Stem Cell Science | Minnesota Medical Foundation

U conducts first clinical test of stem cells expanded by new method

2012-04-19T14:17:40Z

University of Minnesota investigators have opened a Phase I clinical trial designed to test the safety and potency of blood-forming stem cells in umbilical cord blood (UCB) that previously have been multiplied in a new cell-culturing system.

Derrick Keller, an 18-year-old from St. Louis Park, Minn., who has acute lymphoblastic leukemia, was the first patient to enroll in the study. He underwent his transplant at the University on February 7.

Scientists at the Genomics Institute of the Novartis Research Foundation in San Diego, Calif., recently discovered a lowmolecular- weight compound that promotes the expansion of blood-forming stem cells, the parent cells of red blood cells, white blood cells, and platelets.

The U.S. Food and Drug Administration in November approved the initiation of a Phase I clinical trial using this new chemical compound. The University’s John E. Wagner, M.D., an internationally recognized pioneer in the field of UCB transplantation, is leading the trial.

UCB, the blood left in a placenta after the birth of a child, is increasingly being used as a source of blood-forming stem cells for transplant as part of the treatment of children and adults with a variety of life-threatening diseases such as leukemia, lymphoma, and myelodysplastic syndrome.

Expanding the number of UCB stem cells per unit could improve patients’ chances of finding a suitable match among the 750,000 UCB units available worldwide and speed up recovery from the transplant.

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Exploring what's possible

2011-11-02T14:09:36Z

University team harnesses the power of stem cells to repair the brain and spinal cord

For years, doctors treating patients who had brain or spinal cord injury faced a terrible impasse.

“It was always considered impossible to regenerate damaged brain or spinal cells,” says University of Minnesota assistant professor and neurosurgeon Ann Parr, M.D., Ph.D.

For a person who had been in an accident or suffered a stroke, crushed neurons or blood-deprived brain tissue meant uncertain recovery and the possibility that loss of function, like walking or speaking, would be permanent.

But the thinking about brain injury has begun to change, in particular with the latest advances in stem cell research. Today’s stem cell technologies involve a wide range of naturally occurring and engineered cells, and they’re altering the outlook on restoring the highly specialized brain and spinal cord.

In the Medical School’s Department of Neurosurgery, a new group of researchers is focused on stem cells and how their astounding capabilities may be harnessed to help patients regain function.

Scientist Walter Low, Ph.D., the department’s associate head for research, has long been interested in how stem cells might minimize brain damage following a stroke. His research involves using stem cells that exist in umbilical cord blood from the placentas of newborn babies to help repair the brain after an injury.

Low’s group found that a subset of stem cells from cord blood is capable of differentiating into precursors of neural cells in the brain. He was amazed by how the cells repaired brain tissue in animal models.

“We’ve found that if we give stem cells two days after a stroke, we can reduce the infarct volume by 50 percent,” he says. (An infarct is a lesion left behind in the brain after it’s been deprived of blood and oxygen.)

That’s a tremendous opportunity, he points out. A typical emergency room treatment for stroke is the clot-busting drug tPA, which can restore blood flow to brain tissue if it’s given within just three to four hours of a stroke.

A stem cell therapy may increase the window in which treatment can be given.

Low says these cells seem not only to regenerate neural cells, but also to have a protective effect on the vulnerable area of the brain around the site of the stroke.

“We could conceivably preserve a lot of brain tissue with the administration of these cells,” he says.

Low’s next steps involve validating the research findings and beginning to work out parameters to determine, for example, how many stem cells might be needed to be an effective therapy for a person who’s had a stroke.

“Ultimately,” he says, “we’d like to scale up for a clinical trial.”

Reprogramming cells

Neurosurgeon Parr became interested in the potential of stem cells as she treated patients who had suffered life-altering spinal cord injuries.

“They’re very often young people,” she says, “and their lives have been turned inside out.”

In studies of rats with spinal injuries, she found that an infusion of neural stem cells, those capable of becoming brain cells, could restore motor function. Most of those stem cells turned into one specific type of neural cell called oligodendrocytes, which produce the insulating, fatty myelin sheath that protects the nerves.

It’s not clear yet whether the stem cells protect damaged nerves from toxins or provide new insulation for the nerves, Parr says. The cells may even offer a healthy surface for regrowing nerves, she says.

The cells’ beneficial effect prompted Parr’s upcoming research. She is developing the technology to produce oligodendrocyte progenitor cells, cellular precursors to the mature oligodendrocytes, which potentially can be used as therapy. Her research involves taking a patient’s own skin cells, called fibroblasts, and genetically converting them back into stem cells, in essence “turning off” their former genetic identity, Parr says. Then she’ll steer the cells to develop into oligodendrocyte progenitor cells.

“Brain and spinal cord injuries are so devastating to patients, and there’s very little we can offer them,” Parr says. “Our goal with all of these studies is to bring treatments to the clinic where they may provide patients with new hope.”

Redirecting the body’s own cells

Another line of research by endovascular neurosurgeon Andrew Grande, M.D., is addressing the best way to access those potentially life-changing neural stem cells that are found in certain areas of the brain.

Grande is investigating using a microcatheter threaded into the brain to steer naturally occurring neural stem cells from areas known as the subventricular zone and the hippocampus to the area where a stroke has occurred.

“There’s a constantly replenishing source of neurogenerating stem cells in these areas, and the body knows what to do with them,” says Grande, who joined the University in September after receiving the prestigious William P. Van Wagenen Fellowship, an award for a top resident pursuing academic medicine. “The question is, can we somehow lasso this capability and direct these cells elsewhere to produce new neurons in an area of injury?”

The microcatheter may be useful in a range of stem cell therapy techniques, Grande says. He currently uses microcatheters to diagnose stroke and to deliver clot-busting drugs in tiny blood vessels. But he’s interested in developing new ways to deliver stem cell therapies to the brain during neurosurgery.

“With my particular clinical background,” he says, “this is something unique I hope to bring to stem cell therapy.”

Where doctors have had little help to offer people with brain injuries, the horizon is growing brighter. Parr notes that scientists need to pursue these research avenues with great care, looking for adverse effects and possible complications before these advances can move to human clinical trials.

“Patients ask me, how close are we to discovering treatments? I think we’re getting close,” she says. “In the next few years there will be some treatments, especially for patients whose spinal injuries are new. This field is moving very quickly.”

STROKE: By the numbers

6 Percent of all deaths in the United States caused by stroke
795,000 Estimated number of people who have a stroke in the United States every year
60 Percent of stroke sufferers who survive

Source: Centers for Disease Control and Prevention

Spinal Cord Injury: By the numbers

265,000 Number of people in the United States living with spinal cord injuries
12,000 Estimated number of people who suffer a spinal cord injury per year nationally
40.7 Average age at the time of spinal cord injury

Source: National Spinal Cord Injury Statistical Center

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Advancing stem cell science

2011-08-17T15:29:36Z

Current and planned gifts extend alum’s longtime University support

Clayton Kaufman knows a high-impact story when he hears it. His judgment is forged by a broadcasting career that spanned more than four decades. That’s one reason he’s keeping tabs on advances in stem cell science—and why he’s supporting the research through current and planned gifts to the University of Minnesota, his alma mater.

“The importance of stem cell research cannot be overemphasized,” he says, mentioning its potential impact on a myriad of diseases, such as diabetes, cancer, and Parkinson’s disease. That’s another reason Kaufman is interested in the research: he has Parkinson’s.

Then there’s his youngest son, Dan Kaufman, M.D., Ph.D., associate director of the University’s Stem Cell Institute, who’s investigating the use of embryonic stem cells in therapies such as bone marrow transplants to treat patients with leukemia, lymphoma, myeloma, and other cancers.

In fact, Clayton Kaufman, who earned a bachelor’s degree from the University of Minnesota’s School of Journalism in 1949, says since his time as a student, his longtime commitment to the U of M and to stem cell science continues to grow stronger.

Family connections to the U

Dating back to his undergraduate days, Kaufman met his late wife, Nancy—mother to his three sons—when they both attended the University of Minnesota.

A self-described “lifelong Gopher football fan,” Kaufman says that he learned the basics of journalism while working as a sports editor at the Minnesota Daily, the University’s student-run newspaper. That experience, he says, launched his career.

He went on to work as a sports writer and editor for an International News Service and later took a job at WCCO Radio, where he worked for 39 years. He was initially hired as a news writer but eventually became the general manager and then senior vice president for radio. In 2007 he was inducted to the Minnesota Broadcasting Hall of Fame.

The University also helped to shape the careers of Kaufman’s three adult sons. The oldest, Dixon Kaufman, M.D., Ph.D., completed his undergraduate, medical (Class of ’83), and doctoral degrees at the University, as well as his residency and fellowships. Now a transplant surgeon and researcher, he has worked at Northwestern University in Chicago and was recently appointed Transplant Division Chief at University of Wisconsin—Madison’s School of Medicine and Public Health, and at its hospital and clinics. Middle son Douglas Kaufman, M.B.A., earned his bachelor’s degree at the University of Minnesota and is now the finance director of corporate trust services at U.S. Bank.

