Cell Decisions

The science behind stem cell research already has transformed medicine, Medical Center scientists say. The question is what will the future hold? By Mark Michaud

As far as Mark Noble is concerned, the “next medical revolution” arrived more than 30 years ago. That’s when the Rochester professor of biomedical genetics and scientists like him at academic medical centers across the country first began to grasp the potential of stem cells.

Since earning his Ph.D. in genetics during the 1970s at Stanford University, Noble has focused his scientific career on understanding the unique properties of the special cells.

For a biomedical scientist, the fascination is easy to see. Responsible for generating the different—and highly specialized—cells that make up tissues, organs, and other systems of the human body, they are crucial for early growth and development and play a critical role in repairing certain tissues. Without skin stem cells, for example, your body would not be able to create the skin cells it needs to heal cuts and scrapes.

That ability to generate specific types of cells intrigues scientists, who see in stem cells enormous potential for new therapies and new strategies in the fight against cancer and other diseases.

“The future of biomedical research and stem cell science are inexorably linked.”—Seligman

In Noble’s lab and in the labs of scientists across the Medical Center, Rochester scientists have been exploring that potential for several years, helping lead research projects focused on new cancer treatments, the role nutrition plays in early development, and in understanding how to repair damage to the brain and nervous system.

The question of whether Rochester should be involved in such research has long been answered, Noble says.

“It would be like asking what would happen to a medical center that isn’t interested in vaccinations,” says Noble. “It’s beyond comprehension.”

But it’s not completely without controversy. Especially when it comes to the future of stem cell research, few scientific fields have generated as much intense public debate. In July, President Bush used the first veto of his presidency to strike down proposed legislation to broaden the number of embryonic stem cell lines available to scientists using federal research money, and he reiterated restrictions that have been in place since 2001.

Seligman Leads Stem Cell Effort

At the same time, academic leaders at the University and elsewhere say federal restrictions are hampering the ability to fully tap the potential of stem cell research. Last spring, President Joel Seligman led a coalition of 17 New York universities and institutions in calling on state lawmakers to establish a state-based research fund to capture the scientific and commercial potential of stem cells, including research involving embryonic stem cells.

“It is important to understand that the future of biomedical research and stem cell science are inexorably linked,” Seligman says.

Regardless of how the political debate plays out, the field of stem cell research is already transforming medicine at Rochester and universities across the United States. Throughout the sprawling Medical Center, Rochester scientists are uncovering not only the potential of stem cell research to lead to new treatments for millions of Americans suffering from a long list of conditions, but they are also helping to reshape the understanding of human development and diseases.

“Scientists at the Medical Center are making significant contributions to the field of stem cell science and are conducting research that has the potential to lead to new regenerative therapies for spinal cord injury, Parkinson’s disease, heart disease, and cancer, to name just a few,” Seligman says.

LAB LEADERS: Chris Proschel, Mark Noble, and Margot Mayer-Proschel (left to right) have worked together as a team since 1990. They played key roles in identifying—and are considered to be among the best in the world at handling—the four known progenitor cells for the various cells found in the central nervous system.

The field of stem cell science traces its roots to the first discovery of the building block cells more than 40 years ago at the University of Toronto. Since then, researchers have built up decades of experience in working with the cells and, in some cases—notably in using bone-marrow stem cells to treat blood-related illnesses—harnessing the cells to create new treatments.

Nearly a decade ago, scientists at the University of Wisconsin discovered and isolated human embryonic stem cells. Appearing only a few days after fertilization, embryonic stem cells are the master cells of biology, holding the potential to generate any type of cell in the body.

In thinking about stem cells, it’s helpful to imagine the process of cell development as a tree. At the roots are embryonic stem cells, and at the end of each different branch are the mature cells of the body. Before a blood, bone, muscle, liver, or brain cell can be created, stem cells evolve along a series of intermediate stages. Embryonic stem cells give rise to tissue-specific stem cells, which in turn produce cells, called progenitor cells. Those cells are the final step before the emergence of the body’s mature cells.

As a stem cell proceeds along each developmental branch, it becomes more specialized and loses its potential to produce different types of cells. A stem cell can move forward and produce the cell types ahead of it on the branch, but scientists generally believe that cells can’t move backward and produce the cells behind them or the cells on a different branch.

