The days of the unknowable human embryo were swiftly departing. Now that scientists could merge egg and sperm in the shallow of a dish, and quite literally make human embryos, the earliest hours of human development were open to unprecedented study. And meanwhile other novel techniques and tests, such as amniocentesis and genetic analysis, allowed conceptuses to be scrutinized in the womb as they grew to fetal stage and beyond.

This all goes to say that by the time Jamie Thomson decided to strike out after stem cells in human embryos, these enormous little cells were looming a whole lot larger in scientists’ minds than ever before, and the small circle of teams striving for them—in Singapore, the United States, the United Kingdom, Europe, and Australia—was expanding. On China’s southern coast, an immunologist at Sun Yat-Sen University in the city of Guangzhou was also ready to take the plunge. Professor Shunong Li knew this master cell had plenty to say about how the human embryo grows. He had faith as well that it might cure Mediterranean anemia, an inherited blood disease that seemed to show up time and again in children in south China, stunt-

ing their growth and sometimes seriously injuring their organs. Transplanted umbilical cord blood, or really the stem cells in cord blood, could alleviate this anemia. Yet sufficient quantities were hard to come by, which is why, Li believed, stem cells from embryos could prove priceless. Inducing them to differentiate into large quantities of blood-specific cells might be the answer to supplying these stricken children with all the cells necessary to make them well.

In England, sporadic attempts to extract stem cells from human embryos had been going on since the 1980s. The handful of investigators who had given it a try were mainly interested in knowing what stem cells could show them about early development. Christopher Graham at Oxford, for instance, set out in 1987 to investigate factors in human embryos that regulate the growth of their potent cells. “On paper, probably nobody was trying to isolate these cells for therapeutic purposes,” notes Graham in an email. However, “all of us would have been exceptionally stupid not to realise their therapeutic value.” In-vitro-fertilization pioneer Robert Edwards relates that as a young geneticist based at Glasgow University in 1962, he’d been enthralled by stem cells in rabbit blastocysts and their willy-nilly production of cells of all adult rabbit tissues. When he and Patrick Steptoe later teamed up to create human embryos in petri dishes, “their inner cell masses … screamed stem cells!” recalls Edwards. He envisioned a day when stem cells might repair human organs, but in the end decided to discontinue his group’s stem cell work in order “to save all [IVF] embryos for their parents.”

It was tempting to wonder how far along biologists could possibly be in understanding human development, if by the mid-1990s the talented cell that was so central to an embryo’s maturation remained at large. Investigators blamed their failure in this regard on the poor quality of the IVF embryos they worked over. The very best ones were transferred into a woman, while the remainders placed in cold storage could be inferior. For all anyone knew, long-term freezing possibly diminished the quality of IVF embryos still further.

The knowledge that other researchers were having such a tough

time isolating stem cells from IVF embryos had helped convince John Gearhart at the Johns Hopkins School of Medicine in Baltimore, who by 1995 was in the midst of formulating his own plan to try and acquire human embryonic stem cells, that it wouldn’t be such a bad idea to visit an entirely different source: the fetus as opposed to the embryo. Whereas James Thomson was gearing up to go after a stem cell that sat in the hollow of a roughly six-day-old embryo, a leftover product of in vitro fertilization, Gearhart was aiming to isolate primordial germ cells—precursors to egg or sperm—from the gonadal region of an aborted eight-to-twelve-week-old fetus. The first: a dot of an embryo of not more than a few hundred cells that, while previously frozen, bore the potential to be returned to the womb and grown to birth. The second: a young fetus whose attainment of life had previously been ended.

Those differences aside, Gearhart, the director of research for the school’s obstetrics-gynecology department, was pretty sure that an early germ cell from the fetus should be every bit as pluripotent and capable of producing an array of cell types as a stem cell from an embryo. His research would add an interesting twist to stem cell biology. Scientists, not to mention policymakers and church leaders, would increasingly agitate over the pros and cons of deriving stem cells from spare IVF embryos as opposed to the organs of grown people, and here, off to one side, was Gearhart hovering around a cell from the fetal gonads. Its pluripotency, although requiring proof, was entirely plausible since this cell type became the egg and sperm that perpetuated the human race. Moreover, this was the same cell that Roy Stevens, an older friend of Gearhart’s, had shown could take a wrong turn in mouse embryos and grow into a testicular teratoma swollen with differentiated cells. It certainly proved its pluripotency in that instance.

Gearhart’s younger years leave the picture of a shy, inward boy with a shock of strawberry-blond hair, who, after living behind the high stone wall of a Philadelphia orphanage from age six to sixteen, went to college hoping to become a fruit-tree grower and ended up

with his master’s in plant genetics from the University of New Hampshire; then earned a doctorate in fruit-fly genetics from Cornell; then became immersed in studying Roy Stevens’s famous mice and their precocious stem cells; and finally came home to his own species—human development. Along the way, time after time Gearhart had the good fortune to cross paths directly or indirectly with distinguished sorts whose discoveries greatly added to the fast-moving tide of the biological sciences. Embryology, for one, was changing from a sleepy science full of fate maps—maps that trace cells from their origin in the embryo down a specific tissue pathway—into a more experimentally active and deductive discipline. The very term embryology had been growing stale since the ’50s, gradually giving way to developmental biology, a phrase that recognized that a creature’s development extended well beyond the embryo stage and would require the muscle of many disciplines if all was to be revealed.

