Bench to Bedside

January 2016

How Precision Medicine is Reshaping Epilepsy Research


The little girl’s epilepsy was so debilitating that she was virtually nonresponsive. Traditional antiseizure medicines could not reduce the five to 20 seizures she experienced daily when she first came to The Children’s Hospital of Philadelphia.

Trying a new approach, her neurologist, David Bearden, MD, prescribed a drug that targeted a molecular pathway involved in her seizures, and within a month, she was seizure-free for the first time since a few days after her birth.

This success excited hope among epilepsy researchers worldwide that other such successful strategies could soon follow. The case exemplifies the popular concept of precision medicine, which is barreling ahead in cancer but not yet common practice in neurologic disorders such as epilepsy.

“Most drugs for epilepsy work like treating pneumonia with a cough suppressant: It may stop the symptom but doesn’t treat the underlying problem,” said Ethan Goldberg, MD, PhD, a CHOP neurologist and neuroscientist who was senior author of a case report about the little girl’s treatment (of which Dr. Bearden was first author) in Annals of Neurology in 2014. Her treatment, while not yet analogous to an antibiotic, was more precisely targeted to the underlying mechanism of her seizures than most treatments.

The future need for precision medicine is one that epilepsy researchers are approaching with conscious attention to the field’s strengths and unmet challenges. Dr. Goldberg was a presenter at a precision medicine scientific symposium during the American Epilepsy Society annual meeting in December. His colleague, Dennis Dlugos, MD, MSCE, a CHOP pediatric neurologist, was among the major contributors to an international consortium of researchers who authored a roadmap for precision medicine in epilepsy published in The Lancet Neurology this fall.

Finding Genetic Causes of Epilepsy

Several research groups had only recently published findings linking the little girl’s particular genetic form of epilepsy to overactivity of an ion channel, KCNT1 at the time she arrived at CHOP. Recognizing that potential drug therapies blocking KCNT1 might be a useful approach in this form of the disease, Dr. Goldberg searched for existing drugs that could have this effect. Soon, Dr. Bearden developed a treatment plan and prescribed the one drug that fit the bill and already had an established safety profile for use in children, a cardiac drug called quinidine. Quinidine led to her successful, dramatic reduction in seizures, and Dr. Bearden and others have since prescribed it to a number of other children with genetic mutations affecting the KCNT1 channel.

The handful of known KCNT1 mutations are just the tip of the iceberg among epilepsy-related genes — an area where discovery is accelerating progress on the road to precision medicine. Approximately 100 known single-gene causes for epilepsy are known, comprising 10 to 15 percent of epilepsy cases. Half of epilepsy cases have unknown causes that are also presumed to be genetic, with the remaining proportion of cases attributed to known non-genetic causes such as brain injury or infection. Dr. Dlugos and CHOP neurologist Ingo Helbig, MD, were among the leaders of a major international study pinpointing epilepsy mutations in 2014. These findings are all potential targets for precision-medicine therapies — but they are only a first step.

Modeling Mechanisms of Healthy and Epileptic Brains

After identifying epilepsy-causing genes, researchers still need to learn what these genes do, including both their role in the mechanism of disease and in healthy brain functions.

Until researchers better understand those mechanisms, there is a risk that precision treatments, like current antiseizure medicines, could still target the wrong outcome.

“If your output measure is cough, we may be developing better and better treatments for cough, not pneumonia,” Dr. Goldberg said.

Even quinidine, the source of so much hope for precision medicine, could turn out to be little better than an improved seizure suppressant. After treating several more patients with KCNT1 mutations using quinidine, Dr. Bearden noted that most showed improvements in seizures and developmental outcomes, but all remained significantly developmentally delayed. Researchers do not yet know what other mechanisms contribute to the developmental problems in KCNT1-related epilepsy.

A wide array of cell, network, and animal models of epilepsy is key to understanding the mechanisms of the disease and its existing investigational treatments, and to screening for and testing new treatments. Dr. Goldberg and Eric Marsh, MD, PhD, at CHOP, work with epilepsy models including stem cells, fish, mice, and many more. This laboratory study of epilepsy requires a wider range of models than many types of cancer, because neuroscientists find living model systems essential to studying epilepsy as a circuit-based disorder. In contrast, cancer researchers commonly have tumor tissues to directly test treatments on the disease cells, which are more useful as models of that disease’s cell-growth dysregulation.

“All these models together can help us target some of the disease mechanisms, whether testing off-the-shelf medications or going through the process of new drug design,” Dr. Marsh said.

Drug Development and Clinical Testing

Developing new drugs is a challenge because major pharmaceutical companies have not made large investments in developing new epilepsy treatments in recent years, although a few smaller companies are exploring the potential for precision epilepsy treatments. An added challenge with precision treatments is that, by design, this approach targets smaller subgroups of patients, or a smaller commercial market, than do broad-acting drugs.

