the children’s hospital of philadelphia embarking on a new era · 2019. 11. 1. · research...

ResearchAnnual Report

2005The Joseph Stokes Jr. Research Institute of The Children’s Hospital of Philadelphia

Embarking on a New Era

1855

—

The nation’s

first hospital

dedicated exclusively to children is founded by Dr. Francis W. Lewis, with Hewson Bache andR.A.F. Penrose

“... very large numbers of specialties moved towards thesolution of each individualpatient’s problem throughhighly diversified laboratoryand clinical research.”

- Joseph Stokes Jr., M.D., 1967

CONTENTSPURSUING RESEARCH PREEMINENCE 2

PROGRESS NOTES 30

SUPPORTING RESEARCH - STOKES CORE FACILITIES 40

INNOVATION FUELING PROGRESS 46

BUILDING THE INTELLECTUAL COMMUNITY 52

ADMINISTRATIVE ENHANCEMENTS 80

FINANCIAL/AWARD INFORMATION 84

WHO'S WHO AT STOKES 87

It is with great enthusiasm that we introduce the premier annual report for the Joseph Stokes Jr. Research Institute ofThe Children’s Hospital of Philadelphia.

Stokes Institute has a rich and distinguished “bench to bedside” research history. The Institute serves as the home formore than 250 world-class investigators conducting innovative research in the laboratories and clinics across ourcampus. And, as you will see within the pages of this report, our investigators continue to advance the basicunderstanding of pediatric diseases and to develop new therapies that will benefit our patients and their families forgenerations to come.

We’ve witnessed substantial growth in the Hospital’s research program over the last decade. With such growth comesthe need to assess the external factors affecting our continued development, evaluate our current program andfacilities, and challenge ourselves to continue on our path toward pediatric research preeminence.

To position the Stokes Institute as the premier pediatric research center in the world, we have made significantchanges during the past year with the guidance and support of the Institute’s Board Committee. We’ve organized theHospital’s research program under Research Affinity Groups toenhance multidisciplinary collaboration; moreaggressively recruited talented investigators; expanded our training and educational programs; and continued to buildthe research infrastructure to further support our investigators and research staff.

We are fortunate to have recruited Philip R. Johnson Jr., M.D., to guide our way into the future as the Hospital’snew chief scientific officer and director of the Stokes Institute. Dr. Johnson assumed the role of chief scientific officerin January 2005. His predecessor, David Pleasure, M.D., stepped down to focus on his renowned research inpediatric neurology, which flourished in his 30 years of service to Children’s Hospital.

Dr. Pleasure realized his goal of fortifying the Hospital’s scientific environment while managing annual double-digitgrowth. His legacy as director includes establishing the Stokes Investigator Program and reorganizing the academicstructure through affinity groups. He also helped establish centralized core facilities and was instrumental inrecruiting numerous scientists to the institution.

To build on the foundation put in place by his distinguished predecessor, Dr. Johnson brings his extensive experiencein strategic planning, facilities expansion and faculty recruitment as we map the future of pediatric healthcare atChildren’s Hospital.

We are excited about the future of research at Children’s Hospital. We view research as our product pipeline, and thatpipeline — built on the Hospital’s 150 years as a leader in pediatric healthcare — has never been fuller. So pleaseenjoy this inaugural issue of the Stokes Institute’s Annual Report. We look forward to sharing our milestones as theHospital continues its growth and evolution toward pediatric research preeminence.

Steve M. Altschuler, M.D. Tristram C. Colket Jr.President and Chief Executive Officer Chair, Joseph Stokes Jr. Research Institute Board Committee

Embarking on a New Era of Research at The Children’s Hospital of Philadelphia

For more than 80 years, The Children’s Hospital of Philadelphia has built a reputation as a pioneer in pediatricresearch. Vaccines, novel therapies, and other interventions developed and tested at Children’s Hospital have savedthe lives of many children throughout the world and improved the health of countless others. This legacy continuestoday, embodied in our rotavirus vaccine and our TraumaLink program.

The continued success of the Stokes Institute depends not only on building upon the past, but also on planning for the changes and initiatives necessary to achieve preeminence. The future of research at Children’s Hospital isdirectly linked to controlled and deliberate growth, a process that involves constant review and refinement of ourresearch programs.

Growth isn’t just about increasing the amount of research funding, constructing buildings, or winning the war for talent. While these activities are all necessary, they are not sufficient. Growth also involves embracing the entrepreneurial spirit — the notion of “going first and being first” — that has sustained Children’s Hospital for 150 years.

To that end, we must continue to pioneer new therapies, integrate novel technologies, and tackle the toughesthealthcare issues that face our patients and their families.

We can, and must, learn from every patient and family who walks through our doors for care. This is the foundationof the “bench to bedside” nature of our research program. In today’s lingo, this is known as translational research.But Children’s Hospital was in this business long before that phrase was coined. We must continue to lead the wayin harnessing the data derived from patient care to guide and drive laboratory and clinical investigation.

Research is, and will continue to be, a cornerstone of the Hospital’s mission and perhaps the key element in ouroverall goal of improving pediatric health worldwide. At the Stokes Institute at Children’s Hospital, we areembarking upon a new era of research that will change the direction and intensity of our efforts while enhancing the care for our patients and families. I am sincerely humbled to be part of this great aspiration, and look forward to the next 150 years of innovation at Children’s Hospital.

Philip R. Johnson Jr., M.D.Chief Scientific Officer and Senior Vice PresidentDirector, Joseph Stokes Jr. Research Institute

Pursuing Research Preeminence

Research Affinity Groups: A unique structure that fosters collaboration and allows for continued growth

Stokes Institute, with its mission to be a leader in pediatric research, has witnessedphenomenal growth over the last decade. This growth is evident not only in thenumber of laboratory and clinical investigators conducting innovative research butalso in the unique and cutting-edge programs that are the hallmark of research atChildren’s Hospital.

Stokes Institute, recognizing the challenges that often accompany growth, lookedfor a unique way to manage the needs of its investigators, foster interdisciplinarycollaboration and better position the Institute to compete for decreasing

federal research funding.

The solution: Research Affinity Groups.

2005 Research Annual Report

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A new organizing principle of the StokesInstitute, the Research Affinity Group conceptreflects the increasingly interdisciplinary andmultidisciplinary nature of many key research questions. In addition, the affinitygroup structure aligns with the emergingnational consensus that multidisciplinarycenters are essential to advancing the nation’sresearch agenda.

The Institute designed the Research AffinityGroup structure to build on areas of existingstrength, identify new and important researchareas, and explore important, broad andinterdisciplinary scientific questions that mayhave an impact on children’s health.

The groups allow Stokes researchers tocollaborate across disciplines more easily toaddress issues of central importance tochildren’s health. This collaboration has thepotential to link multitalented investigatorswidely dispersed throughout the Institute whohave common research interests.

The following pages highlight each of StokesInstitute’s 13 Research Affinity Groups.

1922Research “Department” is established in thebasement at Bainbridge Street — a 14-by-16-foot room with one centrifuge.


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Cardiovascular Research Group Leader: Mortimer Poncz, M.D.

While atherosclerosis, thrombosis and stroke are not traditionally diseases associated with pediatric patients, there is growing concern in the pediatrichealthcare community about cardiovascular diseases. This concern has increased for a number of reasons, such as a better recognition of the pediatric causes of these adult diseases, an increase in sedentary lifestyles and altered eating habits, and a awareness of disease processes.

In addition, although it saves the lives of more andmore children, modern medical care often entailsinvasive procedures that introduce foreign bodies —often plastic catheters — into patients. This processcan lead to a marked increase in observed blood clots,or thrombi. Iatrogenic thrombi, clots that occur as asecondary consequence of providing medical care, are a major concern and complication in themanagement of many life-threatening pediatricillnesses.

Recent thrombosis and hemostasis research atChildren’s Hospital has focused on the basicmechanisms involved in the so-called “liquid clottingphase” and in clot formation. Hospital investigatorsalso work to develop models for translating currentknowledge into gene therapy-based strategies to treatpatients with bleeding and clotting disorders.

In addition, the Hospital’s cardiology research hasfocused on developing new materials for grafts andstents; designing novel strategies for local genetherapy to blood vessels and the heart; andestablishing a better understanding of normalcardiovascular development during embryogenesis.The focus of the lipid research group has centered onlipoprotein and cholesterol metabolism andatherosclerosis development.

In the past, the Hospital’s research programs inhemostasis and thrombosis, cardiology and vascularbiology, and lipid metabolism and atherosclerosisfunctioned independently. Recognizing the commoninterests between these research endeavors, themembers of the Cardiovascular Research AffinityGroup focus on a common theme: atherosclerosis,vascular biology and thrombosis.


1929Joseph Stokes Jr., M.D., becomes physician-in-chief. He goes on to transform Children’sHospital into a world leader in teaching andresearch.

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Fibrin clot (green) and platelet plug (red) in thrombus, growing at the site of laserinjury in a small vein lacking circulatory Factor VIII. The overlap of the clot andplug is in yellow.

To further its research efforts in this critical area, theaffinity group established an atherosclerosis, vascularbiology and thrombosis modeling system to promotethe establishment of common multiuser models.Within this organization, the group established asystem for measuring new blood growth, watched clot formation under a microscope, and developed acontrolled flow chamber to observe the interactionbetween platelets and endothelial cells.

To encourage growth in this new pediatric researchfocus, the Cardiovascular Affinity Group is pursuingactivities including sharing instruments, establishing anew cardiovascular seminar series, founding a yearlyretreat for fellows to present their research efforts andcoordinating these efforts with colleagues at theUniversity of Pennsylvania.

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A sizable group of people at Children’s Hospital are focused on these areas of investigation and aremembers of the Cell and Gene Therapy ResearchAffinity Group, which aims to develop new treatment methods for children with inherited and infectious diseases.

The affinity group fosters a multidisciplinary approachamong investigators working to discover new gene andcell therapies in search of cures for debilitating andlife-threatening childhood disorders. This approachmay lead not only to a variety of applications in thetreatment of inherited disorders such as hemophilia,muscular dystrophy and cystic fibrosis, but also to thetreatment of acquired and complex disorders,including diabetes, heart disease, infectious diseases,neurodegenerative disorders and cancer.

One of the most notable activities of this affinitygroup is the extremely high-quality seminar series thatattracts distinguished outside speakers who are activein the cell, gene and stem cell research field. Speakersnot only hold public seminars, but also visit withindividual lab members to discuss specific researchprojects. In addition to affinity group seminars, thegroup actively pursues collaborative funding.

Cell and Gene Therapy Group Leader: Katherine High, M.D.Investigator, Howard HughesMedical Institute

Cell and gene therapy and stem cell research offerunprecedented opportunities for developing newmedical therapies for serious diseases that affectchildren. Current research in these areas maycontribute to a new approach for treating disease —regenerative medicine, in which defective genes, cellsor even entire organs are replaced.

One of the most exciting frontiers in modernmedicine is the concept of using a gene to treat agenetic disease. Researchers have made dramaticprogress in innovative gene therapy strategies thatcould cure, or even prevent, disease. The idea ofintroducing corrective genes into cells to stop diseases such as hemophilia, cystic fibrosis andcongenital blindness at the source is rapidly becoming a reality.

Cell therapy is an older discipline that has beenmodified to include blood transfusions, organ andbone marrow transplantation, and modern adoptivetransfer of white blood cells to treat cancer. Recentdevelopments have been focused on using stem cells to replace defective tissues and cure disease. While this work is in the earlier stages of research, thepossibility of taking a person’s own cells and usingthem as stem cells to treat that person’s disease is an exciting frontier.