Meanwhile, Dan, an alumnus of Stanford University and Mayo Medical School, is an associate professor at the University of Minnesota and an internationally recognized stem cell researcher—working with induced pluripotent stem cell, or iPS cells, and embryonic stem cells.

Clayton Kaufman says exposure to medicine through his sons sparked his interest in the field, as did his service on the Minnesota Medical Foundation’s Board of Trustees in the 1980s, and later on the Masonic Cancer Center’s Community Advisory Board in the 1990s. “[MMF] opened the door for me to get involved in a whole new community,” he says.

The importance of stem cell science

Although he provides generous annual support to the Masonic Cancer Center and the journalism school, Kaufman says that embryonic stem cell research is the primary focus of his giving.

Philanthropic support for embryonic stem cell research is hindered by many factors, he says—most notably donors’ tendency to fund research on specific diseases, like cancer and heart disease. “People don’t have stem cell-itis,” Kaufman says.

The lack of a national organization that raises money exclusively for stem cell research and the politicization of the research also deter scientific progress, he says.

“Federal money has been diverted on and off since they started studying stem cells,” says Kaufman’s current wife, Susan. “Private fundraising is the most important financial source for embryonic stem cell research.”

So, Kaufman says, he decided to turn their frustration into action by making two planned gifts that directly support embryonic stem cell research at the University.

The right kind of gift

“For a long time I had thought, “When my day comes, I want to leave some money for stem cell work at the University,”” Kaufman says.

But after learning about the charitable gift annuity—a gift that allows donors to transfer assets to a charity in exchange for fixed payments for life—he decided to accelerate his planned estate gift.

Kaufman funded two charitable gift annuities with MMF in 2008, increasing his current income and securing a partial tax deduction while ensuring continued support for embryonic stem cell research at the University after his lifetime.

“This is a way I could make my gift now, get some benefit from it, and have a major share available for the Stem Cell Institute,” he says.

Kaufman says that he hopes his giving will inspire others to think about the promise of stem cell science and act now—instead of later. “You can’t take it with you,” he says. “But this is a way to give it before you go.”

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U researchers advance crucial stem cell technology

2011-07-12T19:21:57Z

University of Minnesota researchers have developed a new method for creating induced pluripotent stem cells (iPS), which can differentiate into many different types of the cells in the body and are used in medical research focused on diabetes, cancer, and many other diseases. This new process will dramatically speed up the creation of iPS cells and improve their quality, which could accelerate the treatment of many otherwise incurable diseases.

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Supporting body and spirit

2011-06-15T21:00:00Z

Amplatz Children’s Hospital inspires giving from the heart

By Martha Coventry

Of all the things a teenage boy might choose to do with his bar mitzvah money, giving a portion to medical research might seem low on the list. After all, there are Xboxes and iPods and skateboards to buy. But when Matthew, 13, gave his money to a research program led by John Wagner, M.D., at the University of Minnesota, he was sharing a heartfelt thanks.

“His research saved my life, and I wanted to help him save other lives,” Matthew says.

When Matthew was a week shy of his eighth birthday, he was diagnosed with acute myeloid leukemia. As he was undergoing chemotherapy in Miami, where he lives, his parents, Marcy and Harry, were busy researching treatment options in case he relapsed. Matthew had no family or non-related bone marrow match. His best hope, they learned, was a transplant of publicly donated blood from two umbilical cords.

Wagner, director of the University’s Blood and Marrow Transplantation Program and clinical director of the Stem Cell Institute, had pioneered the world’s first umbilical cord blood transplant for leukemia in 1990. Later, he found that, for older children and adults, co-infusing units from two different donors instead of one led to faster recovery and a markedly lower risk of leukemia relapse.

Aware of Wagner’s successes, Matthew’s parents contacted him to learn more about his work. He got back in touch immediately. “The University was the only place willing to offer Matthew a double cord blood transplant if he needed it,” says Marcy.

Within a year, Matthew’s leukemia had indeed relapsed. He came to University of Minnesota Amplatz Children’s Hospital in April 2007 and became the first child in the world to receive a double cord blood transplant specifically to reduce the chance that his leukemia would ever recur again.

Today, Matthew has a clean bill of health, and his parents have made their own financial gifts to the University to support medical care and research. “One of the things that we particularly like about the University is that we know our gifts will go to developing therapies, like Matthew received, that will be brought to the bedside as soon as possible,” says his mom.

A cascade of names

Matthew says he’s excited about seeing his name on the digital donor roster in the lobby the next time he visits University of Minnesota Amplatz Children’s Hospital, which opened a new state-of-the-art facility on April 30. Located on the University’s West Bank, the new hospital stands out because of its inviting, colorful, and “green” design — inside and out — and for its many other special features that accelerate healing and make young patients and their families feel at home.

Cascading down the large digital screen like a waterfall are the names of those who have contributed to the Children’s Health Campaign at the University of Minnesota, which aims to raise $175 million for the hospital building project, as well as pediatric research, education, and care. Thanks to Matthew, his parents, and many others like them, more than half of that amount — $98 million — had been raised by mid-May.

The gift of solace

Ted Thompson, M.D., and his wife, Lynette, have given a lasting — and growing — place of healing and comfort to Amplatz Children’s Hospital.

Dr. Thompson has been in the Department of Pediatrics at the University of Minnesota since 1975. When he comes home after caring for ill or premature newborns, his wife’s garden offers him respite. Lynette, a certified master gardener and former adult intensive care and coronary care unit nurse, knows the consoling power of flowers and plants. The Thompsons wanted to make that solace available to patients and families at Amplatz Children’s Hospital, as well as to the hospital’s physicians, nurses, and other staff.

Near the hospital’s main entrance is the healing garden they have funded and endowed. Paths leading off from the main garden have benches under the trees to create a feeling of peaceful, private space.

“One of the most stressful things in life is to have your child in the hospital,” says Thompson. “We wanted to provide a place where people can go to get away from that stress for a moment, to think and to contemplate.”

Thompson says he is proud to help bring about a dream he and his colleagues have shared for decades: a top-notch facility at the University that gathers the very best of pediatric care, research, and education all under one roof.

To learn about additional recognition opportunities at University of Minnesota Amplatz Children’s Hospital and the many ways to support the Department of Pediatrics, contact the Minnesota Medical Foundation’s Children’s Health Team at 612-626-1931 or childrenshealth@mmf.umn.edu, or visit UofMHope.org.

To become part of our Partners in Care program, contact Jen Foss at 612-626-5276 or j.foss@mmf.umn.edu.

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Clinical trials test power of stem cells to help damaged hearts recover

2011-06-13T14:00:00Z

Just in time

Michael Johnson would have been shocked to learn last summer that his heart would fail by fall.

A seemingly healthy 66-year-old businessman, Johnson had been a patient in the hospital only once: at birth. Then came September 6, 2010, when he suffered a massive heart attack. An emergency angioplasty and stent procedure opened the blockage that caused his heart attack, but only 35 percent of his heart function remained.

“They told me if I wouldn’t have come into the hospital, I would have been dead by the next morning,” Johnson recalls. “I was in disbelief that my heart could suffer so much damage.”

While recovering at Fairview Southdale Hospital and facing a future limited by significant heart failure, Johnson got another surprise: University of Minnesota researchers asked him to participate in an innovative cell therapy study that might improve his prognosis. If he agreed, he would be randomly assigned to receive either an injection of stem cells derived from his own bone marrow into his heart or a placebo injection as part of a double-blind clinical trial. Johnson signed up, and 10 days after his heart attack, he received his injection.

The study in which Johnson is participating, known as Late TIME (Transplantation in Myocardial Infarction Evaluation), is designed to evaluate the safety and effec- tiveness of infusing stem cells into a patient’s heart two to three weeks after a heart attack. Another similar study, known simply as TIME, evaluates the success of this therapy three to seven days after the patient’s heart attack. Both are funded by the National Institutes of Health.

Since the two multicenter trials began last year, more than 200 people have enrolled nationwide. Ten of them are at the University.

“The University of Minnesota has a long-standing tradition in both transplantation and cell therapy initiatives,” explains Daniel Garry, M.D., Ph.D., chief of the Medical School’s Division of Cardiology and executive director of the Lillehei Heart Institute. “Our goal with these studies is to look critically at the benefits of using a patient’s own cell therapy following a heart attack.”

Led by interventional cardiologist Ganesh Raveendran, M.D., the cardiac cell therapy research team includes Garry, cardiologist Cindy Martin, M.D., and cardiothoracic surgeon Ranjit John, M.D.

“There is no doubt that in recent decades we have continued to significantly improve treatments for patients who have had heart attacks. Despite this, their heart function doesn’t recover as well as it should,” says Raveendran. “Ultimately, we hope that cell therapy will improve health outcomes and quality of life for these patients.”

