Bench to Bedside

February 2014

CHOP Research Leader Contributes to Novel Virus Study


The Children’s Hospital of Philadelphia Research Institute’s chief scientific officer, Philip R. Johnson, MD, is among the co-authors of a new study that presents an advanced approach to vaccine design. This innovation, in which artificial proteins are custom-designed as vaccine components, offers the promise of a new way to prevent serious childhood infections caused by respiratory syncytial virus (RSV). More broadly, it may enable the creation of new vaccines against evolving, difficult-to-treat diseases such as HIV, influenza and hepatitis C.

The study, which was published recently online in Nature, was led by William R. Schief, PhD, and colleagues from The Scripps Research Institute (TSRI) in La Jolla, Calif. “This was a proof-of-principle demonstration of a technology that could be very useful against HIV, influenza and other highly variable viruses that have been difficult to stop using traditional vaccine-design strategies,” said Dr. Schief.

Most existing vaccines use inactivated viruses or similar particles to stimulate the body’s immune system to release infection-fighting antibodies. However, rapidly evolving infectious agents such as HIV have been able to change quickly enough to evade traditional vaccine candidates. As a result, vaccine experts have been working to design new vaccines to elicit broadly neutralizing antibodies that strike against hidden vulnerable structures within quick-changing viruses.

The new strategy uses sophisticated techniques to imitate an epitope — a structure specific to each type of invading virus that is recognized by the immune system. The scientists used a new software application that they call “Fold from Loops” to design flexible protein scaffolds to hold the epitope that induces the immune system to produce protective antibodies.

In Nature study, the research team induced potent antibodies in non-human primates against RSV, which commonly makes human babies sick, and kills large numbers of infants worldwide. According to the CDC, each year in the U.S. between 75,000 and 125,000 children under the age of 1 are hospitalized with RSV infections. The investigators’ successful experiment offers proof-of-principle that this approach is feasible for developing a first RSV vaccine in humans, as well as for developing potential future vaccines.

This work builds on previous laboratory research by Dr. Johnson aimed at finding innovative methods in vaccine design. In 2009, for example, his team published a study in Nature Medicine that used gene therapy to produce antibody-like proteins to protect monkeys from the animal counterpart to HIV. And in May of 2013, Dr. Johnson contributed to a Science study calling for a “Human Vaccines Project” to accelerate the development of new vaccines. In the current study, he performed laboratory experiments using his collaborators’ newly designed proteins.

The Nature study “represents the confluence of recent technological advances in computational biology, structural biology and immune monitoring, and offers great potential for accelerating development of next generation vaccines against major global diseases,” said Senior Vice President and Chief Scientific Officer of the International Aids Vaccine Initiative Wayne C. Koff, PhD.

“Bringing these new types of vaccines into clinical use will take years of work, but this study represents an important first step along the way,” noted Dr. Johnson.

To read more about this groundbreaking study, see TSRI’s press release or Nature.

Direct link:

Geography Affects Kidney Transplant Waiting Period


A new study from researchers at The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania has revealed large geographic variation in waiting times for children across the United States in need of kidney transplants, with differences due mainly to local supply and demand. The findings, which appeared in the Journal of the American Society of Nephrology, suggest that broader geographic sharing of kidneys for children should be considered.

Kidneys are distributed to transplant recipients first locally within nearby geographic areas, and then regionally and nationally based on a pre-defined allocation system. Although children receive priority for kidneys from deceased donors who are less than 35 years of age, there are several categories of candidates that supersede children on the waiting list.

Sandra Amaral, MD, MHS, co-director of the kidney transplant program at CHOP, and Peter Reese, MD, MSCE, assistant professor of Medicine and Epidemiology at Penn, led a team that examined whether local organ supply influences waiting times for children. They also sought to examine whether the allocation of organs to other higher priority candidates impacts waiting times for children on the waiting list for kidneys from a deceased donor.

The researchers found that there is substantial and concerning geographic variation in deceased donor kidney waiting times for children across the United States, with median waiting times ranging from as little as two weeks to as long as three years. In some cases, donor service areas with very long pediatric waiting times are right next to donor service areas with very short pediatric waiting times.

The investigators did not find that differences in waiting times were driven by the distribution of organs to other higher priority candidates. Waiting times for children were, however, affected by the local supply of high-quality organs.

“Despite an allocation policy that provides preferential allocation to children, our study findings suggest that the current allocation system is failing children who have the misfortune of living in areas with the greatest organ shortage,” said Dr. Amaral. “These results should be considered when new approaches to reduce inequities in transplant access across the country are examined.”

To learn more about Children’s Hospital’s pediatric transplant services, see the Pediatric Transplant Center.

