At the Heart of it All: Collaborative Stem Cell Studies Promise to Revolutionize Pediatric Medicine

What if, for the one in 100 babies born with some form of birth defect, there were an alternative to medication, surgery, and long term care? What if doctors could grow a new organ from an infant’s own genetic material, reversing the malformation? Or intervene at exactly the right moment to prevent the problem from even taking place?

“Imagine if we could take a defective heart valve, for example, and grow a new one out of existing tissue,” says Daniel Bernstein, MD, the Alfred Woodley Salter and Mabel G. Salter Endowed Professor in Pediatrics and chief of pediatric cardiology at Lucile Packard Children’s Hospital. “There would be no chance of rejection since it would be derived from the patient’s own cells. And, because it would be living tissue, it would grow as the child grows, avoiding the need for replacement surgery later on.”

Just a few years ago, such feats were the stuff of science fiction. Today, innovations in stem cell research could hold the key to an amazing array of new therapies for pediatric ailments ranging from congenital heart disease spina bifida, cerebral palsy, diabetes, and even cancer.

In pursuit of these cures, physicians at Packard Children’s are working closely with basic scientists at the Stanford University School of Medicine to understand how stem cells transform into the incredible variety of specialized tissue that makes up the human body. By studying the mechanisms of cell development in the laboratory, they hope to recognize and correct the errors that cause many of childhood’s most devastating diseases.

A Big Step Forward

The most exciting potential use for stem cells may be regenerative medicine—treating disease by replacing damaged tissue with cells that have the remarkable capacity to produce differentiated kidney, spinal cord, heart, and brain cells. Currently, donor organs must be transplanted to replace those that are damaged; a regenerative approach would reduce the need for transplants and their related medical complications. But first scientists must identify a reliable system for creating stem cell lines. 

Michael Longaker, MD, FACS, and Joseph Wu, MD, PhD, are leading groundbreaking stem cell research that one day may address many of childhood's most devastating diseases.

Recently, Packard and Stanford physician scientists working in several different disciplines choreographed a new method of creating induced pluripotent stem cells (iPS)—adult cells that have been genetically reprogrammed to revert back to stem cells. In a groundbreaking paper published in February in the scientific journal, Nature Methods, Joseph Wu, MD, PhD, assistant professor of cardiology, derived iPS cells from human fat, and then coaxed them into becoming different specialized cell types.

It’s a big step forward in accessing and controlling stem cells, says Michael Longaker, MD, FACS, the Deane P. and Louise Mitchell Professor and director of the Hagey Laboratory for Pediatric Regenerative Medicine, and holds great promise for tracking—and someday treating—a range of pediatric disorders.

Says Wu, “iPS enables us to understand the molecular mechanisms of disease development, and may lead to techniques that will change how we treat heart problems. In a patient with a congenital heart disease, for example, we could take their fat cells, reprogram them into iPS, and then into a cardiac cell. That would give us a platform to study the cells and compare them to normal cells to see why they change, how they behave, and to create a model to test drugs.”

Wu’s research is collaborative by nature, and his study incorporated wide-ranging expertise in stem cell biology, gene therapy, cardiology, and other fields.    

Induced pluripotent stem cells—adult cells genetically reprogrammed to revert back to stem cells—hold great promise or someday treating a range of pediatric disorders.

For instance, he used minicircles—minute rings of DNA—to derive the iPS cells. The small size of the minicircles allows them to enter a cell more easily than other delivery systems and, because they don’t replicate, they cannot alter the cell’s genetic makeup, an ongoing aftereffect that can affect therapeutic applications.

The minicircles technique was developed by Mark Kay, MD, PhD, the Dennis Farrey Family Professor and director of the Program in Human Gene Therapy, as a way to eliminate the complications caused by traditional methods of using viruses to introduce genes into a cell.

Breakthroughs in the Wu Lab incorporated gene transfer techniques developed by Mark Kay, MD, PhD.