In addition to helping to boost heart function after heart attacks, stem cell therapy may also increase the effectiveness of treatments for heart failure.

The U.S. Food and Drug Administration has recently authorized the team to conduct another study, in which patients in severe heart failure receive injections of their own stem cells during the implantation of a left ventricular assist device (LVAD), a device that pumps blood for a heart that is too weak to do so on its own. (An LVAD can allow the heart to rest for a time, or it can serve as a “bridge” therapy until a patient receives a transplant.)

“The holy grail of end-stage heart failure remains myocardial recovery, so our hope is that this therapy will help the heart recover better,” says John, who directs the University’s Ventricular Assist Device Program. “After a period of three to six months, we will gradually wean down the support given by the LVAD—then determine whether the function of the native heart is improving.”

Johnson believes the injection he received is helping. Nine months after signing on to participate in the study, his heart function has improved to 58 percent—just 2 percent below what is considered normal.

And after recently climbing a staircase with a load of briefcases, he noticed his heart pumping—and felt stronger.

“I think it has definitely helped me,” Johnson says of the study. “I feel like I’ve done something really proactive—in addition to exercise and eating better—that gives me the extra edge I need to have the best possible outcome.”

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Finding hope

2010-12-21T17:19:21Z

U researchers’ stem cell breakthrough treatment for a fatal skin disease began with philanthropy

For the first time ever, physician-scientists at the University of Minnesota have demonstrated that a lethal skin disease can be successfully treated with stem cell therapy.

Medical School researchers John E. Wagner, M.D., and Jakub Tolar, M.D., Ph.D. — in collaboration with researchers in Oregon, the United Kingdom, and Japan — used stem cells from bone marrow to repair the skin of patients with a fatal skin disease called recessive dystrophic epidermolysis bullosa (RDEB).

It’s the first time researchers have shown that bone marrow-derived stem cells can repair the skin and upper gastrointestinal tract and alter the natural course of the disease.

Until now, bone marrow has only been used to replace diseased or damaged marrow.

“To understand this achievement, you have to understand how horrible this disease actually is,” says Wagner. “From the moment of birth, these children develop blisters from the slightest trauma, which eventually scar. They live lives of chronic pain, preventing any chance for a normal life.”

That was reality for the Liao family of New Jersey. Theresa Liao tracked down Wagner at a medical conference in New York in 2004, literally thrust her then-2-year-old son, Jacob, at him, and begged him to save her child. It was a promise Theresa had made to her son at birth.

“I used to hold him in my arms and cry,” she says. “I told him I was going to make a difference, and that we were going to fix it or make it better or at least go down swinging.”

The encounter launched Wagner’s work on the disease. The Liao family raised enough money for his team to start a laboratory study with mouse models of RDEB. In 2007 the team found that a rare subpopulation of marrow stem cells could repair the mice’s skin.

With additional philanthropic support, Wagner and Tolar launched a clinical trial to find out if the therapy also could work in humans.

Since that study began at the University in 2007, 10 children with the most aggressive forms of EB have received transplants at University of Minnesota Amplatz Children’s Hospital. Although all of those children have responded to the therapy, the magnitude of each response has varied.

“While the treatment offers a chance for a better life, it comes with significant risk,” Tolar says. “Two children have died from complications related to the treatment, so refinements are needed.”

Jake Liao was one of the two children who didn’t make it. His younger brother, Nate, who also was born with EB, however, has improved significantly since his transplant.

For Theresa Liao, the success is bittersweet.

“I miss my best friend,” she says of Jake, “but I wasn’t afraid, because one way or the other I knew what the outcome was going to be if we didn’t give him a chance.”

And that’s precisely what motivates both Wagner and Tolar to keep improving the therapy.

“My hope is to do something that might change the natural history of this disease and enhance the quality of life of these kids,” Wagner says.

By Nicole Endres

To support this research, contact Elizabeth Patty at 612-625-6136 or e.patty@mmf.umn.edu.

You can make a difference

Help the University of Minnesota save lives, inspire hope, and prepare the world’s future health care leaders. Make a gift today.

Because with your support, anything is possible.

Finding hope

2010-11-16T19:46:43Z

Laurie Strongin’s uneventful pregnancy belied the reality of her firstborn’s medical condition. Born in 1995, Henry had Fanconi anemia, and Laurie and her husband, Allen Goldberg, quickly learned that a matched sibling blood and marrow donor was his only hope.

In 1996, while Laurie was pregnant with their second child—healthy but not a genetic match—the couple learned about the possibility of using preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF), guaranteeing a healthy child and a match. The decision to proceed was easy; their family again would grow, and Henry could get his blood and marrow transplant (BMT) at the University of Minnesota, a leader in using BMT to treat Fanconi anemia.

“I decided early on that I wanted to keep a journal about the entire experience so that when it did work, I could share information,” Strongin says. “That was my way of giving back in exchange for being first.”

Earlier this year, Strongin turned her journal into the book Saving Henry, which chronicles—from a medical perspective, and perhaps more important, from the perspective of a normal, superhero-loving kid—Henry’s life and early death.

For the Strongin-Goldberg family, IVF and PGD failed on numerous occasions, and University pediatric hematologist/oncologist John E. Wagner, M.D., determined that Henry was too sick; they had to proceed with an unrelated donor. Because of the procedure, Henry and his family gained another 2½ years together.

Saving Henry recounts the family’s journey and celebrates Henry’s life. “The book started off as a therapeutic outlet,” Strongin says, “but then it became a story of hope and what it’s like on the medical frontlines.”

Web Extras

Book excerpt: Saving Henry

“This is a story about the power of love and the promise and limits of science. It is a story in which politics, ethics, and advances in reproductive genetics collide…”. Read more here.

You can make a difference

Help the University of Minnesota save lives, inspire hope, and prepare the world’s future health care leaders. Make a gift today.

Because with your support, anything is possible.

U researchers use stem cells to repair the skin of children with a life-threatening disease

2010-11-16T19:12:29Z

Physician-scientists at the University of Minnesota have for the first time demonstrated that a lethal skin disease can be successfully treated with stem cell therapy.

Medical School researchers John E. Wagner, M.D., and Jakub Tolar, M.D., Ph.D.—in collaboration with researchers in Oregon, the United Kingdom, and Japan—have used stem cells from bone marrow to repair the skin of children with a fatal skin disease called recessive dystrophic epidermolysis bullosa (RDEB).

It’s the first time researchers have shown that bone marrow-derived stem cells can repair the skin and upper gastrointestinal tract and alter the natural course of the disease. Until now, bone marrow has only been used to replace diseased or damaged marrow.

“To understand this achievement, you have to understand how horrible this disease actually is,” says Wagner. “From the moment of birth, these children develop blisters from the slightest trauma… They live lives of chronic pain, preventing any chance for a normal life. My hope is to do something that might change the natural history of this disease and enhance the quality of life of these kids.”

Since the study began at the University in 2007, 10 children with the most aggressive forms of EB have received transplants at University of Minnesota Amplatz Children’s Hospital. While all of the children have responded to the transplants, the magnitude of each response has varied.

The research results appeared in the August 12 issue of the New England Journal of Medicine.

“Bone marrow transplantation is one of the riskiest procedures in medicine, yet it is also one of the most successful,” Tolar says. “Patients who otherwise would have died from their disease can often now be cured.”

This research is supported in part by grants from the National Institutes of Health, the University of Minnesota Academic Health Center, Epidermolysis Bullosa (Liao Family) Research Fund, Sarah Rose Mooreland EB Fund, Children’s Cancer Research Fund, and agencies in Japan.

Read the news release, watch a video on the research, and meet some of the children who participated in the clinical trial at www.ahc.umn.edu/eb.

You can make a difference

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Because with your support, anything is possible.

A revolutionary decision

2010-11-16T15:52:58Z

Ten years after Molly Nash became the first Fanconi anemia patient to survive following a controversial transplant, the ethical debate continues

In most ways, 16-year-old Molly Nash is a typical teenager. She argues with her parents. She bickers with her younger brother and sister (but admits to loving them, too). And she is a budding actress, recently portraying Chip the teacup in Beauty and the Beast.

The science that came together 10 years ago to give Molly these opportunities was revolutionary, controversial, and for her family, intensely personal.

“You never thought beyond milestones. Can we make it a month, six months, the first year?” recalls Molly’s mom, Lisa Nash. “Ten years ago we never would have imagined that we would ever reach this mark.”

At birth, Molly was diagnosed with Fanconi anemia (FA), a usually fatal genetic disease. Her only hope was a blood and marrow transplant. But survival rates for those without a matched sibling donor were a dismal 16 percent. And Molly had no siblings.

University of Minnesota pediatric hematologist/oncologist and umbilical cord blood transplant pioneer John E. Wagner, M.D., wanted better numbers. He worked with in vitro fertilization and preimplantation genetic diagnosis (PGD) experts to create better odds.

