Bench to Bedside

April/May 2017

Researchers Recreate Womb Experience to Transform Care of Premature Infants


Every child begins life in a paradise built of biological wonders. The umbilical cord tethering the fetus to her mother’s placenta not only enables the exchange of blood gases in place of breathing air, but it also permits her to float and rotate within the warm incubating amniotic fluid while it delivers her every nutritional need as she grows ready for independent life.

Babies born too soon suffer from the paradise lost. About 30,000 per year are critically preterm — younger than 26 weeks. The most fragile preemies who have any hope of being viable, born at only 22 or 23 weeks, face immense struggles in their first hours and days of life. One of the biggest threats is their fragile, underdeveloped lungs, which are not prepared to take in and out the dry air around them. Extremely premature infants who do survive encounter a 90 percent risk of morbidity and face lifelong, complex medical issues.

“Just looking at [extremely premature infants], it is immediately clear that they shouldn’t be here yet. They’re not ready,” said Emily Partridge, MD, a fellow in the Center for Fetal Research at Children’s Hospital of Philadelphia. “I had many compelling encounters with those patients over the course of my training, all of which really led to the idea that we should be able to do better for them.”

This desire spurred a multidisciplinary team at CHOP to use their ingenuity, innovation, and perseverance to create a unique, fluid-filled environment that mimics as closely as possible how a fetus experiences life in the womb. The system, which only has been tested in animal studies, could one day transform care for extremely premature babies by giving them a precious few weeks to develop their lungs and other organs.

“These infants have an urgent need for a bridge between the mother’s womb and the outside world,” said study leader and senior author Alan Flake, MD, a fetal surgeon and director of the Center for Fetal Research at CHOP and a professor of Surgery and Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania. “If we can develop an extra-uterine system to support growth and organ maturation for only a few weeks, we can dramatically improve outcomes for extremely premature babies.”

The sealed, sterile system is insulated from variations in temperature, pressure, and light, and particularly from hazardous infections. While the idea may at first have sounded more like science fiction than reality, the study team persistently pursued it for more than four years. Many technological revisions to the incubator system and physiologic monitoring of the fetus were necessary to best recapitulate fetal physiology. The study team recently described findings from their inception pilot study through the evolution of four rounds of prototypes in preclinical studies of the device in the journal Nature Communications.

The study team tested the most recent prototype on eight fetal lambs, which have similar prenatal lung development to humans, for up to 28 days, and they remained healthy. Vital signs, blood flow, fetal blood gases, and other parameters were continuously monitored 24/7, which required a continuous attentive presence by team members for the duration of the study.

“It never fails to strike me what a miracle it is to see this fetus that is clearly not ready to be born, enclosed in this fluid space — breathing, swallowing, swimming, dreaming — with complete detachment from the placenta and from mom,” Dr. Partridge said. “It is an awe-inspiring sight every time.”

The device started as a glass incubator tank combined with monitoring devices, and it has become more sophisticated as each prototype advanced. The current preclinical model uses a meticulously designed fluid-filled container that is custom made to fit each fetus and support it as if it were being carried in the uterus. A continuous amniotic fluid exchange system developed by CHOP fetal physiologist Marcus Davey, PhD, supplies nutrients and growth factors that are produced in the laboratory. Dr. Davey also is an assistant professor in the department of Surgery at Penn.

The fetus’ heart pumps blood via the umbilical cord into a low-resistance external oxygenator that substitutes for the mother’s placenta in exchanging oxygen and carbon dioxide. The system does not rely on an external pump to drive circulation because even gentle artificial pressure can fatally overload an underdeveloped heart, and there is no ventilator because immature lungs are not ready to do their work of breathing in atmospheric oxygen.

“We have innovated a circuit in which the flow of blood is entirely driven by the fetus, which is what a fetus does in utero,” Dr. Partridge said. “It perfuses its own placenta, and it regulates that perfusion in a way that we think probably can’t be improved upon. Nature usually has a reason for its design. So rather than trying to impose something artificial, what we have striven to do at every turn is to recapitulate the normal physiology of a fetus.”

In order to allow the fetus to establish and maintain a normal circulatory pattern, one of the team’s main challenges was to find a way to preserve as much of the fetus’ native umbilical cord as possible and then to place cannulas as a gateway from the body’s own blood vessels to the oxygenator’s circuit. The cannulas, which are short pieces of tubing, pass into the umbilical arteries and vein and then connect to the circuit that directs the blood flow to the oxygenator. Once that cannulation is complete and the fetus is stable, then they can cut the umbilical cord and move the fetus into the system’s fluid-filled enclosure.

Dr. Flake stresses that the team does not aim to extend fetuses’ viability to an earlier period than the current mark of 23 weeks. Before that point, limitations of physical size and physiologic monitoring would impose unacceptably high risks. However, he added, “This system is potentially far superior to what hospitals can currently do for a 23-week-old baby born at the cusp of viability. This could establish a new standard of care for this subset of extremely premature infants.”

The system also is not intended to support an infant until full-term at 40 weeks. Its purpose is to stabilize the critical period when a very premature infant is most at risk until she reaches 28 or 29 weeks, when there is an improved chance of survival and good outcomes as she transitions to the care of a traditional neonatal intensive care unit. If more research shows that the animal studies could translate into clinical care, Dr. Flake envisions that in a decade or so the system could be a feasible way to bridge the time from womb to the outside world to reduce mortality and disability for extremely premature babies.

Attempting to recreate the womb experience has been an extraordinary research effort that presented huge engineering and circulatory challenges, but it also has been one of the most rewarding endeavors for Dr. Flake’s laboratory team.

“Having the opportunity to work on a project that I had thought about for years, ever since seeing sick babies in the NICU, was really the realization of a dream,” Dr. Partridge said. “And it has required a pretty heroic effort on the part of the team to make this happen … But it has been nothing but a privilege to do this work because of the potential that it represents. These infants are desperate for solutions and for innovation.”

Read more about the development of this womb-like system in our 2014 Annual Report. See the current press release. And watch a related video.