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Summary of immune responses during AAV gene therapy.

1936Discovery of the whooping cough vaccine, thefirst in a series of vaccines pioneered atChildren’s Hospital that has worldwide impacton childhood disease.

CD8+T cell

CD4+ T cell

Macrophage

Hepatocyte

MHC class I

MHC class II

Cytokines

Cytolyticgranules

Cell and gene therapy affinity group members havesuccessfully competed for NIH Program Projectgrants, including an award entitled “Gene Therapy forHemophilia,” which investigates the use of vectorsintroduced into either skeletal muscle or circulatingblood platelets as a means of treating hemophilia.

Another program project is “Immune Responses inGene Therapy for Hemophilia,” which focuses on thebody’s immune responses in the setting of genetherapy for hemophilia.In addition, members of the affinity group

collaborated to submit an application for cell andgene therapies for muscle disorders. The grant wassuccessfully funded by a competitive Stokes Institutegrant, using monies provided to the Hospital by theCommonwealth of Pennsylvania under the nationaltobacco settlement.

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Child Health Services Research Group Leaders: Louis Bell, M.D., and Jeffrey H. Silber, M.D., Ph.D.

Despite remarkable advances in biomedical research and the treatment of disease,evidence exists that the complex systems of pediatric healthcare and other child-oriented services do not perform well, resulting in poor outcomes for child healthwhile incurring high costs. It is critical that investigators understand thisperformance gap to learn how to close it and provide good health outcomes for all children.

Racial and socioeconomic disparities in child healthcontinue to be well-documented. Recent legislativeattempts to expand health insurance coverage forchildren in the United States have left 10 millionchildren uninsured — and these children are half aslikely to have visited a physician as children withinsurance. The cost and quality of pediatric care varies across geographic regions, types of hospitals and various systems of care. Adding to the problem,therapies and interventions known to be effective —like medications to control asthma attacks — areunderused. Each of these problems and many othersadversely affect the health of children.

The Child Health Services Research andEpidemiology Research Affinity Group is dedicatedto studying the cause and distribution of disease andquality of health in children. It also aims to improvechildren’s health and well-being by analyzing thecauses and distribution of disease and quality ofhealthcare and other child-oriented services.

Because a multitude of factors influence theseoutcomes, research by members of the Child HealthServices affinity group typically involves manydisciplines, including economics, psychology,biostatistics and medicine. For example, researchers in the group developed and applied methods fromtheir respective disciplines to improve the quality ofpediatric health-services research. They also appliedmultivariate matching techniques and econometricmodeling to claims data, surveys and administrativedatabases.

Other examples of the affinity group’s recent effortsinclude projects aimed at understanding theorganization of behavioral healthcare for children with attention deficit and hyperactivity disorder;improving the long-term care of children with asthma; improving screening and early recognition of childhood autism; and identifying the beststrategies for preventing poor outcomes in common pediatric diseases.


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Affinity group investigators have also examinedvariations in the quality of care premature infantsreceive and the resulting outcomes; the impact ofmaternal obesity on neonatal outcomes; optimal discharge time of premature infants from the neonatalintensive care unit; and the impact of medicationerrors in the pediatric intensive care unit.

In addition, investigators have focused onunderstanding the impact of peer influences that lead teenagers to risky behaviors; the impact onhealthcare access for underserved children andfamilies; racial disparities in outcomes; and thedifference in outcomes of similar patients acrossdifferent types of healthcare providers. Members of the Health Services affinity group also exploredmethods to reduce surgical post-operative mortalityrates and analyzed the influence of obesity on surgical outcomes.

1940s — 1950sVaccines for influenza and mumps arediscovered by husband-and-wife team of Drs.Werner and Gertrude Henle. Additionally,along with Joseph Stokes Jr., M.D., theydevelop the first convincing demonstration ofvaccination against influenza and mumps —100,000 eggs a year were used in the study ofviral diseases. They are also the first to provethe effectiveness of gamma globulin inpreventing paralytic polio and the first todevelop a method to prevent hepatitis.

Left page: Louis Bell, M.D. Right page: Jeffery H. Silber, M.D., Ph.D.

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Researchers have defined a hospital stay that is “too long” or“prolonged” based on the typical pattern of hospital discharge.


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Several investigators in the affinity groupmeasure how receptors on the surface of cells transmit information that leads to growthand differentiation of the endocrine or immunesystems. Their work intersects with that ofanother group of investigators who areinterested in viral infections, since viruses often “hijack” normal cellular proteins.

Another critical area of the affinity group’sinvestigation lies with markers of disease, orprotein patterns that are expressed differentlyin people with a particular disease. Someinvestigators are relating modificationscommon to many proteins, such as additions of phosphate or nitrate, to alterations in thefunctions of key metabolic enzymes in normaland defective neonatal development.

Yet a third focus is the question of howproteins misfold, lose their proper structureand therefore become dysfunctional. Threeresearch groups are studying how a special set of cellular proteins, called molecularchaperones, either protect other proteins frommisfolding or correct the defect in the contextof cystic fibrosis, systemic amyloidosis andthalassemia.

A new focus of the group is proteomics, orcataloging all the proteins present in a giventissue at a particular stage of pathology.Knowing these protein patterns will greatlyenhance the current wealth of geneticinformation about a variety of diseases.

Defective Proteins and DiseaseGroup Leader: Yair Argon, Ph.D.

Most diseases are caused by malfunctions of a protein.A defective receptor may preclude proper function of pancreatic cells, an altered protein may lead tomalignant transformation, or the inability of ahormone to be secreted may lead to abnormal organ development. Understanding the changes in the expression or function of proteins is, therefore, key to developing therapies.

Gaining such understanding, however, is no smallfeat, because each of the 30,000 genes in humanDNA can encode more than one form of a protein,increasing the complexity of the informationcontained in DNA. In addition, not every pathologicchange is due to a single gene mutation. In manydiseases, the alteration is an atypical realignment of interacting proteins.

Research conducted in the Defective Proteins andDisease Research Affinity Group focuses on thisproblem by investigating how proteins function, how they interact, and how they differ betweennormal and diseased tissues.


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Separation of complex protein mixtures by multidimensional chromatography.

1954“Rheumatic Fever and Virus ResearchBuilding” the first research building is built for$800,000, including equipment. It is morecommonly known as “The Research Building.”

Run 2:3 mg total protein

* **1

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7.34-7.047.04-6.74

6.44-6.146.14-5.83

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5.23-5.015.01-4.71

4.71-4.414.41-4.11

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Retention time (min)

18 19 2120 22 23 2524 26 270

100

200

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nm

300

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NAS Cells

A new technique developed by the affinity group separates complex protein mixtures bymultidimensional chromatography into hundreds of discrete fractions, and has already improved upon the enumeration of proteins that are present indiseased and normal tissues. Being able to identifyrare proteins may uncover those that play importantroles in an individual disease.

These research advances already hold the promise of discovering signature patterns — proteins that arefound consistently in patients with a specific disease— that will become diagnostic tools.

The Defective Proteins and Disease Research AffinityGroup provides a forum for investigators from avariety of divisions to work together, improving theeffectiveness of their research. Shared instruments inthe Protein Core Facility, a seminar series featuringoutside speakers, a monthly in-house lab meeting and a multi-investigator seed project all allow groupmembers to interact and gain feedback on ongoingresearch.


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Developmental Biology and Pediatric DisordersGroup Leader: Jeffrey Golden, M.D.

Understanding the pathobiology of pediatric diseaseswithin a developmental framework is paramount to the diagnoses, management and cure of manychildhood diseases. Understanding developmentalbiology is, therefore, crucial to the Hospital’s missionof being the leader in caring for children.Accomplishing this goal requires basic research focusedon elucidating the mechanisms of developmentalprocesses.

The Developmental Biology and Pediatric DisordersResearch Affinity Group strives to meet the goal ofproviding cutting-edge basic and translational research in developmental biology and training thenext generation of pediatric physician-scientists. This affinity group augments and elevates existingresearch efforts in developmental biology at Children’sHospital and aspires to implement the “bench to bedside and back to the bench” paradigm inherentwhen developmental biology research is tightly linked to the care of children.

As a new program, developmental biology has focusedon building an infrastructure to support ongoing andnew research. This infrastructure comes under threemain headings: teaching, faculty recruitment andinterdisciplinary research. The affinity group initiated

a seminar series to provide a venue for Hospitalinvestigators to interact with outstandingdevelopmental biologists. This monthly series, now in its second year, has hosted a variety ofinternationally renowned developmental biologists,new investigators with exciting research programs, andoutstanding local investigators at Children’s Hospital,the University of Pennsylvania and The WistarInstitute. A second goal for this seminar series is toprovide a forum for junior faculty, postdoctoral fellowsand students to meet with and learn from potentialcolleagues and mentors.

The affinity group also provides a data/journal club as an informal forum for students and postdoctoralfellows to present their own research or to criticallyreview recently published papers. This series, alsoattended by the faculty, allows students and fellows to present their preliminary research for constructivefeedback or to critically evaluate published studies,both important exercises for those in training.

The affinity group’s second major focus has centeredon faculty recruitment. The group conducts highlycompetitive national searches to identify outstandingcandidates in developmental biology research.


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The final focus of this new program revolves aroundinterdisciplinary research. Establishing and maintainingcutting-edge research in the highly competitive andrapidly changing field of developmental biologyrequires access to state-of-the-art equipment andtechniques as well as economies of scale, all of whichare made possible by sharing ideas and resources. Theaffinity group initiated several programs to facilitateresearch at Children’s Hospital.

The first initiative was the creation of the TransgenicCore, which provides all Hospital investigators withaccess to consultation and application of transgenicand mutagenesis experiments. Another initiativeinvolved establishing common space for intermittentlyperformed functions such as the use of chemicalbenches, thermocyclers, gel electrophoresis anddocumentation, and microscopy.

This shared space takes advantage of economies ofscale and encourages each lab both to use its own spacemore efficiently and to share the cost of equipmentthat can be used in several labs. These common spacesalso provide areas where people from different labs arein regular contact, fostering interaction.

Although the Developmental Biology Research AffinityGroup is a young program, it has made significantstrides toward creating an intellectual environment that will support outstanding scientific investigation.Continued growth and productivity will occur withinthis small but interactive cadre of scientists. Mostimportantly, this program will provide insight intodevelopment and developmental disorders, critical to the care of children and the essence of Children’sHospital.

1950 — 1960sWith his research on the prevention of polio,Dr. Lewis L. Coriell begins to lay thegroundwork for the development of the Salkvaccine. Dr. Coriell and associates also invent a laminar airflow system to keep operatingrooms sterile.

Interneurons (green) that have been labeled with a dyemigrating in a living brainslice.


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As part of this research endeavor, the affinity grouprecently developed an experimental MMC model that closely parallels the human form of the disease.This model is expected to allow for a more in-depthstudy of MMC and perhaps lead to new treatmentstrategies.

Another area of research focus in the affinity groupcenters on congenital diaphragmatic hernia, a defectin the diaphragm that allows the abdominal organs to enter the chest cavity. Hospital investigators arestudying the potential for using fetal trachealocclusion as a treatment for lung hypoplasia, as well as pharmacological and gene therapy approaches topulmonary vascular hypertension. To this end, fetaltherapy investigators are developing models ofcongenital lung malformation and abdominal walldefects.

In collaboration with the Hospital’s Center for FetalDiagnosis and Treatment and the Fetal Heart Programof the Cardiac Center, the Fetal Therapy ResearchAffinity Group is developing techniques for fetalcardiac intervention, specifically to open ventricularoutflow tract obstructions to allow cardiac remodelingand prevent underdevelopment of the heart. Furtherinvestigations into experimental models of humananatomic defects may provide new insights into thepathophysiology of these disorders and allow for thedevelopment of new therapeutic approaches.