Steven Goldman, a professor of neurology, neurosurgery, and pediatrics at Rochester, says that one benefit of working with embryonic stem cells is that they represent a potentially inexhaustible supply of cells. While adult stem cells have proven to be enormously useful in research and may proved to be ideal for transplantation or other clinical treatments, their numbers are limited in the adult body, they’re difficult to isolate, and they can’t renew themselves.

But he says embryonic cells also present unique challenges to scientists.

“Their strength is actually their curse,” he told National Public Radio this summer. “They can generate all the major cell types that we care about, but at the same time we don’t have sufficient understanding, at this point, of the biology of these processes to understand how to make them become what we would like them to become.”

‘Daunting Challenge’

An internationally recognized leader in the field of stem cell research, Goldman leads a group that consists of more than two dozen people exploring the use of stem cells to treat a host of neurological disorders.

“Diseases of the brain and spinal cord present an especially daunting challenge for cell-based strategies of repair, given the multiplicity of cell types in the central nervous system and the precise manner with which they must interact,” says Goldman.

Although many neurological conditions are not yet fully understood, others are candidates for stem cell therapies because they are caused by the loss or degeneration of a single identifiable type of cell.

The question of whether Rochester should be involved in stem cell research has long been answered, Noble says.

A class of neurological diseases called myelin disorders is one example. Myelin—the fatty substance that, like insulation wrapped around a wire, covers nearly all the nerve cells in our bodies—helps signals in the nervous system move crisply from one point to another. In rare childhood neurological diseases, called pediatric leukodystrophies, and in multiple sclerosis in adults, myelin breaks down, interfering with the body’s signaling system.

The result can be dementia, difficulty walking, trouble breathing, and problems with other normal activities, depending on which parts of the brain or nervous system are affected. The conditions are irreversible and worsen over time.

Understanding that these diseases presented a specific target for therapy, Goldman and his team set about finding a way to replace myelin. The key was to identify the right type of cell that would migrate to where it was needed. Goldman’s lab turned to oligodendrocyte precursors, cells found in both the adult and developing fetal brain that are known to be responsible for producing a subset of tissues in the central nervous system that includes myelin.

In landmark results published last year in the journal Nature Medicine, Goldman and his team reported promising results.

“These cells infiltrate exactly those regions of the brain where one would normally expect oligodendrocytes to be present,” says Goldman. “As they spread, they begin creating myelin, which wrapped around and ensheathed the nerve cells.”

While his work in myelin disorders, spinal cord injury, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases has produced promising data, Goldman emphasizes that human therapies are a long way off.

Also exploring the role of stem cells in the brain and spinal cord is a research group that includes Noble, Margot Mayer-Proschel, an associate professor, and Chris Proschel, an assistant professor, both in the Department of Biomedical Genetics. They have played key roles in discovering all four of the known progenitor cells for the various cell types found in the central nervous system.

Working as a research team since 1990 in a journey that has taken them from labs in London to Utah and, beginning in 2000, to the Medical Center, the group is considered to be among the best in the world at handling the cells, pioneering ways to keep the cells alive and to manipulate the signals that the cells use to determine what type of brain cell to become.

The expertise has led to several recent groundbreaking discoveries, including uncovering the origins of a rare childhood neurological disorder, called Vanishing White Matter Disease, as well as critical advances in spinal cord repair.

Unlocking Complex Developmental Problems

While stem cells and progenitor cells can be used to repair central nervous system damage, scientists like Mayer-Proschel are discovering that cell dysfunction also can be the basis for certain diseases.

An example is her work on the impact of iron deficiency on early development. A common nutritional disorder, iron deficiency affects an estimated 25 percent of the world’s children. While often considered a third-world problem, there also is a high prevalence of iron deficiency in the United States due both to poor nutrition and dietary trends, particularly during pregnancy. In addition to problems in the blood system—iron performs the critical function of carrying oxygen from the lungs to the tissues in the form of hemoglobin—iron deficiency can lead to behavioral and cognitive deficits in children, including impaired learning and memory function, and lower IQ.

Long understood to play an important role in the formation of myelin, iron and its role in human development was not precisely understood. At what point does the lack of sufficient levels of iron cause the neurological damage? Most scientists believed it occurred in early childhood, but Mayer-Proschel suspected its roots lay deeper.

