Every day, countless children worldwide are living to see longer, brighter futures thanks to discoveries at the The Children’s Hospital of Philadelphia Research Institute. The 2015 Annual Report places the spotlight on the collaborations, innovations, and breakthroughs that are shaping the health of generations to come.

Leading the Research Institute into the next era of pediatric healthcare is Bryan A. Wolf, MD, PhD, who took on the role of Chief Scientific Officer (CSO) and Director of the Research Institute in April. Dr. Wolf, a diabetes researcher, served as pathologist-in-chief and chair of the Department of Pathology and Laboratory Medicine from 2001 to 2008 and was most recently CHOP’s chief information officer and senior vice president.

Building upon CHOP’s legacy as one of the preeminent pediatric research institutions in the world, Dr. Wolf began in spring 2015 an ambitious, faculty-led strategic planning process to make the most of the Research Institute’s talent, intellect, and energy to ensure continued success every step along the way to improve the health of children.

“I believe this is the ideal time for us to see how far we’ve come at The Children’s Hospital of Philadelphia Research Institute, and to look ahead to where we’d like to go, while paying careful attention to the bumps we’ve encountered in the road and to resources and opportunities now within reach,” Dr. Wolf said.

The strategic plan will ultimately illuminate the next stretch of the Research Institute’s trailblazing path and, in the process, identify and support a handful of transformative research initiatives that will produce the most knowledge and clinical impact.

The future is here, as we create breakthroughs and advance the best in pediatric care to ensure that all children’s lives are full of possibilities.

During doctors’ visits a few years from now, your physician might not only ask how you are feeling but also inquire about how your giant collection of bugs — your microbiome — is doing.

Scientists participating in the new PennCHOP Microbiome Program have extraordinary research opportunities to explore the trillions of organisms that are within us — or on us — and how these microscopic communities can sway our health. The microbiome may play pivotal roles in the likelihood of acquiring conditions such as obesity, gastrointestinal disorders, and autism, and how our bodies respond to those states.

“If we take advantage of what they’re trying to tell us, it’s going to change medicine in the future,” said Microbiome Program Co-director Robert Baldassano, MD, a pediatric gastroenterologist who also directs the Center for Pediatric Inflammatory Bowel Disease at The Children’s Hospital of Philadelphia. Dr. Baldassano also is a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

One hundred billion bacterial and microbial cells fit into a gram of gut material, but despite their tiny size, the microbiome produces metabolites that can have a big voice. Gut bacteria, for instance, help to create about 95 percent of your body’s serotonin, which influences mood, depression, and behavior. Microbes that are associated with your body also help make vitamins, aid digestion, and set your immune tone.

Advancements in deep DNA sequencing technology over the last five to 10 years have made it possible for researchers to characterize the bacterial, fungal, and viral members of the human microbiome. When the Microbiome Program launched in August as a Center of Emphasis at CHOP, it became the only pediatric center in the world with such state-of-the-art facilities and assets, Dr. Baldassano said. The Center gives researchers the ability to identify, measure, and monitor microbiota communities within pediatric biosamples from multiple body sites, including gut, airway, and skin.

These methods generate enormous amounts of sequencing data. Our microbiota contain at least 100 times more bacterial genes than our own bodies have human genes. The program offers bioinformatics and analytical tools from CHOP’s Department of Biomedical and Health Informatics that allow researchers to identify microbes, and pinpoint and interpret genetic differences in nearly identical organisms.

Research teams at CHOP and the Perelman School of Medicine at the University of Pennsylvania share all of the Microbiome Program’s resources, including a population of germ-free (gnotobiotic) mice that are available as animal models. The research collaboration facilitates a diverse range of basic, translational, and clinical research that provides a lifetime perspective on the microbiome from infancy into adulthood.

Microbial colonization begins at birth and continues to develop in early childhood. These formative years for microbiome communities depend on multiple factors such as where you live, your household environment, what you eat, the medications you take, and your genetic composition.

“Many studies suggest that the most important time for the impact of these organisms is during the first few years of life, so this is a significant pediatric issue that will allow us to intervene in disease processes,” Dr. Baldassano said.

The Microbiome Program’s focus on designing human interventions makes it unique, agreed Co-director Frederic Bushman, MD, an adjunct faculty member at CHOP and a chair and professor of Microbiology at the Perelman School of Medicine. As researchers begin to identify microbiome environments that are associated with wellness, they can figure out how to push the microbiome in healthy directions, such as by changes in diet. Scientists also are testing ways to manipulate or engineer microbial populations to influence different disease states.

