Health Sciences Report Winter 2005

The Hard Science of Stem Cells-
Utah Researchers Make Major Progress Amid Political, Technological Debates

By Phil Sahm
Photos By Steve Leitch

Amid the national disagreement over the ethics and bounds of stem cell research, one point doesn't raise much argument: stem cells hold the potential to revolutionize medicine.

Scientists worldwide see in stem cells the possibility to regenerate diseased organs and tissue; the ability to genetically model and even cure or prevent diseases, such as Parkinson's and diabetes; and a way to understand the most complex processes and mechanisms of the brain and body.

"There is no question the value is going to be huge," said Raymond F. Gesteland, Ph.D., University of Utah vice president for research and distinguished professor of human genetics at the School of Medicine. "But there's a lot of hard science to be done."

Although the use of embryonic stem cells (ESC) has captured the headlines since Aug. 9, 2001, when President George W. Bush restricted federal funding of research to the use of 22 already developed lines, U of U researchers using so-called "adult" stem cells and approved ESC lines are making major progress. In August, U cardiothoracic surgeon G. Russell Reiss, M.D., who also practices at the George E. Wahlen Department of Veterans Affairs (VA) Medical Center, received U.S. Food and Drug Administration (FDA) approval to begin one of the nation's fi rst clinical human trials to directly inject adult stem cells into the hearts of patients undergoing coronary bypass surgery. U and VA kidney specialist Christof Westenfelder, M.D., also hopes to begin human clinical trials in Europe next year using adult stem cells to reverse acute renal failure.

In the basic sciences, U researchers are studying stem cells to understand blood development and to learn how stem cells give rise to normal biological development.

Use of stem cells already has transformed medical and biological research through gene targeting, developed in large part by worldrenowned U geneticist Mario R. Capecchi, Ph.D., distinguished professor of human genetics and co-chair of the Department of Human Genetics. Capecchi used mouse embryo-derived stem cells to develop the ability to disable, or knock out, individual genes and thus reveal details about their function. Researchers worldwide now use this knockout mouse technology to study and model countless diseases.

Even with the range of research taking place at the U and nationwide, many scientists worry that, because of restrictions on federal funding for ESC research, the United States has fallen behind other countries in a field that has seen explosive progress.

"We're a little bit hobbled in this country right now in what research we can do," said Gerald J. Spangrude, Ph.D., U professor of internal medicine, who in 1988 isolated stem cells in the bone marrow of mice while a postdoctoral fellow at Stanford University. "Current stem cell lines are of limited research value, because they were derived from techniques developed five or six years ago."

Gesteland, Spangrude, and other U scientists are quick to note that Utah Sen. Orrin Hatch has been a staunch proponent of stem cell research, including the expansion of embryonic cell lines. Five years ago, Hatch spent a day at the U's Eccles Institute of Human Genetics familiarizing himself with the basic science of the issue and has since pushed for federal funding and research support. He also sponsored legislation to set up a national network to let people bank umbilical cord blood, a rich source of adult stem cells.

Earlier this year, the U.S. House of Representatives passed legislation to expand embryonic stem cell research; the Senate is expected to debate a bill in the next couple of months. The issue gained momentum in the Senate last summer when Majority Leader Bill Frist, R-Tenn., himself a cardiac surgeon, reversed his position and came out in favor of limited expansion of ESC research. President Bush, however, has said he'll veto any legislation to fund expanded ESC research with federal money.

The University's research into stem cells began with the start of the Blood and Marrow Transplant (BMT) program about 15 years ago, according to hematologist James P. Kushner, M.D., distinguished professor of internal medicine and chief of the Division of Hematology/BMT. The U received a grant to set up a Center of Excellence in Microbiology, and Spangrude, who received his Ph.D. in experimental pathology from the U, was recruited from the National Institutes of Health to lead the effort.

The BMT program performs up to 150 bone marrow transplants a year in cancer patients whose hematopoietic stem cells, those that form blood cells, have been destroyed by high doses of chemotherapy and radiation, according to Finn Bo Petersen, M.D., professor of internal medicine in the Division of Hematology and BMT director.

The U was one of the first BMT programs to show that, when patients receive a bone marrow transplant, their new immune system identifies antigens to fight tumors. This is called Graft-versus-Tumor Effect, and Petersen is conducting research to identify the difference between that and Graft vs. Host Disease, in which the patient's own cells do not recognize and will not accept the transplanted stem cells, which can lead to rejection of the transplant.