Ultimately, the Nashes would become the first to use PGD to have a child who was guaranteed to be free of FA and an exact blood match for a sibling.

“We knew this was going to be a hotly contested ethical issue. But we also knew that it was Molly’s best chance,” Wagner says.

In the spotlight

To start the process, Lisa Nash’s eggs were extracted and fertilized. Genetics specialists tested the resulting embryos to be sure they were disease-free and a match, and the selected embryos were implanted.

It doesn’t always work immediately—it took the Nashes five tries before a successful pregnancy. Adam was born on August 29, 2000, and Molly received his cord blood on what her family calls her “second birthday,” September 26, 2000.

“We recycled Adam’s cord blood—he didn’t need it anymore—and gave Molly life,” Lisa Nash says.

There were critics—vocal critics—who accused Wagner of playing God and manufacturing designer babies. Others took issue with selecting embryos for a trait such as blood match that was not of benefit for the resulting child. Through the firestorm of worldwide publicity, however, the overriding response was supportive.

The Nashes found the international attention overwhelming. “We weren’t doing it for the world’s approval or disapproval,” Lisa says. “We were flat out doing it for our family, so we could have a family.”

But it wasn’t a decision that the Nashes or their doctors took lightly. Wagner consulted with Jeffrey Kahn, Ph.D., M.P.H., director of the University’s Center for Bioethics.

“We made a conscious effort to be public and discuss this in a transparent way,” Kahn says.

A lesson in living

Ten years later, the ethical debate continues. Many embryos are created to get one perfect genetic match for patients in need of a transplant. Alternatively, before preimplantation genetic screening was an option, some families chose to abort healthy but non-matched fetuses, Kahn says.

From a scientific perspective, much has changed. “This technology is now being used for many different diseases, and many places offer it,” Wagner says. “While the debates continue, we use these technologies for good.”

And the FA survival rates are vastly improved—about 90 percent for transplants involving unrelated donors and 100 percent when the donor is a matched sibling.

Meanwhile, Molly Nash, who will always be a “first,” goes about her typical life.

“Molly’s taught us to live life,” Lisa Nash says. “To this day we live life to the fullest because we still have no idea how long we will have her on this earth, so we make every second special.”

By Sara E. Martin

Web Extras

Companion Story: Finding hope

Excerpt from Saving Henry: A Mother’s Journey by Laurie Strongin

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U awarded $8.6M to manufacture stem cell therapies

2010-05-04T19:37:00Z

The University of Minnesota has been awarded an $8.6 million contract to help speed the development of novel stem cell- and immune cell-based therapies from the laboratory to clinical trials through the Production Assistance for Cellular Therapies (PACT) program.

The award, from the National Heart, Lung, and Blood Institute, was given to five academic centers, including centers at the University of Minnesota, Baylor College of Medicine, Beckman Research Institute of the City of Hope, Harvard Medical School, and the University of Wisconsin-Madison. These sites will serve as national resources for the development of new treatments for patients with various heart, lung, and blood diseases.

The University of Minnesota team will continue to work on establishing national best practices for the development of cellular therapies. Investigators here have been at the forefront of research on umbilical cord blood and the development of regulatory T cells and natural killer cell therapies to enhance the effectiveness of blood and marrow transplants and reduce their complications.

“Few institutions in the U.S. have the combined expertise and resources in one place to take an idea from the research bench to the patient bedside as we have at the Molecular and Cellular Therapeutics Facility,” says principal investigator John E. Wagner, M.D., who together with David McKenna, M.D., and Jeffrey Miller, M.D., will lead the University program.

The PACT award is the second fiveyear contract Wagner has received at the University to help accelerate work on cellular therapies. The University’s first contract, awarded in 2003, fundamentally transformed the pace of new cell-based therapies.

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Great expectations

2009-11-03T23:27:59Z

The potential to transform medicine looms large as the Stem Cell Institute embarks on its second decade of discovery

Amid the fanfare over the University of Minnesota’s new TCF Bank Stadium, scientists working in labs across the street from it are engaged in quieter but higher-stakes activities. These leading researchers at the University’s Stem Cell Institute along with others performing stem cell research across the campus may hold in their Petri dishes the keys to unlocking the mysteries of diabetes, cancer, heart failure, brain injury — even aging.

Established in 1999, the Stem Cell Institute was the first in the nation to take an interdisciplinary approach to the burgeoning field of stem cell science. “Minnesota was on our radar as one of the places that had made a strong commitment to stem cell research,” recalls U of M cardiac researcher Doris Taylor, Ph.D., a Duke University faculty member at the time.

Progress was stymied nationally, however, when the government severely restricted federal funding for human embryonic stem cell (hESC) studies, and the science itself proved extremely difficult to master.

But today, as the Stem Cell Institute marks its first decade, another “medical revolution” is taking place, says John E. Wagner, M.D., clinical director of research at the institute and director of the blood and marrow transplant program in the Department of Pediatrics. Fueling that revolution are promising new discoveries using stem cells — embryonic stem cells, which have become more available under revised federal guidelines, as well as stem cells from skin, bone marrow, and umbilical cord blood.

Housed just a stone’s throw from the new football stadium in the McGuire Translational Research Facility, the Stem Cell Institute is drawing on expertise from across the University to launch its next decade of discovery. The state-of-the-art facility — anchor to the University’s emerging Biomedical Discovery District — was made possible in large part by a $10 million gift from the William W. and Nadine M. McGuire Family Foundation that also triggered state bonding.

The facility is at the core of our discoveries, says Stem Cell Institute director Jonathan Slack, Ph.D., F.Med.Sci. “But the wider group of 32 labs across campus is also essential for our continued success.”

Unprecedented opportunity

It’s well known that all stem cells share an ability to reproduce themselves and to differentiate into specific cell types. What’s shaken up the field lately is a monumental discovery that occurred in 2006. Researchers in Japan announced that they had taken a handful of genes and turned an ordinary skin cell backward in its development until it became an undifferentiated stem cell.

Known as induced pluripotent stem cells, or iPS cells, they present an unprecedented opportunity. They come from a plentiful, easy-to-obtain source — skin — and they’re not controversial in the way that embryonic stem cells have been.

One of Slack’s first actions was to set up a facility to introduce iPS technology to Minnesota. Led by research associate James Dutton, Ph.D., the Stem Cell Institute has made a number of new human and mouse iPS cell lines and has helped several other groups at the University make their own iPS cells.

Meri Firpo, Ph.D., an assistant professor of endocrinology, is at the forefront of this new technology. Recruited by the University four years ago to investigate stem cell treatments for type 1 diabetes, she is working to develop transplantable, insulin-secreting cells.

The University has a world-renowned program in pancreas cell transplantation, but cells from donor cadaver organs are in short supply, and transplant patients are at risk of suffering an adverse immune response. Now, with iPS technology, Firpo hopes to develop productive islet cells that work in humans and sidestep the rejection problems inherent in transplantation.

“Stem cells provide another potential source of islets for transplantation and offer us tremendous potential to conquer this complicated disease,” says Firpo, whose research got a major boost from a $40 million pledge made last December by the Richard M. Schulze Family Foundation to a group of University scientists aiming to develop a cure for type 1 diabetes.

A powerful weapon

For Dan S. Kaufman, M.D., Ph.D., associate director of the Stem Cell Institute, iPS cells offer a new take on another difficult challenge. Trained in hematology and immunology, Kaufman completed his postdoctoral work at the University of Wisconsin- Madison in the very lab where human embryonic stem cells were first isolated. Indeed, while at Wisconsin, he was the first to produce blood cells from hESCs.

Now Kaufman is investigating the use of iPS cells to create hematopoietic stem cells, the blood-reconstituting cells found in bone marrow and cord blood, to be used in such therapies as bone marrow transplants to treat patients with leukemia, lymphoma, myeloma, and other cancers. He’ll compare the effectiveness and efficiency of using iPS cells with using embryonic stem cells to derive blood cells suitable for these therapies.

That does not mean that Kaufman has closed the door on embryonic stem cells. In fact, he recently turned hESCs into disease-fighting natural killer (NK) cells that are able to completely eliminate human leukemia cells when transplanted into a mouse model. His dramatic results showed that the hESC-derived NK cells were significantly more potent killers of cancerous tumor cells than other NK cell populations tested, including those derived from umbilical cord blood. He also has shown that the hESC-generated NK cells are highly effective in killing breast cancer, prostate cancer, testicular cancer, and brain tumor cells. Kaufman believes that iPS cell technology holds potential for generating NK cells from a patient’s own cells. But work along those lines only intensifies research on hESCs, he says, because in order to coax iPS cells to differentiate into mature NK cells, researchers will need to know much more about how “the real McCoy” does it.

“Human embryonic stem cells provide the gold standard against which to compare iPS cells,” Kaufman says. “We want to use all available avenues to determine the optimal source of cells to treat cancer.”

