Adrenoleukodystrophy

Dr. Joanne Kurtzberg speaks of miracles as though they were decidedly routine. In her upside-down world, they are. Her little shop of wonders houses sixteen tiny rooms where children are rescued daily from the brink of death, saved in part by modern science and in large measure because Kurtzberg earnestly believes that they can be.

Desperate parents seek her out because they have heard that she is willing to test the boundaries of modern science, to take leaps of faith where others can't or won't. Within minutes, a day at most, Kurtzberg responds to pleas from desperate parents up to a dozen per day - who are begging for a sign of hope when others claim that none exists.

"We really believe we can treat and cure these children," she says with characteristic humility. She is speaking of her life's mission at Duke University Medical Center, saving children with rare immune deficiencies, metabolic diseases, and bloodborne cancers, all by using the same technique - infusing them with precious stem cells derived from umbilical-cord blood.

Once discarded as the refuse of childbirth, umbilical-cord blood is now viewed as the Garden of Eden for progenitor cells, a source teeming with stem cells that can transform into virtually any type of cell in the body. These wondrous little cells know just where to go, homing in on defective tissue in need of repair. Accordingly, Dr. Kurtzberg has applied their immense capabilities to cancers of the blood and genetic disorders that have previously been viewed as utterly hopeless.

Mouthfuls of obscure diseases tumble from Kurtzberg's lips as though they were days of the week - adrenoleukodystrophy, metachromatic and globoid leukodystrophy, to name a few. When pressed for details, she casually confesses to being the first in the world to use cord blood from an unrelated donor to treat and cure several of these rare metabolic diseases. So prolific is her transplant experience that cord blood is now considered standard care for recurrent leukemia, lymphoma, and neuroblastoma.

The numbers speak of her overwhelming success. In a decade, Kurtzberg's team has performed more than 460 transplants using umbilical-cord blood, nearly quadruple the number performed by any other medical center in the world. Indeed, her breakneck pace belies the warmth and compassion that she exudes to families and children, who often claim there must be multiple clones of her to accomplish so much in a single day.

Yet in her laboratory she heralds the cures that support her success, and she continually tests the limits of science with even bolder technology aimed at broadening the scope of stem-cell use.

IMPROVING ON MOTHER NATURE

Mother Nature created a near-perfect thing in stem cells. but Kurtzbera seized upon a way to make them even better. By manipulating stem cells in the lab, she is nudging them in the direction she wants them to go, coaxing more of them into becoming fighter T-cells.

"We lose kids most often because they have no Tcells to fight infection," says Kurtzberg. "It takes thirty to ninety days before the immature stem cells engraft and become immune-system cells capable of fighting for themselves. We want to reduce that precarious window by making cells engraft sooner."

So Kurtzberg pondered, is there a way to bolster cord blood's restorative powers so that it engrafts sooner than it would on its own? The answer appears to be yes.

With a little help from modern science and technology, Kurtzberg's team is literally growing cordblood cells in a laboratory incubator to increase the number of immune T-cells it produces, reports Kirsten Krapnell, a research fellow at Duke. The expanded pool of T-cells will then be infused into the patient within a few hours of the transplant to speed up the patient's ability to fight infections.

Krapnell serves as the master chef of this cordblood concoction, mixing the bricks and mortar of the recipe and then adding a pinch of vital ingredients that will promote T-cell growth.

The cord-blood expansion process begins with what appears to be an elf-sized muffin tray. The tray has twenty-four small wells, in which the patient's skin cells are placed. Krapnell then irradiates the skin cells to stop them from dividing, yet they continue to produce important growth factors that are critical to the recipe's success.

Next, she puts a million white blood cells derived from the cord-blood sample - into each well, along with five growth hormones and chemical messengers called cytokines. Just as a baker would test her product, Krapnell samples the mixture's readiness at ten, fifteen, twenty and finally, twentyfive days. In a little less than a month, she has a hundred-fold increase in T-cells. A high-tech process called flow cytometry confirms the number of T-cells by detecting markers on the surface of cells that distinguish one type of cell from another.

The ingenious part about the recipe is that Krapnell uses the patient's own skin as the framework for growing the T-cells. Skin cells provide the meshwork on which white blood cells grow, but just as importantly, they produce their own growth factors and cytokines that would be nearly impossible to reproduce in the lab.

"We are recreating in the lab what the body does naturally," states Krapnell. "We couldn't possibly isolate and reproduce all the hundreds of important factors that cells produce, so we're doing the next best thing by allowing skin cells to create them on their own."

The first test of the recipe's viability will come from experiments in sheep. Kurtzberg's team will transplant expanded human T-cells into sheep and track them to see where they go and what function they perform. Testing in humans should begin within the next six months.

"All the components we are using to expand stem cells either belong to the patient or are substances that are currently being used in other clinical contexts, so there is no risk to the patient," says Kurtzberg. "We use the patient's own skin cells to ensure that the child won't reject them as foreign invaders, and cord-blood cells are closely matched to the patient's HLA type to reduce the chances of rejection and graft-versus-host disease."