Direct link:

Genetic Investigation Explores Heart Disease Risk


New research from The Children’s Hospital of Philadelphia and the University of Pennsylvania strengthens the case that one well-known type of cholesterol — low-density lipoprotein, or LDL — is a likely suspect in causing heart disease, but also casts doubt on the role played by another type, triglycerides. The findings may guide the search for improved treatments for heart disease.

Most of us have heard of the “good cholesterol” and “bad cholesterol” coursing through our bloodstream. In the conventional wisdom of the past 30 years, having more of the “good” variety — high-density lipoprotein, or HDL — can lower your risk of heart disease, while more “bad” cholesterol — LDL — increases your risk. Indeed, over the years, clinical trials and other studies have found that drugs that lower LDL also lower your probability of heart disease.

However, drug trials have not shown heart-health benefits to increasing HDL or to lowering triglycerides, a third type of blood lipid. Now a new study led by researchers from Children’s Hospital and UPenn sheds light on the role of genes and blood lipid levels in cardiovascular health. Newer tools for gene analysis show how variations in DNA are underlying actors affecting heart disease, a major worldwide cause of death and disability.

“Now we are able to pinpoint gene signals that actually cause some of these conditions,” said geneticist Brendan J. Keating, DPhil, of The Center for Applied Genomics. “Unraveling how genetic variants that influence lipid traits are related to heart disease risk is a step toward designing treatments.”

Dr. Keating collaborated with clinical epidemiologist Michael V. Holmes, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania, in a blood lipid study published in the European Heart Journal.

Raising questions about the role of “good” cholesterol

The study team used a recently developed epidemiology tool called Mendelian randomization (MR), which analyzes genetic variations using a method that identifies genes responsible for particular diseases, independent of confounding factors such as differences in behavior or environmental influences that often limit the conclusions of epidemiology research. This was one of the largest studies to date using MR.

The researchers analyzed DNA data from 17 studies including over 60,000 individuals, of whom more than 12,000 had experienced coronary heart disease, including heart attacks. Because previous studies had found signals from nearly 200 genes to be associated with blood lipid levels, the study team aggregated data into composite groups, called allele scores, for each of three blood lipids: LDL, HDL, and triglycerides, then calculated their relationship to coronary heart disease.

The European Heart Journal study confirmed that higher levels of LDL, the “bad cholesterol,” were more likely to cause heart disease. But there were new results: high levels of triglyceride also caused higher risk of heart disease. At the same time, there was little evidence that higher levels of HDL, the “good cholesterol,” had a protective effect.

The novelty of their approach, say the authors, lies in their use of a gene score MR analysis using individual participant data. These results build on previous findings and help clarify in further detail the separate roles of triglycerides and HDL in risk for coronary heart disease.

Previous genetic studies, including by Dr. Keating and others, found associations among gene variations (single nucleotide polymorphisms, or SNPs) and heart disease, but did not indicate causality, as found in the current study. “These findings are important in understanding which blood lipids cause heart disease, and will enable clinicians to better target those lipids with drugs to reduce the risk of heart disease,” noted Dr. Holmes.

To read more, see the European Heart Journal study, or the press release about the investigation.

Direct link:

Pediatrics Study Finds Tonsillectomy Care Quality Variation


A recent study of perioperative tonsillectomy care that involved several researchers from The Children’s Hospital of Philadelphia found “substantial variation” in the quality of tonsillectomy care across children’s hospitals in the U.S. The study, which was recently published in Pediatrics, was led by Sanjay Mahant, MD, MSc, FRCPC, of Toronto’s Hospital for Sick Children. Children’s Hospital’s Ron Keren, MD, MPH, as well as the University of Pennsylvania’s Russell Localio, PhD, also contributed to the investigation.

With this study, Dr. Keren and his colleagues sought “to describe the quality of perioperative tonsillectomy care by assessing perioperative dexamethasone and antibiotic use and revisit rates in a large multicenter cohort of low-risk children undergoing same-day tonsillectomy at US childrens hospitals.”

Tonsillectomy is a common procedure, with more than 500,000 tonsillectomies performed each year on children in the U.S., the Pediatrics study notes. In an effort to assess routine tonsillectomy care quality, the investigators examined 139, 715 tonsillectomy admissions for children aged 1 to 18 year across 36 U.S. children’s hospitals between 2004 and 2012.

