The call went out from a Subaru wagon as it rapidly approached Boston on a crowded Massachusetts turnpike. It was an April morning in 2001. At the downtown offices of the cord blood banking company Viacord, which were located two floors above the Hard Rock Cafe in Boston’s russet Back Bay neighborhood, one of the twenty-five phones in the calling center lit up and was promptly answered. Viacord’s operators were on tap twenty-four hours a day for their clients, far outdoing the bar below, where the only light that had remained on all night was the blood-red neon sign in the window: “No Drugs or Nuclear Weapons Allowed Inside.”

“My wife’s in labor; we’re on our way to the Brigham,” said the caller, referring to the Brigham and Women’s Hospital. “Yes, we remembered the kit. It’s in the trunk.”

The caller was George Daley. No stranger to hospitals, he himself was an M.D., a hematologist-oncologist who had served as chief resident in medicine at Massachusetts General Hospital some years earlier. Approaching midpoint in his career, he was in an enviable position, spending a portion of his time attending to the needs of cancer patients at Mass General and the rest of his time developing strategies against a rare form of leukemia in his laboratory at the prestigious Whitehead Institute across the Charles River. As for “the kit,” every Viacord customer received one. They in turn had to remember to give it to their obstetrician or midwife right before their

newborn entered the world. Resembling a square shoe box, it contained several items that facilitated salvaging blood from an infant’s umbilical cord and attached placenta for the sake of storing this natural resource long-term. Included were a standard blood-collection bag, an umbilical cord clamp, a two-inch needle for drawing the blood from the cord, and an anticoagulant to ensure the bagged blood wouldn’t clot, which would have ruined the usefulness of certain of its cells. The whole point of bagging the blood was to save these special cells.

Ideally, most of little Nicholas Daley’s cord blood—about three ounces’ worth—would end up frozen in a blood-storage facility several hundred miles away that Viacord leased from the University of Cincinnati. The sample might very well sit there unused for the rest of Nicholas’s life. As far as his parents were concerned, that would be their wish. Tucked away, the blood would be medical insurance at its most basic, and were it ever needed, it would be because Nicholas, a sibling, or some other relative had encountered a serious, life-threatening illness, and the hope at that point would be that the special cells in Nicholas’s cord blood, which floated in rare numbers among other types of blood cells, would come to the rescue.

The cells held in such high regard were stem cells—in this case, stem cells specific to a baby’s cord blood and therefore a shade more differentiated, or specialized, than the stem cells present in early development, in the early embryo. In either case, what generally sets a stem cell apart from other cells is that it is of immature status (some versions more than others) and unspecialized (some versions more than others) and more fancy-free than a mature cell that has specialized.

When it divides, a stem cell can be of two minds; it can generate more stem cells just like itself—scientists refer to this as “self-renewing”—or it can produce specialized fare. This is said to be why scientists call it a stem cell—because of the different cells that can stem from it. While mature cells—the heart’s myocytes or the liver’s hepatocytes or epithelial cells in the lungs—are apt to stop dividing after

several dozen divisions, the beauty of stem cells is that they can keep dividing indefinitely, renewing themselves and/or churning out differentiated progeny. As a result, they are terribly important tissue regenerators. Notes ophthalmologist Kenneth Kenyon, who later enters our story, “The essence of a stem cell is that it is a gift that keeps on giving.” Without stem cells, and the specialized tissue they provide, says Kenyon, “we’d be short-lived, short-limbed, and short-sighted as well.” We’d be nothing, actually, nor would any other multicellular living thing.

Of the several different versions of stem cells that Nicholas Daley would benefit from before and after birth, the one that begins it all is the fertilized egg, or zygote, which scientists consider the ultimate, or “mother,” stem cell. The zygote is totipotent, meaning that it has the capacity to give rise to every type of cell that festoons every tissue associated with the embryo and eventual adult, including the umbilical and placental structures that support the growing embryo. Because a totipotent stem cell has total potential to become any cell, it has what is referred to as unbounded “stemness.”