Damage repair

John Wagner and colleagues Jakub Tolar, M.D., Ph.D., and Bruce Blazar, M.D., were the first to demonstrate that stem cells found in bone marrow can repair skin. In a rare but devastating skin disease called epidermolysis bullosa, in which the skin continuously blisters and scars, these stem cell have been shown to “home” to the skin and replace the missing protein collagen 7 that anchors the skin to the body.

“This is the first time ever that stem cells have repaired an extracellular matrix disease, and the implications for the treatment of many diseases are substantial,” says Wagner, who holds the Children’s Cancer Research Fund Hageboeck Chair in Pediatric Cancer Research and the McKnight Presidential Chair in Hematology and Oncology.

Changing the world for people with diseased hearts, or “reversing aging” is what occupies Doris Taylor, now director of the University’s Center for Cardiovascular Repair. She and her team have started their search with repairing the heart and more recently investigated the use of bone marrow stem cells in treating plaque buildup in animal models of atherosclerosis and found that the cells can reverse blood vessel damage. They have also shown that stem cells differ in men and women and that those differences may begin to explain why men develop heart disease earlier than women.

Taylor also is interested in exploring the “nature vs. nurture of stem cells,” and she has just the tool to investigate that question. She and her lab made news around the world last year when they used a detergent to rinse away the heart cells from a cadaver rat heart, leaving behind the extracellular matrix. On the remaining scaffold, the team then rebuilt beating muscle and blood vessels.

Since stem cells respond to cues from the environment they’re introduced to, researchers can use that extracellular matrix to understand how a stem cell perceives its mission. “Does it know where it came from,” Taylor poses, “or does it know what it should be?” The tool may also reveal whether stem cells act differently when introduced to an area where injury, like a heart attack, has occurred. By altering genes and cell markers, “we can learn what it takes to rebuild functioning tissue,” she says.

Taylor, who holds the Medtronic-Bakken Chair in Cardiovascular Repair, believes chronic disease and aging are basically failures of the body’s stem cells and also is working with her team to develop stem cell approaches to repair early aging-related injury.

Walter Low, Ph.D., professor and associate head of research in the Department of Neurosurgery, is working on tissue repair, too — in the brain. He and his team discovered a type of stem cell within human umbilical cord blood that has properties of multipotent stem cells (which can form cells of many kinds of tissue), and they are investigating whether these cells can restore brain tissue following an ischemic stroke, ultimately improving limb mobility.

They are also taking a close look at stem cells that cause damage rather than repair it. Two years ago, Low and John Ohlfest, Ph.D., assistant professor in the Department of Neurosurgery, identified and characterized mutated neural stem cells that are capable of causing brain tumors. These socalled cancer stem cells or brain tumor stem cells are the source of the selfrenewing cells within tumors, explains Low, who holds the Fesler-Lampert Chair in Aging.

The researchers developed a brain tumor vaccine that could destroy brain tumor stem cells, and recently, they obtained FDA approval to launch a phase 1 clinical trial to determine the safety of their brain tumor vaccine for patients with glioblastoma multiforme — a dire prognosis. The vaccine may eradicate the malignancy and, Low hopes, “other types of cancers where cancer stem cells are the source of the tumor.”

An eye to the future

The diversity of such top-level expertise throughout the University will ensure that the Stem Cell Institute remains internationally competitive over the next decade, notes Slack, holder of the Edmund and Anna Marie Tulloch Chair in Stem Cell Biology.

Slack, who came to Minnesota two years ago from Britain’s University of Bath, is internationally known for his discovery of the molecular cues that control embryonic development. His more recent work has focused on the basic science of regeneration — and specifically on how tadpoles can regrow the muscle and spinal cord of injured tails and the mechanisms whereby one cell type can change into another.

As the institute’s director, Slack is forging partnerships with scientists not only across the University but also beyond its walls. The Stem Cell Institute is working with researchers at the University’s Lillehei Heart Institute and the University of Wisconsin- Madison, for example, to study heart and blood progenitor cells to learn more about normal heart and blood development and investigate possible therapies using the progenitor cell populations.

Slack has also worked with University neurology professor John Day, M.D., Ph.D., director of the Paul and Sheila Wellstone Muscular Dystrophy Center, and scientists at the Katholieke Universiteit Leuven in Belgium to create a pig model of muscular dystrophy that will enable more accurate studies of cell therapy to treat the disease.

Other key partners include the Blood and Marrow Transplant Program and the University’s Molecular and Cellular Therapeutics Facility, which has the capability to grow large numbers of cells and the expertise to translate stem cells and their derivatives into therapies for patients.

“This is a very exciting moment,” Slack concludes. “The future of cell therapy is really limitless.”

By Kate Ledger

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Revised stem cell policies open new doors

In a White House ceremony last March, President Barack Obama signed an executive order to lift restrictions put in place by former President George W. Bush that cut off federal support for any research involving human embryonic stem cells except for lines that had been derived before August 9, 2001.

“[Scientists] are no longer restricted to the 62 lines of which only a portion was viable,” says University neurosurgery professor Walter Low, Ph.D., who studies the use of stem cells in nervous system repair. Many of those, Low says, were “grown in conditions that were not conducive to clinical studies.” Any scientist who created new lines of embryonic stem cells or collaborated on embryonic stem cell research had to do so with private funding.

The University of Minnesota designed strict procedures that allowed research to continue without any federal or state funds. Now, under the new federal policy, as many as 700 stem cell lines may be available, with the requirement that they must have been obtained with informed, voluntary consent by the donor.

“Embryonic stem cells will always have a fundamental role in stem cell research and development of novel therapies for a wide range of diseases,” says Dan Kaufman, M.D., Ph.D., associate director of the University’s Stem Cell Institute. These cells remain the gold standard by which to compare other stem cell populations. Even with the advent of new technologies, like iPS cells that can be created from skin, blood, or other cells in the body, he emphasizes that for the best possible science to evolve, “we need to be able to use all available tools.”

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Putting some muscle into her research

2009-10-01T17:15:46Z

For years, Rita Perlingeiro, Ph.D., has been looking for ways to use embryonic stem cells to improve muscle function. Now the University of Minnesota researcher’s findings could advance new therapies for muscular dystrophy, a devastating disease characterized by progressive degeneration of the muscles that control movement.

In a study published in the October issue of Experimental Neurology, Perlingeiro and her team showed that transplanting embryonic stem cells that have “specialized” into skeletal muscle stem cells into mice with Duchenne muscular dystrophy can restore function to defective muscles.

Making muscle cells from embryonic stem cells in a Petri dish isn’t easy to do, says Perlingeiro, an associate professor in the Division of Cardiology who also conducts research aimed at generating new cells to help the heart and blood vessels repair themselves. “We were seeing that muscle cells were inefficiently produced, and not enough of them were being produced to make muscle,” she says.

But using a gene called PAX3, Perlingeiro essentially “instructed” embryonic stem cells to make muscle cells instead of other cell types.

Once enough muscle cells were produced, Perlingeiro’s team injected them into the injured muscles of mice that have muscular dystrophy. Upon transplantation, the cells not only helped to grow muscle tissue but also improved muscle function. The strategy has proved effective for Duchenne and other forms of muscular dystrophy.

“The most exciting thing about this work is that what you are doing might help someone,” Perlingeiro says.

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Major grant funds stem cell research collaboration

2009-10-01T15:54:46Z

Donor support and current technology help draw federal funds

Most major medical discoveries don’t happen in a single lab; they result from close collaboration across multiple institutions, often over many years. That’s why it was big news when University of Minnesota researchers learned in October that they had received a seven-year collaboration grant to help develop the high-potential field of stem cell therapy.

Under the grant, awarded by the National Heart, Lung, and Blood Institute (NHLBI), one of the National Institutes of Health, University researchers will partner with a research team from the University of Wisconsin-Madison to understand how and when stem cells commit to becoming a certain type of blood cell.

“What we want to know is, how do various stem cells decide to become blood or heart or blood vessels? How can you enhance that process so it becomes highly efficient and produces a large number of those cells?” says Daniel J. Garry, M.D., Ph.D., executive director of the Lillehei Heart Institute and leader of the University’s research team.

Scientists are already able to coax stem cells into becoming specific types of cells, Garry says, but they aren’t yet able to make enough cells to potentially treat a human patient.

The collaboration award provides each institution with $750,000 per year and brings together researchers from the heart, lung, blood, and technology research fields. Scientists from partner institutions will meet several times a year to exchange ideas and talk about how they can accelerate one another’s work.

Sixteen other universities throughout the country, forming eight more partnerships, have received similar awards from the NHLBI.

The award not only provides University investigators with a steady source of funding for this research, Garry says, but it also connects them with other leading stem cell labs across the country.

“The point of these networks is to foster collaborations not only with your partner but across the entire network,” he says.

Jonathan Slack, Ph.D., director of the University’s Stem Cell Institute, was a pivotal partner in identifying ways to leverage the University’s strengths and providing the foundation for a standout grant application, Garry says.