When Gearhart went to Cornell for his doctorate, working a few floors above him in the Plant Science Building was Frederick Steward, the botany professor and larger-than-life Cecil B. De Mille figure. “We only do epics,” Steward told his technicians about the experiments they undertook. Steward by then was famous for his masterful epic a decade earlier, the growth of an entire carrot plant from a single mature carrot cell. He had used milk from coconuts for his culture brew. Another scientist had discovered that orchid cells multiplied beautifully in coconut milk, and Steward “was trying to find out what factor in the milk promotes the development of cells,” relates Marc Cathey, president emeritus of the American Horticulture Society and a student of Steward when the carrot drama was unfolding. Coconut milk being the impetus for the experiment—and not the cell or its inward potential—Steward struck it lucky. At the time, “The city of Miami was having terrible trouble with coconuts falling on tourists,” recalls Cathey, and Steward, seeing a good resource, “had them collected and sent to him.”

Coconut milk’s nurturing factor would eventually be identified. But meanwhile, Steward’s precedent of cloning a carrot plant from

just one of its cells, and a specialized cell to boot, drew the research world’s attention to something already known but sorely under-appreciated: Totipotency was not restricted to cells in the early embryo. Mature cells from adult plants could be cajoled to dedifferentiate into totipotent cells! They could be reconfigured to a blank slate.

A cell’s versatility in this regard harkened back to the cell theory that Schleiden and Schwann had postulated over a century earlier. What force accounted for an organism’s growth? Maybe it was central to the whole organism, as fat is to butter, Schwann had supposed. A second possibility was that each cell in an organism “possesses a power of its own, an independent life, by means of which it would be enabled to develop itself independently.” In lower plants the latter seemed to be true, since “any given cell may be separated from the plant, and then grown alone,” Schwann reasoned. He came to the conclusion that every plant cell probably has an “independent vitality,” an observation that has been verified by contemporary plant scientists: Every single cell in a plant has the means to grow into an entire plant.

Although he never studied with Steward, Gearhart thought this was the greatest thing going in biology—to take a mature cell, render it totipotent by putting it in the right culture, and use it to yield a whole new plant. Finishing Cornell, Gearhart set his sights on doing his postdoctoral training in the lab of Jean Paul Nitsch, a French plant physiologist who had performed yet another epic when he had grown a tobacco plant from a grain of pollen. The equivalent in animals would be starting an embryo with only a sperm cell. But a few months before Gearhart was to leave for France, Nitsch was tragically killed in a car accident, and, in the fall of ’70, Gearhart ended up instead in the laboratory of Beatrice Mintz at the Institute for Cancer Research in Philadelphia, where, for the next five years, he would probe the weird tumors of Roy Stevens’s famous 129 mouse strain and their precocious stem cells.

Once again, Gearhart found himself working in a building steeped in cloning history. Less than fifty feet from his bench, Rob-

ert Briggs and Thomas King had set the stage for all future animal cloning with their 1950s experiments. Using cells from leopard frogs, they replaced the nucleus of an egg cell with a nucleus from a frog blastocyst. Fooled into thinking it had been fertilized by sperm, the egg cell launched into division and developed into a tadpole. Similar to Steward’s carrot drama, a donor cell’s transplanted genes were persuaded into a totipotent state, from whence sprang a genetic replica of the donor. With Steward, it was the coconut milk that had inspired the cell’s genes to dedifferentiate, or roll backwards to totipotency; in the case of Briggs and King, it was the egg cell’s cytoplasm. It was as though someone took a bath, and something special in the bathwater returned them to infancy.

Beatrice Mintz, in whose laboratory Gearhart was doing his training, was carving major benchmarks as well. Years back, she and Tibby Russell at the Jackson Laboratory had determined the migratory route of primordial germ cells in new mice embryos, a finding that had helped Roy Stevens prove that errant germ cells started teratomas growing in mouse embryos. Her reputation had soared in the early 1960s when her team had “glued” together two mouse embryos in a dish by removing their outer membranes and letting their cells grow together at 37°C. When she put the resulting single embryo into a surrogate mother, the mother had born a pup whose two-color striped fur signaled its two-embryo beginning. (A Warsaw University team headed by Andrzej Tarkowski published similar results.) Valued as one of biology’s all-time classic experiments, this caper had fed the imagination of Gearhart, Thomson, and countless other starting scientists by proving that the mammalian embryo had “a huge amount of flexibility,” remarks Virginia Papaioannou at Columbia. “Its cells were not determined in what they could do; they responded to their environment.”

Mintz discovered that she could combine the cells of as many as ten early mouse embryos into a giant embryo that would revert to a normal-sized embryo when put back into a mouse’s uterus. While others would call the animals that resulted from combining two or

more embryos together chimeras, Mintz prefers the term mosaic. The term chimera “reminds me of monsters,” she notes.

