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Catherine Verfaillies notes from a breakthrough experiment with adult stem cells.

The Magic Seeds
For decades, medical researchers have known that many human organs contain a kind of seed -- stem cells that work to replace that organ's cells as they wear out or are damaged by injuries and illnesses. But a few years ago, University of Minnesota researcher Dr. Catherine Verfaillie discovered a new kind of stem cell, a kind of magic seed. Like a plant seed that, depending on its environment and care, could become an azalea, a zucchini, or anything in between, this new stem cell appears able to become any of the 200-plus kinds of cells that comprise the human body. In other words, these adult stem cells seem to have all the potential of the earliest cells of an embryo, the cells that divide into an entire body. Like the controversial embryonic stem cells, these adult stem cells also hold the promise of cures to diseases that have so far mystified modern medicine.

With publication in November 2001 of the first scientific article about the new stem cells, a tantalizing vision of the future is emerging in the minds of doctors and researchers. Within the next five years, stem cells may begin to treat diseases with a single missing or malfunctioning cell-type, like hemophilia, diabetes, and muscular dystrophy. Later, they could be used to repair damaged or diseased body parts. A person diagnosed with Parkinson's disease, for example, could have some of his or her stem cells removed, genetically corrected, generated into healthy brain cells, and returned to his or her body, curing the disease before the onset of the most serious symptoms.

Verfaillie believes clinics one day could be stocked with already prepared stem cells, ready to repair the heart muscle of a cardiac patient or the brain cells of a stroke victim, perhaps even repair spinal cord damage in an accident victim and reverse paralysis. "Theoretically you can do all this with these cells," she says. "Obviously we are a long way from those things. . . . But theoretically they are all possible."

The University has a 30-plus-year history of using the blood-producing hemopoietic stem cells, the reason bone marrow transplants are effective treatment for many diseases. But the treatment potential of these new cells is much greater. "What we have found [in animal transplant trials] is that the entire body takes these cells up," says Dr. John Wagner, who leads the Stem Cell Institute's efforts to turn hard research into patient care. "They actually integrate with your body. They go to the lung, they make lung; they go to the gut, they make gut; they go to the muscle, they make muscle." And, he points out, they go most directly to damaged areas. Not only could correctly programmed stem cells cure the underlying disease, they could repair damage the disease has already done.

These multi-potent stem cells appear to be present in everyone, although their numbers decline with age. Unlike almost every cell in the human body, however, their potential does not seem to decrease with age. A self-triggered enzyme repairs the cell each time it is called into action. "These stem cells have found a way to essentially stay young," says Morayma Reyes, a University student working with Verfaillie.

While stem cells are found in many places throughout the body, Reyes hypothesizes that this new cell may be, in essence, a master stem cell for the entire body. "It may be that these cells reside only in marrow and then migrate to where they are needed to become that organ s stem cell population," she explains. If that is the case, the Stem Cell Institute, as a world leader in working with these cells, "is that much more important."

Astonishing accidents
Verfaillie and Reyes stumbled upon the enormous power of these cells in 1997. Dr. Charles Peters is an expert in Hurler's syndrome, a devastating childhood disease in which sugars build up in organs and permanent damage quickly occurs in many parts of the body. Peters asked Verfaillie to generate bone and ligament using mesenchymal stem cells, also found in bone marrow, something that appeared possible based on the research of others.

Because they hoped to rush results to patients, Verfaillie directed Reyes to work on the cells without a common cow-based serum for fear of mad-cow disease. "That's how this set of experiments that got us to this very strange multi-potent stem cell came about," Verfaillie says. As the months wore on and the cells continued to divide and grow, something unexpected was happening. "When looking at the cells we had induced, they appeared different from what other people had published. . . . From certain things on the cell surface, we figured out that maybe they could make endothelium, the lining of blood vessels, which nobody with mesenchymal stem cells had ever been able to do."

From this finding, it appeared that mesenchymal stem cells might branch into any cell of the cell family called mesoderm bone, blood vessels, and blood, among others. It was like discovering a seed that could grow any kind of vegetable plant. In a subsequent experiment, Verfaillie and Reyes set out to turn mesenchymal cells into blood. But this time an even more astonishing result faced them: "It appeared that we induced the cells not to blood but to cells consistent with neuroectoderm, or brain," part of an entirely different cell family, Verfaillie says. It was as if a vegetable seed had produced a pine tree. "When the mesoderm went to a different kind of cell, that was against the rules of embryology. But I guess those rules weren t completely set in stone."

The third major kind of cell endoderm, which comprises internal organs was their next target. "We were able to show that these cells differentiated into cells that look, and now behave, very much like liver," Verfaillie says. "We were thinking we had mesenchymal stem cells, but it turns out that a subpopulation of these cells has a much, much, much, much greater potential.

"So the initial [discoveries] were accidents, but since then we ve had planned accidents," she adds. "Informed guessing is essentially what you do, based on what we know about embryology."

A consolation career
Since those experiments, Verfaillie has been pushed into national prominence. In December 2000, U.S. News & World Report named her one of 10 "Innovators 2001." At the same time, the University of Chicago tried to hire away Verfaillie. But the University created the Stem Cell Institute and named her its director, a move that helped convince Verfaillie to stay. Her decision was accorded local media attention unusual in the normally quite world of lab research.