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GRIN’s Power in Numbers: Three Major Pediatric Institutions Collaborate


Leaders of the Genomics Research and Innovation Network (GRIN) indeed have a lot to smile about. The groundbreaking collaborative has established an exceptional model that pools the resources of three premier pediatric academic medical institutions to accelerate genomic discovery and foster a culture of data sharing.

Going it alone to create a patient cohort population that is large enough to study can be a time-consuming process for an individual genetic scientist who wants to make a difference in a pediatric disease. That’s because many pediatric diseases are so rare that a single hospital may treat only two or three patients with a specific condition. It can be difficult to find enough patients to effectively explore these rare diseases’ genetic underpinnings.

And if a researcher is interested in common disease traits that contribute to complex conditions such as diabetes or obesity, large numbers of patients are needed to participate in genetic association studies in order to magnify the statistical significance of the findings.

Recognizing that there is power in numbers, chief executive officers at Children’s Hospital of Philadelphia, Cincinnati Children’s Hospital Medical Center, and Boston Children’s Hospital contributed equal funds to form GRIN in November 2015. The concept was transformative: Begin sharing clinical and genomic data and give access to a virtual repository that their talented researchers could utilize to catalyze new projects and boost progress in pediatric genomics to advance children’s health.

“The ultimate goal is to have this resource populated with over 100,000 cases that would include individuals’ clinical data at a high resolution, genotyping data, and associated biospecimens so that you can move discovery forward,” said Ian Krantz, MD, an attending physician in the division of Human Genetics at CHOP who serves on GRIN’s executive team.

Dr. Krantz also codirects the newly established Roberts Individualized Medical Genetics Center at CHOP. He knows well the diagnostic odyssey that families can encounter when the cause of their child’s condition is unknown. It took a decade for Dr. Krantz and his colleagues to discover that a mutation in the gene AFF4 was behind Leta Moseley’s cryptic constellation of symptoms that included cognitive impairment and coarse facial features, heart defects, obesity, pulmonary involvement, short stature and abnormal bone development. They named the disease CHOPS Syndrome in Nature Genetics in 2014, and genome sequencing has since helped to identify a handful of other children who have the same clinical characteristics and faulty gene. If GRIN had existed at the time when Dr. Krantz had first met Leta, arriving at that breakthrough perhaps could have taken months instead of years.

“With GRIN, we could say: ‘This is the only patient like this who I’ve seen, but does she match up with any of the other clinical phenotypes at Boston or Cincinnati?’ And if you get hits, then you might have your cohort right away to study and ask important genetic questions,” Dr. Krantz said.

Sawona Biswas, MSc, MS, CGC, a genetic counselor and CHOP’s program manager for GRIN, pointed out that another way the new initiative helps to overcome barriers to research in pediatric genomics is by addressing the problem of too much data and too little time. A wealth of data is available through electronic health records, clinical trials, and data registries, but it not feasible for individual researchers to comb through all this information and extract what they need to identify large patient cohorts with deep phenotyping. GRIN aims to make this process more consistent, precise, and seamless for its members by establishing a data trust that will allow for more comprehensive analysis of complex disease.

“Instead of working in silos, by sharing data and samples we’ll be able to collectively increase their power,” Biswas said.

Building GRIN involved many representatives — executives, clinician-researchers, program managers, bioinformatics experts, technology transfer advisers, and biobank operators, to name a few — from across all three institutions to interconnect the new shared community. The steering committee and workgroups spent much of the last year putting into place GRIN’s legal and regulatory infrastructure. They decided on memorandums of understanding, material and data transfer agreements, and institutional review board protocols so that the network members could work together.

“We’ve formed a very close and trusting relationship,” Dr. Krantz said. “We’ve built a really effective, interactive, collaborative group.”

The result is the establishment of a large cohort that includes patients who are universally consented to allow all types of their data, such as data generated by electronic health records, whole-genome and whole-exome sequencing, and imaging results, to be collected, shared, and compared consistently across GRIN sites for research purposes. Patients who participate also agree to be re-contacted if a GRIN investigator needs additional information.

Three pilot projects tackled how different aspects of GRIN’s new model would be implemented. For example, one of these projects looked at epilepsy and novel genetic causes. It enrolled 10 trios (patients and their parents) from each institution to do exome sequencing. The study team agreed on standards for the data collection. They also needed to build a cloud-based data repository and analytics platform so that the data could be accessed easily and analyzed reliably by the investigators. The other two pilot projects focused on short stature due to growth hormone resistance and childhood obesity in African-Americans.

While GRIN is getting up and running, it currently is only open to investigators at the three member institutions, but the idea is to invite other institutions to join GRIN in the future. Before any investigator dives into this unparalleled resource, GRIN’s scientific committee will vet their research proposals. The network’s sustainability committee also is considering how to handle commercial interest, such as from pharmaceutical companies.

“This is a very valuable resource that could be leveraged for drug discovery and therapeutic trials,” Dr. Krantz said. “Having access to this type of well-characterized and accessible cohort with available biological samples is very appealing.”

GRIN’s planning team also anticipates that the new network will be attractive to external funding sources due to its large sample size and open data sharing philosophy. Several CHOP investigators already have shown interest in GRIN’s broad data capabilities by asking for letters of support from GRIN’s leadership to submit as part of their grant applications.

For Dr. Krantz, the most exciting aspect of GRIN is that it heralds a culture change in the scientific and academic world that promotes swifter discovery. He described the traditional “every man for himself” system as a slow process that offers few alternatives when a researcher reaches a dead end because of the limited numbers in a patient cohort for rare genetic conditions.

“You can accelerate discovery and breakthroughs by doing collaborative research,” Dr. Krantz said. “And the reality is it’s fun to collaborate … For the individual investigator who might be a little wary about sharing the samples he or she has collected, the advantage is they will have access to a much larger number of additional samples, and it opens up new questions that can be asked and propel novel discoveries.”

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Research First Line of Defense as NFL Moves to Improve Player Safety


Researchers at Children’s Hospital of Philadelphia often find themselves at the cusp of diverse fields, and for child safety expert Kristy Arbogast, PhD, they are intersecting at the 50-yard line.