Although BMTs are most commonly used for leukemia and lymphoma patients, the U is expanding the use to include people with kidney and breast cancers. The program has treated a number of kidney cancer patients with good results, according to Petersen. So far, three breast cancer patients have received BMTs: one patient did not survive; a second one is two years in remission; and a third is still early in the process. Petersen would like to use bone marrow transplants for people with lung, prostate, ovarian, and other cancers, but insurance companies won't pay for those procedures, because they would be considered investigational, he said.

Along with bone marrow, the U program also transplants umbilical cord blood into children with cancer. Petersen envisions the day when cellular therapy is widely used, to the point that oncology centers will have generic stem cells to give to cancer patients.

Today, U of U researchers in hematology, genetics, neurobiology, microbiology, nephrology, cardiology, and other disciplines are studying stem cells.

The U also is home to a stem cell laboratory started in 1990 to collect and enrich stem cells for the BMT program. Headed by Linda L. Kelley, Ph.D., associate professor of internal medicine in the Division of Hematology/BMT, the lab recently underwent a $1.3 million expansion in Research Park and now is known as the Utah Center for Cell Therapy.

Stem cells are like tiny factories that have the ability to divide and replicate themselves endlessly. When a stem cell divides, it forms two daughter cells. Each daughter can remain a stem cell or become a specialized cell. When a stem cell receives certain biochemical signals, it transforms into blood, fat, muscle, bone, or essentially any part of the body.

Stem cells are broadly categorized as embryonic (ESC) or adult. ESCs usually are taken from a blastocyst: a group of 100-150 cells formed less than a week after a human egg is fertilized. Stem cells in the blastocyst are pluripotent, meaning they can develop, or differentiate, into any cell in the body.

By about the third week in development, stem cells begin to differentiate into three layers in the embryo from which a fetus will develop: the endoderm (inner layer), which gives rise to cells that form the pancreas, liver, lungs, and other organs and tissue; the mesoderm (middle layer), which produces cells for bone marrow, blood vessels, skeletal, smooth, and cardiac muscles, and other tissue; and the ectoderm (outer layer), from which the brain, skin, eyes, ears, and other parts of the body develop.

The ability to differentiate into any cell in the body makes ESCs potentially valuable for medical therapy. Although most ESCs are extracted from unused embryos created by in vitro fertilization, another highly technical and controversial process, somatic cell nuclear transfer, has been developed to clone human embryos as a source of ESCs. A group of South Korean researchers recently announced finding an efficient way to accomplish this, which may lead to the ability to `produce ESCs in the laboratory. But this process also raises the specter of cloning human embryos and ensuing ethical questions.

"Adult" stem cells--a term some scientists find misleading, because certain types of these cells can come from fetuses--are specialized cells that lie dormant in organs or tissue, such as the brain, muscle, and bone marrow. An injury or disease triggers them to activate, or be mobilized from the bone marrow, from where they can reach injured organs via the circulatory system. Adult stem cells in organs can be harder to isolate than ESCs, and, because they are already differentiated into specialized cells, are thought by some to have less potential therapeutic value than ESCs.

Two U of U physicians, however, see lifesaving potential in adult bone marrowderived stem cells for millions of people, right now, who suffer from two common and deadly illnesses: kidney and heart diseases.

Cardiothoracic surgeon G. Russell Reiss, M.D., is preparing to start Phase I of, ultimately, a 92-patient clinical trial using adult stem cells to rejuvenate heart muscle in patients with coronary artery disease and associated left ventricle dysfunction. In these patients, the heart doesn't pump enough blood with each beat: a condition known as depressed ejection fraction.

Reiss, visiting instructor of surgery at the U medical school, is clinically based at the VA, and is principal investigator for the clinical trial entitled "Stem Cell Therapy as Adjunct to Revascularization: STAR." Also referred to as the STAR Trial, it was granted federal funding through the U.S. Department of Veterans Affairs in 2003. Because stem cells are regulated by the FDA, Reiss has been working closely with the Center for Biologic Evaluation at the FDA for nearly two years to gain Investigational New Drug approval to begin the STAR Trial. David A. Bull, M.D., U cardiothoracic surgeon and associate professor of surgery, is a co-investigator on the trial, along with Utah Center for Cell Therapy director Kelley.

"I am confident this is going to be, at least, a powerful adjunct to conventional therapy, if not replace it in the long run," Reiss said.

Reiss' own studies with animal models have shown adult stem-cell injections into the damaged heart reduces the deleterious dilation that occurs with cardiac injury by up to 22 percent, allowing the left ventricle to pump blood more efficiently with each heartbeat.