Even after the fertilized egg cleaves once, then twice, its multiplying cells continue to be totipotent, although in the space of a few more divisions this magic appears to be gone. Starting on day 4 post-fertilization, however, just as it reaches the uterus but before it implants therein, the early human embryo acquires another category of stem cell. As it evolves into a hollow round ball—a blastocyst—a little heap of cells appears on its inner wall. This small clump, which represents the first glimpse of the embryo proper, is composed of stem cells that are considered pluripotent by most scientists. Whereas the totipotent (totus meaning entire) version of a cell can generate every cell type associated with the growing individual, the pluripotent (plures meaning several) version nearly can, the exception being the cells that make up the embryo’s outer layer (the trophoblast) and the embryo-supporting placenta that forms from those cells.

The stem cells heaped inside the blastocyst, or early embryo, look not unlike a clump of seeds inside a round pod. But each of

these cells is much tinier than a plant seed. On day 5 post-fertilization, the human blastocyst itself “is smaller than a period set in six-point type,” describes William Lensch, a stem cell scientist in George Daley’s lab, now located at Children’s Hospital in Boston. For these embryonic stem cells to be seen with any clarity, they need to be magnified by as much as five hundred times. Yet as extraordinarily small as an embryo-residing pluripotent stem cell is, it is astonishingly powerful. Through an exhaustive process of division and differentiation, or specialization, the blastocyst’s inner handful of stem cells will grow into a bigger and bigger bundle of cells that ultimately arrange themselves into organized tissue and an individual.

By the time an embryo becomes a fetus, organs are beginning to form, and yet a third category of stem cell is coming into existence: adult stem cells. (In the case of human development, biologists usually cite week 8 post-fertilization as the beginning of the fetal stage.) Many an organ will have its own resident stem cells. So, too, as we’ve seen, do the umbilical cord and placenta. Stem cells in organs are few and far between—in some cases as rare as one in every 15,000 cells. Often, however, they will bear the responsibility of regenerating an organ’s entire population of specialized cells. As the fetus grows, one particularly striking example of organ-dwelling stem cells are those that migrate into the developing testis or ovary, for these precursors of sperm and eggs cells will perpetuate the species. The outcome is one of Nature’s most miraculous stunts: A highly specialized egg from a female will join with a highly specialized sperm from a male to produce a zygote, an unspecialized but fabulously totipotent cell that will bring about a new individual. Then round the circle will go again.

His wife’s pregnancy had made George Daley think hard about this amazing phenomenon. Speaking at a gathering at Whitehead Institute right around the time that his son Nicholas was born, Daley noted how remarkable it was that a sperm from his “aged, decrepit body”—leanly built and smartly tailored, forty-year-old Daley hardly appeared decrepit—could fuse with an egg from his wife to bring

about “a cell that is completely rejuvenated.” Each of us might age and cease to be, but as a species, “we’re immortal,” he was led to conclude. Daley’s topic that day was the future of stem cells in medicine, and in addressing a roomful of journalists, he swung between exuberant futuristic descriptions of cell-based therapies and cautious add-ons about how long this all could take. He couldn’t hide his fervent belief, however, that stem cells would increasingly emerge as the basis for new, more rational medicines.

Once little Nicholas entered the world, his muscles, his skin, his brain, his blood, his intestines, and certain other organs would retain rare populations of adult stem cells that would continue to replenish his tissues for the rest of his life. Differentiated cells such as the brain’s hippocampal cells or bone’s osteocytes carry out the body’s innumerable special tasks. Yet trace any mature cell back to its origins, and you always arrive at a stem cell, which, by the way, is the strongest argument to be made for what medicine stands to gain. The fact that stem cells are so pivotal in forming and maintaining tissues is seen as proof of their usefulness in medicine, and the best thing about them is that no chemist has to spend a lifetime at the bench coming up with such an ideal salve, because Nature already has done so. Some organ stem cells produce only one type of specialized cell. Those in the testis, for example, yield only sperm cells. But most adult stem cells are multipotent, meaning they produce many cell types. For instance, the hematopoietic (or blood-forming) stem cell that hovers in a person’s bone marrow constantly regenerates the blood and immune systems’ eight or so specialized cells. (One of many unsolved mysteries is, how do stem cells know how many mature cells to make or replace?)