Preclinical modeling that helps to group different genetic epilepsies into related pathways may help meet that challenge, Dr. Marsh noted. In his modeling, he seeks out signs that many different genetic causes of epilepsy could lead to the same neuronal mechanism of disease, to see if a targeted drug could act on that mechanism — essentially grouping different genetic epilepsies together by function.

Designing clinical trials once new potential precision drugs are identified is difficult for the same reason — dividing a rare disease into even rarer subtypes with tiny patient populations. Making trials even more challenging, the outcome measure in epilepsy studies is patient- or parent-reported incidence of seizures, not a direct biological marker of disease.

“How do we design trials with clinical seizure reporting as the primary outcome measure when you have very few patients and not a lot of options for a big trial?” Dr. Dlugos said. “That’s an open topic for discussion right now between us, the NIH, and the FDA about how that is going to happen.”

Conducting trials for off-the-shelf medicines such as quinidine poses its own set of challenges: Doctors can freely prescribe them off-label before rigorous evidence demonstrates their effectiveness. For that reason, Dr. Bearden has begun a clinical registry for children with KCNT1 mutations to track their physicians’ treatment plans and outcomes, in hopes of gathering useful effectiveness data about various approaches.

The early success treating one little girl with quinidine, while promising, only marked the start of a long road ahead for developing and validating precision treatments for her disease.

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Championing Trauma-Informed Care in Pediatrics


Imagine a trembling child in the Emergency Department (ED), with a parent about to collapse in tears while squeezing a tiny hand. A nurse notices the family’s rising distress and takes a few moments to talk with them about their fears and concerns, and to suggest specific ways to cope with the procedure that’s about to happen. She is practicing trauma-informed care, a skillset that most clinicians realize is pivotal but for which very few providers have had specific training.

Integrating a trauma-informed approach into healthcare settings is a way that medical teams can help to prevent or minimize emotional trauma for children and families facing injury, illness, and hospitalization. As just one example, by integrating these principles into ED care, medical personnel can potentially improve health outcomes for the 8 million children who are treated in EDs each year for unintentional injuries resulting from motor vehicle crashes, falls, and other causes.

About one in six children seen in the ED for an unintentional injury — and one in six of their parents — experienced clinically significant psychological symptoms, including post-traumatic stress and depression, several months after injury, according to a study recently published in Pediatric Emergency Care. The study included 263 child-parent pairs who completed standardized psychological assessment measures five months after receiving ED treatment, with the parents reporting on overall recovery for their children.

“Five out of six go on to do pretty well, so we don’t want the message to be that if you get injured, you’re going to have psychological problems,” said Nancy Kassam-Adams, PhD, associate director of behavioral research at the Center for Injury Research and Prevention (CIRP) at The Children’s Hospital of Philadelphia (CHOP) and director of the Center for Pediatric Traumatic Stress at CHOP, who led the study. “But nearly one-third of families in our study had either a parent or child who was struggling emotionally months later. This result argues for the importance of trauma-informed care, including anticipatory guidance about emotional recovery for the whole family.”

Online Game Serves as Screening Tool for Kids With Coping Difficulties

Clinicians can help parents and children understand common emotional reactions to an injury and also to recognize when they could become problematic. Evidence-based resources that CHOP researchers developed to promote emotional recovery after an injury are available, such as a website for parents of injured children,, along with downloadable assessment and patient education tools at

Once children and parents leave the ED, however, it is difficult for clinicians to know who is having trouble coping well in the following weeks. Dr. Kassam-Adams and her team’s ongoing research is looking at how to use an online game platform called Coping Coach as a screening tool after discharge. The game starts with a short symptom assessment each time a child logs on.

“By building this game that kids can play with for a month or two after leaving the hospital, we can keep track of how they’re doing and then send messages to their parents and doctors if it seems that they may benefit from intervention,” Dr. Kassam-Adams said. The project is funded by the National Institutes of Health, and supported by the SPRINT program at CHOP’s Office of Entrepreneurship and Innovation.

Research conducted by the Center for Pediatric Traumatic Stress at CHOP and its collaborators has helped to identify some of the risk factors that can worsen a parent or child’s trajectory for recovery. They include families who have had prior traumatic experiences, children whose pain was not well-controlled during their hospital stay, and children who tended to cope by withdrawing or avoiding anything that triggers memories of the trauma.

According to Dr. Kassam-Adams, trauma-informed healthcare providers can help to address those risk factors early on: “For example, a clinician who learns that a child previously witnessed a neighborhood shooting can be aware of how those stress symptoms may manifest during the child’s ED experience,” she explained. “The care families receive can help them better manage any pain and distress in the short run, and may open the door for additional help after they are back at home.”

Clinicians Want More Training in Trauma-informed Care

Many medical providers agree that they have a key role in supporting children from a psychosocial perspective. An international online survey of 2,600 hospital ED staff showed that more than 90 percent viewed psychosocial care as an important part of their job — yet only 14 percent felt confident about educating children and families about traumatic stress reactions. Nearly all the respondents desired training in this area, according to the study published in The Journal of Pediatrics.

