Examples of Packard Translational Research

Nearly all Packard faculty are involved in some type of pediatric translational research. Here are just a few examples of their pioneering work:

Jill Helms, DDS, PhD, associate professor of plastic and reconstructive surgery, is conducting translational research on the developmental biology of the face and skull. "The overall goal of our lab is to investigate the underlying causes of certain birth defects and to devise early diagnoses that would prevent them from occurring," Helms says.

One example is a birth defect called holoprosencephaly (HPE), the most common malformation of the forebrain. An estimated one in 10,000 children in the United States is born with HPE each year. HPE can produce a wide range of facial abnormalities, from cleft lip to cyclopia -- a fatal form of the disease characterized by the development of a single eye.

While there are some hereditary forms of HPE, most cases are not genetic. "Some result in severe mental retardation, although there are milder forms of HPE where kids have moderate learning disabilities but shortened lives," Helms explains. "We're still not sure what causes this wide spectrum of symptoms."

To find out, she and colleagues Dwight Cordero, MD, and Minal Tapadia, MD, conducted a series of experiments in which they treated chicken embryos with a harmful plant extract called cyclopamine. "We showed that we could recreate the spectrum of HPE in developing chicken embryos by varying the timing of their exposure to cyclopamine," she says. For example, early exposure produced embryos with cyclopia, the most severe form of the disease, while later exposure resulted in milder symptoms.

Helms and her co-workers are now investigating whether women who consume alcohol and other potentially harmful compounds during various stages of their pregnancy put their babies at higher risk for developing HPE. "When we think about translational medicine, we think about prevention," she says. "Our global strategy should be to develop new techniques to prevent all birth defects."

Elizabeth Mellins, MD, professor of immunology and transplant biology, studies autoimmunity. The projects in her laboratory cover the spectrum from basic cellular processes to questions about how specific diseases develop. Trained as a pediatric rheumatologist, she is particularly interested in rheumatic diseases of childhood, which are estimated to affect one out of every 1,000 children born in the United States.

A major focus in her lab is systemic-onset juvenile rheumatic arthritis (SOJRA), which is believed to affect thousands of children each year, causing persistent pain and swelling of the joints that can be accompanied by a high fever and skin rash. Although SOJRA represents only 10 to 20 percent of all juvenile rheumatoid arthritis cases, it's responsible for twothirds of the arthritis-related mortalities in children. And 25 to 50 percent of kids diagnosed with SOJRA will have significant joint damage and may face the need for joint replacement.

"In older adults, arthritis occurs because the joints wear out after years of use," Mellins says. "But with SOJRA, we believe the child's body is making some kind of mistake that results in inflammation of the joints. Perhaps the immune system thinks there's an infection, and it responds by attacking the joints."

To find the biological mechanisms that cause SOJRA, she and her colleagues have been collecting blood and urine samples from children at various stages of the disease. "About 50 percent of children with SOJRA have the monocyclic variety: They experience one major episode that may last a year or so," she says. "The other 50 percent follow a polycyclic course with chronic episodes that may recur over many years."

Mellins and her co-workers are now analyzing genes and proteins in the children's blood cells and plasma in hopes of identifying unique biomarkers that will allow researchers to predict which course the disease will take and to develop therapeutic targets to fight that particular type. The task is daunting.

"The challenge we face is that the immune system is very flexible and redundant," she says. "It deals with an ever-changing sea of germs. It never puts all its eggs in one basket. Otherwise, germs could figure out how to attack that one basket."

Alan M. Krensky, MD, the Shelagh Galligan Professor in the School of Medicine, is chief of the Division of Immunology and Transplant Biology at Stanford. An important focus of Krensky’s lab is on the biology of T lymphocytes, or T cells—white blood cells that play an important role in regulating the immune system.

"Our goal is to design treatments for children who have undergone an organ transplant, or who are battling cancer, or infectious or autoimmune diseases," Krensky says. One example is a remarkable protein called granulysin, which is naturally expressed in T cells in adults and children. Granulysin is capable of destroying tumors and a variety of pathogens, including bacteria, fungi, and parasites.

"Our lab has investigated a number of potential uses for granulysin, including as a topical salve to cleanse wounds and as an antibiotic to fight a wide range of diseases that affect thousands of children worldwide, from tuberculosis to leprosy to cholera," he says.

Granulysin could even prove to have important antibacterial properties against pediatric infections that no longer respond to conventional antibiotics. "So far we have found no evidence that E. coli and other bacteria are resistant to granulysin, so it may turn out to be useful when other antibiotics don't work any more."

Krensky's lab is applying the fundamental aspects of immunology to another protein called HLA, which protects the liver and other organs from being attacked by the body's own T cells. The researchers hope to develop an artificial form of HLA that could be used to dampen the immune response in children who have undergone organ transplants. Their work also may help in the early detection and prevention of juvenile diabetes, which results when the child's immune system attacks and destroys insulin-producing cells in the pancreas.

After 21 years in the School of Medicine, Krensky is optimistic about the future of pediatric research at Packard: "Stanford always has been a leader in translational medicine for one reason: Cutting-edge technology always has been available right here on campus. I'm confident we'll retain our leadership role well into the 21st century."

Michael Cleary, MD, is professor of pathology and pediatrics at Stanford and the first holder of the Lindhard Family Professorship in Pediatric Cancer Biology. His lab studies the role of cancer genes in leukemias and lymphomas, their function in normal embryonic development, and their value as clinical diagnostic markers and novel therapeutic targets. His studies have contributed substantially to the current view that leukemia results, in part, from alterations in the cell’s gene regulatory machinery.

"Our research focuses on developmental pathways that regulate normal blood cell growth and are disrupted when cells become cancerous," Cleary says. "We are particularly interested in the role of human cancer genes, or 'oncogenes,' and the functions of the proteins they encode, which have been implicated in the development of pediatric leukemias and lymphomas. Our studies have demonstrated that several of these oncoproteins play an important role in gene regulation and disrupt growth control processes that otherwise produce normal blood cells."

In one recent mouse study, Cleary and his co-workers discovered that a protein called menin has the ability to both suppress and promote certain forms of acute leukemia that represent 5 to 10 percent of all leukemias in children and adults. If these results apply to humans, "we would probably stop a leukemia dead in its tracks and have a promising target for design of molecular therapies," Cleary says.

In addition to studying leukemia pathogenesis, he and his colleagues are devising new diagnostic procedures for detecting and monitoring leukemia patients based on molecular genetic abnormalities in their malignant cells. In fact, Cleary helped establish the first molecular diagnostics laboratory at Stanford and was recently chosen to lead the cancer biology program within the Center for Cancer and Blood Diseases at Packard Hospital.

"The unifying theme of the Program in Cancer Biology is the study of the molecular biology and genetics of cancer," Cleary says. "We seek to understand the mechanisms responsible for cell transformation and oncogenesis, particularly as they relate to pediatric cancers. With this knowledge, we will be better positioned to design new diagnostic and therapeutic approaches to improve the prognosis for children with cancer."