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The Right Stuff
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| As a toddler, Ryan Tamayoshi received experimental treatment at the Children's Hospital for acute myeloid leukemia (AML), a relatively rare form of cancer. Today, five-year-old Ryan's cancer is in remission. Campaign-supported programs that apply the latest science to care make Packard an ideal place to treat such difficult cases. |
Ryan was doubly lucky because Dahl happens to be one of the nation's experts on AML. He and his Packard colleagues have been conducting long-term genetic studies to determine how AML patients respond to various therapies. For children like Ryan, the treatment can be debilitating – months of chemotherapy and countless blood transfusions.
As difficult as these procedures were, Ryan's cancer went into remission, and three years later, he's still doing well. Meanwhile, Dahl and his colleagues continue to look for therapies that are both effective and tolerable, especially for a child as young as Ryan.
Dahl's approach is known as "translational medicine," translating basic science into practical treatments. Today, dozens of Packard scientists are working around the clock to develop innovative surgical techniques and novel therapies for treating and diagnosing a wide range of childhood illnesses. In fact, translational medicine has become a pillar of the Packard approach to care – and support for such "bench to bedside" research has been a key objective of the Campaign for Lucile Packard Children's Hospital.
"The whole idea of translational medicine is to advance children's health by bringing very sophisticated technologies to clinicians," says Alan M. Krensky, M.D., the Shelagh Galligan Professor in the Stanford School of Medicine.
As chief of the division of immunology and transplantation biology in the Department of Pediatrics, Krensky is quick to point out the advantages of having a major pediatric hospital in proximity to Stanford's world-class schools of Medicine, Engineering, and Humanities & Sciences. "When you add in the environment of Silicon Valley, you see that this indeed is a very special place," he says.
During the past two years, Krensky has played a leading role in establishing the new Children’s Biotechnology Initiative, an innovative effort to develop new techniques using gene and protein analysis to diagnose childhood diseases. Part of the plan is to recruit scientists and develop additional lab space for pediatric biotech research. Financial support from the Campaign is crucial, Krensky notes, to meet the everincreasing demand for new diagnostic tools.
"Our Biotech Initiative has gotten off to a terrific start," he says. "We've recruited Jim Schilling, Ph.D., as our director, and we’ll be expanding the laboratory to an offsite space soon because of the growth of the program."
Schilling is a specialist in medical proteomics – a field that looks at the role proteins play in the development of disease. "Stanford is already very strong in genetics and genomics, but we thought there was a real opportunity in the area of proteins as well," Krensky notes. "Perhaps there will be proteins we can measure in the blood or urine that will help us diagnose diseases or determine which patients will respond to therapy. We are embarking on several pilot projects simultaneously where we're going to get blood or urine from patients and look for diagnostic markers of disease."
The pilot projects are focusing on children with juvenile diabetes, cancer, necrotizing enterocolitis (a disease that causes ulceration in the intestines of premature babies), and Kawaski disease (an inflammatory condition that can lead to serious heart problems).
"There are many diseases of childhood that we can develop diagnostic markers for," Krensky explains. "The question is, in a given disease, is there a marker that will tell you that this is someone who's going to respond to a certain therapy, or that they're going to have a good outcome or a bad outcome, or that you have to try harder or try something different."
"This is actually very sophisticated technology not generally available to clinicians," he says. "As we grow, the opportunity will be there for any doctor in the Packard system to come forward with a project that lends itself to the genomic-proteomic technique."
Pediatric surgery is another area where visionary science is expected to yield phenomenal advances in patient care. One example is organ transplantation. The number of transplants performed in the United States has more than doubled since 1988, yet the supply of healthy organs has not kept pace with the demand. As a result of this acute shortage, many desperately ill children are forced to wait months, even years, for a liver, kidney, or other vital organ essential for a long and healthy life.
Packard scientists have launched a bold research effort designed to meet this challenge. Their goal is nothing short of revolutionary – instead of relying on organ donors, why not develop technologies that use a child’s own cells to grow replacement tissues and organs?