Fetal Therapy ResearchGroup Leader: Alan Flake, M.D.

The convergence of technologies in modern medicinesuggests that within the next decade essentially allanatomic and genetic diseases could be diagnosedearly in gestation. Early diagnosis could enablephysicians not only to treat fetal disease, but also to anticipate childhood and adult disease.

The Fetal Therapy Research Affinity Groupinvestigates the possibilities for treating manydisorders during fetal development, which mayprovide a therapeutic window of opportunity for treatment.

As part of its mission, this affinity group facilitatesinteraction between a diverse group of Children’sHospital investigators interested in fetal biology andtherapy. The group brings together investigators formutually beneficial discussion, collaborative studiesand, ultimately, the application of successful clinicaltherapies. Investigators focus on fetal diagnosis andtreatment, maternal aspects of fetal therapy, newmethods of minimally invasive surgical or fetoscopicintervention, treatment of anatomic malformations,and fetal stem cell or gene therapy.

Recent fetal therapy research has focused on a numberof common fetal anatomic malformations, mostnotably prenatal surgical closure of myelomeningocele(MMC), a condition in which the backbone andspinal canal do not close before birth. Children’sHospital is one of three surgical centers in an ongoing federally sponsored clinical trial designed to compare prenatal surgical closure of MMC withstandard postnatal treatment.


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1963Stanley Plotkin, M.D., develops rubella(German measles) vaccine; clinical trials areconducted.

In utero gene therapy studies also involveinvestigations of early gestational injection methodsusing a high-resolution ultrasound system that allowsmicroinjection into the amniotic space. This hasresulted in high efficiency transduction of epithelialstem cells in experimental models.

Hospital researchers are also investigating stem celland gene therapy in utero. With the clinical goal oftreating sickle cell disease and other hematologicdisorders, investigators continue their aggressivepursuit of strategies to increase engraftment of

hematopoietic stem cells in the fetus and have madesubstantial progress toward improving donor cellhoming to, and engrafting in, the fetal liver. Part ofthe stem cell research project involves strategies ofhighly selective myeloablation of the fetus usinginnovative reagents that specifically targethematopoietic stem cells and progenitors.

Early gestational gene transfer by ultrasound-guided intraamniotic injection of lentiviral vector.

Micropippete Amnion

E10 murine fetusEpidermal Stem Cell Transduction

Skin and Hair

Cornea And lens


Genes, Genomics and Pediatric DiseaseGroup Leaders: Nancy Spinner, Ph.D., and John Maris, M.D.

Genetics is a discipline that has unique implications for pediatric medicine andaffects all aspects of childhood healthcare. The field has undergone tremendousgrowth in recent years as new technologies have allowed for increasingly preciseprobing of the genome. The recent completion of the Human Genome Projectprovided the essential roadmap for these studies while innovative genetic models ofhuman disease and high-throughput technologies such as DNA microarrays haveprovided the tools necessary to exploit this information.

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Genetics and genomic research at Children’s Hospitalis multifaceted and spans many divisions. Theseresearch efforts are conducted in the Genes,Genomics and Pediatric Disease Research AffinityGroup. The affinity group houses an outstandingprogram focused on the molecular genetic basis ofhuman disease. Major recent advances includeidentifying the gene for Cornelia de Lange syndrome,a rare developmental disorder, and identifying therole of mutations in a cellular signaling pathway,known as Notch2, in human disease.

Investigators also focused on continuing their studyof the 22q11.2 deletion syndrome — an abnormalityof chromosome 22 that can lead to a myriad ofhealth problems; increasing the understanding of afatal nervous system disorder called Batten disease;

and gaining strides in unraveling the role ofmutations in a tumor-suppressing gene known ashSNF5/INI1 in causing certain pediatric tumors.Also, investigators have been engaged in largecollaborative research efforts focused on theinteractions between human genes andenvironmental exposures.

Another area of investigation for affinity groupmembers is neurogenetics. Investigators have focusedon studying the cause of several neurologic disorders,including various muscular dystrophies. They havebeen actively involved in the clinical and researchcomponents of neurogenetics in order to understandthe mutated genes and pathways and translate thatunderstanding to diagnosis and treatment.


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Page 16 (left to right): Nancy Spinner, Ph.D., with student Athma Pai. Page 17 Researcher Kristina Cole and John Maris, M.D.

Cancer is a genetic disease, and many Hospitalinvestigators have focused on the genomics andproteomics of common pediatric cancers. In the past year, investigators have made major advances inunderstanding neuroblastoma, an aggressive cancerthat occurs in infants and young children. Researchstrides in neuroblastoma include the development of a more precise algorithm for predicting prognosisbased on genetic alterations in the cancer cells. Thiswork is being applied nationwide within theChildren’s Oncology Group Clinical Trials network, a National Cancer Institute-supported group thatcoordinates cancer clinical trials at 238 memberinstitutions, including the cancer centers of all majoruniversities and teaching hospitals.

Children’s Hospital investigators have made significant progress in understanding the underlyingabnormalities in pediatric solid tumors and leukemiasand translating these findings to the clinic. Forexample, by demonstrating that many neuroblastomasare dependent on activation of a gene called Trk, aspecific inhibitor of Trk has been developed with alocal pharmaceutical company and is now in clinicaltrials for children with neuroblastoma.

Because genomic medicine is by definitionmultidisciplinary, the formation of a research affinity group was a natural extension of ongoingcollaborative research efforts at Children’s Hospital.Monthly affinity group meetings provide a forum toshare and critique research programs and to developstrategic goals. The affinity group also has a successfulmonthly seminar series that draws internationalexperts. This group also provides a forum forestablishing and extending collaborations withcolleagues at the University of Pennsylvania.

Finally, in the last year the affinity group organized an external advisory committee of internationalexperts to critique its program and provide advice ongenetics and genomics research at Children’s Hospitaland the University of Pennsylvania.

1965The balloon catheter is invented by WilliamRashkind, M.D., the “father of interventionalcardiology,” allowing the first nonsurgicaltreatment of certain heart defects.


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The group boasts many multidisciplinary researchprojects across a wide range, includinggastroenterology, hepatology and nutrition,endocrinology, psychiatry, cardiology, hematology,nephrology, rheumatology, pulmonology, neurology,nursing, child development and neonatology. Obesityis a common theme across many of the specific areasof research.

The obesity epidemic across all groups of children is a growing concern and is increasingly becoming aproblem in the pediatric patient population. Majorresearch efforts include evaluating the behavioral and medical treatments for obese adolescents, theschool-based obesity intervention programs, theeffect of obesity on bone strength, prevention and the treatment of diabetes, and the effect of obesity on sleep apnea, asthma and other pulmonarycomplications, and disorders of lipid metabolism.Recently, the Commonwealth of Pennsylvania’s HealthResearch Formula Fund State Tobacco ResettlementAct funded the Hospital’s project “Risk Factors for the Pediatric Metabolic Syndrome” to evaluate thecontribution of obesity, obstructive sleep apnea,fasting insulin levels and family history of diabetes tooverall glucose tolerance, insulin sensitivity, and lipidand blood pressure abnormalities.

Abnormalities of growth and body composition inchildren with chronic diseases is another majorresearch theme. Various research projects are underwayto describe the timing, magnitude, causes andconsequences of growth failure and altered bodycomposition in children with sickle cell disease, cysticfibrosis, Crohn’s disease, renal insufficiency, juvenilerheumatoid arthritis, Down syndrome, intractableepilepsy, liver disease, lupus erythymatosis and cardiacmalformations.

Metabolism, Nutrition andPhysical DevelopmentGroup Leaders:Babette Zemel, Ph.D., and Rebecca Simmons, M.D.

Disorders of nutrition and metabolism affect themajority of patient populations cared for at Children’sHospital. Failure to thrive, obesity and bone deficitsare common complications in a wide variety ofchronic conditions. Malabsorption, inflammation,reduced physical activity, altered dietary intake andmedical treatments often have a profound effect onnutrient metabolism, growth, body composition, andhealth and disease outcomes. In addition, many of themajor chronic diseases of adulthood, such as diabetes,hypertension, osteoporosis, cardiovascular disease andsome cancers are nutrition-related and haveantecedents in childhood.

The goal of the Metabolism, Nutrition and PhysicalDevelopment Research Affinity Group is to identifythe causes and consequences of metabolic andnutritional disorders of childhood and to identifyeffective strategies for disease prevention andtreatment. An additional goal is the prevention ofobesity and nutrition-related diseases in adulthoodthat have their origins in infancy and childhood.


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Left page: Babette Zemel, Ph.D. Right page: Rebecca Simmons, M.D.

The program of research in the area of lipoproteinmetabolism and atherosclerosis seeks to understandthe contribution of reverse cholesterol transport —the process by which excess cholesterol is transportedto the liver for excretion from the body — to the roleof high-density lipoprotein (HDL) in preventingplaques in arteries. Recently, emphasis has been on theHDL receptors, known as scavenger receptor class B,type I (SR)-BI and ATP binding cassette transporterAI (ABCA1), and understanding the mechanisms bywhich they modulate cholesterol transport at cellsurfaces. These proteins are thought to prevent plaquebuild up in arteries because both can mediate theremoval of excess cholesterol from cells.

Progress is being made in defining the structure ofapolipoprotein apoA-I, the principal protein of HDL,which is involved in binding to the lipid transporterABCA1 and construction of HDL particles.Investigators continue to work on defining thestructures of HDL precursors.

Affinity group members also developed and used anassay for evaluating reverse cholesterol transport inmodels that express SR-BI in the liver anddemonstrated that hepatic SR-BI expression is apositive regulator of reverse cholesterol transport.Studies in models lacking apoA-I indicated that theincreased atherosclerosis can be attributed to bothimpaired reverse cholesterol transport and increasedinflammation. These studies are continuing to providenovel understanding of the mechanisms by whichHDL protects against the development ofatherosclerosis.

The affinity group has several seminar series topromote interdisciplinary interactions and generationof innovative lines of research. The Nutrition SeminarSeries meets weekly and hosts both internal andexternal speakers on a wide array of nutrition-relatedtopics.

1965The Clinical Research Center (CRC) isestablished for hard-to-diagnose, hard-to-treatpediatric diseases and use of new treatments.CRC is the forerunner of the General ClinicalResearch Center, which has been continuouslyfunded by the National Institutes of Health formore than 40 years.


20

Mind Brain ResearchGroup Leader: Michael Robinson, Ph.D.

A startling number of children are afflicted with diseases of the nervous system,including epilepsy, stroke, head trauma, autism and attention deficit hyperactivitydisorder. In addition, many genetic disorders, such as inborn errors of metabolism,manifest with primary brain dysfunction. Concern for pediatric health related tothese diseases has heightened because of evidence that the incidence of some of thesedisorders has increased over the past three decades.

Although some of these disorders, like stroke, havetraditionally been associated with the elderly, recentstudies suggest children are also at risk. Researchindicates that the incidence of stroke during the firstyear of life is as high as that observed during the sixthdecade. Additionally, the Centers for Disease Controland Prevention estimates the incidence of autism is ashigh as 1 in 166 births, and up to 5 percent ofchildren experience at least one seizure. These disorderscollectively place a significant strain not only onchildren and their families, but also on society.

Children’s Hospital follows the largest and most diversepopulation of children with neurologic, psychiatric anddevelopmental disabilities in the country. Outstandingclinical and basic researchers complement the clinicalcare programs throughout the Hospital.