“This is very good news here about healthcare professionals’ strong commitment to the best care for injured children and their interest in learning more to improve psychosocial aspects of this care,” said Dr. Kassam-Adams, one of the investigators involved with the study conducted through PERN, an international collaboration of emergency medicine research networks.

Even better news is that as the idea of trauma-informed care is catching on, CHOP’s Violence Prevention Initiative rolled out a comprehensive model to help a wide spectrum of healthcare providers, including ED staff, receive on-the-job training for trauma-informed care. The framework is based on research from CIRP that appeared in JAMA Pediatrics. Lead author Meghan Marsac, PhD, a pediatric psychologist and behavioral researcher at CIRP, encourages clinicians to remember the three R’s:

Since July 2013, CHOP has trained more than 1,000 staff members in trauma-informed care, with plans to train many more departments in the upcoming year. While future research is necessary to determine the effect of network-wide implementation on patient and staff outcomes, CHOP’s commitment to a trauma-informed systems approach already is being incorporated into the policies, practices, and culture of the entire institution.

Online training courses and other resources on providing trauma-informed care are available at

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New Collaboration Uncovering a Mitochondrial Mystery


Mistakes happen. Inside every cell, the functions of life rely on the basic process of building proteins. But, about half the time, cells make errors when building proteins and have to recycle the pieces and start again. One important player in the cell’s recycling process, an enzyme called N-glycanase 1 (NGLY1), is at the center of a new, fundamental biological mystery that researchers at The Children’s Hospital of Philadelphia are setting out to solve.

Two young patients brought this mystery to the team’s attention. Both children arrived within a short time of each other with symptoms of suspected mitochondrial disease at CHOP’s Mitochondrial-Genetic Disease Clinic, which Marni Falk, MD, directs. Mitochondria are the organelles inside of cells that act as the cell’s energy generator, and diseases of mitochondria can have wide-ranging effects across every organ system and commonly include neurological and cardiac complications.

“There are a lot of areas of mitochondrial biology that are still not known at all,” said Dr. Falk, an attending physician at CHOP. “We’ve been so intrigued with this project because, every time we asked a question, three more questions followed.”

Dr. Falk and her team found that, instead of a primary mitochondrial disease, these two children had an extremely rare genetic disorder that was only recently identified, caused by an inherited deficiency in the protein-recycling enzyme, NGLY1. This was fundamentally weird. There was no evident logical reason for a disease of NGLY1 dysfunction to so closely resemble diseases of mitochondrial dysfunction because the proteins in mitochondria do not require NGLY1’s services, or so says conventional wisdom.

Evidence Builds for Mysterious Two-Way Connection

These proteins are believed to be unadorned with the modification (a carbohydrate addition called N-linked glycosyl groups) that NGLY1 removes when recycling proteins. Still, there appeared to be some connection. When the CHOP team looked closer at tissue samples biopsied from their two patients with NGLY1 deficiency, the mitochondria appeared abnormal both in quantity and appearance.

“We were intrigued with why something that’s involved in how you deglycosylate, and turn over your cellular proteins, should affect your mitochondria,” Dr. Falk said. “If the proteins in your mitochondria are not glycosylated, why should it matter at all?”

Preliminary evidence continued to mount that, for whatever reason, the action of NGLY1 did have some association with mitochondria, and past studies suggesting otherwise might be mistaken. When Dr. Falk collaborated with Zhe Zhang, PhD, in CHOP’s Center for Biomedical Informatics to evaluate data available about gene expression changes in nearly 100 mitochondrial disease patients from across eight different studies, they found that the NGLY1 gene was highly dysregulated in patients with mitochondrial disease. In fact, it was the second-most upregulated gene across all mitochondrial disease patients. They knew something had to be going on.

Multidisciplinary Approach to Understanding Mitochondrial Proteins

Now Dr. Falk and a multidisciplinary team of investigators from CHOP and the University of Pennsylvania intend to dissect the process further to find out more about this mysterious two-way connection between mitochondrial disease and protein deglycosylation by NGLY1. Under a newly awarded multi-PI NIH grant to Dr. Falk, Yair Argon, PhD, and Miao He, PhD, at CHOP, and Penn biochemist Eiko Nakamaru-Ogiso, PhD, the team will combine their complementary expertise in subjects including mitochondrial disease, clinical genetics, protein synthesis, glycosylation, and biochemistry. Their study will look in detail at the possible glycosylation of mitochondrial proteins that carry out the fundamental chain reaction of chemical processes within mitochondria that generates cellular energy, known as the electron transport chain.

For this study, they have access to cells from many dozens of mitochondrial disease patients who have enrolled in the CHOP mitochondrial disease research study, as well as cells from more than a dozen patients now identified with this rare NGLY1 deficiency, through collaboration with a natural history study of NGLY1 disease that is coordinated at the NIH by Lynne Wolfe, MS, CRNP. Thanks to a generous contribution by collaborator Tadashi Suzuki, DSci, of the Riken Advanced Science Institute in Japan, the team has embryonic fibroblast cells for study from a nonviable NGLY1 knockout mouse model.

