The Stem Cell Dilemma

The Scientific Breakthroughs, Ethical Concerns, Political Tensions, and Hope Surrounding Stem Cell Research

Leo Furcht, William Hoffman

• Publisher: Arcade
• Year: 2011
• ISBN:
  9781628721812
• Topic: Biowissenschaften
• Subtopic: Wissenschaftliche Forschung & Methodik

Today's scientists are showing us how stem cells create and repair the human body. Unlocking these secrets has become the new Holy Grail of biomedical research. But behind that search lies a sharp divide, one that has continued for years. Stem cells offer the hope of creating or repairing tissues lost to age, disease, and injury. Yet, because of this ability, stem cells also hold the potential to incite an international biological arms race. The Stem Cell Dilemma illuminates everything you need to know about stem cells, and in this new edition the authors have included up-to-date information on scientific advances with iPS cells, clinical trials that are currently underway, hESC policy that is in the U.S. courts, stem cells and biodefense, developments at the California Institute for Regenerative Medicine, and growing international competition, plus all the basics of what stem cells are and how they work.

Chapter One

AGENTS OF HOPE

Knowing is not enough; we must apply. Being willing is not enough; we must do.

—Leonardo da Vinci

Toward the end of his life, Leonardo da Vinci was a guest of King Francis I of France. Leonardo lived in the manor house at Cloux near the king's Amboise chateau in the Loire Valley. It was a pastoral setting that gave the artist time to reflect, put his notebooks and drawings in order, and make out his last will and testament. It is recorded that he asked his assistant Francesco Melzi to get a treatise for him, On the Formation of the Human Body in the Mother's Womb, by the thirteenth-century theologian Giles of Rome. Now, at the end of his life, Leonardo was thinking about how life begins.

Human reproduction had always fascinated him. In 1512, at the height of his powers, he drew The Fetus in the Womb.“The womb, split open like a burst seed-case, reveals the coiled fetus, shaped into compelling roundness by the rhythmic curves of his pen,” wrote Leonardo authority Martin Kemp in Nature. One of his most famous anatomical drawings, it depicted what he called “the great mystery,” a mystery in many ways more profound than the enigmatic smile on his Mona Lisa. With The Fetus in the Womb, the study of science, medicine, and human reproduction were brought to bear on that mystery. “The navel is the gate from which our body is formed by means of the umbilical vein,” he wrote. What Leonardo could not have imagined as he examined the umbilical cord attaching the fetus to the mother was that it is a treasure trove of stem cells—cells with regenerative powers that someday may eradicate any number of diseases. Stem cells that already have saved the lives of people with diseases of the blood and bone marrow. People like Molly Nash.

Like most girls her age, Molly Nash loved to dance. But that was before 2000, when the Colorado child began suffering from the effects of Fanconi anemia, a genetic disease that causes catastrophic failure of the bone marrow. Bone marrow makes life-saving blood cells: white blood cells that fight infection, red blood cells that carry oxygen to organs and tissues, and platelets that produce blood clots to stop bleeding. As their bone marrow deteriorates, people with Fanconi anemia suffer extreme fatigue, frequent infections, nose-bleeds, and bruises. Those who survive into adulthood are at risk for developing a host of cancers. By the time she was six, Molly had already been diagnosed with an early form of leukemia.

Molly's parents, Lisa and Jack Nash, set out to save their daughter with the help of John Wagner, a pediatrician at University of Minnesota Medical Center in Minneapolis, director of the Division of Hematology-Oncology and Blood and Marrow Transplantation, and codirector of the Center for Translational Medicine. Wagner proposed a rescue plan never before attempted. On the surface, his plan sounded simple: doctors would replace Molly's diseased blood with healthy blood. Problem was, the healthy blood needed to be a perfect match. Furthermore, the perfect match had to be Molly's sibling, a newborn whose umbilical cord blood contained the stem cells that could create the healthy blood. Since Molly had no such sibling, her parents had to conceive one. In fact, to make sure the new sibling's blood would be free of Fanconi anemia, the Nashes had to create a dozen embryos through in vitro fertilization from which the perfect match could be chosen via genetic testing. Finally, nine months after Lisa was implanted with the chosen embryo and delivered a healthy infant, Molly would receive a bone marrow transplant using the blood-forming stem cells from her new sibling's umbilical cord.

The plan worked. As Molly held her newborn brother, Adam—dubbed “the world's first designer baby” by a national news program—his donated stem cells made their way to her bone marrow and set about rebuilding her entire blood system with healthy cells. Three weeks later, she started to dance again. Eleven years later, she is in good health.

