A Blueprint for the Future: Children's Surgical Research

BY MARK SHWARTZ

The new Center for Children's Surgical Research will house engineers, scientists, and doctors who will develop innovative technologies, like tissue engineering, to help children with life-threatening diseases.

SPRING 2002 - Imagine a young girl, blind since birth, whose vision is restored overnight thanks to artificial optical nerves surgically implanted in her brain. Or picture a 7-year-old with juvenile diabetes getting a healthy new pancreas that was grown in a laboratory from the child's own stem cells.

These examples may seem the stuff of science fiction, but such innovative therapies are expected to become a routine part of pediatric care at Lucile Packard Children's Hospital in the 21st century.

In a bold attempt to bridge the worlds of medicine, engineering, and the physical sciences, Packard is working with members of the pediatric program at the Stanford School of Medicine to develop a oneof- a-kind Children's Surgical Research Program. Their aim is to boost the Hospital's clinical and surgical services by developing a cutting-edge research program that combines the expertise of Stanford's schools of Engineering, Medicine, and Humanities & Sciences.

In 2000,Michael T. Longaker,M.D., FACS, one of the nation's leading surgeons and researchers, was recruited to Stanford from New York University to build Packard's Surgical Research Program.Much of Longaker's work has focused on laboratory growth of tissues, particularly the repair of craniofacial hard and soft tissue in infants.

"Developmental biology and engineering will be the cornerstone of our research," says Longaker. "It's best to have engineers, scientists, and clinical researchers working closely with surgeons, and Packard is the best place to do that."

Center for Children's Surgical Research

Longaker has been overseeing the recruitment of researchers for the new Center for Children's Surgical Research -- a 13,000-square-foot facility near Stanford University School of Medicine. Slated for completion in spring 2002, the Center is dedicated to research in tissue engineering, gene therapy, stem cell transplantation, and other yetundreamed- of biomedical breakthroughs.

"We're assembling a very exciting team, but we're embryonic, " notes Longaker, who serves as the Center's director. "We need to grow, and moving into the new building is the first step. It allows Packard and children's surgical research to have its own identity. It's near Stanford Hospital, the Medical School, and the Bio-X Center, but even in this large medical quad, we'll have our own footprint."

The University's new Bio-X program is an unprecedented academic effort blending biomedical, bioscience, and bioengineering research across the campus. Bio-X, combined with Stanford's location in the heart of Silicon Valley, has been a major factor in attracting the best and the brightest to Packard's Surgical Research Program.

The exciting advances that emerge from the Center in coming decades will be limited only by the imagination of the engineers, scientists and doctors involved in the program, says Alan Krensky, M.D., chief of the Division of Immunology Transplantation and Biology at Stanford.

"The major reason we're here is to help children, but our clinical care and surgical programs will be no better than the research we do in the future," Krensky maintains. "One day, we'll be able to replace body parts at will, like replacing parts in an automobile. There's no question that will happen.

"We have already recruited the leading organ transplantation surgeons in the world," he says. "Now we want to hook up all of our pediatric surgeons with Bio-X and begin collaborative research efforts."

Tissue Engineering

A primary area of research in the new Center will be tissue engineering -- the development of laboratory-grown cells and tissues to enhance and replace damaged body parts.

"Children are dying every day waiting for an organ or tissue we don't have," Longaker explains. "We'll look at transplantation; can we do it differently? Can we use stem cells to grow organs and tissues rather than having children wait for donors?"

Children's Surgical Research team members Karl Sylvester, M.D., Peter Lorenz, M.D., and Michael Longaker, M.D., (left to right) confer with architect Dick Smith over plans for the new Center for Children's Surgical Research.

Livers, hearts, and lungs are extremely complex, and most experts believe that successful organogenesis -- growing a whole replacement organ in the lab -- is years away. In the near term, Longaker expects to see breakthroughs in the bioengineering of structural tissue -- skin, bone, and cartilage that can be grown in the lab and provided to children with a variety of medical needs.

Longaker is currently working on a technique called distraction osteogenesis. The technique uses bone separation to treat children with dwarfism and pathologically tiny jaws. "It turns out that when you divide the mandible, then pull the two bony ends apart, the jaw lengthens," Longaker says. "We're using laboratory rats as a model for understanding why that extra bone forms."

