight. Another Japanese postdoc in Yana’s lab, Hideo Akutsu, began wondering whether something in the reprogramming of the adult cells was going awry. Jaenisch was the perfect person to ask. While the Hawaiians had perfected the cloning technique, Jaenisch was making headway in exposing the molecular mysteries of reprogramming—how a mature, adult cell turned back the clock and rewrote its developmental history. Eggan would learn the nuclear transfer process from Akutsu, and Akutsu would come to Massachusetts to pick up more knowledge about the unknowns of molecular reprogramming.
For Eggan, it wasn’t a bad way to spend a summer. “The day would start at seven o’clock, and because of the hormonal cycles of mice, we’d basically be done by three,” he recalls. “I would get on Hideo’s bike, I would ride down to Waikiki, I would surf until sunset, I would go back to my hotel room, pass out, and the next day we’d do it all again.” He grins. “It was pretty good.”