When she first started gluing mouse embryos together, people thought her experiments would beget exactly that—monsters. But she had no fear of this, she says, because she knew that in the womb, albeit on rare occasions, twin embryos can unite into one embryo, and that, less rarely, one embryo will split into identical twins. And she was right. The chimeric mice she created were completely normal, in spite of their having cells with dissimilar sets of genes. This joining of embryos was the reverse of Hans Driesch’s experiment from the 1890s, in which he had shown that an early sea-urchin embryo’s separated cells could develop into independent larva. Either way you looked at it, the embryo and its immature cells were extremely malleable. You could add cells to the embryo or subtract cells, and like one of those bottom-heavy plastic dolls you can’t bat down, the embryo righted itself to normalcy.

As for why she made chimeric mice in the first place, there was a method to Mintz’s apparent madness back then. During graduate school at the University of Iowa, she recounts, she studied “all those classical experiments” whereby Driesch and other experimenters, adding and subtracting cells to and from embryos ad infinitum, had used dye and other markers to follow the fate of cells as these embryos grew and developed. No marking method had ever worked very well, “and I thought, oh my gosh, the way to trace what a cell is doing is to exploit its genes as a marker.” And that’s what a chimeric mouse, being composed of genetically different cells, allowed one to do. To use an inexact example, let’s say you add green cells to an embryo that has red cells; by looking retrospectively at patterns established by the green versus red cells as the embryo expands into organized tissues, you could infer the otherwise “invisible developmental history”—Mintz’s phrase—of cells differentiating in an embryo. Chimeras also provided a stage for analyzing the earliest cellular beginnings of certain genetic diseases.

The glimpse that her chimeric mice gave her into the fates of

cells in the embryo made her tremendously aware, says Mintz, that a “hierarchy of stem cells” was a ruling force in development. A handful of stem cells in the embryo virtually populate and outfit the whole adult. From there on “I realized that the only sensible way to look at development was from the standpoint of stem cells.”

When John Gearhart joined Mintz’s Philadelphia lab in the fall of ’70, Mintz and her coworkers, along with designing chimeras, had begun working with the only embryonic stem cells available from mammals at the time, the embryonal carcinoma cells—or EC cells—that lived in the tumors of Roy Stevens’s infamous mouse strain. Relates Gearhart, “There was already a cottage industry of scientists working with EC cells in culture, and it was everyone’s goal to see if these cells could be used in chimeras.” What seemed invaluable to Mintz would be to exploit the genes in teratoma stem cells as markers as a way of tracking differentiating cells and the tissues they became. By putting teratomas cells from one mouse strain into the early embryo of another mouse strain, you’d have an animal with two sets of genes, and you might follow which cells evolved from which set.

Gearhart acknowledges that once he started working with carcinoma stem cells in Mintz’s lab, “I had a little bit of a love affair” with them. “For the very first time ever, we had a pluripotent cell in a dish that could form every other cell type in a dish.” It was biology at its basic best. He tried to maintain pure populations of undifferentiated EC cells, yet would admit to defeat. The cells seemed bound and determined to specialize into mature cells; he could never quite hold them back. Still, what an eyeful it was when, in response to some inner drummer, they turned to nerve or muscle or blood or other cells.

In 1972, Gearhart had the chance to meet the man whose research had shoved teratomas and their stem cells into prominence. The occasion was a biology symposium in Venice, and the younger scientist’s encounter with Roy Stevens turned out to be even more

memorable than it might have been, although not for any scientific revelation.

One evening midway into the conference, a large group of junior and senior scientists had gone out to eat and drink together, ending the night at Harry’s Bar, or in that general vicinity. “We got back to the hotel quite late, and a little later there was a knock at my door,” Gearhart relates. “Roy was missing. He hadn’t come back to the hotel, and they were forming a posse to search for him. He was quite inebriated, and the concern was that he had fallen into a canal.” The search party scoured the area—but no Roy. As it happened, Stevens, possibly bored with his cohorts or disenchanted with the conference, on a whim had jumped on a vaporetti, floated up the Grand Canal to the train station, and boarded the Orient Express. “When next heard from, he was in Istanbul,” Gearhart recalls.

Stem cells from the tumors of Stevens’s mice were so malignant that if they were put into the body cavity of a grown mouse, the mouse would be dead in a matter of weeks. Yet, as Ralph Brinster, Beatrice Mintz, and, in England, Richard Gardner showed in their respective ’74-’75 findings, when these tumor stem cells were injected into early embryos, they could enter into normal development and the making of normal tissues. Gearhart had helped grow EC cells for this experiment before leaving Mintz’s lab in ’75. Indeed, Mintz’s was the only team that used genes as markers, which permitted the tracking of cells down specialized pathways.