In the upcoming STAR Trial, patients will have bone marrow aspirated from their hips, just prior to being sedated for surgery. While a vein is taken from the leg and used to bypass obstructed arteries in the heart, the marrow will be rushed to the U of U cell therapy facility. Kelley's team will process the bone marrow for adult stem cells, which takes about three hours. Once the stem cells are isolated, they will be returned to Reiss' team in the operating room to be injected directly into the patient's heart before surgery is finished.

STAR Trial investigators could be the first in the United States to inject stem cells directly into the hearts of coronary bypass surgery patients. In this country, stem cells have been injected into the heart through catheters, but they have never been injected directly into the heart of coronary bypass patients as Reiss and Bull plan to do.

It's not known exactly how stem cells function to rejuvenate heart muscle, but Reiss theorizes that they rescue damaged cells from apoptosis, a process in which tissue undergoes cell death in response to injury.

In hearts more severely damaged by heart failure, a Left Ventricular Assist Device (LVAD) often is needed until the patient can receive a transplant. Bull, with Reiss and their colleagues at the U, are planning clinical trials to inject stem cells into the heart when an LVAD is implanted. Repair of heart tissue following the combined LVAD/cell therapy procedure will take place over weeks to months, after which some patients may not need a heart transplant if the stem cells reverse the heart failure.

"This is a lofty goal, but if we can stop people from dying while they wait on the heart transplant list, it's every bit worth focusing our efforts as a team to achieve this aim," Reiss said.

Medication and technology have prolonged the lives of many people with ischemic heart disease; but today's drugs and present technology have gone as far as they can to help these patients, according to Reiss. "Since 1953, when the first heart-lung machine was developed and used for open-heart surgery, there has been very little science in the operating room and cath lab in terms of how we treat ischemic heart disease," Reiss said. "Cell therapy has introduced the paradigm shift we have been waiting for, and has birthed the new field of regenerative medicine. Stem cells could be the long-awaited therapy that treats heart disease at both the molecular and cellular levels."

While Reiss focuses on using stem cells to repair diseased hearts, Christof Westenfelder, M.D., a kidney specialist, professor of internal medicine, and chief of nephrology at the VA Medical Center in Salt Lake City, is using stem cells taken from bone marrow to repair kidneys in mice and rats with acute renal failure.

"The United States spends $17 billion a year on patients with sepsis, often with multi-organ failure, including acute renal failure," he said. "In this setting, or when patients have severe acute renal failure, there is essentially no effective therapy that is able to reduce the unacceptably high mortality rate of 50-80 percent. This problem prompted us to focus our research on this unresolved clinical problem."

When an organ such as the kidney or heart suffers injury, biochemical signals are sent that activate stem cells from the bone marrow, which home to the sites of injury. This response suggests that mobilized stem cells support tissue repair. But in severe or multi-organ failure, according to Westenfelder, the body's intrinsic repair mechanisms, including mobilization of stem cells, are obviously inadequate for repair and patient survival. Based on this hypothesis, Westenfelder postulated that boosting the numbers of stem cells delivered to severely injured kidneys or other organs should improve the ability of these organs to recover. Westenfelder, who works with one of the largest BMT groups in Europe, based at the University of Hamburg, Germany, uses mesenchymal stem cells, which "professionally" form cartilage, bone, muscles, and other mesodermal tissues. After extracting the cells from bone marrow, Westenfelder cultures, expands, and purifies them in the laboratory. Then, using a sterile solution, he injects 1.5 million mesenchymal stem cells through an arterial catheter into rats with severe ischemic acute renal failure.

The success in the laboratory has been highly reproducible, with treated animals experiencing marked improvement in kidney function. Depending on which treatment protocol and acute renal failure model is used, kidney function returns almost immediately and continues to improve rapidly in the following days.

"The early success with our stem cell-based therapy has placed us ahead of most competing laboratories," said Westenfelder, who is corresponding author on a major paper of the study published last July in the American Journal of Physiology-Renal Physiology. A number of other publications from Westenfelder's laboratory have identified the stem-cell mobilization and homing signals that are generated by the injured kidney and underlie the recruitment of these cells into the injured kidney.

Contrary to generally accepted concepts, the injected mesenchymal stem cells don't differentiate into kidney cells, according to Westenfelder. Rather, they change the course of the disease by delivering growth factors and by activating genes in surviving kidney cells that support the survival and repair of the kidney and, importantly, by powerful suppression of organ inflammation.

Westenfelder has identified one biochemical signal that triggers the release of stem cells to the kidney site. He's working to identify other signals, as well.