The Mind Brain Research Affinity Group facilitatesthe development of targeted investigation and fostersthe interactions necessary to translate research rapidlyinto best clinical practices. The affinity groupidentified four areas of research as priorities for mindbrain researchers: neuroprotection, epilepsy, stressbiology and autism/complex neurobehavioral disorders.

Recently, mind brain investigators established apediatric stroke program and obtained funding toorganize a multisite study of the incidence andoutcomes of stroke in children and adolescents.Researchers also developed a new program projectgrant to investigate the changes in neurons that lead toepilepsy and to understand how a ketogenic diet —high in fat, and low in carbohydrates and protein —reduces seizure frequency.


Page 20 (left to right): Michael Robinson, Ph.D., and labtechnician Elizabeth Genda. Above: Abnormal neuron withimmature synopsis, intracranial brain wave recordings and frequency analysis.

In addition, the affinity group obtained funding toprovide continued support for the InstitutionalMental Retardation and Developmental DisabilitiesResearch Center, which has been active for the past 15years. This center strives to coordinate and enhancemental retardation research at Children’s Hospital andthe University of Pennsylvania. It provides services tomore than 90 NIH-funded projects with an aggregatevalue of more than $12 million.

Children’s Hospital researchers also helped to developa Center for Dynamic Imaging and developed theCenter for the Management of Attention DeficitHyperactivity Disorder. By creating clinical centersthat focus on specific disease groups, investigators candevelop disease-based research models that may beused to produce targeted treatment approaches for avariety of conditions.

1967Drs. Werner Henle and Gertrude Henle, alongwith Dr. Klaus Hummeler, discover theassociation between infectious mononucleosisand the Epstein-Barr virus, which ultimatelyproves that a common virus may producemalignancy.

21

The mind brain research community is strengthenedby the neurodevelopmental disabilities training grantthat supports postdoctoral fellows; the LeadershipDevelopment through Interdisciplinary Training,commonly known as LEND; and the yearly fellows’poster day, where postdoctoral trainees present theirresearch to the community. The group also organizesseminar series and meetings to attract esteemedscientists from around the world.


22

cell biology and bioinformatics. Linking newtechnologies and integration holds promise for betterdiagnosing, treating and preventing pediatric diseasesof the hematopoietic system.

Recent hematopoesis research at Children’s Hospitalhas focused on leukemia, the most commonchildhood cancer, and its two major subtypes: acutelymphoblastic leukemia (ALL) and acute myeloidleukemia (AML). Whereas most children diagnosedwith ALL can be cured, the prognosis remains poorfor the 20 percent of patients diagnosed with AML.

Hospital researchers have focused on synergisticstudies with the long-term goal of developingpreventative strategies and leukemia-specifictreatments for various forms of pediatric AML. A particular form of AML, which occurs as acomplication of anticancer chemotherapy, has anespecially poor prognosis. One project has examinedhow disruption of the cellular protein calledtopoisomerase II causes chromosomal breakage thatleads to this particular form of AML. A mechanisticunderstanding of the cause of this form of AML couldlead to safer chemotherapy regimens and protectivecompounds.

Normal and MalignantHematopoiesis Group Leader: Carolyn Felix, M.D.

Gene and protein networks that signal bloodcell maturation from primitive bone marrowprogenitor cells, as well as networks thatregulate the balance of cell growth and death,are especially relevant to hematopoiesis.Research at Children’s Hospital into this fieldfocuses on networks that regulate thedevelopment of specific blood cell elements innormal and diseased states.

The Normal and Malignant HematopoeisisResearch Affinity Group aims to addressproblems in these networks to develop targetedprevention and more effective treatments fordisordered hematopoiesis, leukemia andlymphoproliferative diseases in children.

The progenitor cells in the hematopoieticsystem give rise to heterogeneous cellpopulations — red and white blood cells, aswell as platelets — that execute specificfunctions. Technologies like gene expressionprofiling and proteomics have revealed globalpictures of the networks that distinguishspecific blood cell elements in normal andmalignant states. Current research in theaffinity group involves deciphering whichelements in these networks can be targeted fornew treatments and, ultimately, for preventingdiseases of the hematopoietic system.

The Normal and Malignant HematopoeisisResearch Affinity Group brings togetherinvestigators engaged in clinical, translationaland basic research who are skilled in oncology,hematology, stem cell transplantation,cytogenetics, biochemistry, epidemiology,pharmacology, pathology, immunology,


23

Image of GATA-1 created by Chime SquareTM Animations, a molecular graphics resource at Southern Illinois University.

Another focus of hematopoesis research in the affinitygroup is GATA-1, a critical transcription factorprotein that programs the expression of genes inblood-cell development. Patients with Downsyndrome are especially susceptible to AML, and theGATA-1 transcription factor is abnormal in the formof AML associated with Down syndrome.

Investigators in this affinity group are also pursuinga strategy to reduce the complications and mortalityfrom infections associated with intensive AMLtreatment regimens by determining individual geneticvariations that underlie infection risk.

Other affinity group research has focused ondissecting signaling pathways in immune cells calledNKT cells to determine their role in the immuneresponse, which may prove relevant to thedevelopment of immunity against tumors.

These interdisciplinary projects ultimately have thepotential to advance the current knowledge of normaland malignant hematopoiesis, as well as to translateknowledge of the science of hematopoiesis to reducemorbidity and mortality in heterogeneous forms ofleukemia in children.

Activities of the research affinity group, including arich seminar series and annual retreat, facilitate theprogress of an ever-expanding web of researchers witha common interest in broad areas of hematopoiesiswithin the Stokes Institute and the Children’sHospital’s campus and beyond. This avenue ofcombining expertise in specific areas from newinterchanges beyond the clinic and the individuallaboratory will speed the Hospital’s advances inpromoting bench-to-bedside research.


Pediatric Injury ResearchGroup Leader: Flaura Winston, M.D., Ph.D.

24

Pediatric injury research at Children’s Hospital hasfocused on sources of injury such as automobilecrashes, home safety, sports and bicycling, and abuse,neglect and violence, among others. The PediatricInjury Research Affinity Group brings togetherphysicians, nurses, engineers, behavioralists,epidemiologists and outreach professionals fromthroughout the Hospital to conduct focused researchon the root causes of injury as well as to develop andtest interventions that prevent or minimize the impactof injury.

Pediatric injury research experienced tremendousgrowth in the past year, particularly in the area ofautomobile crash injury prevention. The Hospital’scrash-investigation team was designated a member ofthe Crash Injury Research and Engineering Network, amultidisciplinary research network that provides theNational Highway Traffic Safety Administration, theauto safety engineering community and the medicalprofession with the ability to jointly study real-worldcases of serious injuries sustained in car crashes.With a

five-year grant and facilitation from the NationalScience Foundation (NSF), the Hospital alsoestablished a unique NSF Industry/UniversityCooperative Research Center called the Center forChild Injury Prevention Studies (CChIPS) — the onlyNSF center devoted to injury prevention. The centerunites Children’s Hospital and University ofPennsylvania researchers with automotive andinsurance industry members to translate researchfindings into tangible innovations in safety technologyand public education programs. Currently, there are sixfounding industry members who contribute researchdollars to support the CChIPS agenda: Britax ChildSafety Inc., Nissan North America Inc., State FarmInsurance Companies, Takata Corp., Toyota MotorNorth America Inc. and Volkswagen of America Inc.

Unintentional injuries are a major concern for pediatric patients. Accidental injury isthe leading cause of death for children older than 1 year of age, outnumbering theother leading causes combined, including cancer, congenital anomalies andhomicide. Information on the causes for this high rate of injury is valuable forparents, educators, policymakers and product manufacturers.

The Hospital has continued its longstanding researchpartnership with State Farm through Partners forChild Passenger Safety (PCPS), an ongoing researchand advocacy program funded through 2007. Since itslaunch in 1997, PCPS researchers have publishednearly 50 scientific articles and seven publiclyavailable reports, and they have created a multimediaWeb site, www.chop.edu/carseat, available in Englishand Spanish.

Other Pediatric Injury Research Affinity Groupinvestigators have received federal, corporate andfoundation funding to support work in a wide rangeof areas, including suicide prevention, bullyingprevention, community injury prevention, childprevention of persistent traumatic stress after injury,child crash-test-dummy design, injury biomechanics,and teen driver safety and training, among othertopics.


0

10

20

30

40

50

60

70

80

90

100

Newborn 1yr 2yrs 3yrs 4yrs 5yrs 6yrs 7yrs 8yrs

AGE OF CHILDREN

Child Restraint Use by Age: 1999 vs. 2004

% R

ES

TR

AIN

ED

1999

2004

25

1972The Joseph Stokes, Jr. Research Institute iscreated. It includes 70,000 square feetdedicated to research.


26

Four axioms define the current state of pediatrictherapeutics: limited opportunities exist to studypediatric populations; funds for such endeavors aresparse; some assumptions regarding adultpharmacotherapy are portable to pediatric populationswhile others are not; and the diversity of variouspediatric subgroups based on age, indication, diseaseor illness makes generalizing across such groupsproblematic and potentially dangerous.

The emphasis of the Pharmacologic Basis of PediatricTherapeutics Research Affinity Group centers on thepremise that more informative clinical trials areneeded in targeted populations for which the medicalneed is greatest. Such investigations are moreproductive when therapeutic area knowledge regardingclinical indications, drug actions, developmental statusand other factors that may alter drug kinetics ordynamics are assembled into quantitative models thatdescribe the intended clinical setting. The addition ofresearch tools and techniques to improve the qualityand information content of data collected from suchinvestigations are also essential elements to the studyof pediatric pharmacology.

The affinity group’s efforts have therefore focused onassessing drug utilization within the inpatient hospitalsetting, and developing robust, analytical methods tosupport pharmacokinetic studies. As part of its effort,the affinity group also integrates modeling andsimulation approaches to facilitate clinical trialsimulation before protocols are finalized.

This recipe has been used for several collaborativeinvestigations with Anesthesia/Critical Care Medicine,Neonatology, Infectious Disease and Oncology withagents including dexmedetomidine, clonidine,fluconazole and actinomycin-D.

Pharmacologic Basis of Pediatric TherapeuticsGroup Leader:Jeffrey Barrett, Ph.D.

Pharmacotherapy is generally concerned with the safeand effective management of drug administration. Itimplies an understanding of drug pharmacokineticsand pharmacodynamics — how the body uses thedrugs and the physiologic effects of medications — to optimize a patient’s response to treatment througheffective dosing.

Pediatric pharmacotherapy presents several challenges:developmental changes in children may alter drugkinetics, pathophysiologic differences may alterpharmacodynamics, and the cause of a disease in achild may be different from that in an adult. Otherfactors may also result in great variation in safety andefficacy outcomes. The situation becomes morecomplex for critically ill children and neonates giventhe paucity of well-controlled pediatric clinical trials.


PET images of the brain showing (18F) trovafloxacin uptake over time.

27

0.5 HR 2.0 HR 6.0 HR100

80

60

40

20

0

Moreover, the affinity group, with its heightenedunderstanding of clinical-trial modeling andsimulation techniques, guides such investigations andprovides mentorship opportunities for Children’sHospital investigators seeking to learn thesetechniques. The group maintains close collaborationwith the NIH-governed Pediatric PharmacologyResearch Unit (PPRU) network, which has reviewedand endorsed several investigations.

The Pharmacologic Basis of Pediatric TherapeuticsResearch Affinity Group’s other collaborations include pharmacometrics training and analysis withthe Metrum Research Group, an informatics approachto pediatric pharmacotherapy with the U.S. Food andDrug Administration, and mechanisms for studyingdrug utilization with the National Institute of ChildHealth and Human Development.