“This was a golden opportunity for us,” Slack says. “We already had expertise in embryonic stem cell/iPS cell biology, hematopoietic development, cardiac development, decellularized organs, cell transplantation, and imaging technology — in other words, all the technology required.”

Philanthropy is another reason behind the University’s grant success. Last year the Engdahl Family Foundation funded an interdisciplinary study by cardiology professor Jay Zhang, M.D., Ph.D., and stem cell scientist Dan S. Kaufman, M.D., Ph.D., aimed at identifying which factors are important in promoting cardiac regeneration. That study provided enough preliminary data to make the University a strong contender for the NHLBI grant, Garry says.

“Gifts that support novel research ideas often set the table for our scientists to later earn much larger grants from agencies such as the NHLBI,” he says. “A gift to start-up research like this often gets a huge return on the donor’s investment.”

And, thanks to the exchange of tools and information through the NHLBI-funded collaboration, the return on investment is only likely to grow.

To make a gift to heart research at the University of Minnesota, visit www.mmf.umn.edu/heartlung or contact Julie Crews Barger at 612-273-8593 or j.barger@mmf.umn.edu.

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Major grant funds stem cell research collaboration

2009-01-01T18:14:29Z

Most major medical discoveries don’t happen in a single lab; they result from close collaboration across multiple institutions. That’s why it was big news when University of Minnesota researchers learned in October that they had received a sevenyear collaboration grant to help develop the high-potential field of stem cell therapy.

With the grant from the National Heart, Lung, and Blood Institute (NHLBI), University researchers will partner with a research team from the University of Wisconsin-Madison to understand how and when stem cells commit to becoming a certain type of blood cell.

“What we want to know is, how do various stem cells decide to become blood or heart or blood vessels? How can we enhance that process so it becomes highly efficient and produces a large number of those cells?” says Daniel J. Garry, M.D., Ph.D., executive director of the Lillehei Heart Institute and leader of the University research team.

The collaboration award provides each institution with $750,000 per year and brings together researchers from the heart, lung, blood, and technology research fields. Scientists from partner institutions will meet several times a year to exchange ideas and discuss how they can accelerate one another’s work.

Jonathan Slack, Ph.D., director of the University’s Stem Cell Institute, was a pivotal partner in identifying ways to leverage the University’s strengths to make a standout grant application, Garry says.

Philanthropy is another reason behind the University’s grant success. Last year the Engdahl Family Foundation funded an interdisciplinary study by cardiology professor Jay Zhang, M.D., Ph.D., and stem cell scientist Dan S. Kaufman, M.D., Ph.D., aimed at identifying which factors are important in promoting cardiac regeneration. That study provided preliminary data that made the University a strong contender for the NHLBI grant, Garry says.

And thanks to the exchange of tools and information through the NHLBI-funded collaboration, the return on investment is only likely to grow.

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Help the University of Minnesota save lives, inspire hope, and prepare the world’s future health care leaders. Make a gift today.

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Alumnus's book provides a layperson's look at stem cell science

2008-10-01T20:57:15Z

As a career-long faculty member at the University of Minnesota Medical School, Leo Furcht, M.D., has had a front-row seat for many breakthroughs in stem cell science over the last few decades.

A resident in the Class of 1975, Furcht has conducted his own research on cancer stem cells. He also is a past president of the Federation of the American Societies for Experimental Biology, a national group of biomedical researchers that advocates for policies promoting research in this field.

While working with legislators in Washington to draft the Stem Cell Research Enhancement Act, he realized something: “There were lots of well-intentioned people who really didn’t know some of the important issues about embryonic and adult stem cells,” he says.

That realization inspired Furcht to write The Stem Cell Dilemma: Beacons of Hope or Harbingers of Doom? Released this year by Arcade Publishing, the book is meant to provide laypeople with an unbiased look at the pros and cons of stem cell research, says Furcht, who co-wrote the book with William Hoffman, a longtime University writer and editor.

Furcht, who is head of the Medical School’s Department of Laboratory Medicine and Pathology, is pleased with the book’s early success.

“It’s been received quite well,” he says. “We’ve received a number of reviews.” One of those was by Kirkus Reviews, which called the book a “[t]imely, levelheaded investigation of stem-cell medicine.” Other reviews are available at stemcelldilemma.com.

Furcht and Hoffman also recorded a one-hour “Book TV” feature for C-SPAN2 in April at the University of Minnesota Bookstore, the first time the bookstore’s author events program has been recorded for “Book TV.” They’ve done a few local media interviews as well.

As for upcoming media events? “I’m holding out for [Comedy Central’s] ‘The Colbert Report,’” Furcht says wryly.

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Family turns grief into hope with research fund

2008-10-01T19:16:37Z

When Jay and Lonni Mooreland of Folsom‚ Calif.‚ heard about the experimental epidermolysis bullosa (EB) treatment being developed at the University of Minnesota‚ they knew they wanted their infant daughter‚ Sarah‚ to have it.

They also knew the treatment would be risky. Only two other people had undergone the blood and marrow transplant (BMT) aimed at curing the devastating skin disease.

On top of that‚ 9-month-old Sarah had had some previous kidney and heart problems. But Jay and Lonni felt that the chance of curing Sarah’s EB was worth it. Without the transplant‚ there was a strong chance that Sarah would live a painful life and die of skin cancer in her teens or early 20s.

So the Moorelands moved their family across the country to Minnesota while doctors prepared Sarah for the BMT. But before she could receive the transplant‚ Sarah died from complications of the chemotherapy that preceded it. Doctors believe that her heart—while it appeared to be functioning well during tests—may have been predisposed to weakness because of her earlier heart problems‚ her parents say.

“While we are very saddened at her loss and sob daily for her‚ we felt the potential reward outweighed the risk‚” says Jay Mooreland. “We had to try—for her. If people don’t step forward and take the risk‚ doctors will never be able to improve upon their strategies.”

The Moorelands are taking another step to help University physician-researchers improve upon the EB therapy. They’ve created the Sarah Mooreland EB Fund to provide innovators John Wagner, M.D., and Jakub Tolar, M.D., Ph.D., with funding to continue their work.

So far‚ about 30 friends and family members have contributed $50‚000 to Sarah’s fund. Jay and Lonni themselves have given $28‚000 in Sarah’s honor.

“We know Sarah didn’t die in vain‚ but it helps to see how her death can influence others to donate‚” says Lonni. “Those donations help the doctors‚ which ultimately brings hope to other families where there wasn’t any before.”

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Small cells, big hopes

2008-04-01T21:02:05Z

After 40 years, the U continues to lead the charge against cancer and other disorders with lifesaving blood and marrow transplants

Packed into the hollows of your bones, pulsing through your arteries and veins, are millions of immature cells that play a very big role in keeping you alive.

Known as hematopoietic stem cells, or HSCs, these cells produce the blood cells that carry oxygen, keep you from bleeding to death, and defend you against incursions by bacteria, viruses, and other adversaries. HSCs are also the stars of blood and marrow transplantation (BMT), a lifesaving therapy that has given thousands of children and adults a new source of blood cells.

Forty years ago, University of Minnesota pediatrician Robert Good, M.D., Ph.D., made history when he performed the world’s first successful BMT using bone marrow taken from a matched sibling donor, saving the life of a baby boy with an inherited immune deficiency.

Since then, University researchers and clinicians have led the way in applying BMT to a variety of disorders. In 1975 physicians here performed the first successful BMT in a patient with lymphoma. Seven years later, the University was the first to use BMT to treat an inherited metabolic disease. In the 1980s researchers developed a protocol to use a patient’s own marrow to treat chronic myelogenous leukemia. And over the past decade and a half, University physician-researchers have pioneered the use of umbilical cord blood as a source of HSCs for transplant and improved the applicability and success of BMT in both children and adults.

And that’s just the beginning, says Daniel Weisdorf, M.D., professor of medicine and director of the adult blood and marrow transplant program.

“We’re still one of the major centers in the world,” he says. “We have a new generation of very able people in clinical and preclinical research. They’re going to take the program to the next phase of success in the next 10 years.”

Multiple hurdles

In October 2006, Valerie Rosenberg’s immune system gave out. The marrow inside the 27-year-old sculptor’s bones stopped producing sufficient blood cells to carry oxygen, halt bleeding, and fight infection.

The good news? Rosenberg had recently moved to the Twin Cities. Her mom, who lives in Boston, had suggested she go to a clinic attached to a major hospital; her boyfriend happened to have a parking pass for the University of Minnesota Medical Center, Fairview. Seemingly by chance, and certainly by good fortune, Rosenberg ended up at one of the world’s premier BMT centers.

Six weeks after a diagnosis of myelodysplastic syndrome, Rosenberg underwent chemotherapy and total body irradiation to destroy the remnants of her own failing marrow. She then received an infusion of HSCs from her older brother, Mike. That was followed by months of uncertainty as the donated cells and her body struggled to get along. But she made it through—thanks, she says, to the expertise she found at the University.