“We are gathering this kind of data to circle back to patients,” Dr. Bushman said. “We can use this knowledge to try experimental therapies to improve patient welfare.”

Dr. Bushman also sees future applications for metagenomic analysis of the microbiome in diagnostics. For example, if an immunocompromised patient has been sick for a long time, and nobody can determine why, deep sequencing could allow clinicians to identify outgrowths of opportunistic bugs that they may not have previously considered.

In a recent research project, Dr. Baldassano, Dr. Bushman, and colleagues James Lewis, MD, MSCE, and Gary Wu, MD, at Penn showed that dysbiosis — when the variety and balance of microorganisms in the microbiome are disrupted — appears to lead to the perpetuation of pediatric chronic inflammatory bowel diseases. They collected half a trillion bases of sequencing information from the biosamples of 90 pediatric patients and documented that multiple environmental stressors altered these children’s microbiota. The researchers anticipate that the biomarkers they found will be useful in devising new diagnostic approaches and therapeutic targets.

Endless other possibilities exist at the Microbiome Program for investigators to discover the microbiome’s true potential. “Everybody finds this incredibly exciting, and many, many people are coming by,” Dr. Baldassano said. “We can empower them to expand their current research interests into the microbiome and further science.”

The HIV epidemic in 2015 and beyond is a dramatically different one than ever seen or imagined during the height of the AIDS crisis in the 1980s and ‘90s.

“In the early days, up to a quarter of all infants born to women with HIV became infected. Now it’s less than one percent,” said Richard Rutstein, MD, an HIV clinical research leader and medical director of the Special Immunology Service at The Children’s Hospital of Philadelphia since its inception in 1989. “For those infected, HIV has changed from a rapidly fatal disease to a chronic illness.” Dr. Rutstein is also a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

At the front line of this evolution, CHOP researchers are helping infected pregnant women, infants, children, and youth around the world live full, productive lives.

Pediatric HIV Care Grows Up

In past decades, a major focus of pediatric HIV research was blocking viral transmission to infants before and after birth. Now that successful therapeutic strategies are available to prevent perinatal transmission, there is a new frontier in pediatric HIV research: Adolescents. HIV/AIDS is among the leading causes of death in adolescents worldwide, and mortality in this group has tripled since the turn of the century.

One major group of high-need adolescents is in sub-Saharan Africa, home to 90 percent of children with HIV. Most were infected perinatally, and many grow up managing the infection well until normal adolescent behaviors — independence-seeking and risk-taking — upset the balance. CHOP research is showing that parents may miss this cue to add support.

“Without understanding that that developmental transition is normal, some families are going to miss the need that’s there,” said Elizabeth Lowenthal, MD, MSCE, research director for CHOP Global Health, who has led research along with other CHOP investigators and international partners on the role of parental involvement and education in supporting these aging-up teens with HIV. Their work has deepened understanding of how this support and disclosure of a youth’s HIV status affects health outcomes and treatment adherence. Dr. Lowenthal is also an assistant professor of Pediatrics and Epidemiology at the Perelman School of Medicine.

In the U.S., getting infected with HIV during adolescence, as opposed to growing up with the infection, is a more frequent and growing challenge, especially affecting teens in stigmatized and disadvantaged groups including LGBT youth and youth of color. Adolescents represent more than a quarter of new infections in the U.S., and most do not know they are infected.

Nadia Dowshen, MD, director of adolescent HIV services at CHOP, leads research identifying barriers to routine adolescent HIV testing, using social media to encourage teens to get tested, and developing an app to improve medication adherence among youth with HIV. Her team is also studying factors affecting HIV prevention, diagnosis, and care among young transgender women. Transgender women are 50 times more likely to become infected with HIV than other individuals. Dr. Dowshen is co-founder and co-director of CHOP’s Gender and Sexuality Development Clinic, among only a handful of such specialized pediatric centers in the country. Dr. Dowshen is also an assistant professor of Pediatrics at the Perelman School of Medicine.

Halting HIV’s Impact On and In the Brain

Whether children grow up with HIV or become infected as adolescents, keeping them healthy includes managing and understanding their risk for complications, including neurologic ones. A broad and advanced array of research approaches at CHOP is illuminating the complex interconnections between HIV and the brain — and pointing toward interventions to prevent damage.

