The Art and Science of Medicine
Volume XXVI Number 1
Photo © 2003 Tyagan Miller
An umbilical cord--a baby's first lifeline. Through three spiraling blood vessels, it supplies oxygen, provides complete nutrition, and carries waste away from a growing fetus. A miracle of efficient design, the umbilical cord can do its job even when it becomes tangled or compressed in the close quarters of the womb. For months, a fetus in utero is completely dependent upon the umbilical cord.
And then, the day the baby is born, the cord becomes entirely unnecessary. It becomes, in fact, medical waste.
But as pioneering research by Hal Broxmeyer, chairman of the Department of Microbiology and Immunology at the Indiana University School of Medicine, is demonstrating, an umbilical cord can continue to be a lifeline long after birth, not just for babies but for children and youth, and perhaps for adults, too.
An umbilical cord contains a small amount of blood, the same blood that was circulating in the baby at the time of birth. That blood, for reasons that are not yet clear to scientists, is rich in hematopoietic stem cells, "master cells" that come from bone marrow and can give rise to any kind of blood cell. A newborn's own blood is rich in these cells at the time of birth, but within a day, the number of stem cells in the baby's circulating blood drops dramatically.
"We don't know why," says Broxmeyer, who is also the Mary Margaret Walther Professor of microbiology and immunology and professor of medicine at the IUSM. "It could be that the stem cells go back into the bone marrow. We don't know why there are so many stem cells at birth, and we don't know where they go."
The cord blood, however, remains stem-cell rich, a little leftover of the blood on the day of a baby's birth. When that blood is collected, it can be stored and even frozen¤for 15 years or more, Broxmeyer's recent research suggests¤without significantly damaging the stem cells it contains.
And that means that cord blood can play an important role in disease treatment. In many leukemias, anemias, and other diseases treated with bone-marrow transplants, cord blood is providing an alternative source of the all-important master cells. Bone-marrow transplants, after all, are stem-cell transplants, too. When blood cells have been destroyed by disease or treatments such as chemotherapy, stem cells can generate new ones. In some types of leukemia, for example, doctors use chemotherapy to kill all the body's white blood cells; then they transplant stem cells from bone marrow, cord blood, or another source to establish a new, disease-free generation of white blood cells.
Perhaps no one has a better sense of the therapeutic potential of cord blood than Broxmeyer. One of the world's leading figures in hematopoietic stem-cell research, Broxmeyer conducted the background studies and helped coordinate the first successful transplant of cord-blood cells. He also established the world's first cord-blood bank at IU's Walther Oncology Center. It was, in fact, Broxmeyer's blood bank¤and his expertise¤that yielded the stem cells used in that first successful cord-blood transplant, which cured a child of the fatal genetic disease Fanconi anemia in 1988. Since then, thousands of cord-blood transplants have been performed worldwide, with success rates comparable to those of the bone-marrow transplants.
Broxmeyer, a native New Yorker with a Big Apple accent to prove it, is quick to point out that he and his laboratory staff did the scientific benchwork that led to the first successful transplant in Indiana, his transplanted home. He came to the School of Medicine 20 years ago, drawn by an attractive offer and the opportunity to delve more deeply into his longstanding area of research.
"Cell regulation has always been my interest," says Broxmeyer. "Early on, I chose the blood-cell system as the model to study cell regulation, because it's a very dynamic system." He adds that increasing our knowledge of cell regulation is not only important to advancing basic science, but is also a key to understanding how and why cancer begins.
Broxmeyer's research intersected early on with studies aimed at breaking cancer's codes--in 1976, he was given a special fellowship from the Leukemia Society of America. "I do what is called translational research,'" Broxmeyer says. "It's very basic science, but always with the thought that something could be used in a clinical setting, to help people."
With its strong research programs and renowned hospitals, IU offered an excellent setting for such translational research. Broxmeyer joined the IU faculty as an associate professor in 1983, and in 1988, became the founding scientific director of the Walther Oncology Center, a position in which he continues to serve. Under his leadership, the center has collaborated with seven different Medical School departments, recruiting more than 30 scientists to serve as primary investigators on a wide range of research projects.
In 1997 Broxmeyer became chairman of the Medical School's microbiology and immunology department, which "has undergone an enhancement in research efforts, with many new faculty members recruited," he says. "In terms of National Institutes of Health rankings, it has risen from somewhere in the 70s in 1997 to No. 30 in the last fiscal year. It is now the third-highest NIH-ranked and NIH-funded department in the Medical School."
Broxmeyer's dream of using cord blood for stem-cell transplants grew along with his IU career. "In collaboration with other investigators, we spent a lot of years thinking about it and working toward it," he says. "It was only pie in the sky at first. We had no idea where our work might lead. We only hoped that maybe it could go as far as it has."
Broxmeyer vividly recalls the emotions sparked by that first transplant: "We had so much hope, and then it worked. And it was incredible. It was the just the most incredible feeling."