Here it was two decades later, and Gearhart was trying to corner the same primordial cell in a human fetus that Stevens had shown misbehaved in a mouse fetus and led to those “funny little tumors.” Gearhart’s reason for pursuing this cell were very different than the reason Thomson and others were pursuing stem cells in IVF embryos. After finishing his postdoctoral training, Gearhart had known this much: He wanted to devote his career to demystifying a mammal’s first weeks of development. No other corner of science could possibly be more interesting. Taking a position as a mouse

developmental biologist at the University of Maryland, his knowledge base expanded considerably thanks to the countless evenings he spent dissecting stillborns with Gladys Wadsworth, a fellow faculty member and astute anatomist. “She taught me all this—embryo and fetal anatomy,” he recounts with the true ardor of a developmental biologist. Ten o’clock would arrive, and they might still be leaning over the open chest of a fetus with Wadsworth in full oration about the heart and its “great” vessels, or the complicated nerve network next to the armpit. Recalls Gearhart, “Always the question Gladys worked with was, What in the very early embryo led to this being formed this way?”

Gearhart had all the more reason to throw himself into the subject of mammalian development, when, in ’79, he was hired by Johns Hopkins to both teach human embryology and research mammalian embryogenesis. He pored over moldy embryology tomes and visited the famous Carnegie collection of pale human embryos suspended in solution, then housed at the Smithsonian in nearby Washington, D.C. Meanwhile, “everyone began jumping into transgenics,” he recounts, notably transgenic mice. “Transgenic” animals have much in common with “knockout” animals. Essentially, scientists transfer a gene from one animal into another. “It became a standard procedure to try and get at a gene’s function this way,” says Gearhart.

Gearhart had jumped in, too, hoping to identify genes that drove the growth of the early embryo. Simultaneously on the side he had a small project going in which he was analyzing the genes of mice that had genetic abnormalities similar to those seen in Down’s syndrome. By the early ’90s, having spent over a decade on this project and by then regarded as a first-rate Down’s mouse researcher, he was itchy to extend his investigation beyond mice. “I began thinking, wouldn’t it be nice to study this disorder directly in the human embryo and heed Alexander Pope’s maxim, ‘The proper study of mankind is man.’” That’s when he formed the following plan. Down’s syndrome arose in humans who inherit three copies of chromosome 21 instead of the normal two. He was sure that if he could retrieve stem cells

from human embryos afflicted with the disorder as well as stem cells from normal embryos, then compare how these different versions differentiated, his lab might grasp a tremendous amount about the disease’s progression during embryogenesis.

Stem cells in mouse embryos had been isolated; why not those in human embryos? Any other researcher might have faced the stumbling block of obtaining human embryos. But having directed Johns Hopkins’s IVF lab for several years during the ’80s, Gearhart was pretty sure that some of the couples he had worked with would be more than willing to donate their surplus embryos. When he shared his research plan with David Blake, the medical school’s assistant dean for research was afraid that Gearhart might be headed for trouble. A researcher who chose to work with IVF embryos was playing with ethical dynamite. “David’s response,” recounts Gearhart, “was, ‘Is there any other way of getting these cells?’ and I said, ‘There’s Peter Donovan’s way—from fetal tissue.’”

Peter Donovan at the National Cancer Institute had recently shown that you could keep primordial germ cells from mouse fetuses growing in culture, as had, in separate work, Brigid Hogan at Vanderbilt University. Both scientists were interested in this cell primarily because it transported an animal’s genetic blueprint to the next generation, and not because its counterpart cell in humans might correct disease or assuage aging due to its chromosomes’ long telomeres. “Normally these cells last only about a week” in the mouse fetus, notes Michael Shamblott, a developmental biologist in Gearhart’s lab. “So the critical milestone” for Donovan and Hogan “was getting them to survive and multiply” in a petri dish, and for a long duration. When these sperm and egg precursor cells did this, they actually converted to a cell that was a phenomenon of culture—an embryonic germ cell, or EG cell, as Donovan called it. Unlike the cell it came from, along with dividing endlessly it could give rise to every type cell. What they did to it in a dish actually worked to give it more potential.

Thus, three different kinds of stem cells were now obtainable

from mice: EC cells derived from tumors; ES cells freed from embryos; and now EG cells from the forming testis or ovary of fetuses.

Blake’s recommendation to Gearhart was that he should obtain stem cells from aborted human fetuses and stay away from the more controversial realm of the embryo. People who saw an IVF embryo as a complete human being would hold a researcher responsible for disassociating its cells and causing its demise. An aborted fetus, on the other hand, had already met its demise within legal limits of the law and apart from any decision made by the researcher. “Researchers are not complicit in the termination decisions,” Gearhart today stresses. From a personal standpoint, Gearhart never had had a problem with abortion and fully supported the right of a woman to end a pregnancy. Nevertheless, he would make a thorough sweep of “the inflammatory subject”; he would read countless books on abortion (to this day he starts reading at about three in the morning due to his orphanage-ingrained habit of rising before the birds) and struggle through the mountain of federal, state, and institutional laws and policies that pertain to aborted tissue’s research use, not only because he would have to build a strong case for his research to a university review panel, but also for his own peace of mind.

This in-depth review failed to make Gearhart think any differently about abortion. “My shelves are now laden with books and articles, but even after extensive reading and continual discussions, I remain convinced of my position,” he maintains. When a fetus is aborted, “a pathologist makes sure that the entire conceptus has been removed from the uterus, and once the pathologist signs off, the fetus is discarded. Discarded,” he repeats with a shudder. It’s the throwing away of fetal tissue that’s unethical, he feels, since its cells might translate into lifesaving therapies. He can sound just like Jamie Thomson on the subject of surplus IVF embryos. Thomson told a reporter that using these embryos in research “was not only acceptable, but throwing them out when you could do something useful with them would be unacceptable.”