Dr. Arbogast, co-scientific director and director of engineering for the Center for Injury Research and Prevention at CHOP and a research professor of Pediatrics at the University of Pennsylvania, is part of the National Football League’s (NFL) $60 million commitment to improve player safety through encouraging advances in the engineering development of protective equipment. She is tackling concussions in the NFL from a unique vantage point — inside the players’ helmets.

Concussions can result from a blow or jolt to the head or body that causes the brain to deform within the skull. Football helmets were designed originally to prevent skull fractures and the most serious brain injuries, but not specifically to manage the rotational forces that are an important aspect of how concussions occur.

As a consultant for the NFL Players Association (NFLPA), Dr. Arbogast provides her expertise in traumatic brain injury prevention and the role of protective equipment in reducing injury risk.  The NFL initiated an effort to catalyze transformations in helmet design, called the Engineering Roadmap, and reached out to Dr. Arbogast via the NFLPA to play a leadership role.

Dr. Arbogast’s scientific contributions to the project also will be a win for children. While the NFL’s game plan for precision protection is geared toward professional athletes, the results likely will spark new technologies for helmet designs and other protective equipment that will gravitate to youth sports.

Three years ago, as the NFLPA’s representative on the NFL’s Head, Neck and Spine Engineering Subcommittee, Dr. Arbogast helped to develop a helmet testing program using detailed statistical analysis to evaluate how helmets performed in a laboratory test designed to mimic impacts in the NFL. The committee completes testing annually and creates posters with these rankings that are posted in all NFL teams’ locker rooms so that equipment managers, trainers, and players can make informed choices about their protective equipment. The decision of which helmet to wear is ultimately up to the player who is permitted to use any model that is approved by the National Operating Committee on Standards for Athletic Equipment.

“I do think players are interested in their own safety,” Dr. Arbogast said. “Creating the posters has contributed to a depth of conversation between equipment managers, players, and the committee. We took engineering science backed by rigorous statistics to give players information.”

This effort gave rise to a concerted plan to encourage innovation in protective equipment. The NFL’s Engineering Roadmap launched in 2016. A main goal of the Roadmap’s research plan is to better understand the types of impacts that players are experiencing on the field: What is the magnitude of the impact, how much does the head rotate and how fast, from what direction are impacts coming from, and how do those factors vary depending on the position that they play? New insights about this “loading environment” will lay the groundwork for concepts such as designing position-specific helmets that could help keep players safer.

“An offensive lineman experiences different kinds of impacts than a wide receiver,” Dr. Arbogast said. “They have different pads. They might choose different shoes. Maybe they should have different helmets too?”

One way researchers are gathering this information is by using game-day videos to meticulously reconstruct concussions cases that have occurred in the NFL during the last two years. While this approach gives a view of what the helmet is doing, it does not show what happens to the head upon impact. Dr. Arbogast’s charge is to identify or develop a sensor package that would allow researchers to measure directly and accurately what the head is doing.

“We want to continuously gather data to get a comprehensive view of what the loading conditions are,” Dr. Arbogast said. “At the end of the game, we’d collect the sensor, download the data, and then analyze the accelerations and velocities that the players’ heads experience during the game … With this data, we would now know what types of impacts we need to ask the helmet to protect against.  This would lead to the innovative helmet designs to meet these specifications.”

Dr. Arbogast and her colleagues first will assess the variety of sensors that are currently available in the marketplace for both commercial and research purposes. They also are speaking with athletic trainers, equipment managers, and players to find out which sensors would be accepted by players as a standard part of their equipment. Implementation of the sensor program requires approval from the NFLPA.

The Engineering Roadmap also creates opportunities for input and innovation from outside of the NFL. At a symposium held in November in Washington, D.C., the NFL issued the first HeadHealthTECH challenge, an open innovation and crowdsourcing program to solicit ideas for advances in protective equipment. Led by Barry Myers, MD, PhD, MBA, at Duke University, a scientific review panel will review the proposals and make recommendations for funding promising technologies. Dr. Arbogast spoke at the symposium, which was attended by researchers, biomechanics experts, engineering students, protective equipment and sensor manufacturers, and others. She applauded their pursuit of collaborative science.

“This body of work will be really fundamental in understanding, at a very detailed mechanical level, the scenarios in which injuries are happening,” Dr. Arbogast said. “And that, I think, will allow us to stimulate innovation in the right way, because you don’t just want to say to these innovators, ‘Oh go out and build a new helmet.’ With the Engineering Roadmap research plan, we’re going to have the data to really direct the development of these innovations in a way that’s evidence-based and real.”

As a leader in the field of child safety, Dr. Arbogast also wants to make certain that the voice of youth are heard during the Engineering Roadmap process, even though it centers on professional football athletes’ safety.

“I feel it’s my responsibility that, as we learn these new things, to say: What does this mean for kids?” Dr. Arbogast said. “I see this initiative as a way to ensure that other sports are played safer too. It is an opportunity to be part of team that could shape something that is very applied and that really affects the lives of kids.”

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SHARE Project Explores Patients’ and Parents’ Pediatric Palliative Care Experiences


Parents of children who live with serious illness often describe their experiences as being on an unfolding journey. Pediatric palliative care teams are specially trained to help families facing a life-shortening illness navigate these daunting twists and turns.

More than 100,000 children in the U.S. living with life-shortening conditions could potentially benefit from pediatric palliative care, which broadly helps with three things: 1) pain and symptom management through medical and psychosocial interventions, 2) decision-making support, and 3) coordination of care across the continuum of healthcare settings. All three of those areas can be better informed with reliable research data, according to Chris Feudtner, MD, PhD, MPH, director of the department of Medical Ethics at Children’s Hospital of Philadelphia and director of Research for the Pediatric Advanced Care Team.

Dr. Feudtner, who also is a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, has seen remarkable growth over the last 15 years in the establishment of pediatric palliative care teams within hospitals, but there has been substantially less progress for robust research in the field. One of the challenges to pediatric palliative care research is that no one hospital is likely to have a sufficient number of children with a particular condition to be able to fully explore epidemiologic and health services questions. That is why four hospitals that are part of the Pediatric Palliative Care Research Network (PPCRN) are launching an innovative multicenter project called SHAred Data and REsearch (SHARE).

