The sky was robin’s-egg blue the spring day in 2001 that I walked down Clarendon Street in Boston’s Back Bay neighborhood—past the rusticated stone of Trinity Church, past the skyhigh Hancock Tower—arriving in the next block at a brick building that housed the Hard Rock Cafe on its ground floor. “No Drugs or Nuclear Weapons Allowed Inside,” the red neon in its window commanded. Upstairs at Viacord, I was to meet with a biochemist who had offered to explain the science behind why a baby’s few ounces of cord blood deserve to be preserved and not tossed away like bath water.

Because of stem cells, which were so tiny in size and yet so enormous in their potential, were we on the brink of a truly modern era of medicine? Or were we being led down the garden path by the false presumption that medicines woven from the body’s very essence—its cells—might work better against disease than the chemical compounds amassed by the pharmaceutical industry?

One of the very first stem cell scientists I had interviewed was George Daley at the Whitehead Institute in Cambridge. Being an oncologist, Daley had initially approached stem cells from the perspective of cancer. An older view of cancer held that it arose when specialized cells abnormally dedifferentiated back into embryonic or

stem cell form, then divided uncontrollably. But opinion was changing, and Daley had aligned himself with the new perception that cancer was a developmental defect. Stem cells themselves might be the problem; if they didn’t differentiate when they were supposed to, but kept self-renewing, watch out! It could amount to a malignancy. From there, Daley had gone on to appreciate what these powerful cells might mean for medicine because they could differentiate.

Possessing a fiery eloquence, Daley was an inspiring messenger when talking to the public about stem cells. Since stem cells theoretically could give rise to any tissue, give them time and they “could transform the practice of medicine,” he had lately told an audience at Boston’s Museum of Science. They might lead to therapies for everything from baldness and decayed teeth to the degenerative diseases that had come to represent medicine’s “dominant challenge.” Cancer, heart disease, brain failure, kidney failure, and other afflictions felt by an aging population “are not easily treated by drugs and their small molecules, but need cells,” Daley asserted. With an out-spokenness admired by his colleagues, he shared his pet peeve with museum listeners, which was the United States government’s paltry backing of stem cell research.

A month later, during a press seminar at Whitehead, Daley really got going on the subject. The issue of funding stem cell research had become “a political football,” in which the United States would be the loser, he charged. Without the “unfettered” support of the National Institutes of Health, the arrival of valuable stem cell therapies would be held back because hundreds of laboratories couldn’t contribute their resources. Already stem cell science in the U.S. was falling into the hands of private companies, which dangerously removed it from public oversight. Furthermore, fired off Daley, other countries, in particular England and Germany, had announced they would support investigations into human embryonic stem cells, putting U.S. scientists “at a significant competitive disadvantage.”

Just prior to Daley’s Whitehead talk, his son Nicholas had been born, and the newcomer’s cord blood had been extracted by his M.D.

dad and subsequently cryopreserved through arrangements made by Viacord. Very possibly, Daley told me a short time later, the stem cell in cord blood possessed nearly the same powers as the bone marrow stem cell that put so many transplant patients on the road to recovery. “You really should go over and talk to the folks at Viacord,” he urged.

That spring, the hype over stem cells and their regenerative prowess was at an all-time high. Garrison Keillor even got in the act when a resident of Lake Wobegon began giving shots of stem cell to her tomatoes to make them grow extra large.

Assuredly, a remarkable string of discoveries had just transpired. James Thomson and John Gearhart were still receiving accolades for having collected embryonic stem cells from human embryos and fetuses, respectively, and the press, catching up to the science, was running tantalizing descriptions of what these embryonic cells could be made into: endothelial cells for regenerating damaged blood vessels; osteoblasts for bone repair; islet cells for treating diabetes; kidney cells and liver cells for those respective organs; one type of neuron for Parkinson’s disease and another for Huntington’s; one type of muscle cell for muscular dystrophy, another for incontinence. At meetings that I attended, researchers traded insights into which growth factors induced ES cells to graduate into a specific mature cell. But clearly this was a difficult art and had a long way to go. The goal of simply “whistling” at ES cells to transform them into a desired cell was still some distance off.

Adult stem cells, the kind that populate the organs of babies and adults, had become a category unto themselves. In fact, just when Thomson’s and Gearhart’s ’98 reports were causing so much commotion, incredible tidings about cells in the adult human brain arrived that fit with the evidence gathered for years from nonvertebrates. Leading up to this news, neural stem cells had been found in rodent brains, confirming Joseph Altman’s earlier work. When set in a dish, they morphed into the nervous system’s three main cells—neurons, astrocytes, and oligodendrocytes. Experimenters had even

shown that when you put neural stem cells back into rodents, they could migrate to a brain site in need of repair. Harvard Medical School’s Evan Snyder had injected neural stem cells into the tail vein of newborn “shiver” mice, mice that have tremors because of poor myelin sheathing around the axons of neurons, and the cells journeyed through the blood all the way to the brain, recreated the fatty sheaths, and stopped the shivering of sixty percent of the mice.

As for the news in late ’98, a co-effort between scientists at the Salk Institute in California and Sweden’s Sahlgrenska University Hospital left sweet evidence that the human hippocampus, the brain’s small curled region that figures so prominently in memory and spatial orientation, makes new neurons throughout a person’s lifetime. The headlines blazed: The adult human brain regenerated, just like so many other organs. Possibly hundreds of new neurons were added to the human hippocampus every day. Where new neurons lurked, neural stem cells must lurk, and by the new millenium the evidence was irrefutable. The adult human brain contained neural stem cells.