RESEARCH TEAM: Steve Goldman leads a research group that includes more than two dozen people exploring the use of stem cells to treat neurological disorders.

“This is a direct example of using our knowledge of stem cell lineage—what it does, what it was made for—and then taking that knowledge and applying it to a disease paradigm,” says Mayer-Proschel.

Using animal models, Mayer-Proschel discovered that if iron was not present in sufficient amounts during a narrow window of pregnancy, a cascade of cellular malfunction ensued. The embryo fails to accumulate an adequate pool of oligodendrocyte progenitor cells, which, in turn, leads to a lower than normal production of myelin.

One of Mayer-Proschel’s most interesting discoveries was that impact of the deficiency is permanent—once the window of cell accumulation has passed, the problem cannot be fixed. No matter how much iron you feed a child after birth, the proper cellular balance cannot be restored.

Mayer-Proschel also has explored whether the disruption in precursor cell behavior had a measurable cognitive impact. In collaboration with Anne Luebke, an associate professor who holds appointments in neurobiology and anatomy and biomedical engineering, she examined the auditory brain stem responses of rats who were born from iron-deficient mothers. They have discovered that the signals that transmit sound throughout the brain were slowed or, in some instances, lost.

“We found that even a small loss of myelin globally in your brain has direct consequences for your auditory brain stem response in terms of how you hear,” says Mayer-Proschel. “And it is not just about how well you hear; it is how you hear when we speak, so this has immediate implications for language. We believe that some of the many cognitive problems which are seen in iron-deficient children are a direct or indirect consequence of auditory impairment.”

The work has helped open new ways of thinking about early human development. Mayer-Proschel estimates that a substantial amount of what are now considered developmental diseases probably have their origin in precursor cell malfunction.

Goldman’s work in myelin disorders, spinal cord injury, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases has produced promising results.

Mayer-Proschel’s lab also is examining the impact of viral infection on precursor cells, whether or not the vulnerability of precursor cells is inherited, and the role of precursor cell disruption in genetic diseases. In addition to Mayer-Proschel’s work, Lisa Opanashuk, an assistant professor of environmental medicine, and Noble have also identified precursor cells as vulnerable targets of normal levels of environmental toxicants.

In the case of iron deficiency, Mayer-Proschel says fixing the problem “requires a relatively benign approach.”

“If we are right, then giving the right diet at the right time to a pregnant mother could prevent this small but accumulative disruption of precursor cell function in the embryo,” she says. “We are not talking about high-power, high-money transplantation, where maybe one person would benefit once a year. We are talking about changing prenatal care with nutritional intervention.”

Cancer: The ‘Dark Side’

The idea that stem cells may play an important role in cancer has been around for over 30 years, but only in the past decade or so have scientists have been able to examine the connection more closely and develop new approaches to combating cancer.

Craig Jordan, associate professor of medicine, and Monica Guzman, a senior instructor of hematology and oncology, both with the James P. Wilmot Cancer Center, are leading efforts to understand the role of stem cells in cancer and to develop ways to destroy them, eliminating the underlying cause of the disease.

Just as normal organs and tissue arise from stem cells, scientists now believe that certain forms of cancer originate with stem cells. Jordan and Guzman focus their work on leukemia, a family of cancers affecting the blood-

forming cells in the bone marrow. Such cancers are thought to arise from rare but malignant stem cells.

In leukemia, the normal course of mature blood cell creation is interrupted. The cancerous cells grow without regulation, accumulate in the blood stream, and eventually interfere with other tissues and functions. Noble, who collaborates with Jordan, describes the phenomenon as “when stem cells go over to the dark side.”

Existing cancer treatments often work well to eliminate most of a tumor, but cancer stem cells, which are difficult to detect because they make up a small fraction of cancerous tissue, have proven particularly resistant to such therapies.

“Leukemia therapies have not really changed much in the past 30 years,” says Jordan. “We’ve really just been tweaking how the same drugs are used rather than developing truly new approaches.”

A Novel Approach

“Just like in normal tissue where you imagine stem cells being at the heart of the process, if something happens to the stem cell and it is somehow removed, the tissue runs down and cannot regenerate itself,” says Guzman. “Take that analogy to a tumor: If you can somehow eradicate or isolate that cancer stem cell, then the tumor can no longer grow.”