In Daley’s eyes, the blood-forming stem cell, around which so much of his lab’s cancer research revolved, was without a doubt “the granddaddy of all stem cells,” at least from a research standpoint. Scientists had fastened on it ahead of other versions of stem cells and pushed it into the limelight as a model for all stem cells—what they are like and how they behave. To physicians, moreover, the hemato-

poietic stem cell in bone marrow was already a distinguished hero. It, and it alone, was the reason that a bone marrow transplant, usually in combination with radiation or chemotherapy, had the ability to effectively treat many blood-related disorders, among them malignancies like leukemia, immune disorders like lupus, and genetic disorders like severe combined immunodeficiency disease (SCID) and sickle cell anemia. It was easy to have faith in this cell’s therapeutic virtues, when, by the new millennium, patients receiving a bone marrow transplant sometimes had a fifty percent or better chance for improvement, depending on the blood-borne disease.

Yet three years earlier in 1998, Daley, a prominent member of the still-small stem cell biology field, had been distrustful of the stem cell that instead floated in an infant’s umbilical cord blood. Without a doubt, it was related to the stem cell found in a baby’s or adult’s bone marrow. But whether the cord type could reestablish the blood system as successfully as the marrow type was unclear. In mice, it was possible to restore a full complement of red blood cells, white blood cells, and platelets—virtually the entire blood and immune systems—with just a handful of bone marrow stem cells. Did the umbilical cord’s stem cell have the same ability?

When the Daleys’ first child was due, several things fell into place that led them to preserve Jack’s cord blood, despite the unknowns. George Daley’s interest in cord blood’s immature cells was growing as the evidence built that these hematopoietic cells, just like those in bone marrow, could breathe life back into destitute blood and immune systems. By the turn of the millennium, over 2,000 patients had received cord blood transplants, many saved from fatal illnesses. Studies were even suggesting that the cord variety of stem cell, when given to an unrelated recipient, provoked less of a negative immune reaction than the marrow variety. Cord blood stem cells apparently were so immature, they weren’t readily detected by the recipient’s patrolling lymphocytes. Daley in the meantime had accepted an invitation to become the scientific advisor of T Breeders, a biotech company that was attempting to grow and expand

stem cells, and, as a gift, the company’s founder offered the Daleys the opportunity of having their firstborn’s cord blood stored by Viacord, a cord blood salvaging company that was betting its existence on the stem cells in cord blood.

By 2001, with his second son’s birth fast approaching, Daley’s doubts about the value of preserving cord blood had vanished. “This time I was completely, solidly behind the whole effort,” he recalls. The stem cells that course through the umbilical cord and placenta might not be identical to those in bone marrow, but for the purposes of transplant therapies they were close enough.

Others in the research community and beyond have now come to the same conclusion, as indicated by the Cord Blood Stem Cell Act of 2003. Introduced into Congress by a bipartisan group of U.S. senators, the bill proposes establishing a National Cord Blood Stem Cell Bank Network that would work to collect enough cord blood units from births all over the country to provide an immunologic match for ninety percent of people needing a cord blood stem cell transplant.

This isn’t to say, Daley acknowledges, that cord blood transplantation doesn’t continue to face sizable hurdles. For instance, although a large majority of cord blood recipients ultimately engraft—the transplanted cells start dividing and generating more cells—“a significant percent of these patients die during the therapy itself because they don’t engraft soon enough,” says Daley. This happens, it seems, because so few cells in cord blood are the stem variety. The solution might be to infuse larger populations of cord stem cells into recipients. In the meantime, Daley is just glad to know that both of his sons’ cord blood cells are safely stored away in some dark, cool place where they will escape the unhealthy mutational changes that the outside environment inflicts on cells. This way, these regenerative cells should remain fresh as daisies—or “pristine,” as Daley observes.