The temptation has existed ever since to correlate the brain’s production of new neurons with brain power. Reminiscent of Fernando Nottebohm’s canary work, however, scientists have found no easy way to tell if neurogenesis enhances learning and makes a person smarter. The function of new neurons remains undetermined. A study in 2000 revealed that the brains of deceased London taxi drivers had “significantly larger” hippocampi, presumably because of more cells therein, than control subjects who hadn’t navigated roads for a living. Can one draw the conclusion that the quantity of neurons in the brain has a bearing on intelligence? Researchers point out that intelligence probably is a lot more complicated.

The new realization that the human brain is capable of regeneration, and isn’t the fixed stone of old, has flooded the neuroscience field with optimism. Brain diseases that before seemed untouchable seem approachable now. Cells constantly divide in many regions of the adult human brain; however, according to the current consensus, only in two areas do the daughter cells take the form of neurons: the

hippocampus and the walls of the brain’s lateral ventricle. These new neurons, and the migratory streams they’re part of, might be therapeutically useful. So might the progenitor cells that produce the brain’s glial cells. Throughout the brain’s white matter, “a vast reservoir of progenitor cells” continuously divides and generates glial cells, notes Steve Goldman at the University of Rochester Medical Center. Exciting Goldman and others is that in a dish these dividing progenitors can be induced to make both glia and neurons. And so a central avenue of research now includes harnessing these in-body progenitors and directing their differentiation so that they might replace dead neurons. White-matter progenitors, for instance, might be a solution for replenishing neurons lost in numerous early-childhood myelin-robbing diseases, “every one worse then the next,” Goldman notes.

Researchers in the spring of ’01 were beginning to flock to the fledgling field of stem cell biology from every direction. No corner of the sprawling biological and medical sciences was immune to news about these evergreen cells. They had something for everyone, whether hydra specialist, developmental biologist, anatomist, geneticist, biochemist, or pathologist. Sensitive to how easily scientific findings can get blown out of proportion, investigators made gallant attempts to talk about the potential of these flexible cells with level voices. So many scientists were coming to believe in stem cells so fiercely, however, they often unwittingly were a party to the hype.

A few weeks before visiting Viacord, I had attended a seminar at the Dana-Farber Cancer Institute in Boston, where some of the field’s top players were lined up to speak, including John Gearhart of EG cell fame and Irving Weissman. Weissman’s Stanford lab had persevered in highlighting a stem cell that was the furthest-back ancestor of blood cells ever identified in bone marrow, first in mice in ’88 and then in humans a few years later. The meeting’s atmosphere in some ways told me more about where stem cell biology was going than did the science discussed that day. Dana-Farber’s Jimmy Fund Auditorium was so packed with students and faculty, who lined the walls

and even sat on the stage, that scores of others couldn’t extend so much as an arm into the room and listened from the corridor.

Once the talks got underway, the audience exuded an intensity that only a crowd of medical mavericks could. On every side of me there was enthrallment, curiosity, and—could it be?—an unspoken spirit of affirmation. When Gearhart forcefully pronounced, “We can do this, grow stem cells in certain growth factors and prod them to differentiate,” he seemed to be responding to the positive vibes around him, for there seemed to be nothing in that room that day if not faith in the future. I would see this same intense enthusiasm at one stem cell meeting after another; and I would hear it over and over again when speaking with scientists. That day at Dana-Farber, it reminded me of the physician I’d recently heard interviewed on television. Asked for his opinion on stem cells and their treatment value, he had energetically responded, “I have to want to believe in these cells. I took the Hippocratic Oath, didn’t I?”

As I climbed the two flights to Viacord, admonishments clung to me nonetheless. Watch out for what you believe, some scientists had warned; hopes for stem cells and their future in medicine could be as overblown as the promise of gene therapy was back in the ’70s. About to cross Viacord’s threshold into the competitive cord blood industry, I braced for someone in a shiny suit who would wax propagandistic about how the cord blood category of stem cell was free of the controversy that the embryo’s stem cell was mired in—even the Pope was behind using it—and about what a waste it was that every year in this country nearly four million umbilical cords got the heave-ho, in spite of their cells’ ability to rebuild the blood and immune systems.

But there were no shiny suits to be seen at Viacord. Timothy Moffitt, blond and blue-eyed, wore a wholesome pale yellow button-down cotton shirt and spoke earnestly. To be expected, he recited the advantages of transplanting umbilical cord cells as compared to those in bone marrow. The cord stem cell could treat the very same blood diseases, he said, while at the same time, be-

cause it was a more immature cell, it was more compatible with the immune system and posed a lower risk of graft-versus-host disease, the complication that results in a significant number of bone marrow transplant fatalities. Then he patiently responded to my “What abouts?” What about freezing cord blood for decades and suddenly having need of it? Would its stem cells still be viable? Can’t say, he admitted, because no one had stored cord blood for longer than twelve years. But there was every reason to think that it could withstand long-term preservation, since the body’s blood had been stored for over fifty years. What about the need to multiply cord blood cells into larger quantities for transplanting into adults? Wasn’t that important, and wasn’t that technology lagging? I’d heard that a child’s umbilical cord held only enough stem cells to sufficiently revitalize a child’s blood system, but not necessarily an adult’s. It was important, he replied, and the technology for expanding the cells was being worked on. I would later learn that the first adults to benefit from this new technology already had received cord blood transplants a year earlier, in 2000.