“I was so lucky to be right where I was,” Rosenberg says.

BMT is conceptually simple: out with the bad HSCs, in with the good. In practice, it’s a complex and uncertain process involving multiple hurdles. Among the first is finding a suitable source of donor cells. Next, doctors must figure out just the right mix of chemotherapy and radiation to destroy the patient’s own HSCs and suppress the immune system (to avoid rejection) while minimizing damage to other tissues. After the transplant, the focus is on coaxing the body and new cells to accept one another. Meanwhile, the body must endure the temporary absence of an innate source of immune, clotting, and oxygen-carrying cells. The process of devising and refining each of these steps has required—and continues to require—enormous amounts of research.

Expanding the universe

One area in which University researchers are making exciting inroads is finding, and fine-tuning the use of, novel sources of HSCs. In some cases, certain of the patient’s own HSCs can be removed and reimplanted after treatment. More often, HSCs come from the bone marrow or blood of a donor whose cells are compatible with the recipient’s. Rosenberg was one of the lucky ones: She had a sibling whose cells matched hers closely enough to serve as a source of HSCs. But one out of four patients needing a BMT can’t find adequately matched blood or marrow from a donor.

In the 1990s University researchers played a key role in introducing what has become an increasingly important source of HSCs—umbilical cord blood. Recently, research led by John c, M.D., professor and director of pediatric hematology-oncology and blood and marrow transplantation, showed that for some types of leukemia a transplant of imperfectly matched cord blood works as well as, if not better than, matched bone marrow.

“This study suggests that cord blood need not be considered a second-line therapy any longer,” Wagner says. “The fact that cord blood is banked and readily available with little notice is a great advantage. Now, the timing of transplantation can be dictated by the patient’s needs as opposed to the availability of matched bone marrow.”

The University of Minnesota also pioneered the use of blood from two umbilical cords in the treatment of adult patients. The double transplant not only provides the quantity of HSCs an adult needs but also appears to boost the immune system—a bonus doctors had not anticipated, Weisdorf says.

University innovations in the ways patients are prepared for transplant are making BMT an option for more patients. Until recently, individuals who had other illnesses, were elderly, or were weak from cancer therapy were not considered candidates for BMT because of concerns they could not withstand the required chemo- and radiation therapy.

But recent research has led to a reduced-intensity protocol that makes such transplants possible with less severe chemotherapy and radiation therapy preparation. Last fall, Claudio Brunstein, M.D., Ph.D., assistant professor of medicine, reported success using reduced-intensity preparation for transplant with blood from two partially matched umbilical cords to treat patients with leukemia or lymphoma who otherwise might have been in-eligible for transplant. The procedure, known as the “Minneapolis regimen,” will be tested in a national multicenter trial beginning this summer.

“We are getting good engraftment and survival in people we would have turned down a few years ago,” Weisdorf says.

Researchers are also stretching the boundaries of BMT by using natural killer (NK) cells to knock stubborn cases of leukemia into remission so the patient can undergo transplant. NK cells cruise the bloodstream killing viruses and cells that seem foreign to them. Because cancerous cells are actually “self” cells gone bad, NK cells don’t always recognize them as invaders.

“About 10 years ago I was thinking about these cells, and I realized that NK cells from a partially matched donor might be able to do the job on leukemic cells that a person’s own NK cells can’t,” recalls Jeffrey Miller, M.D., professor of medicine and associate director of the Masonic Cancer Center, University of Minnesota.

He began testing his hypothesis, with promising results. Eight years ago, after extensive research, Miller and colleagues began clinical trials using donor NK cells to prepare patients with acute myelogenous leukemia for BMT.

“So far, 10 of the 32 patients receiving NK therapy have gone into remission,” Miller says. Buoyed by the success, researchers are now developing protocols for mobilizing donated NK cells against other cancers, including non-Hodgkin’s lymphoma and breast and ovarian cancer. They also have completed the first clinical trial using NK cells from cord blood, are looking at ways to combine NK treatment with BMT in a single procedure, and are working to increase the sensitivity of cancers to NK cells.

“Our goal is to take what we learn in patients back to the research laboratory to test new ideas that optimally exploit NK cells as cancer therapy,” Miller says.

Safer transplants

A major complication of BMT is graft-versus-host disease (GVHD), in which donor cells attack the recipient’s tissue. Occurring in about two-thirds of BMTs, GVHD is responsible for one-third of deaths after transplant.

In hopes of reducing GVHD, Bruce Blazar, M.D., professor and section chief of pediatric blood and marrow transplantation, has turned his attention to regulatory T cells, or T-regs. Present in the blood in minute quantities, T cells act as a natural brake on immune reactions.

“The idea arose from rodent studies in our laboratory that showed donor T-regs could control adverse immune response,” says Blazar, holder of the Andersen Chair in Transplantation Immunology.

Researchers led by Brunstein recently began a clinical trial to find out whether infusing T-regs with BMT diminishes GVHD. So far, the results are promising.

“If [the use of T-regs] reduces the prevalence of GVHD and doesn’t blunt the transplant effect, it would make transplant substantially safer,” Weisdorf says. “This is the first trial actually testing how to do this in people. We’re leading the pack because of work in Bruce Blazar’s lab.”

Blazar hopes to improve BMT in other ways as well. “We would like to find new approaches to reduce … injury to critical organs, such as the thymus and lung, and reduce relapse rates after BMT,” he says. “In addition, we plan to examine new approaches to preventing or repairing tissue injury using protein-, gene-, or cell-based therapies.”

Meanwhile, Jakub Tolar, M.D., Ph.D., assistant professor of pediatrics, is studying ways to use selected HSCs to boost recovery from the chemotherapy and radiation patients must undergo to prepare for BMT.

Beyond cancer

Cancers are the conditions most commonly treated with BMT. But physicians also use BMT to treat patients with genetic disorders characterized by the inability to make certain proteins. Known as inherited metabolic and storage diseases, these rare ailments cause bodily functions to deteriorate as toxic substances build up in the absence of the enzymes that Break them down. Depending on the enzyme involved, these diseases can lead to lethal dysfunction of various organs, including the brain.

Researchers discovered in the 1980s that, in some cases, transplanted HSCs can supply the missing enzyme. Today University physicians perform nearly two transplants a month for a variety of metabolic and storage diseases, including osteopetrosis, which causes debilitating thickening of the bones; inherited leukodystrophies, which damage the brain; and Hurler syndrome, which affects a number of organs.

The availability of cord blood is a boon to this type of treatment because these diseases are often rapidly progressive—tragic deterioration can occur in the time it takes to find and obtain cells from a suitable marrow donor.

“We’ve made a lot of recent advances in how we’re doing transplants, so the outcomes have improved,” says Paul Orchard, M.D., associate professor of pediatrics and medical director of the inherited metabolic and storage disease bone marrow transplantation program.

The University’s BMT program made national news last fall when Wagner treated Nate Liao, a toddler from New Jersey, with stem cells to correct a life-threatening skin disease called recessive dystrophic epidermolysis bullosa (EB). EB is a genetic disorder in which the protein that anchors skin and lining of the gastrointestinal tract to the body is missing, so the tissues come off with minimal trauma—just coughing or walking, for example. Tolar, Blazar, and Wagner had previously demonstrated in animal studies that BMT might be able to help correct the disorder. In just one year, Wagner and colleagues translated this novel approach into a treatment for people with EB.

“This is just one more example of how basic investigators and clinicians can work together to develop life-saving new therapies,” says Wagner, who holds the Variety Club Chair in Molecular and Cellular Therapeutics, the Children’s Cancer Research Fund Hageboeck Chair in Pediatric Oncology, and the McKnight Presidential Chair in Hematology and Oncology. “While not all such treatments will work in humans, stem cell research brings hope to hundreds of thousands of children and adults with life-threatening, debilitating diseases. We are on the verge of a medical revolution.”

By Mary Hoff

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Companion story: California family finds Minnesota the right place to be

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Cord blood results surpass bone marrow transplant outcomes for leukemia

2007-10-01T21:58:39Z

After analyzing clinical data from transplant centers around the country, University researchers reported in June that umbilical cord blood transplants may offer blood cancer patients better outcomes than bone marrow transplants, previously considered the gold standard.

The study, which appeared in the June 9, 2007, issue of The Lancet, compared outcomes of pediatric leukemia patients who received bone marrow transplants from unrelated donors with those who received umbilical cord transplants. While all bone marrow donors were matched, nearly all cord blood donors were mismatched.

Investigators found that mismatched cord blood performed as well as matched bone marrow, as measured by leukemia-free survival rates, as long as the degree of mismatch was limited and the number of cord blood cells available was sufficient.

Participants who received matched cord blood had a 20 percent higher survival rate than matched bone marrow recipients, although the number of matched cord blood transplants was small.