STEM-CELL PLASTICITY

Exactly why doesn't the patient reject cord blood and its fledgling stem cells as foreign invaders? and its fledging stem cells as foreign invaders? Why don't the stem cells attack their new host? And how do stem cells instinctively know to become the blood or immune cells that they need to be?

It is a biological paradox that stem cells can be at once so compatible, making themselves at home in a foreign host, yet so versatile that they transform themselves into almost any cell that the body requires.

The answer lies in stem cells' immaturity. Because they are young, they lack the requisite knowledge and power to wage war on their new host's body. Meanwhile, their youthful inexperience allows the body to nurture their development in the direction most needed.

"There is convincing evidence that cord-blood cells extend much farther than the blood-forming and immune systems, and that they can differentiate themselves into brain, heart, liver and bone cells," says Kurtzberg. "We believe they are actually correcting genetic defects that arise in these organs."

This notion of stem-cell "plasticity" sprang, in part, from clinical observations of children with metabolic diseases, who appeared to respond better to cord blood than to bone marrow. Such children are missing critical enzymes needed to break down complex sugars in various cells. As sugar accumulates in vital organs such as the liver, heart, and brain, cells become damaged and die.

"We had observed that kids with metabolic diseases who receive cord blood tend to advance more rapidly than kids who get bone marrow," Kurtzberg explains. "Their brain function seemed to be restored more rapidly. We believe that stem cells are traveling to the brain sooner, and that more of them are responding to signals that differentiate them into brain cells. The new cells then produce the needed enzyme."

Kurtzberg needed hard evidence to confirm her clinical observations, so she used x-ray imaging to illustrate that nerve cells in the brain were actually forming new myelin sheaths - the coating on nerve cells that is damaged if the enzyme is missing.

Can she prove that stem cells from the donor's cord-blood are responsible for improved brain function? Not definitively - yet. But she is well on her way to doing so. By studying heart and brain tissue donated from children who have succumbed to their diseases, Kurtzberg will be able to determine whether donor cord-blood cells have successfully infiltrated other organs and transformed themselves into nerve, liver, or heart cells.

"We are looking for specific cell-surface markers that indicate what type of cell it is, and whether that cell originated from the patient or the donor," says Kurtzberg.

Specifically, her research team will look for subtle differences, known as HLA (human leukocyte antigens), that differentiate one person's blood type from another's. If the HLA markers on a particular cell match the donor's, they will know that the cell originated from the donor-cord blood. The most convincing evidence will come from sex-mismatched donors, in which the donor is of the opposite sex to the recipient. Testing for gender is much easier and more clear-cut than HLA typing, says Krapnell.

Already, preliminary data are showing that stem cells from donor-cord blood have crossed the bloodbrain barrier and differentiated into nerve cells in the brain, says Kurtzberg. Just as exciting, her laboratory is attempting to grow cord-blood stem cells into non-blood cells, such as heart and muscle cells.

Using distinctive markers on a cell's surface, scientists can tell whether a stem cell is destined to become a blood cell or another type of tissue cell. Kurtzberg's team will use these markers to select cells that are slated to become non-blood cells. Then, she will manipulate them in such a way that they become the desired cells.

"We would use these cells to repair damage in the brain or other tissues that are damaged by chemotherapy and radiation," says Kurtzberg.

Proof of stem cells' migration to other parts of the body will mark an enormous clinical milestone, as well as an important economic victory for patients whose insurance companies refuse to pay for socalled "experimental" therapy.

Indeed, Kurtzberg believes her therapies are by no means experimental. She has living proof in the form of 235 children who are alive and thriving. Five years ago, 50 to 60 percent of her children died. Today, that number is 25 percent.

Such rapid progress would have been impossible without external funding to cover the huge expense of transplantation, states Kurtzberg.

"Many of these diseases are so rare and obscure that enrolling enough patients to conduct a clinical trial would take decades to conduct, as well as millions of dollars in NIH funding that are simply not available for the study of obscure diseases," she notes. "In the meantime, we would have needlessly lost thousands of patients."

"Insurance companies have a moral obligation to pay for treatments, even if they have not withstood rigorous clinical testing," she adds. "Parents take out health insurance with the expectation that it will cover unforeseen illness, and these diseases clearly represent the unexpected."

It is also clear that Kurtzberg's passion is stirred by her patients, not just their diseases. Her program has enjoyed widespread acclaim because she has assembled a critical mass of people who are dedicated to taking care of patients and their families.

"Our team members aren't doing this for the money," says Kurtzberg. "It's quite a difficult job, so you have to truly care about the families you're treating. Our staff has both a diverse and highly specialized set of skills to deal with the incredible scope and diversity of the diseases we treat. And I think that's what makes us unique."

Becky Levine is a science and medical writer at Duke University Medical Center. She holds a B.A. from the University of Michigan, Ann Arbor, and a master's degree in journalism from the University of Maryland, College Park.

Copyright National Forum: Phi Kappa Phi Journal Winter 2003
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