“We’ve been working together to figure out how to isolate really pure mitochondria, so that we can apply sensitive methods to determine if the mitochondrial proteins, and specifically the proteins that work to directly make energy, are N-glycosylated,” Dr. Falk said. “Then, we can begin to understand how those protein modifications may be changed in either primary mitochondrial disease or NGLY1 disease.”

‘The Implications are Profound’

They suspect the answer has to do with cellular stress. To better understand the roles of NGLY1 and mitochondria in the cell’s stress response, and to translate that understanding into meaningful therapies, the team is combining its NIH-funded work with a project funded by the Grace Wilsey Foundation. They are working with cell lines and animal models of NGLY1 deficiency to characterize the nature of both cellular and mitochondrial stress responses that occur when NGLY1 is missing, and to develop possible NGLY1 disease therapies they can test in these models.

At the same time, the obscure-sounding scientific mystery of whether mitochondrial proteins are N-glycoslated after all, could add substantial pieces to the puzzle of some aspects of basic cell biology.

“The implications are profound,” Dr. Falk said. “If we’re right in our belief that mitochondrial proteins are glycosylated, there’s going to be a whole machinery to do this, potentially inside the mitochondria. That might open up understanding of new diseases or opportunities for new therapies. If you don’t even know a process is happening, you can’t possibly account for it, monitor it, and treat it.”

In addition to her titles at CHOP, Dr. Falk is an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Dr. Argon is chief of the Cell Pathology Division in the Department of Pathology and Laboratory Medicine at CHOP and professor of Pathology and Laboratory Medicine at Penn. Dr. He is co-director of the Metabolic Disease Laboratory at CHOP and assistant professor of Pathology and Laboratory Medicine at Penn. Dr. Nakamuru-Ogiso, is a research assistant professor in the Department of Biochemistry and Biophysics at Penn.

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Speeding Up Success with Precision Medicine Cancer Trial


An innovative new clinical trial launching this year at The Children’s Hospital of Philadelphia may not only help patients who have no further proven treatment options for neuroblastoma, a high-risk cancer, but may also be a model for how precision medicine clinical trials can spur better and faster cancer therapy discoveries in the future.

The trial uses a dynamic design, which allows researchers to quickly translate findings from the lab based on the evolving individual characteristics of each patient’s tumor. It is the first time such a strategy is being applied to a prospective clinical trial in children with cancer. Known as the NExt-generation Personalized NEuroblastoma THErapy (NEPENTHE) trial, it is moving forward with a new $1.5 million grant from Alex’s Lemonade Stand Foundation (ALSF), announced in December.

“The novelty of this trial could be viewed on numerous levels,” said principal investigator Yael Mossé, MD, a CHOP pediatric oncologist and assistant professor at the Perelman School of Medicine at the University of Pennsylvania. “It’s based on rigorous preclinical data, understanding the molecular drivers that are important in this disease. It’s combining multiple novel drugs, not just one at a time. And it’s bringing that to the clinic and assigning patients to therapy based on what their tumor genetics are teaching us at the time that they meet us with relapsed or refractory cancer.”

Going Beyond Traditional Clinical Trial Designs

The three-year Bio-Therapeutics Impact Award from ALSF seeks to strategically advance research-based treatment of neuroblastoma, an often lethal childhood cancer that remains difficult to cure. Usually appearing as a solid tumor in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy. The NEPENTHE trial will enroll children who have suffered a relapse of neuroblastoma or whose neuroblastoma did not respond to the initial treatment.

Neuroblastoma is “a microcosm of the childhood cancer problem,” Dr. Mossé said. It is a group of tumors that has one name and generally looks similar under the microscope. Yet, by working with patients, researchers have learned time and again that the disease is extremely heterogeneous, due in large part to the many different underlying genetic and molecular causes of disease, which can both interact to affect treatment responsiveness and change over time in cases where the cancer relapses after treatment. That pattern — one disease by name, many diseases at the molecular level — has not routinely been addressed in the design of traditional clinical trials for childhood cancers.

“We’re setting ourselves up for failure,” Dr. Mossé said, of those traditional clinical trial designs. Most trials of new drugs enroll patients with relapsed or refractory disease for whom no curative options remain — regardless of whether there is any reason to think that the investigational drug will act on the molecular cause of the patient’s cancer. And they test just one drug at a time.

“Our improved understanding of neuroblastoma biology and treatment will guide this trial and help us to continually design combination therapies that are potentially more effective and less toxic for our young patients,” said NEPENTHE Co-investigator John Maris, MD, who leads CHOP’s internationally prominent research laboratory focused on neuroblastoma.

Looking Ahead to Future Precision Medicine Clinical Trials

The NEPENTHE trial will be a collaborative effort, enlisting the expertise of numerous other specialists throughout CHOP and other institutions. Dr. Mossé hopes that ultimately investigators can use NEPENTHE as a model for future precision medicine clinical trials — dynamically linking clinical needs to preclinical insights — that could apply more broadly to other childhood cancers.