CHOP, Boston Children’s Hospital, Seattle Children’s Hospital, and Children’s Hospitals and Clinics of Minnesota all have “remarkably good” pediatric palliative care programs, Dr. Feudtner said, and they will collaborate to build a standardized and organized infrastructure to collect and merge patient- and parent-reported clinical data with hospital administrative data into a SHARE database. The resulting dataset will provide a wealth of information regarding hospital-based care for a cohort of 800 patients receiving pediatric palliative care, including patient demographic and diagnostic information, patient or parent reported symptoms, and parent reports on their levels of distress and how their goals of palliative care change as their child’s serious illness progresses.

“We will follow them over time to identify distinct patterns of how things play out, and how those patterns affect the ways that they think about making decisions for their child,” Dr. Feudtner said. “All of this will hopefully improve the care the kids get and the outcomes for them, their parents, and family members.”

For example, he pointed out that researchers don’t have much data yet on how long a typical pediatric patient receives palliative care, although previous CHOP research suggests that it is for more than a year. They also know little about the symptoms these children experience, such as pain, nausea, shortness of breath, fatigue, and depression. They know even less about how these symptoms may vary over time and which ones tend to break through despite clinicians’ best efforts to manage them. Once SHARE helps to gather information about these key aspects of pediatric palliative care, then researchers can figure out the effectiveness of specific interventions to ameliorate suffering and reduce symptoms.

Another area that SHARE researchers plan to study is how families in the midst of such a tumultuous time contemplate how to best care for their children. Previous studies conducted by Dr. Feudtner and colleagues have focused on the roles that emotions and sense of duty play in parental decision-making, along with families’ thoughts on how their child is doing medically. Several themes have emerged from that research that suggest as a seriously ill child’s condition worsens, some parents tend to re-evaluate their initial set of curative goals and replace them with a set of more attainable goals such as keeping their child comfortable. Researchers call this combined psychological and social process “regoaling.”

“We have people devoted in our pediatric medicine ranks — social work, psychology, ethics, and other areas — to help support parents with the decisions that they’re facing,” Dr. Feudtner said. “But what is the best way to do that? We have a lot to learn.”

In Dr. Feudtner’s experience, families welcome the opportunity to participate in pediatric palliative care research because it allows them to represent what they’re going through in a meaningful way. Families who join the SHARE study will, with the assistance of interviewers, complete a series of questionnaires when they first join the cohort, and then participate in follow-up interviews every six months for a total of two years.

Dr. Feudtner expects that the collaborative SHARE project will be a catalyst for many future studies using the SHARE data and research infrastructure. He envisions large multicenter studies could be accomplished to perform intervention research — such as drug treatment studies or evaluating bundled therapies for symptom control  — and quality improvement work within and across hospitals — such identifying the best care delivery model to transition patients seamlessly from hospital to home care.

“I would hope that the legacy of the project, looking back on 10 years in the future, would be that we have deepened our understanding of the ability of interventions that are in the palliative care continuum to improve the well-being or reduce potential suffering of a child and also how they affect the well-being or suffering of a parent,” Dr. Feudtner said.

For families embarking on the palliative care journey, such evidence-based strategies can lend valuable insights to help guide them toward compassionate and knowledgeable end-of-life care for their children.

SHARE’s other multi-principal investigator joining Dr. Feudtner is Joanne Wolfe, MD, of the Dana-Farber Cancer Institute and Boston Children’s Hospital; site investigators include Ross Hays, MD, of Seattle Children’s Hospital; Stefan Friedrichsdorf, MD, of Children’s Hospitals and Clinic of Minnesota, and Pamela Hinds, PhD, RN, of Children’s National Health System.

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What’s in a Name? New Genetic Disorder, MBCS, Named After CHOP Scientists


At first, pediatricians were confused: The newborn patient wouldn’t eat, didn’t cry to be fed, and wouldn’t grow. She had been through an odyssey of tests and treatments, from feeding therapy to swallow studies to tonsillectomies, with no definite explanation for her failure to thrive. Her parents wondered if perhaps they were doing something wrong.

When scientists at Children’s Hospital of Philadelphia looked at the patient’s chromosomes by a SNP array test, however, it clicked: The unusual pattern on her chromosomes matched those of three or four other children with growth failure who had been identified by the Genomics Diagnostic Laboratory at CHOP, and soon, a dozen patients with the same genetic growth condition would be recognized across the globe.

More than eight years and 13,000 genetic tests later, three scientists at CHOP had enough material to pen a paper published in Genetics in Medicine. Better yet, they had a clear, definable disorder complete with phenotype and genetic etiology. Earlier this month, the authority on genetic diseases, Online Mendelian Inheritance in Man, gave the disorder a name: Mulchandani-Bhoj-Conlin Syndrome (MBCS), named after the scientists themselves: Surabhi Mulchandani, MS, genetic counselor and manager of the Genomic Diagnostics Laboratory; Elizabeth Bhoj, MD, PhD, clinician-researcher in the division of Human Genetics; and Laura Conlin, PhD, director in the Genomic Diagnostics Laboratory. The classification would bring much relief to many parents.

“It is rare, but very likely under-diagnosed,” Mulchandani said.

Chromosomes in Common

MBCS is characterized by mild prenatal growth deficiency, slow growth, and the lack of desire to eat. At its heart, MBCS is an imprinting disorder. Normally, people inherit one copy of each chromosome from each parent. However, children with MBCS have both copies of chromosome 20 from their mother, and none from their father. While the exact cause of MBCS is unknown, the researchers predict that the disorder is caused by the lack of paternally inherited genes on chromosome 20.

“Going to the literature, there’s some really well-described syndromes caused by inheriting either both of mom’s or both of dad’s chromosomes, but no one had really looked into what inheriting both copies of your mom’s chromosome 20 did,” Dr. Bhoj said. “This very unique chromosomal difference also truly brought [the children] together because there’s many things, genetic and non-genetic, that make babies have trouble gaining weight — a baby could have congenital heart disease, acid reflux, muscular problems. But this genetic change is very specific.”

For Dr. Bhoj and her colleagues, the next step was to find clinicians from institutions across the world who had seen patients with the same unusual chromosome pattern and weren’t sure how it related to that patient’s medical problems. Eight children between the ages of 4 and 12 were studied who shared a very similar phenotype: All were born at a smaller-than-normal size, experienced difficulty feeding in their first years of life, and grew extremely slowly. Six of the children needed a gastric feeding tube. Most stood at a shorter stature than normal.