On numerous occasions, Gearhart, his postdoctoral fellow

Michael Shamblott, and John Littlefield, the former chair of pediatrics at Johns Hopkins and one of the fathers of amniocentesis, huddled together to discuss the related questions of whether to use stillborn fetuses or fetuses obtained through elective abortions, and whether to work off private or public funds. “Our primary worry about using stillborns” and other spontaneously expelled fetuses, says Shamblott, “was that the tissue might not get to us in fresh enough condition, and if the tissue wasn’t intact, it would be a lot harder to find the tiny fetal gonad.” This minuscule region, wherein lies the even more minuscule germ cells that they were after, is smaller than a grain of rice. They therefore decided to use fetuses that were aborted for therapeutic reasons, which were more likely to reach them in a fresh state. At the time, this fetus category was eligible for research funding from the government; however, the Hopkins researchers saw advantages in opting for the shelter of private funds. Those who opposed fetal tissue research would not be able to accuse them of spending so much as a dime of taxpayers’ money.

Johns Hopkins’s review board gave the go-ahead for the project, but only after a long and rocky review process that lasted from the fall of 1993 to the fall of 1996. “It was clear in my mind from the very beginning that people at Johns Hopkins who had a say in this really didn’t understand the potential of where all this was going,” voices Gearhart. “The biologists around me got it,” but most others didn’t.

A bright spot was that Michael West from Geron materialized in ’96 and clearly did get it. Hearing of Gearhart’s bid for the primordial germ cells, the cell that conferred immortality on the human race, he swooped down on the Johns Hopkins scientist one spring day as suddenly as he had descended on James Thomson some months earlier. “He knocked on the door, introduced himself and his purpose, and took me to lunch,” remembers Gearhart. Initially funded by Johns Hopkins, the stem cell venture soon moved under Geron’s financial wing, although for Geron “the collaboration was really a hedge,” notes West. “I didn’t know how easy it would be to

grow [stem] cells from blastocysts,” in which case he saw Gearhart’s sought-after primordial germ cells as a fallback. One way or the other, whether it came from embryo or fetus, West wanted to have a human immortal cell, complete with its chromosomes’ long telomeres.

That’s how it ended up that in the fall of 1996, in a warren of subterranean rooms a few buildings away from the medical school’s towering Jesus Christ, the statue that greets Christians and non-Christians alike who stream to Johns Hopkins’s medical complex from around the world, that Gearhart’s lab began working with fetuses supplied by Bayview Medical Center, a Hopkins-affiliated hospital that had an abortion clinic.

Much of the nitty-gritty benchwork was done by Gearhart’s postdoc Michael Shamblott. When it came to a hunt for the cells that perpetuate the human race, Shamblott was a perfect accomplice. He had been curious about what living things were made of ever since his uncle, a prominent microbiologist at the University of Minnesota, had performed an experiment for Shamblott when he was nine or ten. “I’m sure that it’s why I ended up in science,” he relates. It was a typical Minnesota summer’s day, as he recalls. The black flies were out in full force, and Gary Litman, his uncle, and Litman’s labmates “had rigged up all sorts of creative ways of trapping flies, from squirt guns to fancy swatters.” For the boy’s enlightenment, Litman put a few of these dead specimens into the chamber of a large lyophilizer—an instrument that sucks all the water out of an object, essentially freeze-drying it—closed the small door, ran the instrument for a few moments, “and in the end pulled out black fly dust,” recounts Shamblott. The boy saw that the fly wasn’t really much of anything minus its water. “My uncle challenged me and asked, ‘What would happen if we added water back to this dust, do you think we’d get a fly again?’ I thought and I thought; it was the first time I thought about biology as a question rather than things I had to memorize. We added water back, but only got black paste.”

Now, aided by ultra-fine scissors, micro-forceps, and his own steady hand, Shamblott was able to reach into the human fetus and

remove its incredibly small genital ridge, the structure that represents the premature testis or ovary. The fetus had to be at just the right stage for primordial germ cells to have migrated into this little area. Any earlier in development, and they wouldn’t be there yet; any later, and they might have already begun to differentiate into older, less pluripotent cells. “It was like hitting a moving target,” compares Shamblott.

In about a week he and Gearhart had trapped these early manifestations of human egg and sperm cells. There was elation in the lab, but it was short-lived. Placed in culture, the captured cells failed to keep dividing and promoting their continuation outside the fetus in a petri dish clearly would require a better mix of growth factors and feeder cells. For inspiration, they only had to realize that Peter Donovan and Brigid Hogan had gotten the same exact cell from mice to continuously divide in the “outside” world.