The founding grant for this trial was provided in 2014 by the Band of Parents and Arms Wide Open, dedicated to supporting new treatments for neuroblastoma. Additional charitable support came from Solving Kids’ Cancer Foundation and the Open Hands Overflowing Hearts Foundation.

NEPENTHE is not the only clinical trial for neuroblastoma that Dr. Mossé hopes to get up and running early in 2016. Read more about her team’s recent published findings of a drug compound with promising preclinical results against a treatment-resistant neuroblastoma mutation on our blog, Cornerstone.

For more information, see the CHOP press releases about the NEPENTHE trial and next-generation ALK inhibitor.

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Possible ‘Central Hub’ Proteins Found in Cancer Cell Growth


A study from researchers at The Children’s Hospital of Philadelphia may add new lines to the textbook description of how cancer cells divide uncontrollably and develop into tumors. Their study, published in Nature Communications, identifies and describes an epigenetic mechanism in cancer cells that amplifies the expression of many genes and could be a central hub in cancer cell growth. Unlike most molecular cancer discoveries that advance knowledge of the disease by dividing it into narrower subtypes, this finding could directly apply to multiple cancer types.

“We know the signaling pathway known as the Rb pathway is altered in pretty much every single tumor that you can find in clinical settings,” said Patrick Viatour, PharmD, PhD, the study’s senior author, an investigator at CHOP and assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Viatour’s research focuses on a family of proteins in the Rb pathway, called E2f transcription factors, that are an important part of the process of cell division — the cell cycle of reproduction that is carefully controlled in healthy cells but proceeds out of control when cancer cells proliferate. Transcription factors, including the E2f family of proteins, bind to specific target regions of DNA and help to either activate or deactivate expression of certain genes.

How E2f Transcription Factors Go Awry

As a result of Rb pathway alteration, E2f factors are steadily turned on in cancer. In the study primarily using a mouse model of liver cancer, Dr. Viatour and his team found that E2f1 progressively accumulates as cancer progresses.

“E2f1, an activating E2f transcription factor, is frequently overexpressed in late stages of many types of cancer, both pediatric and adult,” Dr. Viatour said. “We know it’s linked to late cancer stages and poor prognoses, but we didn’t know what it was doing.”

The scientists showed how E2f1 enables excessive gene activation in the cancerous cell: As E2f1 accumulates, it amplifies gene activation by other members of the E2f family by binding to a molecular complex of the DNA-unzipping proteins Pontin and Reptin. When bound to this complex, the adjacent chromatin molecules that store and protect DNA open up and allow all of the other activating E2f proteins to enter and bind to their target sites.

They found that when excess E2f1 forms the Pontin/Reptin complex on DNA in cancer cells, not only do cell-cycle genes become overactivated, but many more genes are also overexpressed. This occurs because, in the presence of amplified E2f factors, more of these factors will bind to genes that possess lower affinity for them.

In particular, some of these other genes regulate a long-known process of rewiring the energy metabolism in cancer cells for rapid growth, known as the Warburg effect. Dr. Viatour and colleagues believe many more genes are activated by this amplification mechanism, as well. They suggest that the mechanism connects excess cell proliferation together with other characteristic features of cancer cells that collectively make up the process of tumor formation.

A New Way of Thinking About Cancer Progression

“This finding really expands what’s been considered textbook material,” Dr. Viatour said. “We thought E2f was mostly promoting cancer growth through aberrant cell cycle activity. If you only have a little E2f activity, it is just the cell cycle. But if you have a lot of E2f activity, as you have in cancer, it’s way more than that. These factors promote cancer progression by actually activating multiple gene programs.”

Although most of this work was done in a mouse model of hepatocellular carcinoma, a form of liver cancer primarily affecting adults, Dr. Viatour and his team performed further experiments using human cell lines from multiple types of pediatric and adult cancers. In just over half of these human cell experiments, they found the same Pontin/Reptin complex binding with E2f1, suggesting that the same mechanism may occur in many human cancers.

The team’s next phase of research will seek to better understand this mechanism of amplified gene expression to determine whether it is not only associated with cancer progression, but truly critical to it. If so, Dr. Viatour said, there is potential to pursue cancer treatments that would target the E2f1/Pontin/Reptin complex in cancer cells to stop excessive gene expression before it starts. Transcription factors such as E2f1 itself are so ubiquitous and essential in healthy cells that they do not make good targets for disease treatments, he noted, but targeting protein-protein interactions has been successful in other cancer therapies.

“I think we have a mechanism that is very general,” Dr. Viatour said. “Maybe we’re wrong, but maybe we’ve hit something that is going to be very relevant to a lot of cancer types. Testing that hypothesis is very exciting.”

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Baby Poop Study to Link Infant Microbiome and Obesity


New parents who find themselves surprisingly attentive to their babies’ poop are in good company. Researchers at The Children’s Hospital of Philadelphia and the University of Pennsylvania are beginning the second phase of a study that is exploring whether baby poop is an important data source to learn how the risk of obesity develops early in life.