While these aspects of MBCS slightly set the children back in their first few months or years of life, the study also found that the disorder came with hope: Four of the children had been put on growth hormones and gained growth velocity. None experienced developmental delays, and all currently attended mainstream schools at age-appropriate grade levels. If a parent worried that MBCS might affect their child’s later development, they could be assured that their child would likely mature well.

“It’s pretty empowering to have a diagnosis of what’s going on, but also to know that there is very little recurrence risk in the family, and to know that if you do give growth hormone, patients can catch up,” Mulchandani said. “There aren’t really long-term major structural issues that the families have to be prepared for.”

The Power of a Name

While it may seem like a simple thing, naming a set of symptoms can have many far-reaching implications. For physicians, Dr. Bhoj explained, the classification will hopefully eliminate treatments that doctors might prescribe because of the vague nature of the patient’s prognosis.

“I think the most important thing is that patients won’t get unnecessary medical interventions to fix this because they weren’t sure what was causing it,” Dr. Bhoj said. “Now we know the natural history, and we know that if you just help them through the initial period, either by using a gastric tube or intense feeding therapies, then they’ll outgrow it, and there are no lasting effects as far as we can see.”

Mulchandani and Dr. Conlin added that the classification has increased awareness of the disorder, and they hope that knowledge will continue to spread to more doctors, most especially endocrinologists.

“Often the genetic testing we do in the laboratory, the SNP array, isn’t the first test that an endocrinologist might order for patients presenting with growth deficiency,” said Dr. Conlin, who also is an assistant professor of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania. “But now, if they know that there’s this syndrome out there, maybe they can try to test for it.”

For families, the classification changes lives.

“It relieves the guilt that’s put on parents for why they can’t appropriately feed their child,” Dr. Bhoj said. “[Feeding] is the most basic thing you do when you have a baby, and parents have a lot of emotional distress around not being able to have their children gain weight.”

Dr. Bhoj told the story of an infant in California who had been under the supervision of Child Protective Services because he was believed to be malnourished. When the parents learned of MBCS and had a SNP array done, however, the baby was found to have MBCS, returned to the parents, and received proper treatment.

“It wasn’t because the parents were at fault,” Dr. Bhoj said. “He had this intrinsic lack of desire to eat.”

Already, other families are approaching the scientists at the Genomics Diagnostics Laboratory at CHOP to take a look at genetic tests done at other labs to see if their children might have the imprinting disorder, Mulchandani said. As for the parents of the eight children reported on in Genetics in Medicine, the study conducted by CHOP scientists has brought them together in more obvious and everyday ways: Those who live locally have planned a picnic to discuss their experiences struggling to find the right diagnosis, work through the consequent emotional issues, and reflect on how far they have all come.

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Center for Parent-Teen Communication Sees Adolescence as Age of Opportunity


Not a single piece of material from the new Center for Parent-Teen Communication (CPTC) at Children’s Hospital of Philadelphia will start with the words “survival guide.”

According to Ken Ginsburg, MD, the Center’s co-founder and a physician in the division of Adolescent Medicine at CHOP, it’s time to chip away at the ongoing and undermining narrative about adolescence that’s as potent and played out as an old wives’ tale: In that narrative, teenagers are destined for disaster and riding on a frenetic wave of poor decisions. Fueled by decades of research and funded by the John Templeton Foundation, the CPTC will re-frame adolescence not as a time of impending disaster, but one of opportunity.

“Adolescents quite literally represent our future, and it is critical that we create the right developmental milieu for them to become their best selves,” Dr. Ginsburg said. “Core to that development is their relationship with their parents. With so many undermining messages about that relationship, we want to give positive developmental messages that will change the tone and tenor of the conversation.”

The CPTC received a three-year grant and will consist of a multi-disciplinary effort between researchers, clinicians, and experts to promote the health, character, and well-being of adolescents through education, research, and advocacy. Alongside Dr. Ginsburg, Carol Ford, MD, chief of the division of Adolescent Medicine at CHOP, will co-lead the Center. It will house two cores that focus on two very different but equally powerful places where researchers believe they can improve parent-teen communication: the doctor’s office and the web.

Dr. Ford will direct the Research Core (RC), conducting primary parent-teen research in clinical settings, while Dr. Ginsburg will direct the Translation and Dissemination Core (TDC), translating the best of what is known from parenting and character development research into practical information that will be disseminated widely, including through a comprehensive website (set to launch online at the end of 2017) and across social media platforms. The two cores share one goal: Foster effective parent-teen communication so that parents can help adolescents become young people prepared to thrive.

“I think that people feel like it’s difficult for parents and teens to communicate,” Dr. Ford said. “One of goals of the center will be to make parent-teen communication easier.”

Clinicians’ Role in Parent-Teen Communication

Doctors and nurses have a unique opportunity to help adolescents make responsible decisions about their health. They have face time with both teens and their parents during one-to-one appointments, which might be used to facilitate effective and open parent-teen communication.  Much research has been done on how to improve teen health in clinic settings, but researchers have not yet dug into the specific ways physicians can help parents and teens talk about health and what to expect from high-quality healthcare, according to Dr. Ford. The CPTC’s Research Core hopes to change that.

“We tend to overlook the power of parents to help us do our job, which is to improve adolescent health,” Dr. Ford said. “Parents and doctors both want the best health outcomes for their teens, and we really need to understand how doctors and nurses can better partner with parents, while also respecting their values, cultures, and parenting styles.”

One of the CPTC’s first agendas under Dr. Ford’s guidance is the Strengths Intervention Project led by Victoria Miller, PhD, director of research in the division of Adolescent Medicine at CHOP. Dr. Miller and Dr. Ford will study how clinicians can help parents foster better communication strategies with their teens about teen strengths. While studies are just getting on their feet, current and previous research from CHOP demonstrates precisely why this is a potent and promising field of study.