Nicholas Edmondson Daley was born at 4:13 on the afternoon of April 30, 2001, one of the four million births that take place every

year in the United States. But unlike what happens over ninety-seven percent of the time, his cord blood did not wind up in the “red bag,” the receptacle into which the rest of the umbilical cord and placenta, along with the bloody gauzes, tonsils, IV lines, and other potentially infectious waste collected from throughout the hospital would get thrown for special handling and disposal. A few minutes after his son’s birth, George Daley himself took the long needle from Viacord’s kit and inserted it into the large vein that spirals down the length of the umbilical cord, draining the blood into a collection bag. The cord blood industry’s refrain must have been running through his mind: What a deplorable waste if a baby’s cord blood ends up in a bag in some hospital basement, when the special cells in its midst might save a life. A phone operator at Viacord was soon notified of the birth and in turn sent a courier to pick up the blood sample. Today, suspended in liquid nitrogen at a cool –196°C, these cells wait out an indefinite future.

What are these regenerative cells all about? How much promise do they really hold for medicine? One way to measure the future is to first search back through the past and take stock of how humans have gradually awakened to these distinctive, often camouflaged, cells in our midst and slowly come to recognize their worth.

What follows, then, is a continuum of experimenters and experiments that starts as far back as 1740 and proceeds into the present. In gathering together these threads, I’ve largely looked at stem cells in terms of where they might lead our medical community. These cells are such stunning creations, however, that anyone stopping to peer at them can’t help but admire them for qualities that go far beyond their uses as simply tools for human medicine. Stem cells are basic to the regeneration of every multicellular plant and animal, and as scientists discover more about them, these flex-

ible worlds-unto-themselves should open our eyes to the presence of forces in Nature that are far greater than anything humans could imagine or invent. As neuroscientist Evan Snyder has aptly put it, “Even the dumbest stem cell is smarter than the smartest scientist.”

Botanists have actually been probing stem cells in plants for much longer than zoologists have studied stem cells in animals. They refer to them as “meristem cells” as opposed to stem cells, which helps to distinguish them from cells in a plant’s actual stem. (Meristem comes from the Greek word meristos, for “divided.”) Similar to the animal kind, meristem cells exist in plant embryos and are present as well in the organs of an adult plant. Roots have clusters of meristem cells at their tips, and as these cells divide, roots inch out through the soil, notes Susan Singer, a biologist at Carleton College. Above ground, self-perpetuating meristems at the tips of shoots attend to a plant’s dazzling ability to branch and leaf. Flowers meanwhile bloom due to floral meristems, while trees add girth because of meristem cells in their cambria. Grasses such as corn have another type of meristem in their stalks that contributes to their elongation, says Singer. “If you go out into a field on a summer’s night when the corn is still quite short and hear a popping sound, it’s because of the really rapid growth of those cells.”

On the whole, it’s thanks to their stem cells that plants are such outstanding specimens of regeneration. Because it is rooted, a plant depends mightily on its regenerative growth for flexibility, notes Singer. For instance, its regrowth can be crucial for its reproductive life. “A plant wants to flower when its pollinators are around,” says Singer, and it will “produce floral meristems at just the right time,” with environmental cues like light and temperature indicating the right season. Regrowth also lends to a plant’s survival in times of adversity. “If someone munches on a plant for lunch, its meristems provide backup tissue.”