Study Findings

Despite the prevalence of the procedure, and of accepted practice guidelines — such as those from the AAO-HNS — the study’s authors found “substantial variation” in the quality of tonsillectomy care across the hospitals observed. The AAO-HNS guidelines recommend perioperative administration of the corticosteroid dexamethasone to children undergoing tonsillectomy. Previous trials have shown dexamethasone “administered on the day of surgery, reduces postoperative nausea, vomiting, and pain,” according to the Pediatrics study. The American Academy of Otolaryngology — Head and Neck Surgery (AAO-HNS) guidelines also recommend against the use of antibiotics, stating that clinicians “should not routinely administer or prescribe perioperative antibiotics to children undergoing tonsillectomy.”

The study team found that some “hospitals provided almost no patients with the current recommended care of dexamethasone and no antibiotics compared with 91 percent at other hospitals. “Of the 139,715 admissions for tonsillectomy, 69.6 percent received dexamethasone and 31.1. percent received antibiotics on the day of surgery,” the authors note.

The investigators also found that 7.8 percent of the study population — 10,868 children — revisited the hospital within 30 days of their procedure, with 36.5 percent of those being admitted and 63.5 percent, or 6,897 children, visiting the emergency department. 93.8 percent of the revisits occurred within 15 days of surgery, and were for bleeding and vomiting and dehydration.

In sum, “further investigation is necessary to understand the reasons for the substantial variation in dexamethasone and antibiotic use and revisits across hospitals,” Drs. Mahant, Keren, Localio and colleagues note. And the “detailed data” used in the Pediatrics study could also be used to inform future tonsillectomy quality measurement and improvement.

“Quality improvement initiatives are needed to implement current evidence into practice, understand and disseminate the practices of high-performing hospitals, and improve the value of health care delivered for children undergoing tonsillectomy,” the authors write.

To read more, see the Pediatrics study, “Variation in Quality of Tonsillectomy Perioperative Care and Revisit Rates in Children’s Hospitals.”

Direct link:

Research Advocates Dispirited Over NIH Funding


Biomedical research advocates had hoped that a surge in research and development funding in the 2014 budget would be the best medicine for the National Institutes of Health, which has been impaired by mandated across-the-board sequestration cuts. Instead, the $1 billion increase slated for NIH in the $1.1 trillion appropriations bill passed by Congress in January was a bitter pill.

While the boost will bring NIH’s 2014 research and development budget to an estimated $29 billion, it remains “well below the level of scientific opportunity,” warned Mary Woolley, president and CEO of Research!America.

“The omnibus has failed to fund NIH at a level that fully reverses the impact of sequestration on the agency’s baseline funding level, much less establishes a growth trend that can fully unleash the potential inherent in the sequencing of the human genome and other research breakthroughs,” Woolley wrote in a statement.

The omnibus bill funds the government through Sept. 30. Congress reached the spending deal in December, but it took a month for lawmakers to divvy up discretionary dollars in the 1,500-page bill that rolls multiple department budgets — defense and non-defense accounts — into one. President Obama signed it into law Jan. 17.

For many governmental agencies, the 2014 budget eased the pain of the 2013 sequester’s 5 percent bite; however, the majority of the 27 institutes and centers under the NIH’s umbrella remain underfunded. NIH funding for research and development is now 2.2 percent below fiscal year 2012 levels, a loss of roughly $700 million, according to estimates by the American Association for the Advancement of Science (AAAS).

Carrie Wolinetz, PhD, president of United for Medical Research, agreed that the $1 billion increase falls short of sustainable funding levels for NIH to accomplish its mission of turning scientific discoveries into better health.

“The proposed package won’t adequately reverse the damage done by last year’s budget sequester and ensure the nation’s biomedical research enterprise makes continued progress in lifesaving research and development,” Dr. Wolinetz stated.

Sequestration resulted in approximately 640 fewer competitive research project grants that were issued in fiscal year 2013 compared to fiscal year 2012, according to the NIH. The 2014 funding levels will gain back some ground for emerging investigators. The NIH would be able to continue all current research programs and begin approximately 385 additional research studies and trials, according to a statement from appropriators.

Yet, many stalled projects will need to seek other funding sources. Delays in medical progress not only put Americans’ health in jeopardy, but they also add to their economic risks, research advocates stressed. For example, the medical innovation sector currently employs 1 million U.S. citizens, according to the NIH, and ongoing funding declines could discourage young scientists who will play a pivotal role as global competitiveness in research and development ramps up.

In an editorial for the Washington Post, NIH Director Francis S. Collins, MD, PhD, worried that “years of effectively flat funding for biomedical research have left scientists facing the lowest chances in history of having their research funded by NIH. Many young scientists are on the verge of giving up, taking with them the talent needed to make tomorrow’s medical breakthroughs.”

In constant dollars, the NIH budget has come down by around 15 percent since fiscal year 2004, according to the AAAS analysis.