But her career in medicine was, she says "an accident." Tall and athletic, Verfaillie was one of the best young athletes in Europe in the mid-1970s. She won the Belgian and European junior (18 and under) titles in the pentathlon, a five-discipline track and field event. While she downplays their significance, her victories certainly showed Olympic potential. In college, studying to become a coach or trainer, Verfaillie injured her knee so badly during her first term that her competitive career was over. "I essentially overnight decided to go into medicine," she recalls. "I still don t know why."

While studying at Belgium's Catholic University of Leuven, Verfaillie focused on blood and marrow transplantation. She came to the University of Minnesota in the mid-1980s to learn more from Dr. Phillip McGlave, a pioneer in transplants from unrelated donors. "The initial plan was six months in Minneapolis, six months in Seattle, then go back to Belgium where there was a faculty position waiting for me at the university," she says.

After six months with McGlave, she felt she had learned all she needed. "So I decided I should at least give it a try in the lab." In Belgium, her teaching and patient care loads would have made it impossible to do lab work as well. It turned out Verfaillie had an affinity for the more controlled conditions and logical progressions of lab work, and she stayed for two years as a post-doctoral fellow. Then a faculty position opened in the blood and marrow transplantation program. "So I applied, got my green card, and stayed," she says.

Reyes came to the University from Puerto Rico. She has completed her coursework for a Ph.D. in microbiology, immunology, and cancer biology and is now a third-year medical student. In her first year at Minnesota, Reyes applied to work in Verfaillie's lab after hearing her lecture on stem cells.

Since that first set of experiments, Reyes and the other members of Verfaillie's lab team have replicated and expanded the results and begun showing that the cells have the potential to be applied to real diseases.

Ethics and questions
When the Stem Cell Institute was created, an ethics board, with regular meetings, was an important piece of its structure. Although adult stem cells are not as controversial as embryonic stem (ES) cells, there are still questions about how far the technology should be taken. Also, researchers want to compare adult stem cell results with parallel work being done on ES cells. Embryonic stem cells are the earliest cells of a developing embryo, the ones that eventually differentiate into an entire body. Since they are taken from fertilized embryos, right-to-life issues surround ES cells. "We want people to know that we have thought about these issues," says Wagner, who leads the institute's clinical branch. "We re not just mad scientists doing whatever we want. . . . Our real goal is to go to Congress and say this is how we believe it should be regulated. And we absolutely do believe it should be regulated. . . . We need to be very careful about it."

Although adult stem cells present fewer ethical issues than ES cells, Verfaillie says it would be a mistake to stop working with ES cells. "ES cells have been kept in culture for close to 30 years and they haven t changed," she says. "The adult stem cells we identified are only two years old. . . . We really have no idea where one will compare to the other."

Adult stem cells do offer some clear advantages, however. If a patient's own stem cells are corrected and returned, the risk of rejection is much smaller. Adult stem cells may be more stable as well. ES cells, when injected in large numbers in laboratory mice, have been known to form teratoma balls of mixed-up tissue that could create disastrous consequences in patients. In several trials with adult stem cells, Verfaillie's team has yet to see a teratoma.

"There are still a lot of questions," Verfaillie says. "I think that, down the line, it will probably turn out that for disease A, embryonic stem cells will be better, and for disease B, adult stem cells will be better." The Stem Cell Institute is planning to hire one or two top-flight ES cell researchers to make side-by-side comparisons with adult stem cells.

Into the clinic
Wagner intends to try adult stem cell treatments first in two rare but devastating childhood diseases Hurler's syndrome and Fanconi s anemia, a genetic disorder in which the bone marrow's blood producing mechanisms malfunction. In 2000, Wagner successfully treated a young girl with Fanconi s using stem cells from the umbilical-cord blood of a newborn sibling. With adult stem cell technology, it may be possible to use a patient's own stem cells or those from a matching donor to accomplish the same thing. In Hurler's, genetically corrected and matching stem cells might not only correct the disease, but go to damaged organs and work to reverse damage there.

"Although this is not going to benefit a major population like diabetes would or Alzheimer's, this is sort of the first step in this process," Wagner explains. If the trials which are at least a year away and rely on raising $5 million to $10 million work as Wagner hopes, they will prove that the stem cells can both correct the disease and repair damage.

"We're also developing programs in muscular dystrophy, sickle-cell disease . . . [and] we will have programs in diabetes and other areas," Wagner says. Stem cell transplants also have the potential to prevent chemotherapy injury, for example, in cancer patients.

Verfaillie believes that removing and correcting stem cells may one day prove unnecessary; instead, drugs could be developed to do the same things inside the body. "Since we all have these cells sitting around [in our bodies], we ought to be able to figure out how to wake them up, move them out, make them go to the heart or the organ that is defective, and have them do their thing. . . . But if I had to guess, I'd say that is at least 10 to 20 years away."

These intriguing visions drive doctors like Wagner, who can't wait to see the technology at work in real patients. "It's so exciting and it has such potential to help people," he says. "I wish I could make it happen tomorrow."