In the coming year the affinity group will exploremicrodialysis, a technique to measure drug levels intissues, and positron emission tomogrophy scanningas research tools to further expand quantitativepharmacologic investigations.

Members of the group are also exploring the use ofdiscrete-event simulation (a probability-basedmodeling approach to simulate trial outcomes) as atechnique to optimize patient enrollment and study-design strategies.

The affinity group participates in a biweekly e-journalclub sponsored by the Metrum Research Group andwill host a spring symposium highlighting newtechnologies.

Page 26 (left to right): James Lee, lab technician and Jeffrey Barrett, Ph.D.


28

Vaccines and ImmunotherapiesGroup Leader: Terri Finkel, M.D., Ph.D.Co-leaders: Steven Douglas, M.D., and Paul Offit, M.D.

Researchers harnessed the protective powers of theimmune system for medicinal purposes with thedevelopment of modern vaccines more than 50 yearsago. Nevertheless, infectious diseases remain a leadingcause of death for children around the world, andresearchers are exploring new ways to use vaccinetechnology to eliminate this threat.

The immune system sometimes continues its attacklong after it eliminates the invading disease. Immunesystem dysfunction is involved in autoimmunedisorders as varied as asthma, inflammatory boweldisease and rheumatoid arthritis. Autoimmunedisorders often develop during childhood and remainas debilitating chronic illnesses that last a lifetime. Asdiscoveries in the laboratory shed light on the healingpotential of the immune system, vaccines will bedeveloped to correct autoimmune disorders by haltingthe immune system’s mistaken attack on the bodyitself.

New vaccines also are being developed to help theimmune system recognize and eliminate cancer. Unlikeinfectious diseases, against which the immune system isprepared to defend, cancer evades detection.Unfortunately, traditional treatments designed to killcancer also destroy healthy cells, leaving the immunesystem weak and the body defenseless.

Recognizing that numerous diseases involve acomponent of immune system dysfunction, theVaccines and Immunotherapies Research AffinityGroup — including researchers from such diversefields as cancer research, gene therapy, immunology,infectious disease, rheumatology and vaccinedevelopment — are applying shared knowledge tobetter understand the immune system and its powersto protect and heal.

Recent infectious disease research at the Hospital hasfocused on developing a safe and effective vaccineagainst rotavirus, the most common cause of diarrheaand dehydration in children. Hospital investigatorshave developed a new oral vaccine delivery system thatcould one day eliminate the need for needles, makingvaccines easier and more cost-effective to administer,especially in the developing world.

Another infectious disease with global impact is HIV.Standard vaccines for HIV have so far provenineffective because the virus has evolved to includesophisticated methods for evading detection by theimmune system. Hospital researchers have worked tounderstand how HIV invades cells and evadesdetection and used that information to designcompounds and delivery systems that target the cellsHIV invades.


29

The Rotavirus Vaccine, RotaTeq®, and delivery system developed by Children’s Hospital researchers and Merck & Co.

1973Hospital named by the federal government asone of only three pediatric cancer research andtreatment centers.

Researchers are also working to understand the highvaccine failure in children with certain geneticdisorders causing immunodeficiency andautoimmunity, and are developing strategies forenhancing vaccine delivery.

Refining treatments for neuroblastoma, the mostcommon and deadly form of solid-tumor cancer inchildren, has been another focus of this researchaffinity group. Until recently, the standard of care for children with neuroblastoma — a combination of surgery, chemotherapy and stem celltransplantation — resulted in survival rates of only 35 percent. Investigators have focused on

new ways to boost the natural immune responseof patients during recovery from stem celltransplantation, a time when patients are extremelyvulnerable to life-threatening infections or a relapse of their cancer.

In addition, Children’s Hospital researchers havefocused on better understanding autoimmunedisorders, the role of genetics, and the ways in whichinfectious diseases alter immune-system functioning.Investigators have begun to work to develop immunetherapies for juvenile rheumatoid arthritis,dermatomyositis and lupus using an immune therapydesigned for treating lymphoma.

Page 28 (left to right): Terri Finkel, M.D., Ph.D.,Paul Offitt, M.D., and Steven Douglas, M.D.

Progress Notes

Innovation on the Way to Intervention

The close relationship between patient care and the vibrant research community atChildren’s Hospital makes it possible to have a direct link from the bench to thebedside. The highlights here, only a sampling of what’s being accomplished at theHospital, demonstrate the progression from recognizing a clinical or biologicalissue, developing a research direction, conducting basic research, applying the

results in the clinical setting and evaluating those results. Each step isessential as we progress toward answering the research questions that

ultimately will affect children’s health.


30

Diego Jaramillo, M.D., M.P.H., chair,Department of Radiology, is investigating theearly diagnosis of growth disorders using MRI.

Hallam Hurt, M.D., Division of Neonatology,is exploring the neurocognitive precursors toadolescent drug use.

1978Dr. William Rashkind and colleagues developan umbrella-like device for nonsurgical repairof certain heart defects.

Progress Notes

31

Dennis Durbin, M.D., and colleagues in theDivision of General Pediatrics are expanding theHospital’s renowned crash investigation andengineering research by participating in the CrashInjury Research and Engineering Network.Through this multidisciplinary research network,the National Highway Traffic SafetyAdministration and medical professionals jointlystudy real cases of serious injuries sustained in carcrashes.

Age in years9 10 11 12 13 14 15

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Cocaine-exposed Control

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10

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Prevention

Injury

In an example of critical foundation-supportedresearch, Sabrina Smith, M.D., Ph.D., Divisionof Neurology, is using funds from the ChildNeurology Foundation for a new study onlanguage acquisition and visuospatial function in children who have suffered from a stroke.

Treating high-risk fetal lung lesions using ex uterointrapartum therapy (EXIT) — a late-pregnancyprocedure for a fetus with large head or necktumors or severe heart or lung problems — wasthe focus of a study by Surgeon-in-Chief N. ScottAdzick, M.D., pediatric surgeon Holly Hedrick,M.D., and colleagues in the Hospital’s Center forFetal Diagnosis and Treatment. After reviewingthe records of numerous patients after resection of lung lesions during the EXITprocedure, which involves maintaining placental blood flow and gas exchange, Dr.Adzick and his colleagues found that theprocedure allows for controlled resection of largefetal lung lesions at delivery, avoiding acuterespiratory problems related to air trapping and normal lung compression. Theresults of the study were published in the Journal of Pediatric Surgery.

Hedrick HL, Flake AW,Crombleholme TM, Howell LJ,Johnson MP, Wilson RD,Adzick NS. The ex uterointrapartum therapy procedurefor high-risk fetal lung lesions.J Pediatr Surg. 2005Jun;40(6):1038-43.


32

1983Dr. Charles Stanley leads his research team todiscover MCADD (medium-chain acyl-coAdehydrogenase deficiency), an inherited diseasethat may go undetected until it causeschildhood brain damage or death.

Stroke Fetal Surgery

15

10

5

0<0.1 0.1 >0.25 >0.5 >1.0 >2.0

-6.0-2.0-1.0-0.5-0.25

SP-B/Phospholipid (%)

ST

mln

(m

N/m

)

B SP-B Grouped Data

Many premature babies suffer respiratoryproblems during their first few weeks of life dueto an insufficient amount of a lung substancecalled surfactant. Neonatologist Philip Ballard,M.D., Ph.D., led a study that found that evenafter infants begin producing their ownsurfactant, it often fails to function properly inpremature infants who continue to have lungdisease after the first week of life. The studyresults, which were published in PediatricResearch, show that infants with continued lungdisease often have abnormal surfactant functionand diminished amounts of surfactant protein B,an important component of surfactant. Surfactantabnormalities are more likely to occur duringperiods of respiratory infection and worsenedrespiratory status. Dr. Ballard and his colleaguesare conducting a pilot trial of surfactant therapy.

Merrill JD, Ballard RA, Cnaan A, Hibbs AM, Godinez RI, Godinez MH, Truog WE, Ballard PL.Dysfunction of pulmonary surfactant in chronicallyventilated premature infants. Pediatr Res. 2004Dec;56(6):918-26.

The immune cells that make and secrete theantibodies used to fight infections have to tightlycontrol the synthesis of these proteins. Animportant control is how well they are folded,and the cells destroy improperly folded antibodiesso they are not helpful in fighting infection.Pathologist Yair Argon, Ph.D., found that toachieve this control, immune cells coordinate the formation of two disulfide bonds between aminoacids called cysteines, unlike the more commoncase, where these bonds are formed one by one.These findings were published in The Journal ofBiological Chemistry.

Elkabetz Y, Argon Y, Bar-Nun S. Cysteines in CH1underlie retention of unassembled Ig heavy chains.J Biol Chem. 2005 Apr 15;280(15):14402-12.

Progress Notes

33

Host Defense Surfactant

Expression phenotypes with the strongest evideice of linkage from genome scans

P-value

<10-11

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5q14 22q13 7q11

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Cis*Cis*CisCisCis

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CisCisCis

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Gene Location Cis/trans

*The most extreme P-values occurred at SNPs located>5Mb from the gene, but linkage evidence within 5Mb of target gene was also highly significant (P<4.3 x 10-7).

Model for Topoisomerase II Involvement inFormation of MLL Translocations

TopoIIII

55’55 ’’

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Vivian Cheung, M.D., Division of Neurology,led a study that involved performing a geneticanalysis of genome-wide variation in human geneexpression. The investigators used microarrays tomeasure gene expression levels and performedgenome-wide linkage analysis for expression levelsof 3,554 genes in 14 large families. They foundevidence of linkage to specific chromosomalregions. The combination of microarraytechniques and linkage analysis allows the geneticmapping of determinants that contribute tovariation in human gene expression. The studywas published in the journal Nature.

Morley M, Molony CM, Weber TM, Devlin JL,Ewens KG, Spielman RS, Cheung VG. Geneticanalysis of genome-wide variation in human geneexpression. Nature. 2004 Aug 12;430(7001):743-7.

A group of anticancer drugs known astopoisomerase II poisons convert an enzyme thatrelaxes supercoiled DNA into a DNA-damagingenzyme. Some studies suggest that these drugstarget areas of the DNA associated with differentforms of leukemia. Incidence of a form ofleukemia known as acute promyelocytic leukemia(APL) has increased in patients who are alreadybeing treated for a different form of cancer. Thisincidence has risen during the same period thatthe use of topoisomerase II poisons as a cancertreatment has increased. Oncologist CarolynFelix, M.D., led a study published in the NewEngland Journal of Medicine that foundtopoisomerase II poisons contribute to DNAbreaks associated with APL.

Mistry AR, Felix CA, Whitmarsh RJ, Mason A, ReiterA, Cassinat B, Parry A, Walz C, Wiemels JL, SegalMR, Ades L, Blair IA, Osheroff N, Peniket AJ, Lafage-Pochitaloff M, Cross NC, Chomienne C, Solomon E,Fenaux P, Grimwade D. DNA topoisomerase II intherapy-related acute promyelocytic leukemia. N EnglJ Med. 2005 Apr 14;352(15):1529-38.


34

Genetics Leukemia

4.5

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Ln (Height)

ControlCrohn Disease

Ln

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boy

girl

Progress Notes

35

Nephrologist Mary Leonard, M.D., led a studythat found that children who take steroids for akidney condition called nephrotic syndrome donot suffer bone loss, a common side effect ofsteroid treatments in adults and in steroidtreatment of some childhood diseases. The study, published in the New England Journal ofMedicine, suggests steroid-related weight gain inchildren with nephrotic syndrome may contributeto bone strength and mass.

Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-doseglucocorticoids and bone mineral content inchildhood glucocorticoid-sensitive nephroticsyndrome. N Engl J Med. 2004 Aug 26;351(9):868-75.

A study led by endocrinologist Adda Grimberg,M.D., found that twice as many boys as girls arereferred to medical specialists for evaluation ofshort stature and poor growth, which may reflectsociety’s gender bias about stature and may haveserious health consequences. The investigation,published in The Journal of Pediatrics, revealedthat girls who were referred were more likely tohave an underlying disease affecting their height,and were less likely to be within normal heightranges. Girls who were referred for evaluationwere significantly shorter than the referred boyswhen compared to same-sex children in thegeneral population and to predictions based ontheir parents’ health. These findings werehighlighted in The New York Times in February2005 and in numerous media venues throughoutthe United States and abroad.

Grimberg A, Kutikov JK, Cucchiara AJ. Sex differencesin patients referred forevaluation of poor growth.J Pediatr. 2005

Feb;146(2):212-6.

1988Dr. Graham Quinn and associates arecoleaders in proving the value of freezingretinal tissue (cryotherapy) to destroyabnormal vessel growth for the prevention ofblindness in premature infants.

Growth Bones

Baseline and Hypercarbic Perfusion Valuesin CHD

Perfusion Unit = 0-50ml/100g/minPt - 22HLHS

$9,000

$8,000

$7,000

$6,000

$5,000

$4,000

$3,000

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$1,000

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$0

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36

Neurologist Daniel Licht, M.D., found thatnewborns with congenital heart disease often have abnormally low blood flow in their brainsbefore they undergo surgery. Dr. Licht and hiscoinvestigators used a novel magnetic resonanceimaging technique, which they modified for usein infants, to conduct the first study to measureinfants’ cerebral blood flow before surgery. Thestudy results, published in The Journal of Thoracicand Cardiovascular Surgery, indicate that reducedblood flow to the brain was associated with injuryto the newborn brain, specifically a conditionknown as periventricular leukomalacia, a scarringof white matter in the brain.

Licht DJ, Wang J, Silvestre DW, Nicolson SC,Montenegro LM, Wernovsky G, Tabbutt S, DurningSM, Shera DM, Gaynor JW, Spray TL, Clancy RR,Zimmerman RA, Detre JA. Preoperative cerebralblood flow is diminished inneonates with severe congenital heart defects.J Thorac Cardiovasc Surg.

2004 Dec;128(6):841-9.

Neonatologist Scott Lorch, M.D., M.S.C.E.,found that inhaled nitric oxide (iNO) is a cost-effective method of treating infants withpersistent pulmonary hypertension of thenewborn (PPHN), a condition in which theinfant’s blood does not pass through the lungs,resulting in oxygen-poor blood. The results alsoindicate that the timing of treatment decisionscould improve efficiency and cost of care forpatients with PPHN treated with iNO. Theseresults were published in Pediatrics.

Lorch SA, Cnaan A, Barnhart K. Cost-effectiveness ofinhaled nitric oxide for the management of persistentpulmonary hypertension of the newborn. Pediatrics.2004 Aug;114(2):417-26.

1990sDr. Robert Levy is cited for his researchmilestones related to the mechanisms andprevention of bioprosthetic heart valvecalcification, and discoveries concerning thefirst report of a gene delivery stent.

Brain Injury Nitric Oxide

CD3

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Progress Notes

37

XLP is a form of immunodeficiency caused bymutations in a gene responsible for theproduction of a protein known as SAP.Oncologist Kim Nichols, M.D., led a studypublished in Nature Medicine that found SAPplays a crucial role in the development of naturalkiller T cells (NKT). Investigators found thatpatients with XLP do not have NKT cells, whichsuggests that the lack of NKT cells maycontribute to the symptoms of XLP.

Nichols KE, Hom J, Gong SY, Ganguly A, Ma CS,Cannons JL, Tangye SG, Schwartzberg PL, KoretzkyGA, Stein PL. Regulation of NKT cell developmentby SAP, the protein defective in XLP. Nat Med. 2005Mar;11(3):340-5.

Calpain is a protease — an enzyme that breaksdown proteins — activated by a cellular receptorcalled NMDA that plays a role in neurologicalfunction and development. This receptor iscomposed of two subunits, NR1 and one ofseveral forms of NR2. Calpain cleaves NR2subunits, which then interact with a proteincalled PSD-95. Neurologist David Lynch, M.D.,Ph.D., found that interactions of the NR2subunits with PSD-95 control the calpain-mediated breakdown of the NR2 subunit. Theseresults, published in The Journal of Neuroscience,provide a mechanism for calpain’s role in theturnover of NMDA receptors. The findingssuggest that calpain could play a role in thedamage seen in stroke and other neurologicdisorders of children and adults.

Dong YN, Waxman EA, Lynch DR. Interactions ofpostsynaptic density-95 and the NMDA receptor 2subunit control calpain-mediated cleavage of theNMDA receptor. J Neurosci. 2004 Dec8;24(49):11035-45.

Neurobiology Immunity

TH CRF-R

TH/CRF-R/µµµ

Significant Percentage of Patients Diagnosed with Evans Syndrome Have

ALPS

0

20

40

60

80

100

None anti-Fas Ceramide Steroid

% A

po

pto

tic

Normal Defective ControlFas- -Apoptosis Fas Apoptosis

Chronic opiate use produces long-lasting changesin the brain. One of those changes, which maythen contribute to continued substance abuse, isdysregulation of the stress response.Neuroscientist Rita Valentino, Ph.D., found thatbrain cells that regulate arousal and behavioralresponses to stress (i.e., locus coeruleus neurons)become sensitized to corticotrophin-releasingfactor (CRF), a stress neuromediator with chronicexposure to morphine. Her studies suggest thatopiate-seeking behavior may occur to counteractthe hypersensitivity of these neurons to stress.These studies also suggest that subjects that arechronically exposed to opiates may be vulnerableto stress-related disorders such as anxiety,depression or post-traumatic stress disorder. Thisstudy, published in The Journal of Neuroscience, isthe first evidence for dysregulation of the centralresponse to stress by chronic use of opiates.

Nichols KE, Hom J, Gong SY, Ganguly A, Ma CS,Cannons JL, Tangye SG, Schwartzberg PL, KoretzkyGA, Stein PL. Regulation of NKT cell developmentby SAP, the protein defective in XLP. Nat Med. 2005Mar;11(3):340-5.

Oncologist David Teachey, M.D., investigatedthe potential overlap between two rare disorderswith overlapping clinical symptoms. The resultsof this study, published in Blood, suggest a highprevalence of autoimmune lymphoproliferativesyndrome (ALPS) among patients with Evanssyndrome. This is a novel finding that hasimportant implications for the prognosis andtreatment of these patients. The results alsoindicate ALPS may be more common thanpreviously thought. A sensitive first-line screeningtest was developed during this study, which usesdeveloping immune cells, or double-negative Tcells, as markers for patients who requiredefinitive testing.

Teachey DT, Manno CS, Axsom KM, Andrews T,Choi JK, Greenbaum BH, McMann JM, Sullivan KE,Travis SF, Grupp SA. Unmasking Evans syndrome: T-cell phenotype and apoptotic response revealautoimmune lymphoproliferative syndrome (ALPS).Blood. 2005 Mar 15;105(6):2443-8.


38

Addiction Diagnostics

Adjusted Risk Factors for ESBL-EK Infectionin Hospitalized Children

Variable Adjusted OR (95% CI) P Value

Third-generation cephalosporin* use in previous 30 d

Female

Infecting organism

Steroid use in previous 30 d

5.82 (1.92-17.68) .002

4.49 (1.49-13.51) .008

3.48 (1.07-11.32) .039

4.04 (1.30-12.50) .016

OR indicates odds ratio; CI, confidence interval.

* Third-generation cephalosporins include: cefotaxime,ceftazidime, and ceftriaxone.

The increased prevalence of infections caused byantibiotic-resistant bacteria has become a concernfor hospitalized patients. Clinical epidemiologistTheoklis Zaoutis, M.D., led a study thatinvestigated the risk factors for infection withantibiotic-resistant bacteria in pediatric patients.The results, published in Pediatrics, indicate thata group of antibiotics, known as cephalosporins,are significantly associated with this type ofinfection. These results suggest that limited use ofcephalosporins may reduce the number ofantibiotic-resistant infections.

Zaoutis TE, Goyal M, Chu JH, Coffin SE, Bell LM,Nachamkin I, McGowan KL, Bilker WB, LautenbachE. Risk factors for and outcomes of bloodstreaminfection caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species inchildren. Pediatrics. 2005 Apr;115(4):942-9.

Hematologist Mitchell Weiss, M.D., Ph.D.,coauthored a study that reported the crystalstructure of a complex between α-haemoglobin(α-Hb) and α-haemoglobin-stabilizing protein(AHSP) that when disrupted contributes to thesymptoms of β-thalassemia, a common inheritedanemia. The study described the structuralchanges that occur in αHb and AHSP when theybind. These findings, published in Nature,illustrate a new facet of hemoglobin homeostasis,and contribute to the body of research designedto find a treatment for β-thalassemia.

Feng L, Zhou S, Gu L, Gell DA, Mackay JP, WeissMJ, Gow AJ, Shi Y. Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protectivemechanism for haem. Nature. 2005 Jun2;435(7042):697-701.

Progress Notes

39

1991The Hospital is designated a Human GenomeCenter by the National Institutes of Healthand awarded a major federal grant for themapping of chromosome 22 (completed in1999).

Hemoglobin Infections

Supporting Research – Stokes Core Facilities

Research starts with a question . . . the path to the answer is the challenge

Sometimes pursuing the answer to a research question involves using aclipboard, a computer or test tubes in a laboratory. At other times, access to

state-of-the-art instrumentation, technologies and skills is critical toinvestigators in their quest to better understand disease and develop

therapies to improve the health of children.


40

The Stokes Institute provides instrumentationand technical skill through 15 core facilitiesthat service both laboratory and clinicalresearch programs. Providing core facilities toinvestigators makes research more affordable,convenient and efficient.

With substantial Hospital support, the StokesInstitute has improved and broadened the corefacilities available for the Hospital’s researchcommunity, investing in equipment, servicesand other capabilities as well as supportingtechnical staff. Each year, the Hospital investsmillions of dollars in sophisticated researchinstrumentation for the core facilities, whichare led by scientific or faculty directors and oneor more technical directors.

1992 — 1995/1999Dr. Terri Finkel and colleagues are the first toshow that HIV does more than infect T cells.The virus also seems to prime uninfected Tcells for suicide, reducing the ability to fightinfection. They are also the first to show thatHIV renders some of the cells it infects death-resistant, thereby prolonging the life span ofthese virus factories.

Supporting Research — Stokes Core Facilities

41

Dr. Hogarty and colleagues in the Division ofOncology previously performed an extensive genomicanalysis that led to the classification of neuroblastomainto distinct types. Each type has signature alterationsin the genome, encompassing scores and sometimeshundreds of genes (out of the more than 30,000human genes).

The current challenge in neuroblastoma research is todiscover which gene leads to the cancer state andaggressive growth of the disease. For this purpose, Dr.Hogarty initiated a research program with Yair Argon,Ph.D., who heads the Protein Core Facility. One ofthe core’s specialties involves identifying changes inlevels of expression of proteins. The core uses a newmethod to identify and list all the proteins whose levelis dramatically lower or higher in each subtype ofneuroblastoma. The list of proteins is then correlatedwith the list of genes implicated by the geneticanalyses.

