Researcher Suzanne Ildstad Facilitates Xenotransplants
by Bruce Agnew

Suzanne Ildstad, M.D.

As a medical student in the mid-1970s, Suzanne Ildstad didn't have much good to say about research. Her professors at Mayo Medical School in Rochester, Minn., "remember me saying that I thought research was a waste of time and money," she says, chuckling. "At that point, I had decided to be a surgeon, and I thought operating was the be-all and the end-all."

Live and learn. Suzanne T. Ildstad, M.D., director of the Institute for Cellular Therapeutics—and professor of surgery—at the University of Louisville, is now a star of medical research. She's the discoverer of a type of bone-marrow cell that may significantly lower immune-system barriers to organ transplantation—including the transplantation of animal organs into humans, known as xenotransplantation. She's the developer of a procedure for "conditioning" transplant recipients that may transform bone-marrow transplantation from a last-resort treatment in fatal diseases like leukemia into a routine cure for a whole host of diseases, ranging from diabetes to sickle cell anemia. And in 1997, she was elected to the prestigious Institute of Medicine—an arm of the National Academy of Sciences—1 of only about 1,200 members, chosen by their fellow scientists as the leaders of their profession.

She changed her mind about research while doing her surgical residency at Massachusetts General Hospital in Boston. She kept asking questions of the head of Mass General's transplant program, Paul Russell, "and he would say to me, 'You know, you really ought to think about going into the lab for a couple of years.' " So she did, and got hooked.

Growing up in Minnesota, "I always wanted to be a doctor, as far back as I can remember," Ildstad says. That may run in her family: Her grandmother was a scrub nurse for Will and Charlie Mayo, the pioneering brothers who founded the Mayo Clinic in Rochester, Minn., early in this century. Her mother is also a nurse—and trained at the Mayo Clinic. "I tell my mom she might have brainwashed me, but it was something I always wanted to do," she says.

In fact, she got an early start. When she was in high school, "one of the neighbors—I used to baby-sit for their children—was a psychiatrist, and he knew I was interested in medicine." So the neighbor helped her get a summer job at an inpatient adolescent psychiatric facility.

Partially as a result of that experience, she has always opened her institute to summer volunteers, ranging from high school to medical school students. "I think the key time for students to be exposed to science, and starting to think about what career they might want to pursue, is when they're in junior high and high school," Ildstad says.

In the other important focus of her life, Ildstad, 47, has been married for 27 years to a fellow physician-professor whom she met at age 19 and married after her first year of college (and his third year). They have two children—a 16-year-old son and a 14-year-old daughter—who may or may not go into medicine themselves. "I think they're still deciding—trying all the possibilities," she says.

Ildstad working in the lab

Many young women who are interested in scientific careers worry that they may have to postpone marriage and a family. According to the scientific stereotype, researchers put in their longest hours, do their best work, and establish themselves (or not) before the age of 35. Ildstad disagrees—although she doesn't exactly counsel impulsiveness, either.

"I don't think you have to [postpone things]," she says. "I think the key thing, though, is finding the right person. You've got to find someone who respects you. It always takes compromise on both sides, but in my opinion, you've got to have that."

She does say, however, that combining a family with a top-echelon research career "takes a lot of planning, and it takes setting priorities." She and her husband try to avoid professional commitments on weekends—physicians can't always do that, of course—and they spend their free time with the children. "So we don't have a very active social life," Ildstad says. "We do activities with the family, and we make sure that we eat dinner together every night and breakfast every morning. I think that's really important."

Recently, one family activity involved a hunt through the attic. "One of my son's friends is into music—he composes songs—and a lot of his favorite songs are the ones from my generation, when I was growing up. We went up to the attic not too long ago and pulled out these ancient records that my son never knew I had—like the Beatles and Herman's Hermits and the Rolling Stones and Jethro Tull. Now they're antiques, right?"

