Pluripotent Potential

Researchers from diverse disciplines seek ways to translate their work into unforeseeable new therapies aimed at a wide variety of diseases.

By Lori Oliwenstein

Stem cells have the potential to develop into many different cell types in the body. In a 4- to 5-day-old animal or human embryo, called a blastocyst, there is a small cluster of cells called the inner cell mass, which will give rise to all the specialized tissues of the body, a property called pluripotency. These cells can be grown in the laboratory for indefinite periods, while retaining their pluripotent status. In some adult tissues, such as bone marrow, muscle and brain, adult stem cells regenerate replacements for cells that are lost through normal wear and tear, injury or disease.

Many scientists believe stem cells may someday become the basis for treating Parkinson’s, Alzheimer’s, diabetes, heart and other diseases. But before the research can be truly off and running, legal and regulatory issues that have fettered the field and hampered funding must be resolved so that scientists can begin to address the complex challenges involved in developing stem cell therapies.

Still, there is a tremendous amount of activity surrounding stem cell research. Here at the Keck School of Medicine of USC, the scientists —and others who will soon join them—are celebrating the appointment of the founding director of the school’s Center for Stem Cell and Regenerative Medicine (CSCRM), as well as a $25 million gift from philanthropists Eli and Edythe Broad to create the USC Broad Institute for Integrative Biology and Stem Cell Research, which will house the new center.

The founding director is Martin F. Pera, Ph.D., who is widely viewed by his scientific peers as a pioneering leader in the development of human embryonic stem cells.

Pera has the opportunity to direct what may become one of the most important stem cell centers in the nation. It will become a place where talented senior scientists will cluster to mentor younger scientists attracted to USC as the center becomes a global focal point in a field that many believe will revolutionize health care to a degree seen only a few times in history.

USC President Steven B. Sample, USC Provost C.L. Max Nikias, Keck School of Medicine Dean Brian Henderson, M.D., and the Keck School Board of Overseers have made stem cell research a clear priority. On a personal level, Pera says, “My goal is to make this an internationally recognized center for basic research in its field, and to create an outstanding intellectual environment for scientists.”

Although Pera officially took the helm of CSCRM (call it see-scream) in April, he has been working with Henderson and their colleagues since September to create an administrative structure for CSCRM that will foster an environment of creative interdisciplinary research. That structure also involves participation from scientists at Childrens Hospital Los Angeles, Caltech and other regional institutions. In this way, CSCRM was on its way to becoming an important regional stem cell center prior to its public unveiling.

“I had the good fortune to be involved in the founding of the field of human embryonic stem cell research, and as a consequence of this role I feel a special responsibility to see this new science realize its promise,” Pera says.

“Martin is an outstanding scientist and one of the real pioneers in the area of human embryonic stem cell research,” Henderson says. “Equally important, he’s a stellar individual who has the attributes of academic leadership necessary to grow a center of excellence that is recognized as a key regional, national, and international research center in the area of stem cell and regenerative medicine.”

Before being named director of CSCRM, Pera served as a research professor and co-director of the Monash Institute of Medical Research at Australia’s Monash University, and director of embryonic stem cell research at the Australian Stem Cell Centre, where he was also one of the founding scientists. Monash has more than 52,000 students on eight campuses. Pera also was a founding scientist of ES Cell International, a Singapore-based biotechnology company focused on using embryonic stem cells to develop treatments for diseases.

The untapped potential of stem cell and regenerative medicine was embraced by California voters through passage of Proposition 71, the California Stem Cell Research and Cures Initiative, in November 2004. But with the promised $3 billion in funding for stem cell research tied up in litigation, progress in the field has required studying the scientific problems at hand, maintaining faith in the importance of the work to be done and a willingness by individuals and institutions with the vision, generosity and means required to support that work.

The CSCRM team recently received a 3-year, $3.16 million stem cell training grant as part of the first round of grants awarded under Prop. 71 by the California Institute for Regenerative Medicine.

“It’s clear that this initiative will give me the best chance to advance the application of stem cell research in regenerative medicine,” Pera says. “I’m looking forward to leading CSCRM into an exciting future and making the institute an international leader in this area.”

CSCRM has moved aggressively to recruit a critical mass of accomplished researchers within the center, enabling rapid progress while creating a nucleus for further recruiting in the field.

The faculty at the CSCRM will take part in basic research programs and will collaborate with scientists at other institutions to develop novel platforms in imaging, bioengineering and nanotechnology that can be applied to stem cell research. They will seek ways to translate their work into unforeseeable new therapies that will be aimed at a wide variety of diseases and conditions, as well as to advance stem cell research and regenerative medicine.