Recent Research Sets the Stage

A study of 136 teens and their parents recently presented by Dr. Ford found that teens and parents have dissonant views on the tone of their conversations: On a weekly basis, parents reported that they communicated with their teens more about strengths rather than weaknesses, while teens generally believed that they talked with their parents about their own weaknesses more than their strengths. The findings highlight the need to uncover why such a perception gap might occur, and how it influences teen’s development.

In another paper published in the Journal of Adolescent Health, Dr. Ford found that amongst 91 parent-teen pairs, the majority of parents and teens had moderate to high levels of interest in learning not just about health issues like weight, driving safety, or acne, but also about how to increase parent-teen communication about a wide range of topics including teen strengths. The paper cites previous research reporting that adolescents generally don’t receive the recommended US Preventive Services Task Force screenings and services for conditions like obesity, depression, obesity, tobacco use, or sexually transmitted infections. If we can improve parent-teen communication about why the recommendations matter, we might improve a teen’s chances of utilizing these primary healthcare services. Dr. Ford believes that the research will also benefit health professionals alongside parents and teens.

“I think physicians will appreciate having help knowing what to say, how to say it, and having research-based materials to give to parents and teens to help them with their communication,” Dr. Ford said. “That’s something that we haven’t had at this point in time.”

Using Social Media to Translate and Disseminate Research

Besides primary investigations, the CPTC will also dig into existing research about positive youth development, parenting, and character development, and deliver it to parents via a comprehensive website and through a space almost all of us visit every day: the online social community.

Seventy-five percent of parents use social media, with mothers using it more so than fathers as a parenting resource, according to a Pew Center Research report. Seventy-nine percent of the parents in the report stated that they garnered beneficial information from these platforms, with 59 percent stating that they came across valuable information specific to parenting in the last 30 days.

Fueled by this new method of communication and information-sharing, Dr. Ginsburg hopes that the CPTC can become the “credible source” from which social media influencers draw their information and that parents come to rely on to learn how best to communicate with their child.

“Social media now sets the discourse for conversation,” Dr. Ginsburg said. “It’s where people now turn to for information. The challenge is that the information is not always rooted in research and doesn’t always give the most productive advice.”

The TDC will translate evidence-informed information into easily accessible, consumer-friendly written and video materials. Based on existing research and clinical expertise, the content will empower parents to build on the foundation of strength in their teens rather than highlight the negative aspects of adolescence. Social media strategists will help present the materials online in a way that stimulates parents to share it with other parents.

Plenty of Topics to Empower Parents and Teens

The topics that Dr. Ginsburg hopes to inform parents about range far and wide, but all share a positive and empowering spin. For example, the CPTC will share research about adolescent brain development, which is an exciting area of science ripe for translation. It will also disseminate information about supporting youth to make wise decisions, and prepare them to lead us in the future. It will offer information about the benefits of balanced parenting, described by Dr. Ginsburg as “parenting that is both loving and warm, and appropriately monitors the children.”

Finally, it will distribute the best evidence-informed strategies to everything from how to build character strengths like integrity and compassion, to how to support the internal resilience of young people. These topics only touch the tip of what the CPTC hopes to share with parents. Future plans include responding to new developments in the emerging research on parenting and youth development.

Both Dr. Ginsburg and Dr. Ford have confidence that by shifting how society perceives adolescence – that is, from a negative narrative to a positive one – we can impact how teens themselves view the world.

“The center is going to work on helping parents, and all of us, really think of teens and adolescent health with an opportunity framework,” Dr. Ford said. “We have this wonderful chance to establish a Center over the next three years, and just grow.”

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New Evidence-based Clinical Guidelines Help to Navigate Growth Disorders


For a child with stunted height, growth hormone treatments can suggest more than just a taller stature: As routine injections of the synthetic protein work to fuel steady cell production in their bodies, the physical gain can evoke a range of social opportunities that previously felt out of reach. Unfortunately, it can also present pediatric endocrinologists with a dilemma.

Not every child responds to growth hormone (GH) treatment, nor should every child receive it. Despite approval from the Food and Drug Administration to treat a range of conditions with GH therapy, managing children with growth failure comes rife with questions of long-term safety, ethical knots, and a lack of consolidated research.

“Every decision in medicine is a risk-benefit analysis,” said Adda Grimberg, MD, pediatric endocrinologist at Children’s Hospital of Philadelphia.

On behalf of the Pediatric Endocrine Society (PES), Dr. Grimberg and six other pediatric endocrinologists – along with a bioethicist and a GRADE methodologist – issued new clinical guidelines for the administration of GH therapy earlier this year. The guidelines are published in Hormone Research in Paediatrics, the official journal of the pediatric endocrine societies of North America, Europe, and South America. They offer evidence-based recommendations bolstered by endorsements from the PES Drug and Therapeutics Committee as well as the PES Ethics Committee – the latter of which has never been included in previous GH recommendations. The guidelines differ from those last issued in 2003 in that they address new demands for medicine to carry the weight of research and data-based answers.

“Since the Institute of Medicine published their recommendations for improving quality and value in U.S. healthcare, there really is an emphasis on evidence-based decision-making,” Dr. Grimberg said. “The current standard for developing guidelines is to include a systematic review and transparent reporting of the quality and quantity of the evidence supporting any recommendations made. For each point we ask, ‘What is the evidence behind that?’”

Collecting the Evidence

The new guidelines offer distinctly separate recommendations for three growth conditions: growth hormone deficiency (GHD), primary IGF-I deficiency (PIGFD), and idiopathic short stature (ISS).

“Due to diagnostic challenges, the boundaries between these conditions are a little blurred, and patients are a little overlapped,” Dr. Grimberg said.

The paper thus outlines criteria and considerations to help physicians establish diagnoses and navigate the proper treatment. For the first time, the guidelines also address the use IGF-I hormone, a therapy that is one step downstream from GH treatment in terms of signaling, and is often more appropriate to treat PIGFD.

After a rigorous review of more than 15,000 citations based on key questions and guiding principles, the final version of the guidelines takes a measured and cautious approach to GH treatment. If a child has true growth hormone deficiency, wherein their body doesn’t produce enough of the powerful protein, the authors “strongly recommend” the use of GH. Collective data demonstrate that over 4,520 patients prescribed GH treatment from multiple studies and registries reached an adult height on par with their genetic potential. Growth hormone deficiency can also result in weaker bones, impaired cardiac performance, and unfavorable lipid profiles. The authors found that while results on cardiac function and lipid profiles were inconsistent, GH therapy did indeed improve bone density and bone composition for children with GHD.