It just so happened that at the University of Wisconsin James Thomson was also up against a culture problem. He had known about this obstacle even before receiving approval for his stem cell undertaking in July ’95. Both Thomson and Gearhart, by the way, were well aware of what the other was up to and had good reason to be, seeing as how they had so much in common. Both teams were pursuing potent cells that could possibly change medicine so much that the current drug-and-surgery era might seem punishingly barbaric some day. Both were drawing heavily on previous animal experiments to get them there. Both were backed by a futuristic firm whose idea man was either nuts or clever beyond belief. And both were on a collision course with the Pope and about to make religious leaders everywhere run to their scriptures for answers to questions that their forebears had never needed to ask.

The culture problem that threatened to relegate Thomson’s embryo research to a back burner had come about because of this scenario: IVF embryos that weren’t immediately transferred into a woman were usually frozen right after they were made, on day 1 post-fertilization. If at a later date a woman decided to make use of

them for another attempt at pregnancy, they were thawed and grown to day 2 or 3, with transfer into the uterus following. An embryo, however, could not be grown in a dish all the way to day 5 or 6, which in human development was the blastocyst stage, at least not a healthy embryo. And yet that was the stage that Thomson was gunning for, the point at which an embryo’s inner cavity forms with its heap of stem cells.

Thomson had gotten Jeffrey Jones, the director of the university’s IVF lab, involved, and, according to Jones, they tried, unsuccessfully, any number of ways of improving the culture. “What was so interesting about this project,” says Jones, “is that things always came together at the right time.” When there seemed no way out of their culture predicament, Jones was at a conference on assisted reproduction in Chicago in May 1996 and nearly fell out of his chair upon hearing an Australian embryologist from Monash University, David Gardner, talk about a culture system he’d invented that kept human embryos thriving and happy straight through to day 5. In the following months, Jones and Gardner discussed the possibility of the Wisconsin team using the Australian’s culture approach for its stem cell endeavor, but logistics slowed headway on the matter. Then came another stroke of good fortune. By sheer coincidence, a member of Gardner’s lab took a postdoc position at the University of Wisconsin in 1997, and Thomson would contract her to make Gardner’s special formula for his project.

What was Gardner’s culture secret? He had been trying to better the success rate of implanted IVF embryos—a dismal twenty to twenty-five percent—when he clicked on the obvious. He realized that embryo cultures had been shortsightedly based on the embryo’s earliest moments, not later ones. “We learned from mom that she provides different nutrients for different development stages,” notes Gardner, now scientific director of the Colorado Center for Reproductive Medicine. So, drawing from vital vitamins and amino acids, he brewed up two media that mimicked the two environments that the embryo sequentially resides in, the fallopian tube and the uterus.

This new approach was so much better than the old one, it would translate into twice as many IVF embryos making it all the way to birth. It also meant the difference between stop and go for Thomson’s project. “Before, we could get blastocyst-like embryos, but they had no stem cells in their inner cell mass,” describes Jones. “The big change was that the inner cell mass was just huge and beautiful”—and stem cell rich.

As 1997 began, John Gearhart in Baltimore was also beginning to think that his project’s culture problem was surmountable. Learning from growth-factor combinations tested by Donovan, Hogan, and others, he and Shamblott were starting to see their embryonic germ cells thrive and last through the weeks, generation after generation.

And then on February 23, out of the village of Roslin, Scotland, swept momentous tidings. For any scientist who might be bearing down on human embryonic cells, the news would have the effect of further muddying waters that had already lost their clarity. Ian Wilmut and his team at the Roslin Institute had done what many scientists imagined was impossible; they had cloned a mammal, specifically a sheep, going about it basically the same way that Briggs and King had cloned their frogs: By putting a cell’s nucleus in an egg cell that lulled it back to a totipotent state so that it would start development all over again. Dolly had been cloned from a stored mammary gland cell—thus the researchers’ tip-of-the-hat to Dolly Parton—that had been taken from a mature ewe. (Cloning has an odd way of changing relationships. The ewe that gave her genetic information for the making of Dolly can’t exactly be considered Dolly’s mother, since Dolly wasn’t the product of sexual reproduction; instead, the older ewe—who actually was dead when Dolly was cloned from one of her cells—really represents Dolly’s identical twin.)

Plant scientists were amused by all the attention given to Dolly, who had been born the previous summer, on July 5. “We said, gee, we’ve been doing that”—cloning—“in plants for decades, and no

one jumped up and down and got excited,” recalls Susan Singer. But sheep, unlike plants, were perilously close to humans. Were humans next in line?

The quick succession of cloned mammals after Dolly suggested as much, and the debate over whether or not cloning should serve as a reproductive outlet for the human race raged. Most objectionable to some people was the idea that humans should have this much control over their existence, when we had always been creatures under an immense sky of a higher order. Cloning also raised the questionable, if not frightening, vision of being able to carbon-copy genetically outstanding attributes at will: perfect teeth, perfect IQ, perfect person. The possibility of selecting for genetic qualities suddenly seemed startlingly real. “Dolly really stirred up the whole issue over manipulating an embryo,” notes Colin Stewart. The scientific procedure itself was suspect. It took 277 attempts at transferring nuclei from mammary cells into egg cells before the Scottish team had achieved a live birth. The lesson that cloning was neither an easy nor efficient way to create life would continue to be borne out by other scientists.