The research team is focused on the miniscule but mighty passengers in baby poop: the gut microbiome. The collection of bacteria and other microorganisms that live within the digestive tract and contribute to processing food could reveal a lot about early excess weight gain.

“We are enrolling moms during their third trimester and trying to characterize their vaginal and gut microbiota, look at the transmission to infants, and follow the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain,” said Babette S. Zemel, PhD, principal investigator of the Infant Growth and Microbiome (I-Gram) study at CHOP, describing the ongoing first phase of study.

In the I-Gram 1 study, after delivering their babies, participating African-American mothers send in fecal samples from their babies at specified time points over the next year. The microbial analysis, just getting underway now, will characterize the communities of microbes in the samples. Participating mothers also bring their babies for periodic visits to CHOP for comprehensive measurements of physical growth and development. On months in between hospital visits, the study team collects detailed information about the babies’ nutritional intake via telephone consultations.

Taking a Close Look at Metabolomics in Infants

Now with new funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the I-Gram 2 study led by Dr. Zemel and Penn gastroenterologist Gary Wu, MD, will follow this cohort — plus an additional group of babies — until two years of age, while adding new forms of molecular analysis of the microbiome. Specifically, I-Gram 2 will enable researchers to sequence the metabolome, or the chemical byproducts of the microbiome’s activities in the digestive tract, giving a clearer idea of not just what species are present in the gut, but how they are functioning in babies’ bodies.

“This will probably be one of the largest studies looking at metabolomics in infants,” said Dr. Zemel, who is director of CHOP’s Nutrition and Growth Laboratory and a research professor of Pediatrics at the Perelman School of Medicine at Penn. “It’s unique because we have very detailed information starting with the third trimester of pregnancy and now following the babies to two years of age.”

Informing Better Strategies to Prevent Obesity

This data is valuable because metabolic products of the microbiome could have a surprisingly large impact on how human bodies function. Gut bacteria, for instance, help to create about 95 percent of the body’s serotonin, which influences mood, depression, and behavior. Microbes in the human body also help make vitamins, aid digestion, and set immune tone.

In the I-Gram study, Dr. Zemel and her collaborators are seeking a detailed description of what happens in the gut microbiome as it becomes established and matures in infants born to healthy weight and obese mothers. Participants are primarily recruited from communities where obesity rates are highest in the city, and children are therefore at heightened risk of later obesity-related health problems. The researchers hope to identify early predictors of weight gain in infancy that might inform better prevention strategies.

The I-Gram study would not be possible without collaboration between Dr. Zemel and numerous other investigators at CHOP and Penn, including I-Gram 2’s Co-Principal Investigator Dr. Wu, a professor at the Perelman School of Medicine and co-director of the PennCHOP Microbiome Program, as well as the interdisciplinary team that includes Frederic Bushman, PhD, also co-director of the PennCHOP Microbiome Program; Michal Elovitz, MD, director of the Maternal and Child Health Research Unit in the Department of Obstetrics and Gynecology at Penn; Hongzhe Li, PhD in Biostatistics and Epidemiology; and Andrea Kelly, MD, in Pediatric Endocrinology at CHOP.

To learn more about the I-Gram study, see the previous article about I-Gram 1 on the CHOP Research Cornerstone blog.

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New Center for Data Driven Discovery in Biomedicine Transforms Big Data


A first-of-its-kind open-access, data driven discovery platform that empowers new diagnostic tools and personalized, precision therapies for rare childhood diseases and pediatric cancers has been developed at The Children’s Hospital of Philadelphia.

The announcement of the Center for Data Driven Discovery in Biomedicine (D3b), by Adam Resnick, PhD, and Philip “Jay” Storm, MD, coincided with Vice President Joe Biden’s Jan. 15 visit to the Abramson Cancer Center at the University of Pennsylvania for the launch of the White House’s “Moonshot” initiative, which aims to break down silos and bring all cancer fighters together to end cancer. In his roundtable discussion with CHOP and UPenn researchers, the Vice President discussed challenges including data sharing and collaboration.

Indeed, a giant leap is needed in order to surpass the challenges of research and discovery in the pediatric cancer arena. New genome sequencing technology generates a large amount of data for analysis, often referred to as “big data.” Genomic scientists must dive deeply into this ocean of information to find subtle signals that could become pearls of insights into pediatric disease.

“Unfortunately, whatever limited pediatric cancer data has been generated to date by ‘big data’ technologies has remained siloed, and genomic and healthcare data remain largely unintegrated and unempowered with limited access or the necessary opportunities for collaborative research,” Drs. Resnick and Storm stated.

The D3b is a new disruptive open-access model for biomedical research that will provide robust pediatric data generation and analysis infrastructure. It is based on collaboration, data sharing, and scientific integration, allowing pediatric researchers to transform how they approach big data, specifically by following these new principles:

This data driven precision medicine initiative, led by CHOP’s Research Institute and Department of Biomedical Health and Informatics, further supports the growth of large-scale interdisciplinary, collaborative infrastructures in CHOP-led multi-institutional research and clinical trial consortia, including the Children’s Brain Tumor Tissue Consortium (CBTTC) and the Pacific Pediatric Neuro-Oncology Consortium.