As simple as it sounds, destroying cancer stem cells in leukemia is a delicate endeavor. Devising ways to target the cancer stem cells while leaving unharmed the normal stem cells of the blood system that are responsible for replenishing the body’s blood supply has proved challenging. In her groundbreaking doctoral thesis, Guzman first identified a unique molecular property of leukemia stem cells that’s critical to their survival, and she demonstrated that it was possible to selectively target and destroy cancer stem cells.

CANCER CENTER: Monica Guzman and Craig Jordan are leading efforts to understand the role of stem cells in cancer.

Guzman and Jordan have identified a compound derived from a daisy-like plant known as feverfew—used for centuries as an herbal remedy to reduce fevers and inflammation—that successfully targets the leukemia stem cells while sparing normal blood system stem cells. Working with colleagues at the University of Kentucky, Jordan and Guzman hope to begin clinical trials early next year.

Jordan, who came to Rochester in 2003 from the University of Kentucky, says he was drawn to the Medical Center because of the opportunity to collaborate with scientists who can bring their knowledge of stem cell biology to bear on his cancer research.

The University has sought to strengthen those ties. Earlier this year, the Wilmot Cancer Center created a Cancer Stem Cell Research Program, one of the first of its kind in the nation, which will include a core set of labs led by Jordan, Noble, and Hartmut Land, the chair of the Department of Biomedical Genetics. That new direction in cancer research holds great promise for the 35,000 Americans diagnosed with leukemia every year, and it may ultimately have applications in breast and brain cancer.

Despite that potential, the rest of the cancer research community is only now starting to catch on. Jordan and Guzman are among only a handful of researchers nationwide specifically studying cancer stem cells.

“It takes time to turn a battleship,” says Jordan. “The leukemia research field is huge and the stem cell and cancer world are just now starting to collide.”

Mark Michaud is associate director of the Office of Public Relations at the University’s Medical Center.

Seligman Leads Stem Cell Effort
Rochester and other New York universities with major biomedical and life sciences programs risk losing their positions as scientific leaders without a strong state commitment to support stem cell research, a group of 17 presidents and chancellors organized by President Joel Seligman told New York lawmakers this spring.

The group argued that without a dedicated state fund for stem cell research, New York risks falling behind economically to other states and regions of the country in an increasingly competitive race to develop biomedical research.

“Biomedical research is a critical component of New York’s 21st century economy,” Seligman said. “This is particularly the case in upstate cities such as Rochester, which are becoming increasingly dependent upon the employment and commercial opportunities that spring from university research, especially in the field of medicine.

“With state support, we will strengthen our universities’ leadership in the field of biomedical research, create new companies and jobs, and develop technologies that have the potential to improve the lives of millions of Americans,” Seligman said. “However, if the state fails to act, universities will begin to lose their best and brightest scientists, and our capacity to serve as engines of innovation for the state’s growing biotechnology and pharmaceutical sector will rapidly decline.”

In an analysis of the scientific, therapeutic, and economic issues related to stem cell research, the group detailed the competitive environment that has emerged in the past several years and its implications for the state’s economy. Titled New York and Stem Cell Research, the report is available online.

Federal funding restrictions on human embryonic stem cell research have prompted several states to establish state-based research funds aimed at capturing the scientific and commercial potential of the new field of medicine. The most prominent example is California, where voters have approved an initiative to establish a 10-year, $3 billion stem cell research fund. Other states, including New Jersey, Connecticut, Massachusetts, and Maryland, have established or are in the process of establishing similar funds.

While New York’s research institutions are widely acknowledged to possess the scientific talent to make the state a major international player in the emerging field, Seligman and other academic leaders fear that researchers will be recruited to institutions in other states where they would have access to more resources to pursue their research.

The loss would have a significant negative ripple effect on a university’s research enterprise as grants, junior scientists, biotech companies, and venture capital will similarly migrate to institutions that are perceived to be on the cutting edge of biomedical research, according to the group’s report.

New York’s academic medical community contributes an estimated $30 billion per year to the state’s economy and generates more than 459,000 jobs. The biotech and pharmaceutical sectors are responsible for $18.1 billion in economic activity and 110,000 jobs.

—Mark Michaud