At the July ’97 International Congress of Developmental Biology in Snowbird, Utah, Gearhart announced to attendees of a biology session that he and Shamblott had achieved a first. They’d isolated germ cells from the human fetus and maintained them for several months. The announcement, while causing excitement in the biology world, attracted minimal media coverage. The Johns Hopkins team still had to prove that their cells were pluripotent and further validate their finding by publishing it. By then, the questions and unease precipitated by a sheep’s cloning hadn’t abated, only intensified, and among the news reports that did cover the Baltimore group’s capture of human fetal germ cells, some were symptomatic of the confusion and nervous speculation that had built up post-Dolly. They included “Huxleyish scenarios,” to quote Johns Hopkins Magazine, that gave the impression that Gearhart was intending to

alter genes in his isolated cells, “implant the cells into a woman’s womb, and create a genetically engineered person.”

The stem cell and cloning details coming at the press and the public weren’t easy, and the science was beginning to get all balled up. It was unlikely that either Gearhart’s cell from a several-week-old fetus or Thomson’s from a six-day-old embryo, if put in the womb, could become a baby. Although both cells have potency, neither cell has a zygote’s total potential. But one could appreciate the confusion, especially when so many biologists were working away at modifyng the genes of stem cells, slipping the cells into embryos, and getting changed mice.

Gearhart, that spring, had his lab members read Aldous Huxley’s Brave New World and thus enter its chilling Center London Hatchery and Conditioning Centre where a “bokanovskified” egg could produce up to ninety-six buds that become ninety-six embryos and then ninety-six identical adults—all identical twins. (The whole process is a bit reminiscent of how hydras bud and produce genetically similar offspring.) The unimaginable was giving way to the imaginable, Gearhart conveyed. Scientists were verging on times when it would be possible to create superior beings akin to the “Alphas” and “Betas” of Huxley’s world, and he wanted his postdocs and techs to be good and ready for the hard questions that lay ahead. “If we are successful in genetically manipulating our cells,” he says today, “it will mean that now, for the first time, we are instructing our cells to behave as we wish. What enormous powers will we then possess? How will we use them? Who will decide?” The formerly quiet, “recessive” boy, as he remembers himself, was increasingly ready to speak out and stand his ground as a scientist.

Over in Madison, Thomson had to think twice about staying or quitting his course when he first heard about Dolly. “When Dolly happened, I wasn’t sure whether I wanted to get caught up in all of this,” he recalls. The human embryo was turning into a cause celèbre, and here he’d be dismantling dozens of donated IVF embryos to

acquire a cell that so far had no great significance in the eyes of the public. As ’97 proceeded, however, the project was spurred along by the chance of growing the embryos to blastocysts due to David Gardner’s new-and-improved culture methods. By the year’s end the legal language between the American and Australian groups was in order; the project was set to go.

After a long slow drudge, Thomson and Jeffrey Jones finally starting growing their first IVF embryo in Gardner’s special media in January 1998. And just as Gardner said would happen, the embryo ripened into a robust blastocyst state. Working in a small room behind the IVF clinic at the University of Wisconsin Hospital, Thomson separated stem cells from this blastocyst—which was the size of a dot, a very small dot—and cultured them as he would have monkey stem cells. From there on in, Thomson, Jones, and those assisting would constantly steal a peek at the cells, hoping and praying they hadn’t gotten away from them and differentiated. If the cells weren’t split often enough and became too packed together, that could easily happen. At one point, one dish’s worth did get by Thomson, their progeny rapidly turning to cardiac muscle cells that beat in unison. “People in the lab were in awe,” relates Jones. “It was so symbolic of the therapies these cells stood for.”

The weeks ticked by, and the Gearhart group’s EG cells and the Thomson group’s ES cells kept right on proliferating, generation after generation. We’ve crossed the line! Thomson and his crew realized. They could maintain their cells in culture indefinitely, making for a renewable source of cells that might fulfill the dream of cell-made medicines. Each group wrote up its report, the unavoidable sprint for earliest publication taking place, and in a stunning climax befitting the importance of these comparable coups, the two papers were published within a few days of each other. Thomson and Jones’s account of extracting embryonic stem cells from human blastocysts ran in the November 6 issue of Science, while Gearhart and Shamblott’s report of their EG cells aired in the November 10 issue of the Proceedings of the National Academy of Sciences. The Baltimore

team had gathered evidence that indeed their fetal cells, like embryo stem cells, could generate cells associated with all three body layers—ectoderm, mesoderm, and endoderm.

Thousands of news groups from around the globe galloped for the story and fastened onto the eye-catching phrase that turned up in both reports: transplantation therapies. Cure like with like. Resod grass with grass; renew forest with trees; replace sick cells with well cells. Therapies that relied on stem cells in bone marrow and skin had already been adopted, and without much knowledge of the regenerative cells at the crux of these transplants. Now that researchers knew the value of stem cells, and could make them live and survive and divide outside the body, practitioners of regenerative medicine had their clay, their basic raw material, and could press forward, suggested Gearhart and Thomson, who were not charlatans out to sell snake oil but scientists from eminent establishments speaking through peer-reviewed scientific journals.