“Working with CHOP leaders, collaborating hospitals, industry partners, and (most importantly) foundations, patients and their families, the Center initiative will build on CHOP’s investment in a new pediatric biospecimen and integrated diagnostics and data discovery open ecosystem,” Drs. Resnick and Storm stated. “Leveraging scalable cloud computing for ‘big data’ access and rapid analytics, Center programs will work with industry partners to provide secure, integrated data discovery and biospecimen sharing platforms.”

Researchers worldwide will be able to access this information and work together to fully empower and share novel ideas and approaches for new biological targets for precise, less toxic clinical treatments on behalf of children.

To rapidly address this expansive mission on behalf of children, one of the first major initiatives and products of the Center is the creation of an open-access pediatric genomic data cloud. D3b teams and industry partners are already heavily engaged in this effort set to go live within the first year of the Center’s launch.

For the first time clinicians and scientists around the globe will not only have access to pediatric big data, but will be newly empowered for secure, collaborative analysis of big data through scalable cloud computing. The pediatric genomic data cloud environment is set to dramatically transform the way pediatric data is analyzed and will accelerate discoveries of precision medicine approaches on behalf of the center’s core mission of empowering a cure for “every child, every time, everywhere (E3).”

Dr. Resnick is the CBTTC’s neurosurgery director and is assistant professor of Neurosurgery at the Perelman School of Medicine at UPenn. Dr. Storm is a key leader in the CBTTC and chief of CHOP’s Division of Neurosurgery. He also is an associate professor of Neurosurgery at UPenn. Joining Dr. Resnick and Dr, Storm in the Center development efforts is Jena Lilly, the Center’s director of Operations and Strategic Planning.

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Research on Human Milk Helps Get Infants Off to a Good Start


While human milk feedings are important for all children, they can be a medical intervention that makes the difference between life and death for critically ill infants at The Children’s Hospital of Philadelphia.

Human milk protects babies from significant disease and medical problems, such as necrotizing enterocolitis, a serious intestinal illness in infants. Growth hormones in human milk help to develop infants’ intestinal systems, and other properties strengthen babies’ immune systems, protect their eyes and brains, and foster neurodevelopment. Another plus is that human milk is easy to digest, which facilitates transitioning of critically ill babies off parenteral (intravenous) nutrition.

These are just a few of the benefits of human milk that new moms with infants at CHOP learn as part of the hospital’s robust Breastfeeding and Lactation Program led by Diane Spatz, PhD, RN-BC, an internationally known expert in the field. About 600 specially trained breastfeeding resource nurses at CHOP provide support to breastfeeding mothers and families, creating a hospital culture that values the provision of human milk.

Dr. Spatz, who also is a researcher and the Helen M. Shearer Term Chair in Nutrition and professor of Perinatal Nursing at the University of Pennsylvania’s School of Nursing, has published a plethora of studies over two decades, many focusing on breastfeeding and medically fragile infants. Her findings have contributed to CHOP’s development of a state-of-the-art Human Milk Management Center and a new on-site human milk bank for hospitalized infants. Yet, human milk science remains largely unexplored.

“The amount of research that needs to be done about human milk and breastfeeding is phenomenal,” Dr. Spatz said.

Making a Big Difference

In a recent study published by Dr. Spatz and colleagues at the Center of Health Outcomes and Policy Research at the University of Pennsylvania School of Nursing, they looked at a national sample of 97 neonatal intensive care units (NICUs) and found that NICUs with better work environments and better educated nurses who provided breastfeeding support had higher rates of very low birth weight infants who were discharged on human milk.

“This research is important because we know that not all hospitals do the best job in providing evidence-based lactation support and care,” Dr. Spatz said of the study that appeared in the International Journal of Nursing Studies. “What we do at CHOP and our messaging about the importance of human milk is so unlike what many hospitals do; that is why we have such amazing outcomes for our mothers and our infants.”

For example, any family who comes to CHOP’s Center for Fetal Diagnosis and Treatment and has a baby identified prenatally with a congenital anomaly receives a personalized, tailored, one-on-one prenatal intervention teaching them about human milk and the importance of pumping for their critically ill infant. This approach has resulted in a virtually 100 percent pumping initiation rate, which is remarkable when compared to national averages in the U.S. that show only about 79 percent of mothers start pumping for their babies. In Pennsylvania, CHOP is tied for number one in all birthing units for its breastfeeding initiation rate.

At the time of discharge from CHOP, 86 percent of  NICU infants go home on human milk (if the infant was born in the Special Delivery Unit or admitted within the first seven days of life). Dr. Spatz and her colleagues wanted to know how long mothers kept breastfeeding for post-discharge, so they conducted a study that followed 165 babies who were born in CHOP’s special delivery unit and then cared for in the NICU. Both the mean and median breastfeeding rate post-discharge was eight months. The duration of breastfeeding/provision of human milk ranged from one week all the way up to 30 months. Results of this study appeared in the Journal of Obstetric, Gynecologic, and Neonatal Nursing.