“The nation’s federal investment in science as a share of the economy currently stands at 0.82 percent — the lowest point in 50 years,” wrote Alan I. Leshner, chief executive office of the AAAS, and Paul Stoffels, MD, chief scientific officer and worldwide chairman of pharmaceuticals at Johnson & Johnson, in an op-ed article for Politico Magazine.

While praising Congress’s bipartisan efforts to put an end to forced budget cuts and fights over discretionary funding, the progress “will not counteract the decades-long decline in federal funding for research and development that is so essential to our economic future and critical to accelerating treatments for today’s major health care challenges.”

Here’s how the NIH’s $1 billion funding increase stacked up against the amounts that some of other public health and scientific agencies won in the 2014 spending package:

Attention now turns to the 2015 budget cycle, which begins Oct. 1. The White House announced that it will release President Barack Obama’s budget for fiscal year 2015 on March 4. House and Senate leaders are hopeful that the momentum they built during the appropriations process will continue so that they can enact a detailed funding plan before the October deadline.

Direct link:

Collaborations Set to Advance Children’s Healthcare


Along with its research partners Drexel University and Hebrew University of Jerusalem, The Children’s Hospital of Philadelphia Research Institute recently hosted a collaborative research symposium that gave researchers from all three institutions the chance to connect and share ideas.

The Advancing Healthcare for Children symposium, held Jan. 27-29, brought together investigators for presentations, discussions, and networking events. Announced in November, the research agreement between Children’s Hospital, Drexel University, and Hebrew University will focus on pediatric translational research and moving investigations from the bench to the bedside. One of the goals of the symposium was to form collaborative “Dream Teams” of investigators who would unite to craft innovative solutions to challenges.

Saying in his opening remarks that “we must dare to cross disciplinary and national boundaries” to meet unmet medical needs, John A. Fry, president of Drexel University, noted “our job is to take bold steps” and break through barriers.

The symposium also featured a visit from Philadelphia Mayor Michael Nutter. The research agreement between Children’s Hospital, Drexel University, and Hebrew University came about in part as a result of a trade mission Mayor Nutter led to Israel in November 2013. CHOP and Drexel’s “partnership with Hebrew University will allow all three parties to share research and ultimately improve children’s healthcare,” said Mayor Nutter when the agreement was signed.

And on the opening day of the symposium, after proudly noting that Children’s Hospital was “the best children’s hospital in the U.S.,” Mayor Nutter said that he could think of no better place to celebrate such a “tremendous collaboration.”

The symposium featured sessions on everything from the nervous system to orphan diseases to pediatric cancers and drug discovery. In addition to several plenary sessions, concurrent breakout sessions on topics such as nervous system disorders, nanomedicine, gene therapy, and autoimmunity promoted dialogue and collegiality between experts.

For example, during the session “Transformative Approaches to Diseases and Disorders of Childhood,” Director of CHOP Research Philip R Johnson, MD, said that defining the future of pediatric medicine “is a tall challenge.” But in Dr. Johnson’s talk, he challenged researchers to consider the interplay of genomics and microbiomes, as they considered ways to advance pediatric care.

Over the course of the symposium, investigators from all three organizations presented. Researchers from Children’s Hospital included Robert J. Levy, MD, Stewart Anderson, MD, Hakon Hakonarson, MD, PhD, and Marni Falk, MD. Drexel University’s representatives included Kenny Simansky, PhD, Amir Toib, MD, and Sriram Balasubramanian, PhD, while a number of Hebrew University investigators attended, including Rami Yaka, PhD, Eylon Yavin, PhD, and Galia Blum, PhD.

On the final day of the symposium, participants were given the opportunity to meet with meeting participants privately for one-on-one discussions. These meetings allowed investigators to follow up on presentations and discussions, and served as the first step in the development of new collaborations.

“The symposium really exceeded our expectations,” said CHOP Research’s Deputy Scientific Director Tom Curran, PhD, FRS, who led the organization of the symposium. “It set the tone for us to work together, transcending traditional boundaries, and forming unique collaborations with the common theme of improving the health and welfare of children.”

The investigators will continue their discussions in the coming weeks and work to develop and hone various “Dream Teams” to tackle pediatric diseases.

To learn more about the Advancing Healthcare for Children symposium, see the symposium’s website.

Direct link:

Examining Neurodevelopment Following TTTS Surgery


The Center for Fetal Diagnosis and Treatment at CHOP serves more than 150 families with complicated multiples pregnancies each year and performs more than 50 fetoscopic laser surgeries annually, one of the highest volumes of prenatal laser surgeries in the nation.