If other factors besides growth hormone deficiency cause short stature, the authors recommend careful considerations for each individual case. If a child has PIGFD, for example, in which their bodies show normal levels of growth hormone but lack the insulin-like growth factor that allows them to make use of that growth hormone, the authors recommend first ruling out any nutritional problems, then turning to IGF-I therapy in severe cases.

Finally, if a child has ISS, in which they have a significantly shorter height than average with no known cause, the authors recommend avoiding the routine use of GH and instead making an informed decision based on each child’s physical and psychological situation. Studies show that not all individuals with ISS respond to treatment, placing them at risk for unknown side effects without any obvious benefit. This uncertainty draws attention to one of the most salient reasons for why we need stricter clinical guidelines: the lack of evidence behind GH therapy’s long-term safety.

Identifying the Knowledge Gaps

Experts simply don’t know how GH therapy in childhood and adolescence affects the body as it ages over time, Dr. Grimberg said. Patients who started receiving recombinant growth hormone when it first became commercially available in 1985 would only be in their 40’s today, and scientists lack sufficient data on those adults. Existing data are conflicted: In a European consortium study of adults with a history of pediatric growth hormone treatment, the French subgroup reported that GH resulted in increased mortality and stroke while subgroups from other countries did not. This uncertainty must be weighed against the potential benefit of treating healthy short children.

“If you have growth hormone deficiency, there are health reasons for wanting to replace the growth hormone, and it’s not just about height,” Dr. Grimberg said. “It’s not controversial, and you treat. When you have healthy short kids who have idiopathic short stature and want to be taller, however, you are exposing them to unknown risks down the road. That is an ethical consideration.”

Directing Future Research

Alongside safety, Dr. Grimberg believes that the guidelines highlight two other conceptual gaps that current and future research will work to address. The first relates to outcomes: How exactly should a physician or researcher measure the success of GH therapy? What factors define improved well-being in a GH-treated child?

“If parents are seeking growth hormone because they are afraid short stature leads to psycho-social challenges, is height really the best outcome measure?” Dr. Grimberg asked. “Should we be looking at measures of psychosocial adaptation as the better metric?”

On top of that, most studies only report short-term outcomes because it is difficult and expensive to follow GH-treated children to adult height. Retrospective analyses are tricky to interpret because factors like defining GH deficiency or GH treatment doses and endpoints may have changed over time.

Another conceptual gap lies in the inconsistency of GH testing itself. Assays and dynamic tests to measure GH and IGF-I production have changed over time, and even current tests are flawed and often differ between institutions and studies.

“In retrospective studies, it’s hard for us to cleanly figure out who has what, and then to assess what we are treating and how we are treating it,” Dr. Grimberg said.

In response to these knowledge gaps, Dr. Grimberg’s current work takes a closer look at the disparities in the diagnosis and treatment of children with short stature. Knowing where these disparities arise will help researchers and physicians better address them to improve clinical care. Later this summer, Dr. Grimberg and her colleague expect to release a new paper that details how both the presence and the absence of evidence shaped the current guidelines.

“We need better diagnostic tests and better outcome metrics,” Dr. Grimberg said. “We also need to test treatments to see if they really do or do not improve various outcomes.”

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Scientific Symposium Emphasizes Future Directions of Research Institute


Synapses were firing throughout the conference room in the Colket Translational Research Building as attendees at the 2017 Research Institute Scientific Symposium held May 2 learned about their colleagues’ intriguing research endeavors. The four sessions’ themes aligned smartly with the Research Institute’s strategic planning process and overall mission of the Children’s Hospital of Philadelphia.

“I’m hoping that what you’re going to hear from each session is a little bit about the really cool stuff that’s happening today, and a little bit about the really cool stuff we expect to see happening in the relatively near future,” said Stewart Anderson, MD, a research psychiatrist in the department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP and professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, in his opening comments as one of the leaders of the Symposium’s planning committee.

Innovating Along the Fetal to Adult Lifespan

And indeed, really cool stuff is exactly what the Symposium speakers delivered throughout the day, starting off with highlights of research projects that are innovating along the fetal to adult lifespan. While generally pediatric care has been most concerned with the here and now of helping a sick child, this line of research also encompasses the before and after.

For example, Raquel Gur, MD, PhD, professor of Psychiatry Neurology and Radiology at Penn who directs the new Lifespan Brain Institute, which encompasses broad collaborations between investigators at CHOP and Penn, spoke about “The Emergence of Psychosis in Youth.” Dr. Gur explained how researchers are identifying biomarkers that could lead to new ways to predict which children will develop psychosis as they reach adolescence and young adulthood. Once researchers better understand how brain circuitry goes awry earlier in life, the next step would be to develop interventions that could help to avert a patient’s first psychotic break.

Finding Causes and Therapies for Rare and Complex Diseases

The second session focused on understanding the causes and development of therapies for rare and complex diseases, such as mitochondrial disorders. Marni Falk, MD, an attending physician and executive director of the Mitochondrial Medicine Center at CHOP who also is associate professor of Pediatrics in the division of Human Genetics at Penn, explained that at least one in 4,300 people have a mitochondrial disease. Each of those patients experiences on average 16 severe symptoms, often requiring referrals to between three and 10 specialists. And, so far, researchers have identified about 300 gene disorders that cause mitochondrial diseases, with different flaws in different genes manifesting with varied inheritance patterns and arrays of symptoms affecting potentially any systems in the body.

All those numbers add up to the same conclusion: These individually rare disorders are challenging to explore. No therapies for mitochondrial diseases have been demonstrated to work in randomized, controlled trials or approved by the Food and Drug Administration (FDA). Yet Dr. Falk assured the Symposium audience: “These will one day be treatable diseases.”