But was their hope for the future of medicine too good to be true?

Far away in China, Professor Shunong Li had kept up his progress as well. A colleague of Li’s, Bruce Lahn at the University of Chicago, maintains that Li succeeded in isolating stem cells from human embryos and had even kept them alive for five divisions before Thomson’s November ’98 paper appeared in print. Li could have used some of Roy Stevens’s luckiness. According to Lahn, Professor Li lost his cell line when the liquid nitrogen tank it was stored in dried up during the heat of summer. Other seekers of human embryonic stem cells—among them Roger Pedersen at the University of California as well as the Singapore-Australian group of Ariff Bongso, Alan Trounson, Martin Pera, and Ben Reubinoff—were making similar strides, and if Thomson and Gearhart hadn’t published when they did, very likely another team or teams would have scored humanity’s magical cells a short while later. “The time was right,” notes Michael Shamblott.

To no one’s astonishment, the twin feats of appropriating stem

cells from embryos and from fetuses raised the controversy over embryo research, over abortion, over gene manipulation, and over the question When Does Life Begin? to a ferocious new roar. To many Pro-Lifers, Anti-Abortionists, and Born-Again Christians, Thomson’s “destruction” of embryos was tantamount to homicide. There were anti-abortionists who considered Gearhart’s reliance on aborted fetuses even more egregious since, because of its older age, the fetus was seen to have more intrinsic value and status than an embryo. It didn’t necessarily register that Gearhart’s research had drawn only on fetuses aborted for therapeutic reasons. Still others “attacked” his work, Gearhart observed in a 1999 letter to Roy Stevens, “on the basis that embryoid bodies”—the little mounds that EG cells piled into if not periodically divided—“were human embryos and that we were making and destroying human beings in culture.”

Thomson and Gearhart discussed the possible benefits of human embryonic stem cells with everyone from congressmen to reporters, medical students to drug executives, children to seniors, endlessly. Beyond transplant therapies, these cells might revolutionize other areas, they offered. They could be employed for gauging the effect of drugs on cells and their tissues. To test drugs for heart disease, for instance, researchers couldn’t exactly scoop cardiomyocytes from a living heart. Yet conceivably they could transform large batches of pluripotent cells into limitless supplies of myocytes for testing. Additionally, human embryonic stem cells and their behavior in a dish might provide a cinematic view of early development and its explosive process of cell differentiation, right down to the gene level. Genes inside the cells of embryos could be identified, the genes that told a cell, You’re going to be a blood cell, or You’re going to be a nerve cell. And grasping normal development was the obvious route to grasping how disease began, and how to thwart it.

As NIH director Harold Varmus summed up to a Senate subcommittee in December 1998 about Thomson’s ES cells, “There is almost no realm of medicine that might not be touched by this innovation.”

When conveying the promise for medicine, the scientists tried to be realistic. Endless unknowns needed fleshing out. How were stem cells to be expanded into massive amounts? How were they to be uniformly coaxed to differentiate into a cell of one’s choice? (Transplanting stem cells themselves was viewed as too dangerous by most scientists, since there was no telling what they might turn into.) Which diseases were the best candidates for transplantation therapy? What was the best way to deliver a batch of mature cells into a patient, and would they integrate with existing cells? How could you be certain there were no stem cells in the batch you were transferring, for fear they would form tumors?

Jamie Thomson, after submitting to intense public scrutiny, would retreat back into his work. Talk, discussion, and explanation, however, would become a way of life for Gearhart. “I decided that I had to become engaged, that I had an obligation to the public to explain the research,” he says. His former diffidence gone, after President George W. Bush’s August 2001 announcement that federal funds would be available for embryonic stem cell research, but only to researchers working off pre-existing cell lines, Gearhart would be at the front of the charge against this White House decision. It was shocking, he put forth, that the United States, the world’s leader in health care, didn’t support stem cell research to the hilt. Today, he frequently draws on what Paul Berg, the Nobel-winning biochemist, said to members of Congress in 2003: “Research and demonstrations of clinical efficacy are the only means for validating whether stem cell-mediated therapies will materialize. We are ethically and morally obliged to pursue them for the benefit of those who suffer.” Asks Gearhart, “How can you say it any better?”

The ideaman Michael West, whose gave his full support to bringing human embryonic cells to prominence, left Geron early in 1998. He felt held back by the company, and wanted to make better headway toward his goal of reversing aging in cells. Later in ’98 he joined Advanced Cell Technology in Worcester, Massachusetts, a company engaged in cloning animals and other futuristic pursuits. As its chair-

man and CEO, West today is more focused than ever, he says, on research that could reverse aging, and on the embryo’s immortal cells that could achieve this breakthrough. He sees therapeutic cloning as the answer. Imagine for a moment that you could start a pre-embryo growing with someone’s skin cell, glean its inner stem cells at day 5, and use them to make hemangioblasts—the cells that, lining blood vessels, fall victim to arteriosclerosis, the proverbial “hardening of the arteries.”

“Think of it!” exclaims West. “You could re-line that person’s arteries. There’s a saying in medicine, which is that you are only as old as your blood vessels.”