A multiyear study at CHOP looked at the neurocognitive effects of twin-twin transfusion syndrome (TTTS) in monochorionic twins who underwent in utero laser surgery. The study’s goal was to provide families more accurate information on what to expect before and after birth and to identify any long-term consequences.

“Overall, there were high rates of normal neurodevelopmental outcomes in these children at age 2,” said Nahla Khalek, MD, MPH, FACOG, a CHOP maternal-fetal medicine and clinical genetics specialist who led the study.

TTTS occurs before birth in about 10 to 15 percent of monochorionic twins who share one placenta but each have their own amniotic sac. The shared placenta contains blood vessels connecting both fetuses, and TTTS results from a blood flow imbalance. The smaller twin (donor) pumps blood to the larger twin (recipient), causing the recipient twin to receive too much blood and the donor to receive too little. Without intervention, TTTS results in the death of one or both fetuses in 80 to 100 percent of cases.

Dr. Khalek and colleagues analyzed two-year neurodevelopmental outcomes in 29 pairs of twins with TTTS who underwent selective laser photocoagulation (SLPC) of placental anastomoses in utero at CHOP between 2009 and 2011. This minimally invasive procedure uses a laser fiber inserted through a fetoscope to identify and disconnect all of the identifiable connecting blood vessels, allowing for redistribution and normalization of blood flow to each fetus.

The researchers assessed the children’s cognitive, language, behavior, and motor skills using three standard neurodevelopmental tests. The mean scores of all three tests were within or above average range or raised no concerns. They noted differences in some outcomes based on TTTS stage and whether or not a twin was a former donor versus former recipient.

“The risk of neurodevelopmental sequelae is low in TTTS with SLPC intervention,” the researchers concluded; however, Dr. Khalek suggested future research should follow neurodevelopmental outcomes as TTTS survivors reach school age. “This data will allow us to further stratify patients and guide us in counseling parents about longer-term neurodevelopmental outcomes for their children,” Dr. Khalek said.

Laura and Adam Epstein, whose daughters Rose and Madeline were treated for TTTS by fetal surgeons at CHOP in 2011, and the Conway Family Foundation, a philanthropic organization run by the twins’ grandparents, provided funding for this study.

“This research is pioneering work that wouldn’t have happened without philanthropy,” Dr. Khalek said.

Dr. Khalek presented the study results at the annual meeting of the Society for Maternal-Fetal Medicine in New Orleans held Feb. 3-8. In addition to Dr. Khalek, study authors from CHOP include Marsha Gerdes, PhD; Casey Hoffman-Craven, PhD; Anjani Villa, BS, CCRC; Okan Elci, PhD; Julie Moldenhauer, MD; Juan Martinez-Poyer, MD; and Mark P. Johnson, MD; as well as former CHOP physician Michael W. Bebbington, MD.

Direct link:

Neurologist Receives “Taking Flight” Epilepsy Award


The Children’s Hospital of Philadelphia’s Ethan Goldberg, MD, PhD, recently received an award from the epilepsy advocacy organization Citizens United for Research in Epilepsy (CURE) to study using transplanted cells to treat epilepsy. Dr. Goldberg was one of three researchers to receive a “Taking Flight” award, a one-year grant of up to $100,000 designed to “promote the careers of young investigators and support them as they develop an independent research focus,” according to CURE.

A brain disorder marked by seizures of varying intensity and type, epilepsy affects approximately 2 million Americans. And per the CDC, roughly 10 percent of the U.S. population — around 31 million people — will experience a seizure during their lifetime. Seizures associated with epilepsy range from short absence seizures to generalized tonic clonic, or grand mal, seizures. These whole body seizures involve loss of consciousness, incontinence, and potentially violent convulsions.

While its cause is sometimes unknown, epilepsy can be brought on by an injury or a medical condition, such as a brain tumor or infection. Though there is no cure for epilepsy, about 70 percent of those who have the disease can have their seizures controlled with medication, according to the National Institute of Neurological Disorders and Stroke. But for many, epilepsy is a lifelong condition.

According to its website, CURE was founded by parents of children with epilepsy to “spearhead the search for a cure.” Since CURE was founded in 1998, the organization has raised over $26 million to support epilepsy research and funded more than 150 investigations. Dr. Goldberg’s project is an investigation of using “specific, defined subtypes of cortical interneuron precursors to treat epilepsy and its comorbidities in an experimental model of acquired chronic temporal lobe epilepsy.” Dr. Goldberg has been working with Children’s Hospital’s Stewart A. Anderson, MD, Associate Professor and Research Director of Child Psychiatry at CHOP, as well Jennifer Tyson, a graduate student in Dr. Anderson’s laboratory.