Whenever possible, she also takes one or both children with her on trips for speaking appearances or to perform operations, sometimes in foreign countries. "I involve them a lot in what I do," she says. Their travels—aided by frequent-flier miles—have included San Francisco, Los Angeles, Texas, France, Italy, and Germany. On one particularly memorable trip, she took her daughter to a university-research retreat in Germany, hosted by the current head of the Hohenzollern family that once ruled Prussia. "She was 11 or 12 then," Ildstad recalls, "and she was seated next to the prince at a formal dinner in the castle, and it was like a fairy tale. She thought I do that routinely. I don't."

Routine or not, what Ildstad is doing now would have sounded as magical as any fairy tale just a few years ago.

Her research has centered on bone marrow, which produces blood and immune-system cells. Conventional bone-marrow transplants are very risky procedures, and are only done in patients with dire conditions such as leukemia. They involve complete destruction of the recipient's bone marrow, and require replacement with marrow from a donor who's as close a match as possible in all immune-system characteristics to the recipient. Finding suitable donors is difficult, and anything short of an identical twin is chancy. Failure is usually fatal.

But in 1994, Ildstad isolated what she calls "facilitating cells" in bone marrow that make it possible for transplanted marrow to take hold and grow even if the recipient and donor are not close matches. These facilitating cells are present only in tiny quantities—less than 0.4 percent of marrow cells. They're extremely difficult to isolate, because they're similar to workhorse immune-system cells known as T cells. Ildstad has worked out a way to remove active immune-system cells—which would attack any host they are given to—from donor marrow while leaving the facilitating cells intact.

Having facilitator-rich donor marrow opens up possibilities for transplantation. When a recipient's bone marrow is partly destroyed and marrow from a donor introduced, the recipient develops a "chimeric" immune system, bearing characteristics of both the recipient and the donor. This should make it easier for the recipient to tolerate transplants of whole organs—heart, kidney, liver—that also come from the marrow donor. Moreover, this should work whether the donor is human or animal.

Ildstad has shown that inducing such a chimeric immune system does indeed ease transplants and xenotransplants in laboratory mice and rats. Now she's demonstrating it in humans. Since early last year, she's used the technique in three heart transplants; one of the patients died from his underlying disease, but the other two are doing well. She's about to test it in human kidney transplants.

Ildstad is also about to aim her technique of induced chimerism at an entirely new class of disorders—autoimmune diseases such as diabetes and rheumatoid arthritis, in which the immune system goes awry and attacks its own body. By chance, some leukemia patients who received complete bone-marrow transplants also happened to have type I diabetes, caused by immune-system destruction of their cells that secrete insulin. In a few of these cases, the bone-marrow transplant had the unexpected benefit of curing the patients' diabetes, too. Apparently, the new immune system these patients got through the bone-marrow transplant didn't go after their insulin-secreting cells, allowing a few surviving cells to recover.

Conventional bone-marrow transplantation is far too dangerous to use against type I diabetes and other autoimmune diseases, because it, in effect, requires complete destruction of the recipient's immune system. But Ildstad has received Food and Drug Administration approval to test her much less destructive "mixed chimerism" methods against severe autoimmune diseases, as well as in patients with serious bone-marrow disorders, such as aplastic anemia.

NIH officials now have provided funding to add another target: sickle cell anemia, a painful and potentially fatal disorder in which people with two copies of a defective hemoglobin gene produce misshapen red blood cells. The idea is to give sickle cell patients the ability to make the normal form of hemoglobin without completely destroying their own bone marrow. Ildstad had applied for funding to test induced chimerism against sickle cell disease six years ago, but was turned down.

"It was nerfed," she says. "They said it'll never work, can't be done, won't be done, and it was ahead of its time." But last year, an NIH official called her up, asked if she remembered the application (she did), and asked her to resubmit it. Its time, apparently, is now: She expects to operate on her first sickle cell patient this spring.

"I think it's going to work," Ildstad says. "It's still a research question, but I think it's going to work." She adds: "If we can cure that one, I think it would be really outstanding. It's a terrible disease."