Although I didn’t broach the subject with Moffitt, some physicians believed that families who privately banked a child’s cord blood paid too much for too little. Usually there was a one-time service charge (at Viacord, $1,500), along with an annual storage fee in the vicinity of $100—a high price, the critics contended, when there was less than a one-in-one-thousand chance that a stored unit of cord blood would ever be needed. Its stem cells were useful in the face of blood- and possibly bone-related diseases, but that left out many other illnesses associated with other organs, that is, unless scientists were to find a way to dedifferentiate blood stem cells back into embryonic pluripotent cells, the way Frederick Steward had his mature carrot cell, and then get them to redifferentiate into specialized cells for whichever sick tissue. Some scientists would have said that option wasn’t even faintly on the horizon. Others would have argued it was.

While companies like Viacord collect and store cord blood for a

family’s private use, also springing up were public banks that collect a newborn’s cord blood free of charge and offer these donated units to anyone in need. A woman from the public blood bank sector told me that processing, testing, and typing one cord of blood can cost as much as $1,400, and that public banks that can’t absorb this cost are forced to close. So the private sector’s fees seem within reason, especially as a couple can rest assured that a baby’s unit of cord blood will be held for that individual or family. Stories circulate of how children have fallen ill, and when their parents have returned to the public bank that took their child’s cord blood, they’ve been told there were no matching units available for their child.

The pertinent question that remains is, how effectively can a baby’s banked umbilical cord blood treat an illness that arises in a child or an adult? Data tied to the less tested procedure of transplanting cord blood into adults to revitalize their blood and immune systems look promising. Far more tested and backed by solid data is cord blood’s ability to robustly reconstitute the blood-immune systems of children in the event of certain malignant and nonmalignant blood diseases. In some instances, cord blood might prove superior to a bone marrow transplant, since it causes less graft versus host reaction. That said, if the child’s sickness arises from an inherited genetic blood aberration, the wisest course of action might be to transplant cord blood from someone unrelated, advises Joanne Kurtzberg, director of the Pediatric Stem-Cell Transplant Program at Duke University. Otherwise, there is the concern that if a child gets his own cord blood cells back, or those of a relative who might have the same genetic defect, the disease could be reestablished, says Kurtzberg. Someday it may be possible to correct genetic abnormalities in the patient’s own cells, she adds. For now the main thrust is to infuse healthy cells that can restore lost tissue.

Moffitt, when I saw him in May of ’01, said that Viacord had banked in the vicinity of 7,000 cord blood units since its start-up in 1993. The company had been presented with its first case of an allogeneic (one person to another) transplant in June ’96; a boy’s cord

blood had been transplanted into his sister, who had acute lymphoblastic leukemia. Only a month before my visit, in April 2001, Viacord had seen its first autologous transplant. A boy with severe aplastic anemia received back his own unit of cord blood, its cells quickly engrafting and returning him to full health. His particular case having no genetic basis, there was no fear that inserting his cells back into him would recommence the disorder.

As of May 2004, Viacord has banked more than 50,000 cord blood units. A dozen have been utilized – ten for allogeneic transplants between siblings and only two for autologous transplants, according to clinical specialist Kate Falcon. Were Nicholas Daley’s blood thawed for use today, there’s a far greater likelihood that it would go toward treating a sibling, a parent, or other relative rather than Nicholas himself. Although a healthy sibling’s blood may contain the genetic aberration responsible for the sick sibling’s disease, it also may not, and at the same time prove to be a close genetic match, paving the way for a transplant that is immune-system compatible. There’s a twenty-five percent chance that Nicholas’s stem cells will be an exact match for a sibling; a fifty-percent chance that it will be a partial match. “This is where the cord blood victory lies,” says Falcon. Because the stem cells from cord blood are more naive than those from bone marrow, there’s that much more chance, she says, that they will be an appropriate stem cell source for a sibling without causing an adverse immune reaction. Falcon believes that the current uses for cord blood are just “scratching the surface,” and that in the future the cord blood stem cell will be a fixture in treatments for more and more nongenetic conditions, potentially including everything from the rebuilding of spinal cord nerves to the reconstitution of injured cardiac muscle.

After my meeting with Moffitt that day, when I stepped back into the bright sunshine, a sorry sight met my eyes. Seated on a stone wall next to the Hard Rock Cafe was a gaunt, shoeless woman whose lower face was smeared with dirt. Armless, she was smoking a cigarette by means of a bare foot. The sight of her sitting there was a

coincidental reminder of where stem cells could lead some day. The notion of creating three-dimensional spare parts, whether limbs or organs, may seem more in the realm of science fiction than reality, and yet, as I’d find out, within a short distance scientists at some of Boston’s finest research establishments were already using stem and progenitor cells to engineer organs, granted in a rudimentary way. One lab was outfitting dogs with bladders; another was close to creating heart valves for sheep. Other scientists were on the trail of the genes that permit a lobster to regenerate its claw or a fish its fin. Too bad this woman couldn’t board a time machine and travel into the distant future, for there’s no telling what she’d find—maybe even a new arm.