Molly's rescue marked the first time that PGD—preimplantation genetic diagnosis—was used specifically to ensure a perfect donor of umbilical cord blood stem cells for transplantation. PGD offers hope not only to patients with Fanconi anemia, but those with leukemia, thalassemia, and other blood diseases that cause the immune system and bone marrow to fail. Because PGD can determine whether an embryo is male or female, the technique can also reveal sex-specific blood diseases like hemophilia. Said Molly's physician, John Wagner, now one of the nation's leading authorities on umbilical cord blood transplantation, “Molly is an example of how the work done to combine preimplantation genetic diagnosis and in vitro fertilization to create a healthy cord blood donor holds great promise.”

The hope of medicine based on the regenerative powers of the stem cell is a powerful hope. Perhaps not since the time of Hippocrates has there been reason for scientists, physicians, patients, and their families to have such hope. No new approach to dealing with the monumental suffering and social costs of major diseases comes close to the promise of stem cell therapy. That promise includes children who suffer from diabetes or genetic disorders like Hurler's syndrome, cystic fibrosis, Tay-Sachs disease, Batten disease, Marfan syndrome, and muscular dystrophy. The promise includes middle-aged adults who suffer from heart disease, Lou Gehrig's disease, multiple myeloma, or spinal cord injury. The promise includes aging adults who suffer from Alzheimer's and Parkinson's disease and macular degeneration, which can lead to blindness. The stem cell could even turn the current understanding of how cancer begins, and how to treat it, on its head. It is the power of hope in regenerative medicine that propels some patients to seek unproven treatment around the globe—in China, India, Thailand, Russia, Ukraine, Mexico, Costa Rica, the Dominican Republic, Ger many, Portugal, the Netherlands, Argentina, and Brazil. In some countries, notably China, such “stem cell tourism” has become a multimillion dollar industry.

Though most people probably don't realize it, the promise of stem cells as a successful therapy in modern medicine is nearly forty years old. It came in the guise of bone marrow, where blood-forming stem cells, like Adam Nash's, set up shop early in embryonic development.

DISEASES AND CANCERS OF THE BLOOD

The first successful bone marrow transplant in humans took place in 1968 at the University of Minnesota Hospital in Minneapolis. The patient was a four-month-old boy suffering from a life-threatening immune deficiency that had already claimed his brother. The donor was the patient's sister, whose bone marrow supplied the blood-forming stem cells that replaced the boy's diseased cells and restored his immune system to health. For the first time, a human body had accepted bone marrow from someone other than an identical twin—someone whose tissue was nevertheless a good match for his own. That boy is now a healthy forty-three-year-old father of twins.

Leading the transplant team was Robert Good, one of the first scientists to view the immune system as a coordinated, complex system rather than a collection of piecemeal blood and tissue components. A year after Good's feat, E. Donnall Thomas performed the first successful bone marrow transplant to cure leukemia. Thomas became known to many as the father of the bone marrow transplant, building the Fred Hutchinson Cancer Center in Seattle into the world's largest bone marrow transplant program. For his innovations in science and medicine, he was awarded the 1990 Nobel Prize.

Before the pioneering work of Good and Thomas, diseases and cancers of the blood that destroy the immune system were a virtual death sentence. Since then, those who suffer from anemia, leukemia, lymphoma, and multiple myeloma have hopes for survival because of bone marrow transplants and blood stem cell transplants. Every year, about 50,000 such transplants are done worldwide. Thirty thousand are done using the patient's own blood-forming stem cells, a procedure called autologous transplants. Another 16,000 procedures are done using bone marrow from a donor who is unrelated but genetically matched as closely as possible; these are called allogeneic transplants. Of the more than 7,000 allogeneic transplants performed in North America in 2002, more than 5,000 were for leukemia or preleukemia. More than 9,000 of the 10,500 autologous transplants performed in the same year were for multiple myeloma, an aggressive cancer of plasma cells that make blood antibodies, or lymphoma, a cancer of the lymph system.

Multiple myeloma kills 11,000 Americans each year. It killed columnist Ann Landers and actor José Ferrer. Former U.S. Congresswoman Geraldine Ferraro, the first woman to be a candidate for U.S. vice president of a major American political party, was diagnosed with multiple myeloma in 1999 and survived twelve years. In late 2003, cancer researchers discovered that a renegade stem cell trafficking among the plasma cells of the bone marrow starts a killer clone that gives rise to multiple myeloma. The renegade cell can survive aggressive chemotherapy and mount a comeback. This means a relapse for far too many persons with the disease. Treatments for multiple myeloma, including thalidomide and other drugs, have not improved survival rates very much in the last twenty years, but transplantation of stem cells recruited from the patient's circulating blood is showing real promise.