Dr. Falk described her pre-clinical studies of drug therapies in animal models of mitochondrial complex I disease. In the first phase of this work, her team found a series of drug candidates that were effective in improving the lifespan of microscopic worms, C. elegans, with mitochondrial defects equivalent to those that occur in subsets of human disease. The next phase of her research is extending these studies into a small vertebrate animal, zebrafish. But taking promising drugs from animal models into traditional clinical trials to evaluate whether they benefit human patients with mitochondrial disease is difficult because few patients share the same genetic subtype of disease, and often their clinical symptoms and treatment goals vary.

In order to expedite precision medicine for mitochondrial diseases and other rare disorders, Dr. Falk encouraged her fellow scientists to consider a new paradigm of conducting research based on “n-of-1 trials.” This strategy is a clinical trial in which an individual patient is the single participant, and the study aims to objectively assess and make an informed decision about the best course of therapy depending on the patient’s unique data and circumstances. This is an emerging approach recognized as having merit for rare disease by the FDA, and it will require the collaboration and engagement of diverse parties, from academia to pharma to regulatory agencies and patients themselves, to design, fund, and effectively implement.

Optimizing Genome Editing

The Symposium’s keynote address by J. Keith Joung, MD, PhD, pathologist and associate chief of pathology at Harvard Medical School, delved into another novel research paradigm: the remarkable genome editing method known as CRISPR (clustered regularly interspaced short palindromic repeats), which was named Science‘s 2015 Breakthrough of the Year.

Dr. Joung spoke in detail about one of the biggest challenges researchers face in genome editing: specificity. When scientists utilize CRISPR-Cas9 – which is one of the more commonly used CRISPR systems – a molecule called Cas9 functions like a microscopic set of scissors to slice into DNA strands at the place that scientists would like to edit. Scientists can then go in and alter the DNA by adding, taking away, or manipulating its pieces. What happens, however, when CRISPR inadvertently snips and clips parts of the genome that it shouldn’t? These so-called “off-targets” occur at parts of the genome that might look a lot like the target sites, but aren’t – thus potentially messing with a scientist’s investigation.

“You don’t want to attribute a phenome to an off-target because of the possible effect,” said Dr. Joung, using the example of cancer risk. What if scientists unintentionally silence a gene that suppresses tumors, or activate one that leads to cancer?

To potentially address the problem, Dr. Joung’s lab designed a technology called GUIDE-SEQ, which marks all of the places in the genome where a break in the DNA occurs, thus creating a “map” for researchers to follow when trying to find off-targets. While popular coverage of CRISPR sometimes skips talking about the risk of off-targets, Dr. Joung explained the importance of acknowledging that even breakthrough tools can go wrong.

“This must be done as part of an overall safety evaluation in research,” he said. “It may be challenging for the researcher, but we owe it to patients to do the best possible job to define these risks.”

Advancing Novel Therapeutics and Devices

The Symposium’s afternoon sessions followed Dr. Joung’s theme of optimizing existing discoveries to drive novel impact. In the third session, titled “Advancing CHOP’s Leadership in Novel Therapeutics and Device Development,” researchers shared different ways we can build on research in thrombosis, cancer, neurosurgery, and surgical devices.

Guest speaker Carl June, MD, director of the Center for Cellular Immunotherapies at Penn, discussed the past and future of immunotherapy in “CAR T-Cells Enter Mainstream Oncology.” His lecture hinged on the question of whether CAR T-cell therapy – which involves a lot of work even in simply harvesting a patient’s cells – was worth it. After telling the story of Emily Whitehead, who is now cancer-free for almost five years, then outlining the subsequent explosion of successful CAR T-cell trials around the world, Dr. June concluded that “clearly, the juice is worth the squeeze.”

Dr. June also discussed the future of immunotherapy, which may very well include the use of CRISPR CAS/9 in CAR T-cell therapy. After harvesting T-cells from a patient, scientists can use gene editing to turbocharge the cells for more optimal cancer-killing effects before re-introducing the cells back into the patient’s body. These edited CAR T-cells may even have a stronger effect on solid tumors since currently, CAR T-cell therapy appears to work better in blood-based cancers, like acute lymphoblastic leukemia.

Promoting Precision Health Research

The fourth and final session, “Developing Breakthrough Precision Health Research,” sent questions firing across the room after each talk. Five researchers shared ways in which precision health, defined as the right intervention for the right patient at the right time, can be applied to a various research subjects including violence prevention at schools, primary care, environmental data, cancer, and health equity.

In this final talk, Tiffani Johnson, MD, an attending physician in the department of Emergency Medicine at CHOP, spoke about her recent research findings in implicit racial bias, defined as an unconscious positive or negative attitude toward children of a certain race. Her team of researchers found that in a study of 91 pediatricians in a large emergency department, about 91 percent held pro-white/anti-black bias, according to Child Race Implicit Association Tests.

Dr. Johnson suggested that a precision medicine approach could help improve minority care, and she used the example of sickle cell disease (SCD) and morphine responses. Currently, studies show a wide variation in how children of different races respond to pain, with minority children tending to experience a higher pain burden and requiring more analgesic. In some cases, this can lead to the harmful classification of minorities as “drug-seekers.”

In order to better understand this variation in clinical response – and alleviate unnecessary suffering – Dr. Johnson shared research being conducted by Dr. Angela Ellison that combines genomic information with a rigorous prospective study of morphine response in a large cohort of children with SCD from all races. Researchers can then predict how children with different gene makeup respond.

According to Dr. Johnson, better diagnostic and therapeutic tools will result in reduced clinical uncertainty, which results in decreased impact of bias which, finally, results in reduced disparities.

“How can we make sure vulnerable populations are getting equal opportunity to the best health possible?” Dr. Johnson asked. “Precision medicine can ensure we’re delivering the right interventions to right patients in the right matter, allowing all children equal access to opportunities to attain the highest quality of well-being.”

The Symposium wrapped up with a quick thank you address from Symposium planning committee members Timothy Roberts, PhD, vice chair of research in Radiology and a professor of Radiology at Penn; Flaura Winston, MD, founding director of the Center for Injury Research and Prevention, and professor of Pediatrics at Penn, and Dr. Anderson to everyone involved, followed by a cocktail reception.

Really cool stuff, indeed.

The Office of Responsible Research Training at the Research Institute sponsored the 2017 Research Scientific Symposium.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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