“This shows that the way we provide care makes a big difference in terms of keeping our infants healthier and also to their mothers being able to achieve their personal breastfeeding goals,” Dr. Spatz said.

Using Donor Milk, An Empowering Practice

Building on the success of the Breastfeeding and Lactation program, in November CHOP opened the Mothers’ Milk Bank, which provides donor human milk that is pasteurized and processed on-site to infants who are hospitalized at CHOP. The CHOP Mothers’ Milk Bank was developed in cooperation with the Human Milk Banking Association of North America (HMBANA), a professional organization that sets the standards and guidelines for nonprofit donor milk banking in North America. It is one of the only nonprofit milk banks located inside a freestanding children’s hospital in the U.S., and donations from mothers of hospitalized CHOP patients began in January.

“The milk is a very safe product,” Dr. Spatz said. “That being said, donor milk is not the same as mom’s own milk — mom’s own milk is always the best because it is specifically tailored to her own child. But donor milk is a very important alternative if mom’s own milk is not available or if for some reason it is contraindicated. At CHOP, we consider donor milk to be a bridge to mom’s own milk or a support.”

An exciting aspect of having an on-site milk bank is that it opens new opportunities for research. Donor human milk offers many of the same advantages as maternal milk such as easy digestibility, but more research is needed to demonstrate if it confers the same benefits in regard to specific health outcomes. Another big question: What are the ideal dosages of donor human milk needed in order to achieve those positive responses?

Already in progress, Dr. Spatz and co-investigators are conducting a retrospective study that covers a four-year period and focuses on all babies at CHOP who received donor milk. The study team will take a close look at the doses and volume of donor milk the babies received, for how many days they received donor milk, and how much this care cost.

“When you look at the cost compared to other medical interventions in the neonatal care unit, the cost of providing donor milk is really quite low,” Dr. Spatz said.

And the benefits to mothers may be priceless. Providing human milk is integral part of motherhood, especially when infants are critically ill. Mothers in this vulnerable situation often feel desperate to comfort their children, and expressing milk becomes a way for them to help their children in a way that no one else can do. Many are eager to share this sense of empowerment by donating milk that may be used when another mom’s milk supply is still being established or when a mom experiences a low milk supply. One of the first donors to the Mother’s Milk Bank had a baby being cared for in CHOP’s NICU, and the mother was pumping about a liter of milk a day.

“Here is a mom who is not only helping her own child, but she is helping countless other children,” Dr. Spatz said. “When she spoke at the press conference announcing the Mother’s Milk Bank, she said, ‘When my baby started getting my milk, I saw how much she grew and thrived, and to know that I can give my extra milk to help other babies grow and thrive and be healthier, it is so rewarding.”

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Palliative Care Experts Study Grieving Siblings’ Psychological Welfare


The experience of grieving for a dying brother or sister during childhood is something that the surviving siblings carry with them for the rest of their lives. Research conducted at The Children’s Hospital of Philadelphia suggests that the experience itself is not a source of serious psychological problems, despite many parents’ concerns that their healthy children could suffer lasting harm from the loss of their sibling. .

“The study comprises a small number of children, but indicates that kids honestly do OK,” said first author Lisa Humphrey, MD, medical director of palliative care at Nationwide Children’s Hospital, who performed the study during her fellowship at CHOP. “When we share this information with parents, this gives them a little glimmer of hope.”

The study team reported findings in the Journal of Palliative Care Medicine from an observational study with families of 24 children receiving palliative care at CHOP who had one or more siblings ages 6 to 11. Most siblings scored within the normal range on behavioral surveys, with clinical scores only slightly higher than those for the general population and control groups in other studies. Some siblings did experience psychological difficulty, but serious psychological issues were rare. The findings also support the idea that healthier family functioning is associated with better psychological outcomes for siblings.

“As a practicing clinician, it’s nice to be able to say to parents who are trying to make sense out of the chaos of what is coming in their lives, that when their primary focus understandably is their dying child, that is OK,” Dr. Humphrey said. “They can’t spare their other children the grief process, but with support from their family and community, they will get through this.”

Senior author of the paper, Chris Feudtner, MD, PhD, MPH, director of Research for the Pediatric Advanced Care Team and Integrated Care Service at CHOP, pointed out that palliative care experts know anecdotally that parents who are facing a child’s terminal illness worry quite a bit about the psychological welfare of healthy siblings. Yet, not much objective data had been reported in the scientific literature, and the studies that were available showed mixed results and mostly focused on the well-being of siblings of children with cancer. The current study may offer families some reassurance.

“A balanced counsel to parents is that their concerns are shared by many other parents in this situation,” said Dr. Feudtner, who also a professor of Pediatrics at the University of Pennsylvania. “What data we have suggests that children who have sick siblings can do fairly well, especially if they are coached to bring out their strengths in resilience and self-esteem.”

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

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