"I'd ultimately love to put organ transplantation out of business," says Michael T. Longaker, M.D., F.A.C.S., director of the Children's Surgical Research Program at Stanford.
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| Michael Longaker, M.D., F.A.C.S., directs Packard's Children's Surgical Research Program, one of the new initiatives funded by the Campaign that brings together medicine and research. |
Longaker oversees a team of newly recruited scientists dedicated to unlocking the mysteries of tissue development in embryos and infants.
"Our goal is to translate discoveries toward regenerating, repairing, and replacement medicine as it applies to children," says Longaker, the Deane P. and Louise Mitchell Professor in the School of Medicine. "All of our faculty are committed to translating what we're doing, not just for the sake of science but to revolutionize the way we treat children. That's a philosophy we have, and it's a philosophy we're passionate about."
The new program is housed in the Center for Children's Surgical Research, a 14,000-square-foot laboratory that opened its doors in spring 2002.
"We're delighted that, with the help of Campaign funds, we've been provided with a freestanding building right in the middle of the Stanford medical quad," Longaker says. "This is really our central command, which allows us to collaborate with other scientists and engineers throughout the campus as a way to leverage our productivity and advancement."
Recruited to head the program in 2000, Longaker has used Campaign support to enlist four other leading scientists who are pursuing a number of novel experiments:
By the end of 2005, Longaker hopes to have recruited two additional scientists with expertise in blood vessel development and regeneration. "Being a plastic surgeon, I tend to be focused on skin and bones, but I’m an equal opportunity tissue engineer," he says.
Longaker's lab is involved in several areas of tissue research, including pioneering experiments using multipotent cells obtained from fat. These specialized cells have the ability to transform into bone, muscle, and cartilage cells, which can then be used to replace diseased or damaged tissue. "More than 200,000 Americans had liposuction last year, and the fat was simply thrown out," he says. "There are about a billion multipotent cells per liter of fat, and an average of two or three liters per liposuction, so that's a heck of a lot of usable cells that are going to waste."
How would tissue engineering ultimately help a child? "Say you have a cancerous tumor removed from the thigh or the knee," Longaker explains. "It's devastating. Do you amputate? Do you insert a metal implant like you would an adult? But this is a growing child. Ideally, we should be able to replace the missing bone with a bio-artificial material that slowly degrades over two years while we re-engineer the tissue with fat cells from the child's body. The good news is that they're the patient's own cells and tissues, so immunologically they're not rejecting anything."
Longaker points out that he and the other scientists in the Center have received generous financial support during the Campaign from the Oak Foundation, Harry and Shirley Hagey, Marcia and John Goldman, Bernard and Susan Liautaud, Barbara and John Packard, and Anaflor Smith. Yet much more is needed to assure that these futuristic lab experiments become a routine part of pediatric care.
"We know that every day children around the world die because of tissue deficiency," Longaker says. "And scarring and its manifestations touch millions of children. Seven to 10 years from now we'd better be in clinical trials to change the way we treat children or I'll be doing something else."
"Science is like a river," Longaker observes. "You sort of meander where the data take you."
And sometimes the data take you to unexpected places, says Marlene Rabinovitch, M.D., the Dwight and Vera Dunlevie Professor in Pediatric Cardiology. Recruited to Stanford from the University of Toronto in 2002, Rabinovitch is a leading authority on pulmonary hypertension – a rare, life-threatening disease in which the heart's ability to pump blood to the lungs is severely reduced because of abnormally high pressure in the pulmonary arteries.
"It's a very devastating condition that essentially affects every age group, from newborns to young children and adults," Rabinovitch says.
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| Marlene Rabinovitch, M.D., divides her time between caring for patients and researching ways to treat and prevent cardiovascular and pulmonary diseases in children. Rabinovitch, a leading vascular biologist, was recruited to Packard as director of cardiovascular research at the Vera Moulton Wall Center for Pulmonary Vascular Disease. The Center was established in 2000 by an anonymous Campaign gift. |
Using state-of-the art lab technology, she and her staff are probing the complex biological factors that contribute to this mysterious condition. Rabinovitch has been trying to find out how a genetic defect is partly responsible for the damage, but in the process, she and her colleagues discovered an unexpected link to cancer as well.