Another area of research is cranial suture fusion. One in 2,500 children is affected by craniosynostosis, the premature closure of the growth plates between the skull bones. The condition can restrict brain growth and cause major deformities of the face and skull -- and sometimes result in blindness or death. "We'd like to know if there's a way to use less invasive surgeries based on a thorough knowledge of which genes are involved in the disease," Longaker notes. "It's the biomolecular approach versus the chisel and hammer."

Fetal Wound Healing

An especially promising area of tissue engineering is fetal wound healing, or the ability of the embryo to heal itself without scarring.

"We're trying to answer the question of why embryos can heal in a fashion you and I could only hope to have," Longaker says. "We recruited Peter Lorenz, M.D., a leading pediatric plastic surgeon from UCLA, to study this phenomenon."

Longaker's own lab is focusing on keloids -- wounds that over-heal, producing excessive amounts of scar tissue. "Understanding embryonic healing and excessive scarring should allow us to understand the mechanics of healing -- to figure out the blueprint of Mother Nature," Longaker points out. "Humans are the only species that over-heal.What is the regulatory mechanism in our 25,000 to 30,000 genes that causes that?"

Although Packard's mission is to treat children, Longaker notes that scarring is also a tremendous problem in adult medicine. "Scars are produced in every organ: in the heart after a heart attack, in the liver as a result of cirrhosis. Understanding scarring in children will ultimately provide important background for treating adults," he predicts.

Stem Cell Research

At the heart of much of tissue engineering lies stem cell research. To spearhead its burgeoning stem cell program, Packard recently recruited Karl Sylvester,M.D., from Yale University.

"There is a lot of national interest in finding adult stem cells that can be programmed to transdifferentiate from one germ line to another," Sylvester says. "Our interest is in taking stem cells found in bone marrow or subcutaneous fat, altering their genetic code in a dish, then re-infusing those cells to replace defective cells that are sick or dying."

Working in collaboration with UCLA, Sylvester and his team are collecting subcutaneous fat from adults who undergo liposuction."With liposuction, we can get liters of fat tissue containing stem cells that can become cartilage and muscle," he notes. "We also hope that these stem cells can cross lineage barriers and become brain and liver cells, which can be used to replace defective tissues."

Sylvester concedes that it will take extensive collaboration among developmental biologists, chemists, physicists, and engineers to bring experimental stem cell research from the lab bench to the patient's bedside. "One of the beauties of Stanford is the depth of expertise that exists across scientific disciplines," he says. "That's one of the things that brought me here."

Clinical Applications

While researchers are concentrating on work in the lab now, the Center's ultimate goal is to give pediatric surgeons better materials and techniques to treat children. "The overall theme for the new Center for Children's Surgical Research is inductive biology -- providing the things that Nature has depleted in children," Longaker observes. "I have a 'wish list' from many of our pediatric surgeons: to engineer a heart valve, a kidney, a bladder -- even sections of intestine."

One of those surgeons is R. Lawrence Moss, M.D., an associate professor of surgery and of pediatrics at Stanford.Moss treats infants with a severe bowel disorder called necrotizing enterocolitis or NEC, which affects one in 20 premature babies.

"I do hundreds of operations a year -- all types," says Moss. "I feel very strongly that meaningful research comes from clinical experience."

To find a cure for NEC, Moss has joined forces with developmental biologists in a research project to determine how the intestine forms in the embryo. "Our hypothesis is that there is something about premature blood vessels that leads to NEC," he explains. "We'll be tracking embryos at both the cellular and genetic level to determine how the blood supply develops in the bowel."

Moss advocates overhauling the state of clinical research in pediatric surgery. In a recent study, he and his Stanford colleagues discovered that the vast majority of pediatric operations routinely performed in U.S. hospitals were developed with anecdotal evidence rather than objective clinical trials.

"I'd like to see Packard eventually become the preeminent center for multicenter clinical research in children's surgery," he says. "Right now, our program is the one that people around the country are looking at."

The seemingly remote frontiers of pediatric surgery will become a reality in the very near future, Longaker concludes. "In the next five to seven years," he says, "we have a fantastic opportunity to change the way we treat children."