“HIV probably enters your central nervous system very soon after initial infection. Once there, the virus appears to both infect certain cells, as well as trigger an inflammatory reaction that causes a lot of secondary cellular and neuronal damage,” said Jennifer McGuire, MD, MSCE, whose research focuses on the neurological impact of acquired infection. She also is linking immune biomarkers to neuronal injury in these youth and combining this work with neuroimaging data. Dr. McGuire is also an instructor of Neurology at the Perelman School of Medicine.

David Bearden, MD, also a CHOP neurologist, is pursuing parallel questions about immune biomarkers in the brain, primarily in younger, perinatally infected children in Africa.

“Neurologic complications are very common in children with HIV, especially in low-resource settings where therapy may be delayed,” he said. Complications result from a combination of factors including direct and indirect effects of HIV on the brain, socioeconomic factors, in utero exposure to toxins, and inflammation.

Meanwhile, a CHOP-Penn team is looking at depression — a common co-occurrence with HIV, and a concern that often arises in adolescence. Depression, immune dysregulation, and susceptibility to HIV infection are all associated, the researchers have reported in adult studies led by Dwight Evans, MD, chair of Psychiatry at Penn. Immune function also improves when depression does, according to the team, which includes Tami Benton, MD, chief of Psychiatry at CHOP, Steven D. Douglas, MD, chief of the Section of Immunology at CHOP and a professor of Pediatrics at the Perelman School of Medicine, and other CHOP and Penn psychiatrists and neurologists.

Now turning their attention to teens, “We are examining the mechanisms of this relationship, specifically, does depression impact your immune system in a way that allows HIV infection to occur and to progress to AIDS?” Dr. Benton said.

Rethinking and Reengineering HIV Eradication

Part of the effort to address HIV in the brain is to eradicate the virus itself from its hiding places there. Dr. Douglas, who also leads several NIH HIV/ADS centers, clinical trials groups, and domestic and international networks, is pursuing this approach in a collaborative effort with Temple University funded by a NeuroAIDS grant.

Dr. Douglas’ internationally recognized work in NIH-supported programs targets a receptor on macrophages that changes the state of these cells from harboring virus in the body to potentially restoring immunity against HIV/AIDS. This tactic may decrease the body’s HIV reservoir and lead to a functional cure for HIV/AIDS.

Meanwhile, another unimagined vista is emerging in preventing HIV infection from taking hold the body. Decades of effort have focused on educating the body’s immune system about how to handle HIV — in other words, developing traditional vaccines. These efforts have largely come up short, with the immune system regularly getting a few too many questions wrong to pass its exam. A new approach is skipping the lecture and giving the immune system a cheat sheet for the test.

Immunoprophylaxis by gene transfer (IGT) was pioneered by CHOP’s former chief scientific officer Philip R. Johnson, MD, and first reported successful in monkeys in a 2009 paper in Nature Medicine. It is a method of genetically engineering the body to produce virus-fighting defenses on its own. This year, the International AIDS Vaccine Initiative partnered with CHOP to launch the first phase 1 clinical trial of the IGT method. More IGT-based trials are being planned around the globe.

This is among the many ways that, as CHOP researchers tackle the new everyday challenges that HIV presents, they continue exploring novel strategies to wipe out the disease.

As a bright-eyed toddler, Noah VanHoutan walked and talked. He giggled and twirled. Then, around age 3, he began experiencing seizures, and within a few months his physical, thinking, and language skills were fading mysteriously.

The eventual diagnosis three years later was Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), known as Batten disease. A recessively inherited brain disease, the disease robs children of their capabilities, leaving them blind, bedridden, and unable to communicate. It is fatal by age 12

Noah’s family received yet another devastating blow when they learned that his then 5-year-old sister, Laine, also had LINCL-Batten disease, but her twin, Emily, was unaffected. Their parents, Jennifer and Tracy, quickly calculated that 40 percent of their family were expected to die in less than a decade. They turned to researchers like Beverly Davidson, PhD, director of the Raymond G. Perelman Center for Cellular & Molecular Therapeutics at The Children’s Hospital of Philadelphia, to help ensure that future young families facing LINCL-Batten disease start off with better odds.

“Our family and our entire patient community are grateful for Dr. Davidson’s efforts to combat this devastating and cruel disease,” said Tracy VanHoutan, who helps to raise Batten disease awareness and research funding through the Noah’s Hope foundation and also serves as vice president of the Batten Disease Support & Research Association. “Without research, both basic and translational, affected children and their families would have no hope. Our patient community now has hope that this research will soon translate into the clinic.”