The story of the transplantation of stem cells collected from circulating blood as a valuable clinical therapy begins with Irving Weissman, director of Stanford University's Institute for Stem Cell Biology and Regenerative Medicine. It was Weissman who first isolated specific blood-forming stem cells in mice, in 1988. Just four years later, Weissman and others isolated the human counterparts of the mouse stem cells. The story picks up with James Thomson of the University of Wisconsin in Madison, the scientist who made the first line, or family, of human embryonic stem cells in 1998. Thomson reported on September 11, 2001—coincidentally the day of the terrorist attacks on New York and Washington, D.C., and the appeal for blood donation that followed—that his team could “direct” embryonic stem cells to form colonies of the normal cells found in blood. The development of stem cell–based blood could have implications for human medicine far beyond the treatment of blood malignancies. Stem cell–based blood also could be used to thwart rejection of transplanted foreign tissue in treating diabetes, Parkinson's disease, or spinal cord injury as well as in traditional organ transplantation. Stem cell–based blood could create a limitless supply of donor blood, eliminating the need for donations in times of massive emergency requests, such as 9/11. Stem cell–based blood could even replace blood destroyed by a radiation-generating nuclear weapon. Radiation kills rapidly dividing cells, including blood-forming stem cells. Big challenges remain making this a reality, however.

It is thought by some medical scientists that umbilical cord blood harbors adult stem cells that have many of the important attributes of embryonic stem cells. In other words, adult stem cells from cord blood can form diverse tissue cell types other than those that form blood. Someday, when the need arises for tissue regeneration—whether it's cartilage for the knee, muscle for the heart, or neurons for the brain—perhaps scientists will have figured out how to reprogram these particular adult stem cells to generate the necessary tissue to repair the problem. Much more research will need to be done before that day arrives.

In the meantime, more and more parents are storing the umbilical cord blood of their offspring in the event of future need—in case disease should strike that is treatable with blood stem cells. More than thirty private cord blood banks were in operation in 2010 in the United States, up from a mere dozen in 2000. Companies like StemCyte in the United States and Smart Cells in the United Kingdom process the blood-forming stem cells, then freeze them in liquid nitrogen at a cost of up to $2,000 per child. Cord blood stem cell registries are also expanding in the not-for-profit sector with several initiatives, including an $8 million investment by the National Marrow Donor Program in 2004. The Germany-based International NetCord Foundation is a network of nonprofit public cord blood banks in the United States, Europe, Israel, Japan, and Australia. These developments make available potential lifesaving blood-forming stem cells at their basic cost with nominal profit. In 2006, the U.S. Health Resources and Services Administration began awarding contracts to public cord blood banks to increase the supply of donations. “We can find donors for everyone,” the University of Minnesota's John Wagner told the Associated Press.

HEART DISEASE

Five hundred years after Leonardo da Vinci's intricate drawings of the heart and heart valves, drawings that continue to inspire heart surgeons today, cardiovascular disease is a massive and growing worldwide public health problem. It is estimated that it kills more than 800,000 people in the United States each year, making it the leading cause of death, with another 140,000 dying of stroke each year. Congestive heart failure—the ineffective pumping of the heart caused by the loss or dysfunction of heart muscle cells—afflicts nearly five million Americans, with 400,000 new cases each year. In 2005, more than seventeen million people died from heart disease and stroke around the world. That number represents 30 percent of all deaths from disease and injury, according to the World Health Organization. And no longer is heart disease primarily a problem of affluent countries with their characteristic high-fat diets, bulging waistlines, and red-zone levels of stress. In fact, heart disease is growing at a rate faster in certain parts of the developing world than in the first world. In India, the country with the world's second largest population, heart disease is a huge health problem. Many Indians think that heart disease is “a ‘Rich White Man's disease,’” Ivan Berkowitz, a scholar at the International Academy of Cardiovascular Sciences, told the Times of India during a conference in 2011. The academy calculates that 80 percent of deaths due to heart disease—thirty-five people every minute—occur in emerging nations.

The “Race Against Time” study by Columbia University's Earth Institute estimated that more than twenty million years of future productive life are lost annually due to cardiovascular disease. The study showed that middle-aged men and women in Brazil experience mortality rates from heart disease that were similar to those in the United States thirty years ago. Today, Brazilian death rates are 40 percent higher for men and 75 percent higher in women with heart disease within the same age group compared to the U.S. rates. If current projections hold, and preventive disease management isn't implemented, Brazil will experience a 15 percent increase in its heart disease–related death rate per decade for the next thirty years.