With this investigation, the researchers hope to discover novel treatments for forms of epilepsy that are resistant to standard medication. Using a mouse model, they will assess the “functional integration of transplanted interneurons” as well as assessing whether transplanted cells can reduce or eliminate seizures in patients with epilepsy.

“A large component of our epilepsy practice here at CHOP is the care of patients with severe, medically intractable epilepsy, either acquired epilepsy secondary to brain injury or due to a genetic cause,” said Dr. Goldberg. “Cell-based therapies offer hope of a future cure for our patients who are in greatest need, although significant additional basic science research is required to realize this potential. This generous grant from CURE will greatly assist in getting this project off the ground and pushing it forward.”

The “Taking Flight” award follows Dr. Goldberg’s May 2013 publication of a paper in Nature Reviews Neuroscience along with Douglas A. Coulter, PhD, director of CHOP’s Epilepsy Research Lab. A review of the mechanisms of epileptogenesis, in their paper Drs. Goldberg and Coulter “suggest that a greater mechanistic understanding of circuit function and circuit-level dysfunction in epilepsy will lead to the development of successful and broadly applicable interventions in epileptogenic processes, which remain a primary unmet need in epilepsy therapy.”

While the authors acknowledge that “significant questions face the field as we move forward,” they note future “research directions should explore the effects of genetic manipulations, dysfunction of defined cell types and alterations in key cell signaling pathways on circuit function.”

“Such analyses establish a framework within which we can analyze potential molecular and cellular targets for pharmacological and genetic manipulation and therapeutic intervention in the epileptogenic pro­cess,” Drs. Goldberg and Coulter write.

The Children’s Hospital of Philadelphia has a robust epilepsy treatment and research program. Part of Children’s Hospital’s Division of Neurology, the Pediatric Regional Epilepsy Program’s multidisciplinary team of clinicians, nurse practitioners, and researchers works with families to design personalized treatment plans that best control epilepsy with as few side effect as possible.

To learn more about the Pediatric Regional Epilepsy Program, see the Hospital’s website.

Direct link:

CRISSP Alumna Finds Future Career Path Through Internship


The Children’s Hospital of Philadelphia’s Research Institute is dedicated to training undergraduates by giving them hands-on exposure to sophisticated scientific and research techniques. The CHOP Research Institute Summer Scholars Program (CRISSP) provides full-time mentored research experience to future leaders in the biomedical sciences, with a special emphasis on advancing laboratory, clinical, behavioral, and translational pediatric research.

CRISSP built a young scientist’s confidence to follow her investigative spirit. The 2013 CRISSP alumna blogged about how her invaluable learning experience revealed her future career focus.

Lindsay Zajac, a Bucknell University student, spent an internship last summer at the Center for Injury Research and Prevention (CIRP) assisting with research studies designed to increase understanding of how to best help children coping with pediatric injury and illness. She described the mentoring she received from Meghan Marsac, PhD, and Nancy Kassam-Adams, PhD, as “truly one of a kind, which was illustrated by frequent meetings with my mentors and their thoughtful advice.”

CRISSP interns train within a designated research laboratory or group from June through August and complete an independent research project that they present at a commencement event. They receive formal instruction in human subject protections, care and use of animals in research, laboratory safety, and responsible conduct of research.

“This program brings undergraduates into the Research Institute and shows them how great science is,” CHOP Research Chief Scientific Officer and Executive Vice President Philip R. Johnson, MD, noted in the Research Institute’s Annual Report.

Zajac’s favorite role was approaching and enrolling families to participate in research studies while they were at the hospital. It exposed her to the rewards of conducting behavioral research for a pediatric population, and she began to develop her professional identity.

“My experience at CIRP has ignited my passion for research and solidified my strong desire to pursue a career in clinical psychology,” Zajac wrote.

With her career plan in place, Zajac was inspired to help other Bucknell students to find their professional paths. The second semester senior is in the midst of organizing an internship panel specifically for psychology students.

Direct link:

Key Alex’s Lemonade Stand Grant to Bridge Funding Gap


A new Springboard Grant awarded by Alex’s Lemonade Stand Foundation will jumpstart a CHOP childhood cancer research project that fell short of funding due to sequester cuts within the National Institutes of Health.

Hematologist Stella T. Chou, MD, will receive $100,000 over the course of one year to fund her research on how an extra chromosome 21 and mutations in a transcription factor gene called GATA1 affect blood development, creating a predisposition to leukemia in children with Down syndrome. One in every 691 babies in the U.S. is born with Down syndrome, according to the National Down Syndrome Society.

For fiscal year 2013, the sequestration required NIH to cut 5 percent or $1.55 billion of its budget. In response to the budget reduction, Alex’s Lemonade Stand Foundation stepped in to advance new projects with high impact potential, such as Dr. Chou’s investigation.