LINCL-Batten disease is within a group of disorders called lysosomal storage diseases that part of Dr. Davidson’s lab focuses on. Although individually rare, cumulatively lysosomal storage diseases occur in one in 10,000 children. Fewer than 450 children in the U.S. have LINCL-Batten disease. It is caused by mutations in the TPP1 gene, which encodes the lysosomal enzyme TPP1 that every brain cell needs in order to get rid of waste.

“We try to understand what is going wrong in the absence of these proteins and how we can develop new therapies to treat these children,” said Dr. Davidson, who also is professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. “Our research is really getting close to being translated to the clinic.”

One approach that Dr. Davidson and her team have been working on for many years is using gene transfer vectors to supply the enzyme directly to the brain. They modify the nonpathogenic adeno-associated virus as a vehicle to deliver the gene to ependymal cells that line cavities in the brain called ventricles. These cells then produce and circulate the enzyme within the cerebrospinal fluid so that it bathes the entire brain.

“The missing protein now has the ability to get into the cells and correct the disease,” Dr. Davidson said. “These cells that are secreting the protein are very, very long lived. This gene therapy should last the life of the individual.”

In mouse and dog models, preliminary data shows that a gene therapy approach to enzyme replacement therapy has a beneficial effect on disease onset and progression. Recognizing the disease at an early stage and starting treatment promptly will be critical to delaying the brain decay, Dr. Davidson said, but a “big unknown” is whether it will be possible to regain any brain function.

Dr. Davidson envisions that children could be treated with a relatively simple 30-minute surgical procedure performed by CHOP neurosurgeons to infuse the vector into the brain. In comparison, another experimental method involves putting the enzyme, rather than the gene, into the brain. Enzyme replacement therapy requires an indwelling device and delivery to the brain every two weeks in the setting of an intensive care unit. If the genetic version of enzyme replacement therapy proves to be successful, it could obviate the need for such an arduous routine.

“We hope to save their lives but at a minimum provide them with greatly improved quality of life with improved functional abilities,” Dr. Davidson said.

The Center for Child Injury Prevention Studies (CChIPS), a National Science Foundation (NSF) Industry/University Cooperative Research Center (I/UCRC), is celebrating 10 years of being on the road to safety, and it has been a fantastic ride.

In a unique partnership, CChIPS researchers from The Children’s Hospital of Philadelphia’s Center for Injury Research and Prevention (CIRP), The University of Pennsylvania (Penn), and The Ohio State University work side by side with industry members to prevent pediatric injury. The 20-member CChIPS Industry Advisory Board (IAB) funds research, establishes investigative priorities, and advises on the Center’s strategic direction. The IAB is comprised of the top five auto manufacturers, two of the top three juvenile product manufacturers, the only anthropomorphic test device (ATD) manufacturer, the U.S. auto safety regulatory agency, and the U.S. national aviation authority, among other organizations invested in child safety.

Currently, CChIPS research is primarily focused on preventing traffic injuries, the leading cause of injury and death for children, youth, and young adults. Let’s take a look in the rearview mirror at how CChIPS has navigated some of these important research challenges over the last decade:

Teen Driving Data Linkage

The New Jersey Traffic Safety Outcome Program, led by Allison Curry, PhD, MPH, CIRP director of Epidemiology and Biostatistics, linked teen driver crash, citation, and licensing data for all N.J. drivers. This data became the foundation for a first-of-its-kind analysis of N.J.’s Kyleigh’s Law, which requires youth 16 to 20 years holding a learner’s permit or intermediate license to display a decal on the license plates of their vehicle. The results published in November 2014 showed crash involvement of an estimated 3,197 intermediate drivers was prevented in the first two years after the decal’s implementation.

“Decal provisions now have the support of science,” Dr. Curry said. “The provision may encourage safer driving behaviors, both among teens and other drivers sharing the road with them.”

Diagnosing Driving

The purchase of an advanced driving simulator from IAB member company Realtime Technologies Inc. in 2010 opened new doors for CChIPS to systematically evaluate realistic behavior of drivers in a safe environment. Several lines of CChIPS research, led by Yi-Ching Lee, PhD, human factors researcher at CIRP, have utilized the simulator to observe the impact of distractions such as peer passengers and technology on young drivers’ behavior.