Core Facilities Play Key Role in New Approaches to Neuroblastoma Research

Neuroblastoma, the most common and deadly of solidtumors in children, accounts for up to 10 percent ofthe cancers and 15 percent of the deaths from cancerin childhood. Most affected children are diagnosedwith this aggressive disease before they are 5 years old.

Despite the sobering statistics, investigators have madetremendous strides over the last 20 years in unravelingthe workings of neuroblastoma and developing newand more effective treatment approaches that reducethe toxic effects of the standard, highly intensivetherapy. However, future novel therapies — andimprovements in the survival rate — depend onidentifying the key protein pathways that change anormal cell into an aggressively growingneuroblastoma.

Michael Hogarty, M.D., Division of Oncology, isaddressing this fundamental question by applyingglobal tumor proteomics to neuroblastoma. His workillustrates the critical roles of the Stokes Institute’s corefacilities in enabling the cutting-edge research ofHospital investigators. The cores house eitherinstrumentation or expertise that is generally beyondthe means of an individual investigator and thereforeare central resources for the entire Children’s Hospitalcommunity.

Top of page 42 (left to right): Michael Hogarty, M.D.,Division of Oncology, and lab technician KellyGoldmith.


42

To achieve a meaningful relation of the proteinsidentified by the protein core to the lists of genes, Dr.Hogarty is working closely with the Stokes Institute’sBioinformatics Core, whose expertise lies incomputational tools that can quickly sift through genelists, and information about altered patterns of theirexpression in normal tissues and in disease.Sometimes, the protein and gene identified are wellstudied, so investigators can infer their role in causing the disease. In other cases, however, theprotein is unknown, leading to a key research question — what does it do?


43

Top of page: Beckman ProteinLab® PF 2D, Proteinfractionation system that identifying changes in levelsof expression of proteins.Bottom of page (left to right): Bioinformatics Coremembers Xiaowu Gai and Juan Perin in server room with director Ge Zhang.

1995The Leonard and Madlyn Abramson PediatricResearch Center opens on the Hospital’s MainCampus, consolidating all the laboratoryresearch of the Joseph Stokes Jr. ResearchInstitute.

The computational tools in the BioinformaticsCore enable the Protein Core staff to projectpossible functions for an unknown protein, likeits involvement in certain metabolic pathways.Investigators can then test such predictions withother Protein Core technology that measuresprotein-protein interactions. Bioinformatics toolsalso provide Dr. Hogarty with the ability to rankorder the likelihood that each protein he finds isrelevant for neuroblastoma.

The predictive value of a newly identified proteinto neuroblastoma depends on how many times itis identified in different patients. To determinethis, Dr. Hogarty will engage the services of thePathology Core, which recently constructed atissue microarray for neuroblastoma. Small tissuepieces from several hundred neuroblastomatumors from patients treated at Children’sHospital, selected to represent the varioussubtypes of neuroblastoma, were arrayed onmicroscope slides and can be probedsimultaneously for the presence of the candidateprotein.

All the data from the protein analysis, geneticanalysis and tissue microarrays will then beorganized into data sets in collaboration with theBiostatistics and Data Management Core. Thecore will determine the statistical significance ofeach of the protein biomarkers, enabling Dr.Hogarty and his research team to rank the dataand prioritize which proteins are worth pursuingfurther as possible therapy targets.

Solving a disease as complex as neuroblastomarequires many approaches, as no one technique canprovide a cure. Through the availability of a host ofcutting-edge technologies in the Stokes Institute’sCore Facilities, Hospital researchers can now mount a multidisciplinary assault on complex childhooddiseases with realistic hopes of finding the most likely causes of disease.

Top of page: Tissue microarray for neuroblastomadeveloped by the Pathology Core.Bottom of page: Biostatistics director Charles Scott,Ph.D., and member Justin Valliyil.


44


45

1995Dr. Scott Adzick leads the establishment of theCenter for Fetal Diagnosis and Treatment,which is at the forefront of research andclinical practice in the emerging field offetology.

The National Center for Research ResourcesShared Instrumentation Grant provides fundsfor expensive equipment shared betweenmultiple investigators. This competitive awardmakes it possible to purchase instruments thatcould not be purchased with individualinvestigator grants.

Stokes won a grant of nearly $300,000 topurchase a Surface Plasma Resonance Biacore3000, which measures protein interactions.Yair Argon, Ph.D., serves as the principalinvestigator on the grant and assumesadministrative and scientific responsibility forthe equipment.

The Biostatistics and Data Management Corehas the distinction of serving as thecoordinating center for the 25-center study onchildhood absence epilepsy, a form of epilepsythat affects up to 15 percent of epilepticchildren. Characterized by brief staring-spellseizures that are frequent and unpredictable,the condition can have an adverse effect on achild’s education and play.

The five-year study will recruit more than 400children who will receive different medicationsfor their childhood absence epilepsy.

The Core’s role in this important studyinvolves providing data and biologicalcollections and monitoring, site coordination,double data entry, site quality assurance,monitoring, Data Safety Monitoring Boardreporting, and interim and final statisticalanalyses.

Innovation Fueling Progress

Vaccine Development Testament to Hospital’s Innovation

During the last century, the life span of the average American has increased byapproximately 30 years. This dramatic increase is attributed to a multitude offactors, including cleaner drinking water, better nutrition and the development

of antibiotics.

Vaccines, however, are the single most significant contributor to thelonger life we now enjoy.


46

Children’s Hospital has a distinguished legacyof developing vaccines to improve the lives ofchildren throughout the world. Pioneeringresearch conducted at Children’s Hospital bythe husband-and-wife team of Drs. Werner andGertrude Henle, as well as Lewis Coriell,M.D., and Stanley Plotkin, M.D., led to thedevelopment of vaccines for whooping cough,influenza, mumps and rubella (Germanmeasles). The Hospital served as a testing sitefor many of these vaccines.

Children’s Hospital was privileged tocollaborate on much of the innovative researchconducted by world-renowned microbiologistMaurice Hilleman, Ph.D., D.Sc., (seen above)who was instrumental in the development ofmodern vaccines, including nine of the 14vaccines routinely given to children today.

Dr. Hilleman, a former director of the Merck Institute of Vaccinology and a longtime advisor to Stokes Institute, passedaway in April at age 85.

1995 The Division of Gastroenterology andNutrition is at the forefront in theidentification, diagnosis and treatment ofEosinophilic Esophagitis (EoE) — a newallergic GI disease in children.


47


48

A prime example of the Hospital’s bench to bedsideresearch philosophy, recent efforts on this frontinvolve a vaccine for rotavirus, a disease that causesapproximately one-third of diarrhea-associatedhospitalizations and nearly half a million deathsworldwide every year in children under five.

“Dr. Hilleman’s contributions to vaccine developmentsave approximately 8 million lives a year and haveallowed us to live longer,” says Dr. Offit, one of thechief developers of the technology that forms the basisof RotaTeq®, the rotavirus vaccine developed byMerck & Co. Inc.

As a reminder in perpetuity of the importance of Dr.Hilleman to Merck and the communities of theHospital and University of Pennsylvania, the MerckCompany Foundation made a gift to the Hospitaland University to establish the Hilleman Chair inVaccinology. Dr. Offit was chosen as the first holderof the chair.

During a career that spanned six decades, Dr.Hilleman contributed to the development of nearlythree dozen vaccines, including those for measles,mumps, rubella, varicella and hepatitis B.

Dr. Hilleman’s successful development of a vaccine formumps started when his daughter, age 5 at the time,complained of a sore throat. After quickly determiningshe had the mumps, he swabbed her throat, weakenedthe virus strain and began working on a vaccine. As aresult of his efforts, the virus has been virtuallyeliminated.

According to Paul A. Offit, M.D., chief, Division ofInfectious Disease, Dr. Hilleman would probablyconsider his greatest success the hepatitis B vaccine,which was the first to use a single protein in vaccinedevelopment, the first to use DNA recombinanttechnology, and, since hepatitis B often leads to livercancer, was the first to prevent a known cause ofhuman cancer.

“Developing just one vaccine can be a lifetime’s worthof work,” Dr. Offit said. “That Dr. Hilleman’sgroundbreaking research led to numerous vaccines —many of which are among those recommended forchildren today — is almost inconceivable.”

Dr. Hilleman conducted many of his most importantvaccine studies with Children’s Hospital researchers,who continue to build upon his research.

Top of page: Paul Offit, M.D., chief, Division ofInfectious Disease, and one of the rotavirus vaccinedevelopers.


49

After one of the largest safety and efficacyevaluations ever performed by a pharmaceuticalcompany — Phase III trials that involved morethan 70,000 subjects — Merck & Co. recentlyapplied for a license for RotaTeq® with the U.S.Food and Drug Administration.

In the United States, rotavirus accounts forapproximately 70,000 hospitalizations, 500,000 visits to primary care offices and 20 to 70 deaths annually.

Children’s Hospital investigators Paul A. Offit,M.D.; and H. Fred Clark, V.M.D.; and StanleyPlotkin, M.D., of The Wistar Institute jointlydeveloped the technology, which forms the basisof Merck’s rotavirus vaccine. The technologywas licensed to Merck in 1991.

1997Drs. Nancy Spinner, David Piccoli and Ian D.Krantz discover the gene responsible forAlagille syndrome, a disorder associated withcongenital liver, heart, kidney, spine, eye andpancreatic disease.


50

Flaura Winston, M.D., Ph.D., and Kristy Arbogast,Ph.D., received two patent awards for developing asafety handlebar and a retrofit safety handlebar thatabsorb energy and therefore reduce abdominal andother injuries to bicycle riders when they collide withthe handlebar.Patent numbers: US6,840,135 and US6,834,565

Drs. Winston and Arbogast, along with RajivMenon, Ph.D., and Kurt Schwinghammer, Ph.D.,developed a sleeping occupant protection system forvehicles.Patent number: US6,827,400

Former Children’s Hospital staff nurse KathleenO’Neill, R.N., invented a device for maintaining apatient’s mouth in an open position during a medical procedure.Patent number: US6,743,017

Robert Levy, M.D., Ivan Alferiev, Ph.D., and formerChildren’s Hospital researcher Narenda Vyavahare,Ph.D., received two patents for their inventions thatteach mechanisms by which to make implantablebioprosthetic devices and tissues more biocompatible.Patent numbers: US6,391,528 and US6,824,970

Robert Levy, M.D., and former Children’s Hospitalresearcher Narenda Vyavahare, Ph.D., were awarded apatent that relates to methods of stabilizingimplantable bioprosthetic devices, making them lessresistant to calcification.Patent number: US6,861,211

Ivan Alferiev, Ph.D., Ilia Fishbein, M.D., Ph.D., andRobert Levy, M.D., received two patent awards fornovel types of polyurethanes that are useful inbiological systems.Patent numbers: US6,900,282 and US6,890,998

Robert Levy, M.D., and former Children’s Hospitalresearcher H. Scott Baldwin, M.D., discoveredmethods for a gene therapy approach specific to thecontrol of cardiac arrythmias. Their patent alsodiscloses novel gene vector compositions and localizeddelivery formulations.Patent number: US6,852,704

Michael Grunstein, M.D., Ph.D., and formerChildren’s Hospital researcher Hakon Hakonarson,M.D., received a patent that includes methods foridentifying genes that regulate responses to anti-inflammatory drugs, methods for drug screening, andmethods for identifying genes that correlate withasthma and other inflammatory diseases.Patent number: US6,893,828

Children’s Hospital investigators have developed a multitude of technologies over theyears that may ultimately improve the health of children through the development of new products and therapies.