In the coming weeks and months, stem cells stayed high in the news, due especially to a development that had been heating up since the late ’90s. It had to do with adult stem cells, the kind found in an animal’s organs. In that they have “committed,” as scientists like to say, to a particular tissue, adult stem cells have differentiated a tad compared to stem cells in the embryo, and it was generally assumed that they therefore could only give rise to the specialized cells of their home organ. This was in keeping with the cardinal rule that said that cell differentiation in animals was a one-way street. Cells, like animals themselves, matured, but they couldn’t un-mature. They could specialize, but they couldn’t un-specialize.

Or could they? Rodent studies and even some human studies were bringing perplexing evidence that adult stem cells perhaps were not restricted in what they could become. Researchers maintained that they had caught sight of bone marrow stem cells morphing into brain, muscle, lung, and intestinal cells; brain stem cells becoming blood cells; skin stem cells turning into muscle and fat cells; fat cells turning to bone and muscle. These results flew straight in the face of dogma. “We really had a hard time convincing ourselves of our own data,” Angelo Vescovi of the National Neurological Institute in Milan, Italy, told the press when his group presented its finding of neural stem cells turning into blood cells in mice. For this to hap-

pen—for mature cells to transdifferentiate, or cross lineage boundaries, and become another kind of cell in another tissue—either they had to dedifferentiate and then redifferentiate, or they morphed directly into another cell, which seemed unlikely.

For the cloning of Dolly, the Scottish group had taken a differentiated cell, plunked its nucleus into the right environment—an egg cell—where it had reverted back to immaturity and totipotency, then given rise to a starting embryo that grew into a new sheep. Essentially, then, a mammary gland cell, through the process of transdifferentiation, ended up producing progeny of different lineages of a new individual. Still, most biologists saw this outcome to be the result of a forced circumstance.

Reports by scientists that suggested bone marrow stem cells could transdifferentiate claimed the most attention. And those accounts kept coming and coming. One of the earliest originated in the lab of Éva Mezey, a neuroanatomist with the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda. Back in ’95, for an investigation into a certain class of brain cell, Mezey had done some bone marrow transplants in mice. Four months after transferring bone marrow from males into young females, she was surprised to notice that some of the females’ neurons appeared to be descended from male cells. The telltale evidence was that the nuclei of these neurons contained the Y chromosome, the sex chromosome unique to males. The only conceivable explanation in Mezey’s opinion was that, once transplanted, the males’ marrow stem cells homed to the females’ bone marrow, bore progeny that populated the blood, and then some of those cells traveled to the brain and turned into brain cells. Roughly one to two percent of a female mouse’s neurons carried the male chromosome. “That’s actually a lot of cells, if you consider how many neurons are in the brain,” says Mezey.

Born in Hungary, Mezey had learned from her mentor, renowned anatomist John Szentágothai, that a scientist had to be ready to believe in observations that others didn’t have the eyes or courage

for. Nevertheless, she was ill-prepared, she says, for the harsh rebukes leveled at her by an extramural board of scientists. “They told me it was irresponsible to come up with unfounded ideas that weren’t in the textbooks.” Cells didn’t jump lineage lanes, and that was that. She sent her report to Science, where, after being held for over a year, according to Mezey, it was finally published in December 2000, alongside a similar claim by Helen Blau and coworkers at Stanford. Much to Mezey’s relief, Blau had also stumbled on the unusual sighting of bone marrow stem cells switching to nerve cells in mice.

In the wake of these reports, the journal Cell published data that were even harder to believe. A collaboration orchestrated by Diane Krause at Yale’s school of medicine held out the discovery that one stem cell plucked from an adult mouse’s bone marrow had yielded skin, gut, lung, and liver cells. It was the first published demonstration that a single bone marrow stem cell could differentiate so broadly, notes Saul Sharkis at Johns Hopkins, the paper’s senior author.

This finding was soon eclipsed by another from the University of Minnesota, Minneapolis. The principal investigator was Catherine Verfaillie, a tall and lanky Belgium-born hematologist who might have become a sports trainer had she not dislocated her knee doing the long jump in school, or a musician had she not broken a couple of fingers also doing school sports, or an engineer had engineering school not called for an entrance exam. And so she had gone to medical school at the Catholic University of Leuven, Belgium, which required no entrance exam. As she conveyed to me in an interview, “Everybody in my family is a perfectionist,” and there’s no mistaking that she falls into the same basket. She gets to the lab at an ungodly hour, is a disciplined treadmill runner, and admits to being “competitive by nature.” During her residency in the mid ’80s, her eyes were opened to the great medical value of bone marrow transplants, she recounts, which by then “weren’t an outrageous procedure anymore.”

Verfaillie’s observations arose from some research that she was

conducting at the request of Charles Peters, a pediatrician at Minnesota. For some time, Peters had been performing bone marrow transplants in children born with rare genetic disorders, one of which was Hurler syndrome, a skeletal disorder that results from an enzyme deficiency. So severe is Hurler syndrome that unless an afflicted infant receives a bone marrow transplant, their organs swell, they become demented, and they frequently die by age five. A bone marrow transplant can save these children; indeed it is the “only proven effective, long-term treatment” available, says Peters. Yet the young patients are left with terrible bone and joint abnormalities that require endless surgery.

