UW researchers take new approach to repairing damaged livers

Thirty-four-year-old Mari-Jo Fraser has a passion for baseball. Not just watching the game, but playing it hard—and exceedingly well. In fact, she loves the game so much she even celebrated her wedding day on the mound. This year, she made the second-to-final cut of the 2006 USA Baseball Women’s National Team, which competed in Taiwan at the Women’s World Cup. And she vows she’ll compete again when team tryouts are held next in 2008.

So three years ago, when she started feeling lousy during a game, she still played through nine innings.

“I thought I had the flu or was just dehydrated,” says the mother of two.
Fraser had gone to the doctor the day before her game, feeling nauseous, suspecting she was pregnant or under the weather—except her eyes were looking very yellow. After returning home and taking some prescribed medication, she immediately became violently sick. Her husband rushed her to the emergency room.

“I felt like I was dying,” Fraser says. And, it turns out, she was.

Fraser was suffering from acute liver failure, which strikes suddenly and unexpectedly with hard-to-diagnose symptoms and confusing causes. This uncommon but life-threatening condition can occur in people with no apparent previous illness, making them critically ill very rapidly due to sudden, severe liver cell damage. Known causes include viruses, medications such as acetaminophen or antibiotics, poisoning, heat stroke and pregnancy. Patients require liver transplants and, even then, the survival rate is only about 10 percent.

When Fraser slipped into a coma, her doctors knew that in order to survive she would need a liver transplant—and soon.

Two days after she was put on the transplant list at the University of Washington Medical Center she received a donor organ.

Today, as a healthy competitive baseball player and mother of two young boys, Fraser is well aware of how close she came to dying.

“I was lucky,” she admits. “It’s pretty emotional thinking of where I’ve been and where I am now.”

But for every patient like Mari-Jo, there are 18 who die each day across the U.S. waiting for a donor organ, according to the U.S. Department of Health and Human Services. The need for transplant tissues and organs far outpaces the supply from donors.

New research could signal hope for future liver patients. Recent ground-breaking discoveries in the pathology labs of the University of Washington could eventually lead to a revolutionary new way of repairing damaged livers using stem cells.

For the first time, a team of UW researchers has isolated, grown and injected human liver stem cells into laboratory mice using a technique that could hold the key to repairing livers severely damaged by hepatitis, alcoholism, drug overdoses—and perhaps even acute liver failure.

“This is a major first step in learning how to repair damaged human livers with stem cells,” says Pathology Chair Nelson Fausto, who led the research.

Nelson Fausto and Chuck Murry. Photo by Kathy Sauber.

Stem cells have remarkable potential. Serving as a repair system for the body, they can theoretically divide without limit to replenish other cells. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a liver cell, a red blood cell or a heart muscle cell.

To make his discovery, Fausto and his team isolated liver stem cells from human fetal tissue donated to research. They then grew the stem cells in the laboratory for up to six months and injected them in mice with damaged livers. The immune systems of the mice were suppressed to prevent rejection of the human cells. These cells, in turn, replaced thousands of damaged liver cells, far beyond Fausto’s expectations.

The team also manipulated the stem cells with special laboratory cultures to become cells of the bile duct, cartilage, bone, fat and blood vessels—cells that one day could have the potential to repair damaged tissue throughout the body.

“The significance of this research is that we were able to both isolate the liver stem cells and grow them into basic liver and bile-duct cells,” Fausto explains. “It was a delight when we witnessed these cells partially repopulating the damaged livers of the mice.”

Scientists have long believed that stem cells, derived from bone marrow, blood or embryos, are capable of repairing damaged tissue by taking on the identity of that organ’s cells—a phenomenon known as differentiation. Simply put, they can respond to the body’s needs and become virtually any type of cell. In recent years, research has expanded because of the promising regenerative potential of stem cells in treating a myriad of diseases.

“What we ended up finding in this study was a cell type that was a stem cell for liver lineage, but that could also become the cells of cartilage, fat, bile duct, bone and blood vessels,” Fausto says. “We found these cells to have an enormous capacity to differentiate.”

Throughout this experimental process, Fausto says the UW research team gained an unprecedented understanding of cell origins, human embryology and how the human liver is put together—knowledge, he says, which is “critical for future research.”

If the research moves forward successfully in coming years, the technique Fausto and his team developed could some day provide a new lease on life for liver patients who otherwise face a bleak prognosis.

But Fausto is quick to emphasize that this is only the beginning of a very long road, and clinical trials “are a long way off.”

Fausto is one of more than 80 faculty members who are part of the UW’s new Institute for Stem Cell and Regenerative Medicine. Regenerative medicine focuses on replacing damaged or dead cells either by introducing new cells into the body or by prompting the body to create new cells on its own.

The institute includes interdisciplinary teams of researchers in medicine, biology and engineering working together to unleash the tremendous power of stem cells and develop therapies—and, ultimately, cures. The mission: to move the long-touted regenerative powers of stem cells from the laboratory into the realm of viable human therapies. The targets: liver disease, heart failure, diabetes, Parkinson’s disease, spinal cord injury, stroke, Alzheimer’s disease, Lou Gehrig’s disease and loss of hearing or sight.

“The liver is perhaps the best organ in the body in terms of its ability to regenerate itself,” says Pathology Professor Chuck Murry. “In the liver, cells that are left over after some type of liver damage are able to go back into the cell cycle and start dividing again.”
But a damaged heart is another story.

“There’s very little new muscle that’s generated in the heart after a heart attack,” he says.