An emerging line of teen driving simulator research being pioneered at CChIPS utilizes machine learning models, where state-of-the-art experimental and analytical techniques are used to create accurate models of teenage drivers’ behavior. Although this research is geared toward the young driver population, it ultimately can be used beyond teens to assist other vulnerable driving populations such as the elderly or drivers with ADHD or other medical conditions.

“What our research tells us is that a validated simulated driving test could be used to assess the driving skills needed to avoid crashes,” said Catherine McDonald, PhD, RN, a teen driver safety researcher at the Penn School of Nursing and CIRP. “If we can identify driving skill deficits in a safe, simulated environment, then we can tell families and driving instructors what to focus on during supervised practice drives or how to help those with citations or crashes who are already licensed.”

Improving Design of Pediatric Crash Test Dummies

Since its inception, CChIPS has been committed to improving pediatric ATDs, or crash test dummies. To be an effective tool, pediatric ATDs must accurately mimic how child occupants move and respond to the forces of a vehicle crash. The research being conducted through CChIPS is delivering the fundamental data needed to improve the design of pediatric ATDs and to develop innovative restraint products to make vehicles safer for children in the future.

In 2006, CChIPS researchers, led by Kristy Arbogast, PhD, co-scientific director and director of Engineering for CIRP, and research associate professor of Pediatrics at the Perelman School of Medicine, with founding CChIPS IAB member TK Holdings Inc. (Takata Corp.), Rowan University, and University of Virginia researchers developed a low-speed human volunteer sled to mimic the crash experienced by children and adults when they ride an amusement park bumper car. This allowed CChIPS to collect the only known data on the kinematics and kinetics of restrained 6- to 14-year-old pediatric human volunteers in low speed impacts. The crash sled has been used in several CChIPS studies to compare child and adult volunteers’ heads, necks, and spines during a bumper car’s safe crash, as well as the same body regions on pediatric ATDs.

Since 2005, CChIPS has conducted more than 106 research projects, and the research team continues to gain momentum and explore new areas of study related to child injury prevention as it enters its next five-year phase of NSF support. Buckle up!

A future free from the toughest and most challenging pediatric illnesses grows closer every day. New fuel to accelerate that journey at The Children’s Hospital of Philadelphia now comes from an extraordinary $50 million gift, equal to the largest ever received by CHOP, from Philadelphia philanthropist Raymond G. Perelman.

“We know first-hand the tremendous resource that CHOP represents to families in the Philadelphia region, across the country, and around the world,” Perelman said. “This gift will help to ensure that critically important pediatric research, conducted on this campus, remains second to none; in addition to making a tangible difference in the lives of children around the globe for many years to come, it is my hope and expectation that advances in medical research funded by this gift will benefit us all.”

The gift, announced in January, establishes CHOP as a global center for innovative pediatric study and provides direct support for a wide range of pediatric research:

• Raymond G. Perelman Center for Cellular & Molecular Therapeutics, designed to re-engineer the body’s immune system to fight and defeat cancer, metabolic diseases, and other catastrophic illnesses through the efforts of the world’s leading experts in immunotherapy and molecular therapy.
• Perelman Scholars, two new tenure-track faculty positions at CHOP to be filled by candidates from among the world’s finest pediatric researchers.
• Perelman Fund for Research Innovation, a permanent source of reliable funding for the CHOP Research Institute to strategically identify and support new pilot research initiatives.
• Perelman Endowed Chair in Pediatric Ophthalmology to support a highly skilled researcher and physician-scientist seeking to break new ground and forge novel paths critical to understanding and treating ophthalmologic diseases in children.
• Research support for general research activities of the CHOP Research Institute.

“The significant research funding associated with this gift underscores the commitment of Raymond Perelman to world-class pediatric research and medicine,” said Mortimer J. Buckley, chair, Board of Trustees at The Children’s Hospital of Philadelphia.

In recognition of this generous gift for research, CHOP also established the Raymond G. Perelman Campus, an eight-acre area just south of the main hospital that will serve as a hub of pediatric research and clinical innovation at CHOP. The campus encompasses CHOP’s most state-of-the-art research and clinical centers, including the Ruth and Tristram Colket, Jr. Translational Research Building, which opened in 2009; the new Buerger Center for Advanced Pediatric Care, which opened in July 2015; and a 2.6-acre landscaped plaza.