He and his European colleagues are developing protocols for human trials, including a "compassionate use" study with BMT patients who have little hope of recovery. If that trial is successful, Phase I and Phase II clinical trials with patients in severe kidney and multi-organ failure are planned at Utah and at other medical centers.

Westenfelder and Reiss both believe that federal restrictions on ESC research and the consequent lack of funding have hurt the U.S. effort in that area. With less federal funding, it's up to individual states to underwrite research. The most prominent example of this is California, where voters approved a $3 billion stem cell initiative last year. With that kind of financial backing, top scientists in the field may gravitate to California, the two researchers said.

While the political and ethical debates have swirled around ESC use for therapeutic reasons, scientists in basic research, like Maureen L. Condic, Ph.D., U associate professor of neurobiology and anatomy, study stem cells to answer fundamental questions of human biology. Using chicken eggs, Condic studies the neural crest, which consists of paired strips of stem cells that migrate throughout the embryo and differentiate into various cell types. The neural crest arises in the ectoderm, near the neural tubes.

By studying the neural crest Condic aims to answer two questions:

  • Once stem cells come into being, what controls their fate?

  • How do neural crest cells migrate as part of development?

She is researching a gene with the endearing name of Sonic Hedgehog (SHH) and bone morphogenic proteins (BMP). SHH plays a role in sensory neurons becoming muscle. BMP, which is important in the differentiation of many cells, may initiate the migration of cells from the neural crest and also influence neurons to become sensory neurons that grow into skin.

"The approach I'm taking is one of basic science: how these kinds of cells give rise to normal development," Condic said.

She believes environment helps determine cell fate. ESCs, for example, cause tumors in adults, but behave normally inside an embryo. That's because adult bodies don't provide the regulation that ESCs need. Conversely, adult stem cells placed inside an embryo have more plasticity, the ability to differentiate into other cells, than they do in adult bodies, according to Condic.

"Environment is a big influence in the way these cells become what they are," she said. "The rules and processes of how this happens are what's fascinating to me."

The potential impact of stem cells on medicine notwithstanding, Condic believes the expectations and emotions surrounding the debate over ESCs have advanced far beyond the current level of research and knowledge.

In August, Harvard researchers added to the discussion when they announced that they had discovered a way to fuse adult skin cells with existing ESCs, effectively coaxing the skin cells to reprogram into stem cells that act like ESCs. Their discovery opens the possibility of one day generating ESCs that don't come from an actual embryo. Whether this is a realistic hope probably won't be known for years, but that's the course of basic science, according to Spangrude.

"We don't know where we're going until we get there," he said. "But it's certain that if we don't do the research, we'll never find the answers and therapies will not occur."

In his current work, Spangrude uses both approved ESCs to study blood development during embryo formation and adult bone marrow stem cells from mice to understand how lymphocytes are generated. Lymphocytes are cells that arise in bone marrow and help the body's immune system. His work may shed light on how to make lymphocytes graft better in BMTs to help patients fight infection.

Spangrude also developed and patented a method for isolating mouse stem cells with a technique that uses fluorescent antibodies to label different types of cells. This enables him to isolate stem cells for study in the laboratory or in animal models to evaluate how stem cells function after treatments for inflammation or chemotherapy.

While stem cell science does present divisive issues, Spangrude believes proper oversight can ensure that universally accepted ethical standards aren't violated. Difficulties with the science itself also may prevent unethical research, he said.

Somatic cell nuclear transfer, for example, might have many clinical applications, but also could lead to the cloning of human beings. This process, however, in which a cell containing the DNA of a person or animal is placed into an egg that hasn't matured and doesn't have a nucleus, is dauntingly complex. Earlier this year a group of South Korean researchers cloned human ESCs and then a dog, but they failed many times before finding a method of somatic cell nuclear transfer that works 33 percent of the time.

Successfully cloning people would be even more difficult, Spangrude said, because the lack of gene regulation would prevent embryo development.

"People in the field believe it is out of the realm of reality that someone could clone a human being without being discovered," he said. "But using somatic cell nuclear transfer to develop ESC lines has real potential for research and clinical applications."

To ensure ESC research stays within ethical bounds, the National Research Council issued guidelines for members of the National Academy of Science, National Academy of Engineering, and the Institute of Medicine to follow. Among them is the recommendation that each institution create a review board to oversee ESC research and ensure that ESCs are obtained legally and ethically.

Spangrude fully endorses the guidelines and anticipates that state and federal funding of expanded ESC research will create even greater need for oversight.

"We need guidelines," he said. "But to block the research is going to really hurt future discoveries."

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