Success will require the coordinated input of diverse disciplines, some with exotic names, many from outside traditional areas of medicine and biology: bioengineering, nanotechnology, small molecule chemistry and drug development, genomics and proteomics, as well as cancer biology, developmental biology, stem cell biology and the clinical sciences.

In addition to its commitment to contemporary research focused on curing diseases, the CSCRM charter recognizes the importance of a long-term commitment to this line of research. Thus, the CSCRM team will take the lead in training future scientists in the field. The $3.16 million stem cell training grant will be used to train graduate students as well as post-doctoral and clinical fellows across 27 departments at USC.

A key feature of the program will be a newly developed course that teaches the social, legal and ethical implications of stem cell work. Another is a tri-institutional stem cell biology lecture course to be taught in conjunction with faculty from Childrens Hospital and Caltech that will train students in gene-transfer technology, medical applications and the state of current stem cell research.

Scientists want to do this kind of basic laboratory study of stem cells to learn about their essential properties and what makes them different from specialized cell types. As scientists learn more about stem cells, it may become possible to use the cells not just in therapy, but to screen new drugs for efficacy and safety and to advance understanding of birth defects. Embryonic stem cells also provide a new tool to study human gene function. Human embryonic stem cells have only been studied since 1998, so the initial focus will be to determine precisely how stem cells remain unspecialized and self-renewing for many years and to identify the signals that cause stem cells to become specialized.

In announcing the $25 million gift from the Broad Foundations on behalf of himself and his wife, Eli Broad said: “This will hopefully be the anchor of a new biomedical corridor in the region, where the nation’s most cutting-edge research is conducted by some of the brightest minds in science.”

Once it is completed—in 2008, according to plan—the Broad Institute for Integrative Biology and Stem Cell Research will house as many as 52 faculty members in its 215,000-square-foot facility, which will have five floors of customizable laboratory modules in each of its two wings. It will have a 20,000-square-foot subterranean imaging center for imaging laboratory animals and humans. A 50,000-square-foot vivarium to house laboratory animals will be connected to an existing one next door at the USC Zilkha Neurogenetic Institute.

One of the two wings of the Broad Institute will house programs in cardiovascular disease, diabetes and other metabolic disorders, as well as transplant biology. The other, with approximately 52,000-square-feet of research space, will be the home of CSCRM.

The CSCRM wing will provide for more than 18 faculty members, most of whom will be newly recruited to the Keck School. This wing will also have a “current Good Manufacturing Practice” facility, or cGMP, regulated by the Food and Drug Administration to ensure that the CSCRM meets all federal requirements for the production of human pharmaceutical products, biologically derived products and medical devices.

For CSCRM director Pera, his work at the center is an extension of his long involvement in stem cell biology and research. He was part of a small group of researchers who pioneered the isolation and characterization of pluripotent stem cells—cells whose development potential, or plasticity, is not fixed. He isolated these stem cells from human tumors of the testis. That work, Pera says, “provided an important framework for the development of human embryonic stem cells.”

His laboratory at Monash University was the second in the world to isolate embryonic stem cells from human blastocysts. And, he and his colleagues were the first to describe how blastocyst-derived stem cells differentiated into somatic (body) cells in a laboratory dish.

Pera’s current research focuses on the extracellular signals involved in allowing embryonic stem cells to maintain a pluripotent state—what sorts of chemicals are required by stem cells so that they can maintain the ability to develop into any of a wide variety of different cell types, rather than one specific cell type. He is also looking at the factors that cause a stem cell to choose a specific differentiation pathway.

“A major hypothesis behind this work is that stem cell cultures represent a community of different cell types, similar to those found in the embryo around the time of implantation into the womb, and that just as communication between different cell populations in the embryo acts to specify cell fate during development, similar conversations control stem cell maintenance and differentiation in vitro,” Pera says.

“This work has fundamental importance for our understanding of stem cell biology, but it also addresses practical questions that must be solved before human embryonic stem cells can achieve their full potential in research and medicine,” he says. “Understanding how to control the differentiation of stem cells is essential [if we are to produce] desired types of mature cells in sufficient quantity and in pure form for use in laboratory research or regenerative medicine.”

And so, even though scientists are hobbled by legal and regulatory constraints, the race is proceeding, at USC and at countless other laboratories and centers throughout the world. The race is not to see who is first to discover new cures or therapies or understanding, but to bring to those afflicted with discouraging, incurable and pernicious diseases the hope and promise of stem cell research.

Alfred Kildow contributed to this story.