While Brazil works to develop a comprehensive strategy to prevent cardiovascular disease, a decade ago, its scientists and clinicians started pioneering the use of adult stem cells to treat heart failure, a common consequence of chronic heart disease. Scientists in animal laboratories had previously demonstrated that blood-forming stem cells could generate new capillaries to deliver blood to tissue damaged by a heart attack. In 2003, Hans Dohmann at Hospital Pró-Cardíaco and Federal University of Rio de Janeiro, in collaboration with Emerson Perin and his colleagues at Houston's Texas Heart Institute, used a mixture of adult stem cells from bone marrow to treat fourteen Brazilians with s evere heart disease. Each patient's damaged heart muscle was injected with thirty million stem cells drawn from their own bone marrow. Two months later, the treated patients had significantly fewer symptoms of heart failure and a greater ability to pump blood than the untreated patients. After another two months, the treated patients showed even more improvement, with stable cardiac pumping activity and no irregular heart rhythms. “Either these stem cells became new blood vessel and new heart muscle cells, or their presence stimulated the development of one or both” from something within the ailing patients’ hearts, wrote James Willerson, president of the University of T exas Health Science Center at Houston and chief of cardiology and medical d irector at the Texas Heart Institute, in summarizing the study's results. Willerson later added a c aveat: “Stem cells here have to be considered in quotations b ecause we've taken bone marrow cells and separated them into cells with a single nucleus, some of which are stem cells and some of which are not.” Nevertheless, the results were persuasive enough that in early 2004, the U.S. Food and Drug Administration approved one of the first clinical trials in the United States to test a bone marrow stem cell therapy for severe heart failure.

Even as Perin and his colleagues at the Texas Heart Institute began planning the new study, results from the first randomized trial of adult stem cell injections in heart failure patients were being reported at the annual meeting of the American Association for Thoracic Surgery in 2004. Cardiac surgeon Amit Patel from the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine, and colleagues from the United States and the Benetti Foundation in Rosa-rio, Argentina, reported that transplantation of bone marrow– derive d blood stem cells can be a viable treatment for congestive heart failure b ecause they promote growth of blood vessels and heart muscle. Ten A rgentine patients received injections of bone marrow–derive d stem cells directly into the damaged muscle of their heart during heart bypass surgery; ten others received only the bypass operation. Six months later, the hearts of the group treated with stem cells were pumping more blood than those who had the bypass operation only. Their approach could revolutionize treatment of heart failure from one of relieving symptoms to one that is “truly regenerative,” said Patel's Pittsburgh colleague, Robert Kormos.

The explosion of interest in stem cells across the globe has detonators in many fields of medicine, but in none are the possibilities more profound or the need for success greater than in cardiology. Yet funding for clinical trials using stem cells in heart disease is extremely low. Compared to trials being done to test traditional and genetically engineered drugs, the industry has little experience with cellular-based therapies. There is also the matter of money down the line. If a patient's own cells may be his or her best therapy, costs could be limited to cell processing, the procedure itself, and the hospitalization and perhaps not require expensive drugs or biopharmaceuticals. This scenario of manageable costs for processing a patient's own cells, however, seems unlikely. A “universal donor” stem cell might be developed, or a stem cell bank might be established, to provide treatments for large segments of the population affected by heart disease. The cells a patient needs would be “matched” to appropriate cells donated to the bank, much like what is done today in bone marrow, kidney, and liver transplantation.

Whether adult stem cells will indeed, in the end, prove to be both safe and effective for treating heart failure won't be known anytime soon. So far, human and animal research programs in South America, Europe, South Africa, Asia, and the United States have yielded inconsistent, even conflicting results. Some patients show a slight increase in cardiac output when treated with their own bone marrow or heart muscle stem cells. Only recently have serious attempts been undertaken, however, to standardize the specific cell type used in treating patients. Indeed, the variety of cells derived from bone marrow used in some of the early studies was described as a witch's brew of bone marrow cells. A large national stem cell study for heart disease showed that transplanting a purified type of bone marrow stem cells into the heart muscle of subjects with severe angina—chest pain or discomfort that occurs when an area of your heart muscle doesn't get enough oxy genrich blood—resulted in treated subjects experiencing less pain than the control group. Such studies need to be confirmed and extended.

Bone marrow stem cells were first used to treat a heart pati...