“It’s a safe, simple process,” says Kay, “and appears to be an important direction to pursue for basic science investigations as well as for preclinical studies. This project is a great illustration of where gene therapy and stem cell biology come together. It’s a model for how we can move forward.”

Pushing Forward

iPS also holds great promise for studying upwards of 5,000 diseases scientists have identified that are caused by single gene defects. These diseases affect the quality life of newborns and children, and their families. Stem cells may allow researchers to create scenarios that duplicate these diseases to learn about process and intervention—how to overcome faulty genetic programming.

“These studies are do-able right now,” says Kenneth Weinberg, MD, the Anne T. and Robert M. Bass Professor in Pediatric Cancer and Blood Diseases. “Research in this area will give valuable insight into the development of pediatric disease. We can ask questions in ways we could never ask before, helping us to identify the most promising avenues for therapy.”

Weinberg plans to use iPS cells to delve into DiGeorge syndrome, a genetic change on chromosome 22 that is responsible for as much as 5 percent of congenital heart defects in the U.S., as well as malformations of the thymus, parathyroid glands, and face. By trying to duplicate the developmental process using stem cells, he hopes to pinpoint the exact moment when the gene involved in this disorder goes awry.

“We don’t know yet what the gene does during development because the process has been unavailable for study,” he says. “Using iPS will allow us to watch both normal and abnormal development side by side, and to observe the process, not only the result.”

Innovation and Information

Many other important advances have originated at Packard and Stanford thanks in large part to a research culture that encourages translational medicine—a close interrelationship between basic science investigators and the surgeons and physicians working directly with patients. Together they are addressing some of the great challenges of stem cells.

For example, as stem cell breakthroughs accelerate at full throttle, scientists are generating a barrage of new biomedical information. All of these data need to be organized in a way that allows researchers to access and analyze ongoing findings, whether it is to study how normal stem cell activities are altered in different disease states or to identify the effect of environmental conditions on cellular response.

“There’s been a virtual fire hose of information,” says Atul Butte, MD, PhD, assistant professor of pediatrics and medical informatics, who oversees complex computational efforts at Stanford that analyze and interpret biomedical data. “Our system allows basic scientists to access a wealth of existing information. We’re able to organize and reorganize it to help spark new research questions.”

Today, Butte and his team are coordinating algorithms using findings from 1,500 stem cell microarrays around the world to identify a certain cell receptor—taking only a fraction of the time such a comparison might have taken in the past. “We can study in a new way virtually everything that’s been measured in the past,” he says. “We do medicine from a data-driven perspective.”

This access to reams of data will help researchers address the many unanswered questions of stem cell biology: How can stem cells be instructed to become a specific cell type? What causes them to differentiate? How can they be regulated to restore tissue function or replace a malfunctioning part?

Partners in Progress

Packard and Stanford physician scientists agree that breakthroughs will continue to take place where there are close collaborations among researchers who are dedicated to advancing stem cell science and building a foundation for the future of regenerative medicine.

“There remain many fundamental questions to be resolved, but we’re positioned for rapid success because of how easily different perspectives can work together here,” says Michael Longaker. “Packard’s alignment with the University places it right at the heart of where these breakthroughs will come from. There’s a network in place that was formed to bridge the gap between scientific research and real-life medical applications, to truly go from ‘bench to bedside’ for the benefit of children’s health.”

It’s important to pursue many different avenues of stem cell research, he adds, because findings in one discipline may relate to a seemingly unrelated investigation, adding to the promise for understanding and treating a range of childhood diseases. Almost every aspect of pediatric medicine may be affected by better understanding and control of stem cells, and by developing a system of accessing reliable stem cell lines for study and potential application.

“Stem cells will be the big innovation in pediatric cardiology,” predicts Dan Bernstein. “There may come a day when we can avoid transplanting a child’s organ altogether by using cell transplants to fix the one that’s already there.”