Much of the progress in childhood cancer survival rates is largely attributable to improvements in treatments and to the high proportion of pediatric patients participating in clinical trials, according to the National Cancer Institute.

“With less than 5 percent of the federal government’s total funding for cancer research each year being dedicated to childhood cancers, Alex’s Lemonade Stand Foundation is dedicated to keeping promising research alive,” stated Jay Scott, co-executive director of the foundation, in a Dec. 19 press release announcing the award. “Through the Springboard Grant, we work to sustain the research of these promising investigators while they reapply for large-scale funding, ultimately resulting in better treatments and cures for all childhood cancers.”

To be considered for Springboard Grants, the applicants must have applied to the NIH within the last six months and scored within the top 20 percent, but outside of the agency’s fundable range.

Dr. Chou’s research aims to “provide new insights into blood cell production, generate new experimental tools for the biomedical community, and elucidate new strategies to study inherited blood diseases.”

Children with Down syndrome are predisposed to “a unique constellation of blood diseases,” Dr. Chou said. These include an increase in total red blood cell mass and a decrease in the number of platelets. In addition, about 10 percent of neonates with Down syndrome are born with preleukemia known as transient myeloproliferative disorder (TMD), which spontaneously resolves in most cases. However, 20 percent of patients with TMD subsequently develop acute megakaryoblastic leukemia (AMKL) by age 5, which responds well to chemotherapy but is associated with significant treatment-related toxicity.

In order to figure out how TMD and AMKL occur, Dr. Chou’s research team will trace the formation and development of blood cells from their early beginnings during embryogenesis and then define how they go awry. They will focus on how two potential culprits — mutations in GATA1 and genes on chromosome 21 (HSA21) — act separately and together to modulate hematopoiesis.

The investigators will use a novel approach that involves the creation and manipulation of patient-derived induced pluripotent stem cells (iPSCs) for the study of genetic disease. iPSCs are a renewable human cell source that can recapitulate the multiple stages of blood formation. They are an alternative to human samples, which are difficult to obtain in sufficient quantities for scientific investigation.

In this study, iPSCs will be generated from blood cells of patients with Down syndrome and TMD. Using iPSCs as the stepping stones, researchers will follow the pathways of aberrant blood formation and create a timeline of the progression to leukemia associated with Down syndrome.

Cancer is the leading cause of death by disease among U.S. children between infancy and age 14, according to the NCI. Approximately 11,600 new cases of pediatric cancer are expected to be diagnosed in children ages 0 to 14 years in 2013. Alex’s Lemonade Stand Foundation has raised more than $65 million toward finding a cure for all children with cancer, funding more than 350 pediatric cancer research projects nationally.

Direct link:

New Director to Build on Center’s Success


As the new director of CHOP’s Center for Pediatric Clinical Effectiveness (CPCE), Theoklis Zaoutis, MD, MSCE, will do what he enjoys most — create, develop, and build new ideas.

Dr. Zaoutis co-founded the CPCE, a Center of Emphasis within the Children’s Hospital of Philadelphia Research Institute. It provides infrastructure for training in and performance of clinical effectiveness research, which is aimed at understanding the best ways to prevent, diagnose, and treat diseases in children.

One of his first priorities as director will be “outreach to increase awareness of the CPCE by developing collaborations and synergies with other researchers,” Dr. Zaoutis said.

He sees tremendous opportunity for population level research to cross over to projects being conducted by bench scientists and translational researchers.

“The link between these two can be phenomenally strong,” Dr. Zaoutis said.

He described the CPCE as an “intellectual home” for clinical researchers. In the same way that scientists learn essential skills at the bench, the CPCE uses a laboratory model to teach junior faculty and other interested clinicians the elements of good clinical research design, implementation, and practices.

“The CPCE has grown tremendously in the six years that it’s been in existence,” said Dr. Zaoutis, who previously served as its associate director of research.

The total grant funding that CPCE has obtained is $71.7 million. A database of funded grants is available for CPCE members to use as examples of effective grant submissions. Another CPCE achievement is the establishment of the Healthcare Analytics Unit, which has expertise in using large datasets to answer research questions.

Dr. Zaoutis is enthusiastic about taking the center’s success to the next level. He envisions more partnership with the hospital to create pathways and guidelines that are real-world applications of the CPCE’s research.

A recent example is a study led by CPCE faculty member Jeffrey S. Gerber, MD, PhD, assistant professor of pediatrics in the division of infectious diseases at CHOP, published in the Journal of the American Medical Association that described an intervention to improve antibiotic prescribing at outpatient practices.