"We have found a gene expressed in cancer cells that can lead to the development of pulmonary vascular disease in animals," she says. "The question we're asking now is, what's the connection between this gene and the aberrant growth of the cells in the blood vessel wall? That's been very interesting research, and it might give us a new window on how the same genetic abnormality can predispose to cancer in some individuals and to diseases such as pulmonary hypertension in others."
Rabinovitch's lab has made other discoveries as well. For example, a gene involved in muscle cell development turns out to play a crucial role in the growth of nerve cells, and an enzyme that causes damage to the pulmonary artery also contributes to the buildup of arterial plaque and plays a key role in other cardio-vascular conditions.
“We're now in constant communication with cancer biologists and other researchers who are working on the same genes," Rabinovitch says.
She credits her lab's current success to the Vera Moulton Wall Center for Pulmonary Disease created in 2000 through a Campaign gift from an anonymous donor. "The Center was absolutely instrumental in allowing us to set up our laboratory," she says. "We've been able to build on the collaborations we had in Toronto and elsewhere and come into a new environment of very different investigators and take the program to great heights."
Tremendous strides also have been made in the treatment of pediatric cancer in the last 40 years, thanks in large part to remarkable advances in genetics, molecular biology, and diagnostics. Packard scientists will be at the forefront of this scientific revolution that is expected to accelerate in the 21st century. With the Campaign's backing, the Hospital recently established the Cancer Biology Program, the laboratory research component of the Cancer and Blood Diseases Center of Excellence.
Michael Cleary, M.D., a professor of pathology and pediatrics, has been chosen to lead the new program. An expert on the role of cancer genes in the development of leukemia, Cleary is also the first person to hold the Lindhard Family Professorship in Pediatric Cancer Biology at Stanford.
"The Center for Cancer and Blood Diseases is committed to outstanding clinical care and research," says Harvey J. Cohen, M.D., Ph.D., chief of staff of Packard Hospital and chair of Stanford's Department of Pediatrics.
"The Cancer Biology Program was the missing link in our research effort," Cohen adds. "Now we're in place to take the new biology that's developed in the last 20 years and translate it to improve the survival rates of children with cancer."
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| Julien Sage, Ph.D., a recent additionl to Packard's newly established Cancer Biology Program, prepares genomic DNA from a mouse tumor. Sage's lab studies the mechanisms of how normal cells transform into cancers, focusing on the retinoblastoma (Rb) family of tumor suppressor genes. |
The first scientist recruited for the Cancer Biology Program is Julien Sage, Ph.D., an assistant professor of pediatrics and genetics, who came to Stanford from MIT in January 2004. "There’s a lot of very good basic science here," Sage says. "But we're also right next to a hospital, and when you do cancer biology, it's always important to know what the doctors do or say, and what the patients look like, to determine how well we're doing in basic research."
Sage's research focuses on answering a fundamental question: How does cancer initiate? To find out, he and his colleagues study the role of tumor suppressor genes in retinoblastoma – a cancer of the retina that usually appears in early childhood. A rare disease, retinoblastoma is treatable by surgery and chemotherapy if caught in the early stages.
Sage believes that understanding how these tumors develop in mice will provide important insights into other cancers as well. "It's hard for doctors to see how a tumor starts," he explains. "But with the mouse you have the possibility of dissecting at the stage right after initiation. With a mouse tumor, you also can do molecular analysis of potential drugs and see how and why they killed the tumor."
A native of France, Sage is surprised and delighted that so many Americans embrace the idea of translational medicine and scientific research in general. "Unlike Europe, here people are into science, and that's great," he says. "I'm amazed by how much money people give, and it makes science so much easier. At Stanford, new technologies are developed every day. Being here, you're always feeling the buzz of Silicon Valley. You don't want to miss the train basically. You don't want to be two years behind."
Adds Longaker: “I'm an M.D. by training, so I'm not doing this solely for the sake of developmental biology and genetics. We want to change the way we treat children. That's our mission.”
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