In April of ’97, “I went over to meet with Catherine,” recollects Peters, “to go over what happens in a successful Hurler’s transplant. And basically the question I posed was, were there any ways of enhancing a transplant to help these children so that the vast majority wouldn’t have to have significant numbers of orthopedic surgeries?” Because of their surgeries, “to put it bluntly, their quality of life really stinks,” says Peters. A journal article had lately reminded scientists of the presence of a second, lesser-known stem cell in bone marrow. This mesenchymal stem cell had been identified in the early ’90s and was a close cousin to the hematopoietic stem cell. While the latter granddaddy rekindles the blood of bone marrow recipients, the mesenchymal stem cell has the important task of generating the body’s bone, cartilage, muscle, and fat cells. (It is named for the embryonic tissue—mesenchyme—from which it originates.) Whenever bone marrow was transplanted, this other stem cell was likely to be present along with its blood-forming cousin.

The idea that Peters and Verfaillie cooked up was that Verfaillie would isolate the bone-making mesenchymal stem cell so that Peters could transplant it directly into his young Hurler patients. “These cells would provide the enzyme missing in these children that breaks down sugars that accumulate in multiple tissues, especially in bone and cartilage, tissues not aided by classical hematopoietic stem cell transplants,” explains Verfaillie.

The rest amounts to an accidental discovery. After Verfaillie and her graduate student Morayma Reyes had isolated what Verfaillie believed to be the mesenchymal stem cell, Verfaillie prompted Reyes, who was tending the cells, to omit cow serum from the culture. If and when she and Peters sought FDA approval for their therapeutic method, Verfaillie knew that “the FDA would crack down on using cow serum” in a culture whose cells would be going into children, she notes. So Reyes left out the serum and moved on to plating the cells at a low density—one cell per well, according to Verfaillie. The cells prospered and divided for the next many months, at which point “we had a hunch that our cell was different from your classic mesenchymal stem cell,” recalls Verfaillie. For one thing, it grew for much longer. For another, it exhibited a curious idiosyncracy. One day Verfaillie and Reyes noticed that their cell had differentiated into endothelial cells, which pave the inside of blood vessels. Your “classic” mesenchymal stem cell wasn’t supposed to be able to do that.

That was the beginning of a culture odyssey, sending the research into a different orbit. Verfaillie and Reyes made another alteration to the medium their stem cells were floating in, and in their culture dish appeared “strange-looking cells that I vaguely remembered from histology class,” recalls Verfaillie. The cells were neurons, oligodendrocytes, and astrocytes, the nervous system’s three chief types. “By accident, we had put in all the right ingredients to make neural cells grow.” So now they had evidence that their human bone marrow cell—which, lacking some stemness, was likely a progenitor cell—could generate cells indigenous to two layers of the body, mesoderm and ectoderm. At this point, Verfaillie recalls, “on purpose we went after cells from the third layer”—endoderm. And got them! Another culture rendition resulted in liver cells. That their human bone marrow cell could produce such a Noah’s Ark of progeny was “absolutely startling”—“a bombshell”—“nothing short of monumental,” other scientists stammered to reporters. Verfaillie went back to rodents and showed that if you retrieved the same progenitor cell from their bone marrow and inserted it into the early mouse em-

bryo, its progeny lent to nearly every tissue in the adult mouse. This seemed to strongly validate her cell’s multipotent versatility.

Could cells really leap from lineage to lineage? A great many researchers didn’t know what to think. Some scientists theorized that, in response to internal emergencies, bone marrow stem cells rode the bloodstream to this or that organ, changing identity when they got there to help repair tissue. This possibility was analyzed and reanalyzed, because if the bloodstream really was a conduit for transdifferentiating cells, scientists might be able to exploit this ferry system as a way of getting more stem cells into sick organs.

Éva Mezey uses multiple sclerosis, a nerve disorder in which the myelin sheath around neural fibers deteriorates, as an example. To try to counterbalance this deficit, the body actually steps up its production of oligodendrocytes, but this attempt can’t fix the problem. If transdifferentiation among cells really does occur, Mezey suggests that a treatment option might be to transplant generous amounts of marrow stem cells into the bloodstream that, if luck held, would enter the nervous system, become neural stem cells, and further turn into oligodendrocytes. An even better approach might be to increase the level of growth factors that bolster the body’s production of nerve cells. Notes Mezey, “We should let the brain do the job, but help it.”

Numerous studies now indicate that when disease strikes, tissues and their cells work even harder to regenerate themselves. Although this repair response is never quite enough to rid a person of the disease, it can restore some function. (Then again, it is possible that the regeneration displayed by so many organs and systems—even the brain—may constantly be keeping illness at bay, and we just aren’t aware of it.) A case in point is what happens after a stroke obstructs blood flow to the brain, eliciting tissue damage. In animal models, this insult can trigger the birth of new neurons in the brain’s hippocampus as well as around its ventricles. Some of these cells migrate toward the damage and may help in the recovery of neural connections. In humans, this cell surge probably doesn’t last longer than a few weeks, yet it may be responsible for the partial recovery

that stroke victims frequently experience. Roy Stevens, for instance, has had several strokes since his retirement from the Jackson Laboratory in 1989, and to a certain extent his verbal and motor capabilities have rebounded after each episode. Were stem cells behind this repair, as well they might be, what a just reward for someone who has been so instrumental in bringing stem cells into the public eye.

Conservative groups wasted no time latching onto the idea that stem cells retrieved from adults might be the handmaidens of cell-based therapies. What need was there to destroy IVF embryos, they asked, if cells from bone marrow, fat, skin, or the placenta could be converted to other specialized cells? By the same token, what need was there for human therapeutic cloning, the process of growing an early human embryo to roughly the blastocyst stage so that its stem cells could be harvested and directed toward therapies? No group had accomplished this yet, although someone soon surely would.