Whether of plant or animal origin, stem cells are, in a word, humbling. Naturalists were in awe of the fruits of their labor long before their actual identification, and even before cells in general

were revealed to be the central units of plant and animal tissue in the nineteenth century. For the story of stem cells in animals is very much tied to the long history of regenerative science, and the absorbing mystery of how, for instance, a salamander can grow back its tail. Here and there in the stem cell field today, one finds a certain stigma attached to regeneration science, perhaps because, as one scientist observed to me, “it brings to mind amphibians who lose and grow back legs, and may make stem cells seem too far out there,” when stem cell researchers want desperately to confer credibility on their field. And yet, the ideology behind stem cells does combine, and so interestingly, these two separate streams. On the one hand, stem cells, or regenerative cells like them, are pivotal when it comes to a salamander regrowing its missing tail—or leg, jaw, eye lens, or retina. On the other, these cells are also the reason why bone marrow transplantation has been saving human lives since the 1970s. This is not to suggest that stem cell advances will enable humans to grow a new leg anytime soon. As a sign of where things are headed, however, in 2003 tissue engineers at the University of Illinois, Chicago, used bone marrow stem cells from rats to make a replica of a human jaw.

After whole organs began to be successfully transplanted in the 1950s and ’60s, there continued to be tissues in the body that were viewed as difficult, if not impossible, to repair—the brain, spinal cord, and heart, for instance. Then stem cell biology and a general turn toward regenerative medicine began warming up, and nowadays, although researchers are still searching for effective treatments for a great many ills, there isn’t a single part of the body that is considered beyond medical reach. The concept of using cells as medicines, and replacing the bad with the good, has helped bring about this new confidence, and it’s understandable why. Constructing a drug out of molecules that must hit an unseeable nail squarely on the head in a specific tissue is a tall order. But with cells, it’s much easier to believe that they can work anywhere, because for as long as anyone remembers they have been working everywhere.

What a blockbuster assignment to make a daisy in the laboratory. How much simpler to go out and pick one.

If one could direct the fate of stem cells—that is, the specialized type of cell they become—the extrapolated mature cells could be transplanted into a problem area, where, if all went according to plan, they would overcome substandard, diseased cells and lead to healing and recovery—for example, islet cells for diabetes; photoreceptor cells for diseases of the retina; hepatocytes for liver conditions; oligodendrocytes for multiple sclerosis; spinal cord neurons for injured spinal cords; one type of muscle cell for a problem heart; another type for urinary incontinence; bone cells for skeletal disorders; or special ear-dwelling sensory cells for hearing. The list is as long as the number of specialized cells in the body that can fall prey to a disorder.

One scientist at the National Institutes of Health observed to me, “I think there’s been a shift in attention to cell biology because drug companies are spending billions of dollars trying to develop things without necessarily understanding the mechanism by which a disease arises—the cell types that are involved, or what’s going on with a cell. In order to develop a drug, you have to be intelligent; throwing money at something isn’t going to solve it. You have to understand how it works before you can fix it.”

In the late winter of ’04, I received the welcome news that an old friend and a new acquaintance, both of whom had been suffering from serious illnesses, were showing signs of improvement for the very first time. Both had received newly designed cell therapies—in one case, stem cells, and in the other case, mature cells—that up until recently did not exist. Novel cell treatments like these seem to be on the increase. And yet fitting cells to the body represents such a

new and complex area that it would be remarkable if unforeseen complications associated with attempts to fashion and apply cell medicines don’t test scientists’ wits and mettle to the utmost for a long time to come.

In the spring such a test arose. Studies, by and large, have invited guarded optimism that bone marrow stem cells can possibly help improve the condition of heart attack victims, perhaps by generating new myocytes, or muscle cells, that fortify the heart. Then came the latest news. Stem cells injected into the coronary artery of dogs led to an overproliferation of cells that clogged the small arteries. In addition, a mouse study found no signs that bone marrow stem cells, when introduced after cardiac trauma, resulted in new myocytes or heart tissue. More analysis is needed to better pin down exactly how bone marrow cells help the heart, which otherwise they do seem to do.

The lead investigator of the dog trial, Richard Vulliet at the University of California, Davis, thinks that his own negative findings “are solvable” and stands by the belief that stem cells or their descendant cells will eventually prove advantageous for human hearts in trouble. Across the stem cell field, one scientist after another voices similar sentiments. They want negative results to come forward; they want to know the worst, so that they can better understand exactly what they are up against and get to the other side. Because, as so many of these early pioneers will tell you, they are in it for the long haul.