But the success of the first transplant¤whose recipient is now a healthy teenager¤was more prologue than postscript. Broxmeyer's work on cord-blood stem cells continues, with several new important questions to answer. "We still don't know all the advantages and disadvantages of cord blood," he says. "We still have much to learn."
Even already established knowledge about cord stem cells often raises new questions. For example, cord stem-cell transplants don't have to be as closely matched as bone marrow transplants, an important fact since currently about three-quarters of cord stem-cell transplants involve donors and hosts who are not genetically related. And although it is known that cord-blood transplants are less prone to host rejection than their bone-marrow counterparts, "we're not sure why," says Broxmeyer. "It probably has something to do with the immaturity of the immune cells in cord blood."
One of the major challenges to cord stem-cell transplantation¤and one of the major focal points of Broxmeyer's ongoing research¤is the relatively small number of stem cells that a single umbilical cord provides in its one to three ounces of blood. That number is generally adequate for transplants to babies and children, but isn't always large enough for the bigger bodies of adults. Researchers are working on two ways around this obstacle.
"You can either develop a way to increase the number of stem cells," Broxmeyer explains, "or you can try to get the stem cells that are there to home'¤that is, go to the marrow¤in greater numbers. My lab is currently working on ways to make stem cells home more efficiently."
Combining stem cells from two or more umbilical cords is currently under investigation, too. But, says Broxmeyer, "what's been found is that the stem cells from one cord tend to become dominant. The others disappear."
Broxmeyer's team is also deeply involved in learning more about self-renewal in stem cells, a research focus that may provide useful information for solving the quantity problem associated with cord-blood transplants.
One chief advantage of cord-blood stem cells is that they are untainted by controversy that surrounds embryonic stem cells. In fact, cord-blood stem cells have been promoted as a possible alternative to stem cells derived from human embryos, though Broxmeyer feels that scientific evidence is lacking for the claim that cord stem cells can fill all the roles of embryonic cells. The embryo's stem cells can develop into any of the body's cell types, from neural cells to specialized cells within organs. But so far, "cord stem cells are hematopoietic," says Broxmeyer, meaning that they can develop only into the body's various types of blood cells. While there are some reports that cord-blood cells might have a broader repertoire, Broxmeyer says the verdict is still out.
"There's a lot of hype right now surrounding this issue. Nothing is proven, and the studies that have been done don't have sufficient rigor" to be conclusive, he says.
Few, if any, people object to the collection of umbilical cords for use in scientific research. Neither mother nor baby needs the cord once it has been cut, and even the collection process is entirely non-invasive. "The fact is that these are cells that would be discarded," says Broxmeyer.
Some controversy and discussion does surround the increasing commercialization of cord-blood collection and storage, though it is mild compared to the embryonic stem-cell debate. In recent years, numerous companies have emerged that approach expectant parents with offers to collect and store their infants' cord blood in case it is later needed for a transplant. Some groups and individuals have charged these companies with opportunism, arguing that the odds of a child needing his or her own cord blood are slim, particularly when weighed against collection and storage fees that can be hefty.
In 1999, the American Academy of Pediatrics said it did not recommend that parents store cord blood unless there was a genetic history of blood disease.
Broxmeyer, who serves on the advisory board of Viacell/Viacord, one of the leading private cord-blood collection companies, believes the choice to store or not to store is a very personal one. "Certainly if there is a genetic predisposition to blood diseases, it's something to seriously consider," he says. "I look at it as an insurance policy, in a way. If it were me, I would do it."
Public cord banking is another option, allowing parents to donate their child's cord blood to be used for anyone for whom it is a match. The National Marrow Donor Program currently has affiliations with a dozen cord-blood banks, maintaining a combined 25,000 units of cord blood coast to coast.
It's also possible to donate cord blood to research, as Indianapolis resident Charlotte Ottinger did after the 1998 birth of her son Sam. At Sam's otherwise normal birth, a team of biomedical professionals was on hand to collect the baby's umbilical cord¤once Sam's dad had cut it¤and whisk it away for use in research.
Ottinger says her interest in donating the cord blood grew out of her experience as a stem-cell transplant nurse at Riley Hospital for Children in Indianapolis. "We thought that it would be such a great legacy for Sam to know that he had contributed to cord-blood research so early in his life," she says.
And while Ottinger knew that stem cells had the potential to save lives, she didn't know exactly what kind of research--or whose--her son's donated cord was benefiting.
As it turns out, the research was Hal Broxmeyer's. And just as Charlotte Ottinger was grateful for the opportunity to contribute to meaningful research in a lifesaving area, Broxmeyer says he feels fortunate to be surrounded by people who are so appreciative of his work.
"I am thankful to the university for giving me the opportunity to work in this area, and I am grateful to both the university and the Walther Cancer Institute (a private, non-profit research organization) for enabling me to carry out my research so effectively," he says.
In short, says the born and bred New Yorker, "I like the people of Indiana very much. That's why I've stayed."
Elizabeth Hunt is editor-in-chief of the Indiana Alumni Magazine.