Since Dolly, the debate had sizzled on many continents about whether to permit either therapeutic or reproductive human cloning. Therapeutic cloning, which many scientists side with, is strictly a medical strategy. Once born, a person doesn’t have embryonic stem cells—only an embryo does—and so this limited cloning procedure can provide someone with their own personal stash of ES cells. One of their cells is cloned, a tiny pre-embryo is advanced to a five-or-six-day-old blastocyst, and stem cells are retrieved that, hypothetically, can be made into specialized cells to treat the person’s ailment. A huge plus of “research” cloning, as it’s also called, is that the stem cells procured this way are a genetic match to the patient; they wouldn’t be rejected by the immune system.

In the case of reproductive cloning, which most scientists vigorously oppose, the blastocyst would be transferred into the womb to produce an infant. This asexual route to human reproduction also had not yet been accomplished. Cloning laws were under review in the United States, where none so far existed at the federal level. In Britain, an added provision to the Human Fertilisation and Embryology Act 1990 made it possible for scientists to therapeutically clone

embryos for research, while another ruling had outlawed reproductive cloning.

Starting in ’91, members of the Far Right seized upon Catherine Verfaillie’s novel bone marrow progenitor cell as the perfect source of cells for transplantation therapies. Verfaillie was less than thrilled. The last thing she wanted was for her research to be hitched onto by people who didn’t understand it and were using it to expedite their own agendas; or for adult stem cells to be touted to the exclusion of embryonic stem cells. Even though she had been raised in a devout Catholic family, she was in favor of scientists employing human embryos in research, if their reasons were solid. She had just been made director of the University of Minnesota’s new stem cell institute, and she went on record as saying that while she felt that her adult stem cells were capable of extensive plasticity, it was too soon to know how they compared to ES cells, and until both were thoroughly examined, the institute’s scientists would “ride the two horses.”

The stem cell field meanwhile grew more divided over whether adult stem cells could switch lineages, with the nonbelievers increasing. Out to test transdifferentation, some groups put marked bone marrow cells into the bloodstream to see if they entered other organs and changed fate. They didn’t appear to, at least not to any significant extent. There were sightings, however, of small numbers of circulating marrow cells fusing with native cells in various organs. To many onlookers, cell fusion was more believable than cell transdifferentiation. Egg and sperm cells fused; so did muscle cells. The point was also raised that scientists who had reported transdifferentiation in bench experiments may not have begun with a single cell. That would be the only ironclad way of knowing that the end progeny arose from a single cell.

Catherine Verfaillie today insists that her experiments begin with a single bone marrow cell, which, through proliferation and differentiation, generates an assortment of cell types. Out of the body, her cells, she acknowledges, are probably free of molecular signals that in the body restrict their differentiation. In other words, in a dish her

cells might be behaving in ways not possible in vivo. If that’s the case, can these cells be therapeutically useful? Verfaillie sees no reason why not. Other investigators aren’t convinced that Verfaillie’s adult progenitor cell is so outstandingly versatile, although that hasn’t stopped Athersys, a Cleveland research house, from attempting to turn this cell into a transplant remedy for genetic diseases.

Verfaillie and Charles Peters still intend to work toward relieving Hurler babies of their skeletal abnormalities. In the meantime, an exciting account coauthored by Duke’s Joanne Kurtzberg relates how umbilical cord blood stem cells managed to restore the missing enzyme in the blood and the brain of seventeen of twenty Hurler infants, reversing most of their symptoms. The high success rate had a lot to do with how cord blood from a donor can get along with a recipient’s immune system.

The clash of opinions over adult stem cells would ultimately teach me a great deal about cells in general, and stem cells in particular. Just when the reports of cell transdifferentiation were tumbling out fast and furiously, I was spending long hours in the basement of Harvard Medical School’s Countway Library, lost in yellowing accounts by early-twentieth-century naturalists about the great lengths they went to in order to try to solve the mystery of how amphibians, crustaceans, worms, and other animals regenerated a missing part, or sometimes even several new selves, as Abraham Trembley had seen hydra do when he cut them into several pieces. (Charles Bonnet agitated over what happens to the soul of a snipped-in-two hydra. “Are there in this Insect … as many souls as there are portions of these same Insects which can themselves become perfect Insects?” he had asked.) Early volumes of zoology are crowded with studies on regeneration, the excitement of the chase barely concealed beneath the crust of academic prose. Here’s an excerpt from one lengthy report written by Thomas Hunt Morgan that appeared in The Journal of Experimental Zoölogy in 1906.

Straining to comprehend how lost appendages were restored, scientists in the early part of the twentieth century were at least one jump ahead of Trembley and his eighteenth-century peers. They knew that the pivotal ingredient in limb replacement were “embryonic cells”—“indifferent” or “undifferentiated” cells. They would detect them in the vicinity of the blastema, the group of cells that form at the border of a missing part. By the 1920s, if not a decade or two before, the regeneration crowd had already reached a surprisingly modern-sounding conclusion about these blastema-related embryonic cells that played into regeneration. Either these immature cells were holdovers from the creature’s early development, when it was a mere embryo, or they were the result of mature cells in the adult animal having dedifferentiated back into a pluri- or totipotent state. Either way, a grown creature’s new appendage could only arise from embryonic cells; they alone had the potential to produce the array of cell types necessary to reform a lost part.