“The research is moving into the community and making an impact on care,” Dr. Zaoutis said.

He feels well-prepared to expand his responsibilities, after working closely with the CPCE’s former director, Ron Keren, MD, MPH, who was appointed recently as CHOP’s vice president of quality and chief quality officer. In his new role, Dr. Keren will be a bridge for the CPCE to disseminate and implement research findings about best practices and safety, Dr. Zaoutis said.

“We have the unique advantage that Dr. Keren’s been on the research side creating this knowledge, and now we have a natural partnership to fulfill the CPCE’s whole mission,” Dr. Zaoutis said.

Dr. Zaoutis is also the Thomas Frederick McNair Scott Professor of Pediatrics and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania and associate chief in the division of infectious diseases at CHOP.

Direct link:

CHOP Researcher Sets Goals as New ISTSS President


Reaching out across the globe to advance traumatic stress research and practice is a top goal that CHOP’s Nancy Kassam-Adams, PhD, plans to accomplish as the new president of the International Society for Traumatic Stress Studies (ISTSS).

Traumatic stress occurs in significant numbers of children and parents after unintentional injuries such as concussions, interpersonal violence, and other difficult medical events, according to CHOP’s Center for Injury Research and Prevention (CIRP).

Founded 29 years ago, ISTSS is an international, interdisciplinary professional organization that includes researchers, psychiatrists, psychologists, social workers, nurses, and others with an interest in the study and treatment of traumatic stress. Dr. Kassam-Adams, associate director for behavioral research at the CIRP, has been an ISTSS member for more than 20 years.

“It has been incredibly valuable to me as a forum in which I hear about the latest work in the traumatic stress field from around the world and get to know other researchers, as well as clinicians who are working in this area,” Dr. Kassam-Adams said.

In her one-year term as ISTSS president, Dr. Kassam-Adams is working to advance the Society’s strategic goals by fostering mutual scientific exchange and engaging ISTSS’ broad international membership. She is excited about fostering a lively professional community online and in ISTSS meetings around the world. ISTSS recently hosted a conference in Norway, and in the next few months will be in Singapore, China, and Chile, among other places.

“I find the international and multidisciplinary nature of the society most exciting and stimulating,” Dr. Kassam-Adams said. “Many of the research collaborations I have developed, with colleagues in the U.S. and in several other countries, have grown from relationships that began via ISTSS.”

ISTSS Past President Karestan C. Koenen, PhD, described Dr. Kassam-Adams as having a “rare combination of passion, intelligence, and kindness. She will be successful because she will motivate ISTSS members through her passion to improve the lives of traumatized children, employ ISTSS resources intelligently, and listen to our members and make sure their views are represented.”

Dr. Koenen, associate professor and director of the Psychiatric-neurological Epidemiology cluster in the Department of Epidemiology at Columbia University’s Mailman School of Public Health, added that Dr. Kassam-Adams’ willingness to take risks will help make the ISTSS a better organization. For example, she is instituting a Spanish track at the ISTSS Annual Meeting in November that will enable ISTSS to expand its reach to new attendees and allow greater interchange among researchers and clinicians in the U.S., Latin America, and Spain. The theme for the 2014 ISTSS Annual Meeting relates to trauma in childhood and its impact for children, adults, and communities.

CHOP research over the past several decades has been at the forefront of understanding the impact of pediatric medical events (illness and injury) for children and their families through the lens of traumatic stress. This includes the work of Anne Kazak, PhD, Flaura Winston, MD, PhD, Lamia Barakat, PhD, Meghan Marsac, PhD, and many others.

“Our research at CHOP has shown that the traumatic stress framework holds up empirically, and that it also makes sense to families,” Dr. Kassam-Adams said. “We recognize children’s and families’ competence and strengths as they face really challenging and sometimes traumatic experiences.”

Dr. Kassam-Adams has completed several large prospective studies of traumatic stress in children and youth in medical settings. With colleagues at CHOP, she developed innovative web-based tools for parents that promote secondary prevention of traumatic stress in ill or injured children.

“I see my involvement and leadership roles in ISTSS as mutually beneficial for ongoing CHOP research in this area, helping to tie us in with the larger field of traumatic stress and promoting mutual exchange of ideas with colleagues around the world who are doing very interesting work in related areas,” Dr. Kassam-Adams said.

Dr. Kassam-Adams also co-directs the Center for Pediatric Traumatic Stress, an intervention development center that is part of the National Child Traumatic Stress Network. She served on the American Psychological Association’s 2008 Presidential Task Force on Child Trauma.

Direct link:

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

© 2017 by The Children’s Hospital of Philadelphia, All Rights Reserved.