Since the success in 1998 by the University of Wisconsin’s James Thomson in deriving human embryonic stem cells from embryos, the stem cell research field has exploded.
The discovery by Japan’s Shinya Yamanaka, MD, PhD, in 2006, of how to transform ordinary adult skin cells into cells that, like embryonic stem cells, are capable of developing into any cell in the human body, has revolutionized stem cell research.
At top, Robert Blelloch, MD, PhD, performs stem cell research. Above, Shinya Yamanaka, MD, PhD, a scientist at the UCSF-affiliated Gladstone Institutes, UCSF and Kyoto University, was recognized for a revolutionary achievement in the field of stem cell science with a Nobel Prize in Medicine in 2012.
In between and since, there has been major progress in scientists’ understanding of stem cells. Today, fueled in part by the robust research enterprise at UCSF, the field is burgeoning. Yamanaka, a senior investigator at the UCSF-affiliated Gladstone Institutes and a professor of anatomy at UCSF, shared the Nobel Prize in Physiology and Medicine with John B. Gurdon of the Gurdon Institute in Cambridge, England, in 2012.
Robust Research Enterprise
In about 125 labs of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF – one of the largest such programs in the country – scientists are carrying out the basic research needed to understand how stem cells could be manipulated to treat diseases, to translate these findings into clinical research and to develop novel therapies.
In studies conducted in the culture dish and in animals, scientists are learning how to prompt stem cells to develop into specialized cells of tissues such as the heart, pancreas and brain. The ultimate goal is to transplant these cells into patients to regenerate damaged tissues.
The scientists also are exploring the use of stem cells as vehicles for delivering drugs into diseased tissues, and are using specialized cells produced by stem cells, such as liver and heart muscle cells, to test the effectiveness of experimental drugs in the culture dish. In addition, they are studying the role of stem cells in generating many forms of cancer, an important first step for targeting the cells for therapies.
The center is structured along seven research pipelines aimed at driving discoveries from the lab bench to clinical care. Each pipeline focuses on a different organ system: the blood, pancreas and liver, heart, reproductive organs, nervous system, musculoskeletal tissues and skin. And each pipeline is overseen by two leaders of international standing – one representing the basic sciences and one representing clinical research. The approach has proven successful in the private sector for driving the development of new therapies.
Variety of Diseases
Among the basic science studies being conducted by UCSF investigators are:
Exploring a novel stem cell strategy for treating brain diseases – Five UCSF labs are pioneering a novel approach to treating brain diseases and injuries, using a particular type of embryonic stem cell to manipulate the brain’s neural circuitry. They recently reported the first use of the cells, which mature into neurons, in creating a new period of plasticity, or capacity to change, in the brains of rodents.
The approach could be used to treat neural circuits disrupted in abnormal fetal or postnatal development, stroke, traumatic brain injury, psychiatric illness, and aging. The labs also reported the use of the cells in dampening the excitation that occurs in the neural circuits of people with epilepsy and Parkinson’s disease. If the research continues to show promise, the team ultimately will attempt to produce the cells in the culture dish from human embryonic stem cells.
Moving in on the cause of adult leukemia – Scientists led by Emmanuelle Passegué, PhD, have discovered one key reason why blood stem cells are susceptible to developing the genetic mutations that can lead to adult leukemia. Their finding also may explain, they say, why some other age-related hematological disorders develop. The study opens a new frontier for studying the molecular underpinnings of adult leukemia.
“Our discovery also suggests a strategy for reducing the risk of leukemia that results from chemotherapy used to treat solid tumors,” says Passegué.“Existing drugs, such as G-CSF and prostaglandins, could be used to induce blood stem cells to proliferate prior to the use of therapy with DNA-damaging agents. This could enhance the precision of DNA repair and thus reduce the risk of leukemia development.” She is discussing this possible tactic with UCSF clinical researchers.
Obtaining a pure sample of stem cells for treatments – Researchers led by Harold Bernstein, MD, PhD, have reported the first success in very rapidly purifying one type of embryonic stem cell from a mix of many different types of embryonic stem cells in the culture dish. The technique, which avoids the need to genetically alter the cells to distinguish them, is a key advance, the researchers say, toward obtaining the appropriate cells for repairing specific damaged tissues.
Identifying a molecular tool to manipulate stem cells and cancers – UCSF’s Robert Blelloch, MD, PhD, is pioneering studies of microRNAs, molecules that regulate the switch between proliferation and differentiation in both stem cells and cancer. He and others worldwide are excited about the prospect of using microRNAs to manipulate cells at will: either inducing adult cells to de-differentiate to stem cells – which could be expanded, manipulated and returned to the patient – or promoting differentiation to produce tissues of choice that would remain robustly integrated in the body once reintroduced.
“MicroRNAs give us a new tool to manipulate the fate of cells,” says Blelloch. “The goal is to use them to reprogram adult cells back to an embryonic-like fate, so that they can then be prompted to specialize as specific cell types and be used to repair damaged tissues.”
Discovering role of tiny filament in development, birth defects, cancers – UCSF scientists led by Jeremy Reiter, MD, PhD, have discovered that primary cilia – the tiny filaments extending from cells – help orchestrate embryonic development. The finding could lead to insights into the development of stem cells, as well as birth defects and cancers, and thus fuel therapeutic strategies.
In studies in the culture dish and in zebrafish and mouse embryos, the scientists showed that primary cilia play a key role in a form of cell-to-cell communication known as Hedgehog signaling. This molecular pathway helps prompt embryonic and adult stem cells to differentiate into specialized cells, such as those of the brain, pancreas and skin. The finding, says Reiter, will advance scientists’ efforts to use signaling molecules to direct the differentiation of embryonic stem cells in the culture dish, with the goal of using them to replace or replenish damaged tissues in patients.
Revolutionizing the stem cell fieldthrough a major discovery – Shinya Yamanaka, MD, PhD, now a senior investigator at the UCSF-affiliated J. David Gladstone Institute of Cardiovascular Disease, UCSF professor of anatomy and faculty member at Kyoto University, received the 2009 Albert Lasker Basic Medical Research Award – often a precursor to the Nobel Prize – for his breakthrough in reprogramming adult skin cells back to an embryonic-like state. He named these cells induced pluripotent stem (iPS) cells.
The discovery has revolutionized the stem cell field, offering a new frontier for scientists to study embryonic development, the ways diseases develop and how cells respond to experimental drugs. The cells also have become a focus of research for their potential use in regenerating damaged tissues of the body. UCSF scientists Robert Blelloch, MD, PhD, and Miguel Ramalho-Santos, PhD, are leaders in efforts to perfect the technique.
New Stem Cell Headquarters
With the February 2011 grand opening of its new headquarters building on the Parnassus campus, the Eli and Edythe Broad Center for Regeneration Medicine at UCSF continues to support a program that extends across all UCSF departments. The facility is constructed on a 60-degree slope, a metaphor for the ongoing political challenges faced by the field and the determination of the UCSF scientific community to pursue the research in spite of these challenges.
The building, a series of split-level floors with terraced grass roofs and solar orientation, consists of open labs that flow into each other, with office and communal areas located on the circulation routes between them. The layout is designed to allow the entire research community in the building to interact, a key to allowing the cross-pollination of ideas that fuels discovery.
The building, which at full capacity will house 25 principal investigators and their teams, will free up space in existing laboratories and offices, allowing for additional recruitments. UCSF has recruited 16 new faculty members to the center in the last three years. The building is located near UCSF Medical Center, symbolizing UCSF’s long-term goal of translating basic science research findings into clinical treatments.