Interestingly, Catherine Verfaillie has a similar either-or explanation for why she believes her bone marrow cell—found in grown mammals—can versatilely go down multiple lineages. “Either it’s a very early stem cell left from development,” she observes, “or it’s a cell that can dedifferentiate and then be pushed to redifferentiate in multiple directions.” What the regeneration literature makes clear is that the stem or progenitor cells in a salamander’s stump are mesenchymal in nature—that is, related to the bone-cartilage-muscle lin-

eage—which could be true of Verfaillie’s cells. At this juncture, her lab plans to study the genes of its stem cells to see if they bear any resemblance to those involved in a salamander’s regrowth ability or that of planarians, microscopic worms.

The evidence nowadays leaves little doubt that the regenerative deftness of hydra, amphibians, worms, and many sea creatures, which Abraham Trembley and his peers were at a loss to explain, is due to mature cells at the injury site backtracking to pluripotency. As such, regeneration incorporates the process of transdifferentiation: Cells of one lineage transdifferentiate into cells of another lineage by first returning to an immature state and then specializing into the diverse cell types needed for forming a new part. Consider what a Max Planck Institute team in Dresden recently witnessed in a salamander’s regenerating tail: Spinal cord cells yielded immature cells, and then those pluripotent cells generated muscle and cartilage cells for a new tail. By comparison, hydra are so laden with stem cells that wherever you slice them, as Trembley left evidence of, no dedifferentiation process is necessary; their stem cells are right there, ready to reform whatever section has been lost.

“The ability to regrow missing parts always depends on the availability of a source of pluripotent cells,” notes Alejandro Sánchez Alvarado, a biologist at the University of Utah School of Medicine. Which may be why humans are such regenerative laggards, Alvarado and others offer. Our cells and tissues may be so specialized that they don’t have the flexibility necessary for regeneration to take place with the same spunk it does in a salamander or zebrafish.

Here the stem cell community was locked in disagreement over whether a mammal’s cells could cross lineage boundaries, and yet if one stepped back for a broader view, Nature seemed replete with situations in which cells switch fate. It can happen when cells are called upon to grow severed limbs. It can also happen when the eye lens of a salamander is damaged, and pigment cells in the adjacent iris dedifferentiate and redifferentiate to regenerate the lens. It can happen when sponges get pounded to pieces by waves, and mature

cells (choancocytes) dedifferentiate, regroup, and differentiate anew to form, by zoologist’s Henry Wilson’s 1907 account, “perfect sponges.” It happens when you take a cutting of a plant, and older tissues regress into embryonic cells that contribute to new root and shoot cells. There are still other ways in which a cell can manifest its flexibility, or plasticity. Put a carcinoma stem cell into an embryo and it can contribute to healthy progeny; or slip a normal embryonic stem cell into a foreign place and it can generate a malignant teratoma.

Dolly the clone is one of the best examples of a cell’s inherent flexibility. An udder cell was made to roll back in time, recapture full potential, and launch the development of a new lamb. “Any cell in the body can behave as any other cell. In principle, that’s what Dolly is telling us,” comments Christopher Potten, a stem cell biologist at EpiStem Ltd., in Manchester, England. Any cell can become any other cell. That’s because, to use humans as an example, a skin cell on your arm contains the same 30,000 or so genes that are present in a cell in your intestine or a cell in your heart. The difference between cell types amounts to which of a cell’s genes are switched on and which are switched off, a difference that is markedly influenced by the cell’s surrounding environment. In one environment, a cell’s genes will tell it to be a skin cell; in another environment they will tell a cell to be a pancreas cell.

Although it was Dolly who really convinced biologists that the nucleus of a mature mammalian cell had the capacity to dedifferentiate, soon afterward an interesting paper in Cell shared its evidence that a mammal’s intact cell could do the same thing if simply put into a special culture. The Dolly experiment reprogrammed a cell’s nucleus by transferring it into an egg environment; here, a cell’s nucleus was reprogrammed by changing the cell’s entire surroundings. Mark Keating, a cell biologist and cardiologist at Children’s Hospital in Boston, and his postdoc Shannon Odelberg took skeletal muscle cells from mice—“the most differentiated cell I could think of,” Keating says today—and put them in a solution that inveigled them back into a multipotent state. They then nudged them

to redifferentiate into cells that appeared to be bone, fat, and cartilage cells. “It proved that the term ‘terminally differentiated,’” which refers to mature cells having run their course, “is a misnomer,” says Keating. In both Dolly and this example, genes inside cells were essentially recalibrated by new environments.

Keating believes that every mature cell in a mammal has this same flexibility, which could be indispensable for any scientist hoping to direct cells to regenerate diseased tissue. Numerous questions remain about regeneration, including what starts it, what maintains it, and what genes account for it. As these molecular enigmas get solved, “I don’t think there’s any reason to think that regeneration can’t be enhanced in humans,” Keating maintains. “The argument has shifted from it can’t be done, to it can be done.”

In his lab above the din of Longwood Avenue, Keating is committed to getting the human heart to regenerate itself. His lab’s most important tool in this respect is the zebrafish, which scientists have lately realized is as good a regenerator as a salamander. This small striped fish can renew it fins, spinal cord, and retina, along with a goodly portion of its heart, Keating and colleagues have shown. Clip away twenty percent of the heart, and within sixty days it grows back to its original size and shape, in sharp contrast to the human heart, which shows hardly any regenerative recovery. The manner in which the zebrafish heart restores itself resembles the cellular process that renews an amphibian’s appendage: Specialized cells dedifferentiate and then redifferentiate—in the fish’s case, into cardiomyocytes, the heart’s muscle cells. Keating and his labmates are searching for the genes and proteins that permit this cardiac comeback in the belief that the human heart has the same capability, although in muted form. A long-term goal is to inject chemicals that would stimulate the heart to rebuild lost tissue, says Keating, whose commitment to the heart ties back to his grandfather’s fatal heart attack when Keating was seven years old.