Murry is using embryonic stem cells to regenerate heart tissue. While there may be some stem cells that live in the heart and are capable of repopulating heart muscle cells, they are too slow, “and they’re not sufficient to meet the demand of the type of large-scale muscle loss that occurs after a heart attack,” he says.

At present, the only tissue replacement therapy for an injured heart is heart transplantation. But stem cell research offers hope for the heart.

Murry’s lab at the UW has grown new cardiac tissue in mice and rats by implanting heart muscle cells grown from stem cells. They found that cells from bone marrow can grow blood vessels, while embryonic stem cells can give rise to heart muscle tissue.

“Stem cell research holds promise because it offers the opportunity to rebuild damaged tissues from component parts,” says Murry, who co-directs the UW regenerative medicine institute and is the leader of the UW Center for Cardiovascular Biology.

If Murry’s work continues to make advances, it may be ready for human trials within the next three to four years.

Both Fausto and Murry are an inspiration to Greg Lipski, a third-year UW medical student who learned about the regenerative powers of stems cells from two perspectives—as a doctor in training and as a patient hanging on to hope.

Diagnosed last year with leukemia, Lipski remembers watching his sister’s stem cells move through a tube into his body as he underwent a bone-marrow transplant at the UW Medical Center. Stem cells have been used for years in transplants for patients with leukemia, like Lipski, and for some blood disorders.

“I tried to visualize what might be happening and what I hoped was happening to my cells,” he recalls. His 41-year-old sister turned out to be a perfect match and Lipski’s greatest chance for a cure.

Today, more than a year after his sister’s stem cells flowed into his body, Lipski is doing well. He’s back in medical school at the UW, finishing up a family medicine rotation in Whitefish, Mont., followed by an obstetrics/gynecology rotation in Rock Springs, Wyo. He’s feeling good, his red cell counts are up, and his doctor even took him off one of his prescribed medications due to his amazing progress. And, in September, he climbed to the top of Mt. Adams.

Now more than ever, Lipski says, he is interested in the advances being made in stem cell research at UW and other institutions around the globe.

“Hope is huge,” he says. “I’ve now been on both sides of the fence with this, as a med student immersed in my studies and as a cancer patient. The type of research being conducted at the UW in this area is truly amazing—it really holds promise for both patients and doctors in terms of new treatments and potential cures.”

Murry agrees. “We are in the beginning stages of what could become the next revolution in medicine,” he says.

UW Medicine receives $6 million for stem cell research

Orin Smith, retired Starbucks president and CEO, donated $5 million for the UW’s Institute for Stem Cell and Regenerative Medicine, the UW announced Oct. 26. Smith, a 1965 UW graduate, is chairman of the board for UW Medicine. UW Medicine also has received a $1 million anonymous gift for stem cell research.

Donating to stem cell research is a good investment, Smith says. “I can’t think of any other area that offers so much potential and promise to thousands—or millions—of people worldwide,” Smith says.

Smith’s $5 million gift is unrestricted. It may be spent however researchers and the University see fi t. Randall Moon, director of the institute, said that “stem cell research is key to the success of developing new therapies for many diseases and injuries, and Orin Smith’s wonderful and timely support of the institute is really a gift to the patients of today and of the future, who will benefi t from these therapies.” Smith noted that the UW already has in place one of the leading stem cell research and regenerative medicine programs in the country.

Speaking at a recent CEO summit in Seattle, Lawrence S.B. Goldstein, UW alumus and professor of cellular and molecular medicine at the University of California at San Diego, noted that the UW needs to keep moving forward with its research. “You need to do more if you’re going to compete with my institution down in the south,” he said.

Progress, he said, in stem cell research and regenerative medicine has been “severely thwarted by federal policies” that state federal funding can only be used for research on certain lines of embryonic stem cells and on adult stem cells. UW scientists have said the existing lines of stem cells eventually will wear out. And adult stem cells, they have said, do not hold the promise that embryonic cells do.

Stem cell basics

Stem cells are different from other types of cells because:

• They are unspecialized cells that renew themselves for long periods through cell division.
• They can be induced to become cells with special functions such as the beating cells of the heart muscle.

Scientists primarily work with two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells. They have different functions and characteristics and differ in the number and type of cells they can become:

Adult stem cells:

• Are limited in the new tissues they can form.
• Contribute to growth of new blood vessels, if they are from bone marrow.
• Do not contribute to growth of new cardiac muscle cells.

Embryonic stem cells:

• Are not limited in the new tissues they can form and have a tremendous capacity for cell division.
• Can make any cell type, including heart muscle and insulin-producing cells of the pancreas.
• Teach us fundamental lessons in human development and disease and are promising candidates for regenerative medicine.

Ethical debate

Today, approximately 400,000 embryos exist in the freezers of fertility clinics across the U.S.—“extra” embryos left over from in vitro fertilization procedures. Most will eventually be discarded. Opponents ask, “Can we destroy a human embryo for the benefit of others?” Advocates ask, “Is it ethical, or even logical, to withhold possible therapy from others while these embryos are already targeted for destruction?”

Cons

• For those who believe life begins at conception, destruction of any human embryo is seen as the taking of a human life.
• With limited federal funding support, further research could end up in the private sector driven by market competition.
• This research is the first step toward human reproductive cloning.

Pros

• Science has safeguards: it is intrinsically self-correcting because peer reviews require reproducing results.
• Decisions on how to proceed should be made by an educated public, not by competitive private sector companies out of public oversight.
• Virtually all reputable scientists think human reproductive cloning is unethical.

Clare Hagerty is the assistant director of Health Sciences/UW Medicine News & Community Relations.