“This study suggests that cord blood need not be considered a second line of therapy,” says lead investigator John E. Wagner, M.D., professor of hematology-oncology and blood and marrow transplantation at the University. “Today, leukemia patients can wait months for an appropriately matched bone marrow donor, during which time their disease might return. Now, the timing of transplantation can be dictated by the patient’s needs as opposed to the availability of matched bone marrow.”

The study involved extensive analysis of clinical data reported by U.S. transplant centers to the Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, and the New York Blood Center. The analysis included transplant outcomes in 785 children younger than 16 who had been diagnosed with acute lymphoblastic leukemia or acute myeloid leukemia.

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A legacy of leadership

2007-10-01T21:56:08Z

Still committed to improving patient care, John Kersey, M.D., returns to research full-time after 15 years as Cancer Center director

For many years, John Kersey, M.D., has been the face of the University of Minnesota Cancer Center. Both as a groundbreaking researcher and as the center’s founding director, he played a key role in bringing together researchers and clinicians from across the University to transform cancer research and patient care.

So when Kersey stepped down as director in March, his colleagues thought they knew why.

And they were right. Kersey traded his directorship and seventh-floor corner office in the Masonic Cancer Research Building for a smaller office a couple of floors down so he could devote more time to his longtime love: research.

“John has always been very devoted to his research, and obviously he still is,” says pediatrics professor emeritus Norma Ramsay, M.D., who first worked with Kersey in the 1970s. “This move is a logical extension of his career that will benefit both John and the Cancer Center.”

In fact, Kersey will remain a familiar face on the seventh floor—the site of his laboratory since the Masonic Cancer Research Building opened in September 1996. The same man who led the team that performed the world’s first successful bone marrow transplant for treating lymphoma hopes to discover better treatments for childhood leukemia and lymphoma.

“To be a part of the team that is hoping to remove cancer from the earth is very exciting,” says Kersey, who holds the Children’s Research Fund Land-Grant Chair in Pediatric Oncology.

Although his leadership of the Cancer Center required countless hours of meetings and administrative duties, Kersey—known for his quiet, methodical style—always made time for research. In fact, being an administrator was never really part of Kersey’s career plan, though it’s certainly part of his legacy.

Today the Cancer Center is not only one of just 39 National Cancer Institute-designated Comprehensive Cancer Centers, it is also home to more than 400 members and receives more than $90 million annually in research funding.

More important, it has provided a place for researchers to share ideas and build on one another’s work. Interdisciplinary research initiatives in the Cancer Center have led to major breakthroughs in bone marrow transplantation as well as in breast, bone, childhood, and tobacco-related cancers

“John was the person who brought all these people together,” says Stephen Hecht, Ph.D., a leading researcher in tobacco-induced cancers whom Kersey recruited to the University of Minnesota. “This is a very collaborative center now, and the director gets the credit for that.”

Homegrown talent

Kersey has devoted his entire medical career to the University of Minnesota. Born and raised in the Twin Cities, Kersey graduated from the Medical School in 1964. He then completed residencies in pathology and pediatrics here before joining the faculty of the Departments of Pediatrics and Laboratory Medicine and Pathology in 1971.

In 1974, Kersey became director of the Blood and Marrow Transplant Program. The following year, he led the team that performed the world’s first successful bone marrow transplant for treating lymphoma, on 16-year-old David Stahl.

“Back then, with the word ‘cancer’ you thought ‘death,’” says Stahl, now a father and technical illustrator working in Golden Valley, who is believed to be the longest-living survivor of malignant lymphoma. “Dr. Kersey saved my life.”

Despite these successes, Kersey believed he and other cancer researchers could do more. Cancer research was being conducted in many different departments and schools across the University, but the researchers weren’t working together.

“There was no cohesiveness, no multidisciplinary approach to care or research,” he says. “We often worked in independent silos, and information wasn’t being shared among basic scientists, clinicians, and epidemiologists.”

Shaping a cancer center

In the 1980s, Kersey began talking to his colleagues and then-Medical School Dean David M. Brown, M.D., about creating a cancer center to bring researchers and their ideas together.

“I didn’t have any idea who should be in charge of it,” says Kersey. “I just knew that our research would benefit if more people interacted with each other.”

Brown was committed to the idea early on, but there was resistance from some faculty and the University as a whole. “Most people said, ‘Show me. Show me that’s better,’” says Kersey. “Occasionally, people said, ‘We don’t really need it.’ And I think they were wrong. We did need it, and we still need it.”

Finally, after years of discussions, the idea for a cancer center garnered support, and the board of regents approved it in 1991.

Brown quickly zeroed in on Kersey to lead the new Cancer Center. After a national search, Brown says Kersey was the clear front-runner.

“John was an outstanding and renowned scientist whose cancer research continued to be cutting-edge over several years, and he was highly respected by his colleagues at the University and nationally,” Brown says. “I knew he had the leadership skills to unite the faculty and to gain the support of the community, the University, and the National Cancer Institute.”

Tucker LeBien, Ph.D., associate director of basic research at the Cancer Center, has known Kersey for 30 years. Lebien attributes much of the Cancer Center’s success to Kersey’s “people savvy.”

“John’s legendary skill is listening to what people are interested in and then pulling them together to work toward a common goal,” says LeBien, holder of the Apogee Enterprises Chair in Cancer Research. “I’ve never witnessed anyone who is as good at that as he is.”

Longtime Cancer Center supporter Barbara Forster says his combination of world-class research credentials and exceptional interpersonal skills have made Kersey a revered leader.

“While he is very clear about the direction and the principles on which the Cancer Center is founded and guided, he is extremely collegial,” says Forster, who currently chairs the Cancer Center Community Advisory Board. “People simply want to work with him.”

Building a winning team

After the Cancer Center’s initial funding was in place, the need for a new research facility to attract top-notch researchers became apparent. Thanks in part to funding from the Masons of Minnesota, the Masonic Cancer Research Building was constructed with more than $30 million in philanthropic support, becoming the first building on campus to be constructed entirely through private dollars.

With this state-of-the-art space as a selling point, Kersey began to assemble an all-star cast of researchers. Hecht was the center’s first major external recruit.

“John impressed me as this open, honest guy, in the true Midwestern spirit,” says Hecht, who holds the Wallin Land-Grant Chair in Cancer Prevention—the first of 15 endowed chairs established in the Cancer Center—and the American Cancer Society Research Professorship. “I liked him immediately. If I hadn’t liked or trusted him, I don’t think I would have come.”

Then Kersey recruited David Largaespada, Ph.D., out of postdoctoral training to lead the center’s research in cancer genetics and to assume the Margaret Harvey Schering Land-Grant Chair in Cancer Genetics.

Douglas Yee, M.D., a nationally renowned breast cancer physician-scientist, was next. Kersey calls Yee, who is the new Cancer Center director, one of his best recruits.

“Part of the reason I came here is because of John Kersey’s efforts to bring laboratory findings to patients,” says Yee, who holds the Tickle Family Land-Grant Chair in Breast Cancer Research. “I think that’s why we all do what we do—we really want to affect the outcome of the disease.”

A reason to celebrate

By the late 1990s, Kersey’s vision for a collaborative Cancer Center was becoming a reality. Leaders were ready to apply for an NCI core grant and for designation as a Comprehensive Cancer Center.

Many cancer centers have struggled for years to get that designation, but LeBien says the University was “spectacularly successful” on its first try, in 1998.

“We popped the cork on a champagne bottle I’d had on my shelf for a long while,” Kersey says.

Since then, the Cancer Center has achieved international prominence in cord-blood transplantation and has discovered techniques to more efficiently identify cancer genes. Its members have created the first animal model for studying and disabling cells responsible for bone cancer pain, identified cancer-causing substances in tobacco, and initiated studies on how genetics, diet, lifestyle, family history, and other factors affect the risk of developing breast and gynecologic cancers.

Their work contributed to research that has led to a significant increase in childhood cancer survival rates—from about 10 percent in 1959 to better than 85 percent today. They also have participated in a prominent long-term follow-up study on medical and social issues faced by survivors of childhood cancer.

A shift in focus

Kersey isn’t totally out of administration yet. In addition to his research responsibilities, he’ll serve the Cancer Center as founding director emeritus, providing a historical perspective and serving as a consultant to Yee and other Cancer Center leaders.

But Kersey is glad to return to his roots in research. He recently led a research team that developed the first mouse model with the gene for acute lymphoblastic leukemia, a rare and frequently fatal form of blood cancer that most often occurs in babies less than a year old. Kersey hopes this model will help his team develop better, safer treatments for the disease.

He has set other priorities as well. “Fishing and grandkids…no golf,” Kersey says. “The grandkids are my top priority. They are the most enjoyable of all.”

He’s also looking forward to spending more time with his wife, Anne, at their log house on Lake Superior, where they’ll hike and explore the great outdoors.

But he’s certainly not ready to retire. Not yet.

“I really like the stimulation of an environment with a lot of students and young people and enthusiasm for ideas,” Kersey says. “That’s an important part of my psyche.”

By Nicole Endres

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