While disagreements continue among scientists over whether adult stem cells in mammals have the means to jump tracks and

become a different cell type, the leading vote is that fusion could explain the reports of transdifferentiation, although there are those investigators who maintain that their data show cells crossing lineages—and not fusing. Whatever might be happening in these experiments, the plentiful examples in Nature of cells being reprogrammed and changing direction bring us back to what Matthias Schleiden and Theodor Schwann proposed in the 1830s: A cell appears to have a life of its own.

As little as a cell’s flexibility has been explored, scientists are already trying to harness this feature to the best of its advantage for medicine. In 2001-’02, Whitehead Institute colleagues George Daley and Rudolf Jaenisch collaborated on an experiment that illustrated how therapeutic cloning, and its creation of stem cells from five-day blastocysts, might come to the rescue of patients in the future. Their subject was a mouse with a genetic blood disorder. Using a cell from the tip of the mouse’s tail, they transferred the nucleus into an egg cell, reprogrammed it, allowed it to develop into a blastocyst, and obtained stem cells. These cells, however, retained the genetic defect, so they corrected the DNA defect, then injected the repaired stem cells into the blood of the original mouse. The cells multiplied and succeeded in ameliorating the mouse’s illness. “It was a very exciting outcome,” shares Virginia Papaioannou. “There were some problems with the procedure, but it did improve the situation of the mouse. This is what we all say therapeutic cloning can do.”

On August 9, 2001, George W. Bush, who had been inaugurated that January, appeared in a televised news conference to announce the White House decision concerning human embryonic stem cells for research. Jordana Lenon, public relations officer at the University of Wisconsin’s primate center, recalls that she watched Bush’s address in James Thomson’s lab surrounded by his postdocs and technicians, although Thomson himself “was reportedly hang gliding,” recalls Lenon. Bush informed the public that federal funds would be available to stem cell researchers who utilized any of the sixty-odd human ES cell lines that were already in place worldwide, a number that

would shrink considerably due to many of the lines being unavailable. It was a striking declaration insofar as it was coming from a president who was a Born-Again Christian, during times that had an aura of déjà-vu conservatism, in a country whose government had never before sanctioned research on human embryos. Recounts Lenon, “I remember that right after Bush said that, the first thing that anyone in the room said was, ‘It’s a start.’”

The August decision was neither an executive order nor a law fashioned from judicial or legislative cloth, according to Lana Skirboll, director of NIH’s Office of Science Policy. The United States remained strikingly bereft of approved guidelines for research on human embryos that had been created in a dish but never implanted. This absence was so different from the United Kingdom, where, maybe because of Louise Brown, the government had gotten an early jump on regulating IVF embryos for research. In 1984, just six years after the birth of Louise Brown, the Warnock Committee and its chairwoman Dame Mary Warnock had recognized the human embryo’s fourteenth day—the onset of the primitive streak—as the very earliest point at which, for research purposes, the embryo began to become a person. This decision set the stage for the UK’s 1990 Human Fertilisation and Embryology Act, which allowed IVF embryos to be used for the study of gene abnormalities and diseases, among other indications. An amendment to the act in 2001 had gone further and given researchers license to derive stem cells and cell lines from IVF embryos, and also to create stem cells through therapeutic cloning—with the day 14 cutoff and other regulations strictly enforced.

American stem cell scientists would become increasingly envious of the UK’s favorable climate, and yet UK researchers could feel hemmed in by the strict regulations. Any group desiring to use IVF embryos for research “has to jump through hoops,” says a member of the Bioscience Unit of the UK’s Department for Trade and Industry. “Our policy is very supportive, but very regulative. So it’s a typical English stoic.”

A little over a month after Bush’s announcement, on September 11, 2001, the World Trade Center suffered its mortal blow by terrorists. Making a narrow escape was a fifty-eight-year-old electrician and Parkinson’s patient who was working on the thirty-fourth floor of the north tower when it was hit. He had received an experimental transplant of fetal dopamine-producing neurons in January 1999, and a year later had been able to go off the drug Levadopa, according to Curt Freed, the University of Colorado Health Sciences Center neuroscientist who performed the transplant with surgeon Robert Breeze. The man was one of nearly three dozen patients enrolled in an NIH study whose advanced Parkinson’s was improved by transplanted fetal tissue, on average by sixty percent, says Freed.

Over the years, the large majority of fetal transplants for Parkinson’s have not borne such positive results. Still, the successful exceptions serve as “proof of principle” that dopamine-making neurons, when transplanted in a certain way, can work, agree many scientists. Realistically, fetal cells may never be a good source of tissue, says Freed, because, even if the controversy surrounding fetal tissue didn’t exist, there isn’t enough fetal tissue for the world’s millions of Parkinson’s patients. A far better source, believes Freed, might be human embryonic stem cells and their output of an unlimited supply of dopamine neurons.

After running down thirty-three flights of stairs, the Twin Towers survivor walked several miles to the train station. To this day he remains off L-dopa, reports Freed. So far, then, he has twice escaped with his life.

This page intentionally left blank.