During fiscal year 2005 alone, the United States Patent Office awarded 11 patents toChildren’s Hospital for technologies, all of which illustrate the translational relevance of research within the Stokes Institute.


51

1997Center for Outcomes Research is established tocreate new methods of health service research,with an emphasis on developing new pediatricoutcomes measures.

Technology Transfer Director Kurt Schwinghammer,Ph.D.; and Chief Scientific Officer and Senior VicePresident Philip Johnson Jr., M.D., director of TheJoseph Stokes Jr. Research Institute.

Fiscal Year 2005 Tech Transfer Statistics:

Invention Disclosures Received - 29Patent Applications Filed - 26Patents Issued - 10Active Licenses - 23 License Revenues -$865,000

Building the Intellectual Community

New Investigators Fortify, Expand Hospital’s Research Program

As a critical step on the path to pediatric research preeminence, Children’s Hospitalaggressively recruits and promotes talented laboratory and clinical investigatorswho are among the best and brightest in their fields. The Institute expects thattheir research programs — whether budding or in full bloom — will make

substantial contributions to understanding the biology that underliespediatric disease, ultimately improving child health.


52

Craig Bassing, Ph.D., is one of the more than20 who joined the ranks of investigators atChildren’s Hospital last year. A member of theDivision of Cell Pathology in the Departmentof Pathology and Laboratory Medicine, Dr.Bassing’s research interest centers onunderstanding the molecular mechanismsthrough which antigen receptor genes areassembled in developing white blood cells.

Specifically, Dr. Bassing investigates the role ofchromatin modification in regulating theinitiation and proper repair of the programmedDNA double-strand breaks. Errors in theprocess of repairing these natural breaks areoften associated with diseases like cancer.

Recruited from Children’s Hospital Boston, Dr. Bassing has an appointment in theUniversity of Pennsylvania Department ofCancer Biology and was named an assistantinvestigator at Penn’s Abramson Family CancerResearch Institute.

V(D)J Recombination

Variable Region

Constant Region

J CDV V J

Germline Gene Segments

RAG1&2

Blunt, 5' phosphorylatedRS ends

Covalently closedhairpin

coding ends1997Dr. Michael Grunstein and colleagues are thefirst to demonstrate that a receptor for IgE ispresent in airway smooth muscle, making itasthmatic in nature. They further found that aprotein that is also present in airway smoothmuscle can protect it from developing anasthmatic response.


53

Cancer

Timothy Roberts, Ph.D., joined the Departmentof Radiology as vice chair of research after servingas a professor of medical imaging at theUniversity of Toronto. Dr. Roberts’ researchinterests include brain-wave recording usingmagnetoencephalography; advanced,physiologically specific neuroimaging withmagnetic resonance imaging; developmentdisorders, especially autism; and neuro-oncologyand imaging of microvascular permeability incancer.

A bioengineer and researcher in pediatric trauma,Kristy Arbogast, Ph.D., of the Division ofEmergency Medicine in the Department ofPediatrics, focuses her research on traffic injury.As part of TraumaLink, Dr. Arbogast aims tomake children safer by understanding how theyare injured in everyday events — like riding inmotor vehicles — as well as how the productsthey use during everyday events influence theirrisk of injury and how those products can beimproved to reduce that risk.

As part of her research, Dr. Arbogast investigatesproducts (such as cars, bicycles and playgroundequipment), the environment (such as skid marksor pedestrian walkways), and protective devices(such as seat belts, helmets and car seats) todetermine what happens when a child is injured.Her technique uses general engineering principlesto understand how the energy of an incident istransferred to a child.


54

Imaging Injury

IPTG

Fraction #+1

+2

–2

–1

222 kDa

97 kDa

66 kDa

46 kDa

30 kDa

21 kDa

Michael Sebert, M.D., who joined the Divisionof Infectious Diseases, investigates the molecularbasis of infections by Streptococcus pneumoniae, a common childhood bacterial pathogen alsoknown as the pneumococcus. Although thisbacterium is a major cause of diseases includingpneumonia, otitis media, sepsis and meningitis, it most frequently is found colonizing the upperrespiratory tract of humans asymptomatically.Such silent colonization is thought to precedenearly all cases of disease caused by this organism. His laboratory studies the coordinated geneticresponses through which Streptococcus pneumoniaebecomes adapted for survival in this environment.The long-term objective of his research involvesdefining new strategies for preventing andtreating diseases caused by this pathogen.

John Germiller, M.D., Ph.D., joined theDivision of Otolaryngology in the Department ofSurgery as a faculty member after completing hisfellowship in otolaryngology. Dr. Germiller’sresearch centers on the factors that control theearly embryonic development of the auditorynerve. The nerve is stimulated by cochlearimplants that help restore hearing to many deafchildren.

He specifically investigates the early growthfactors that stimulate the auditory nerve anddirect it to innervate the early inner ear. His goalis to identify a new auditory nerve growth factorthat may be promising clinically for regeneratingthe auditory nerve in deaf children.


55

Hearing Infection

56


Training Project Focuses on Cell Injections to Treat Congenital Diseases

The field of fetal therapy is expanding rapidly, withthe number of surgeries and interventions rising andthe perception of the fetus as a patient gainingmomentum among physicians and other healthcareprofessionals.

One form of fetal therapy — in utero hematopoieticcell transplantation (IUHCT) — has the potential totreat a large number of congenital disorders, including those diagnosed in the prenatal period, ordisorders like sickle cell disease that may require bonemarrow transplants after birth.

IUHCT involves injecting cells into the fetus, an ideal environment given the fetus’s small size,immature immune system and a large number ofmigrating stem cells. The careful timing of injectionsand the successful engraftment of donor cells,however, have proven to be crucial to the success of the fetal cell transplantation procedure.

The research conducted by William Peranteau, M.D., and his colleagues stems from a model of intravenous fetal bone marrow injection developed bysurgeon Alan Flake, M.D., to better understand theimmunobiology of in utero transplantation.

Dr. Peranteau and his team built upon the results of preliminary studies to establish an injection methodthat would increase the competitive advantage of thedonor cell in the fetal environment.

Dr. Peranteau is one of three trainees whose work issupported by a new five-year training grant from theNational Institutes of Health. The Hospital’s FetalBiology and Therapy Training Program, directed byDr. Flake, trains clinician-scientists who are focusedon fetal therapy and who can envision, develop, investigate and translate new and novel treatmentstrategies for the fetus.

The award ensures that trainees have protected timeto develop their research skills under the direction ofone of the program’s mentors. Patient-orientedresearch opportunities, derived from the Hospital’sCenter for Fetal Diagnosis and Treatment, focus onfetal treatment of myelomeningocele and twin-twintransfusion syndrome. The laboratory researchopportunities under the training grant include fourmajor areas of basic research: stem cell therapy in thefetus; fetal gene therapy; fetal wound healing; andfetal anatomic malformations and lung growth.

Providing the Foundation for Tomorrow’s Researchers

In his stem cell therapy project under the traininggrant, Dr. Peranteau and his research team are investigating the ability of certain donor cells calledhematopoietic stem cells to home to and engraft inthe fetal liver, which plays a critical role at the time ofthe IUHCT procedure.

After inhibiting an enzyme called CD26 in donorcells, Dr. Peranteau and his colleagues injected thecells into their model and found that the CD26-inhibited bone marrow and enriched stems cellshomed to the to the fetal liver more efficiently. Theinvestigators went on to find that transplanting theCD26-inhibited bone marrow in the fetus led togreater engraftment of the donor cells.

Taken together, the studies conducted by Dr.Peranteau and his colleagues demonstrate that inhibiting the CD26 enzyme in donor cells increasedtheir ability to home to specific parts of the fetus,thereby increasing the chances that the IUHCT procedure may ultimately aid in treating or curingcongenital diseases in the fetus.

1997Drs. Flaura K. Winston and Dennis R. Durbininitiate Partners for Child Passenger Safety.Their research shows that young children whouse age appropriate restraints, such as a boosterseats, have a 59 percent lower risk of injury ina crash. They also show that rear seats ofcompact extended cab pick-up trucks areparticularly dangerous. These findings lead to a wide range of enhanced legislation, safety regulation, and automobile and childrestraint design.


57

Image of in-utero hematopoietic cell transplantation(IUHCT). Injection of allogenic bone marrow cellsinto the vitelline vein of a 14-day gestation model.

58


1998Steven Ludwig, M.D., and N. Scott Adzick,M.D., are elected as members of the Instituteof Medicine (IOM).

Training Grants: A Valuable Resource for Investigators

Training and career development for scientists andphysician-scientists is an integral element of themission of Children’s Hospital. It is through in-depth, hands-on training that the Hospital developsthe next generation of investigators by exposingthem to the highest scientific principles, newresearch techniques and the nearly limitlessopportunities for clinical and laboratory research.

Federal or private grants fortify the Hospital’sinternal training and awards programs while offeringadditional opportunities for experience and trainingin specific areas relevant to advancing pediatrichealthcare research. Numerous awards come from the National Institutes of Health, which iscommitted to training research investigators and hasmade such an endeavor part of its overall mission.

Children’s Hospital is the recipient of seven highlycompetitive training grants that provide mentoredresearch training as well as formal coursework, a corecurriculum and training in responsible researchconduct.

In addition to the fetal biology and therapy traininggrant, the grants awarded to the Hospital focus on both general and disease-specific areas ofinvestigation related to pediatric healthcare researchand include programs in arteriosclerosis, cardiology,career development, diabetes, hematology,neurodevelopmental disorders and stroke, andtraining pediatric physician-scientists.

Thanks to its close association with the University ofPennsylvania, Children’s Hospital trainees can alsoget support from the many training grants awardedto the University or can train with faculty members from relevant Hospital departments andthe University of Pennsylvania, thus expanding analready rich and diverse training environment.

Fellows selected for participation in training grantsare expected to devote themselves essentially full-time to research training, which generally lasts twoto three years.

Many Hospital investigators are the recipients of NIHResearch Career Development Awards, also referred toas “K” awards. These awards are essential to ensuringa pipeline of well-trained academic physicians andscientists by supporting their research anddevelopment activities and requiring that applicantsgain additional supervised experience as they becomeindependent research scientists.

The Hospital has 38 active K awards supporting bothbasic and clinical research. Such career developmentsupport helps fortify an investigator’s budding career.Some researchers with K awards aim to develop bettertreatments for a multititude of pediatric diseases andconditions, while others explore the underlyingbiology that can play a role in disease.

For example, attention deficit hyperactivity disorder(ADHD) is the focus of the K award to JamesGuevara, M.D., M.P.H., who is investigatinginterventional care for children with the disorder.

Among the most prevalent chronic health conditionsamong children, physicians are increasinglyidentifying ADHD in pediatric practice. Effective treatment for ADHD helps minimize theeffects of the disorder on academic achievement,delinquency, self-esteem; and relationships withfriends and family.

Dr. Guevara’s K award involves studying the effects of collaborative behavioral care — the sharedmanagement of care for children between families,primary care providers, schools and mental healthspecialists. The award supports research on thecollaborative care among primary care providers andthe impact on children with ADHD. Dr. Guevara’sproject will also develop and pilot a collaborative careintervention with ADHD that will provide newinformation and interventions for patients.


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ADHD in Pediatric Practice

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Immunologist Jordan Orange, M.D., Ph.D., is invested in learning more about natural killer (NK)cells, white blood cells that help the body defendagainst disease by detecting and destroying tumor cellsand protecting against microbial pathogens. Patientswho have a decreased number of NK cells or whoseNK cells do not function properly are more susceptible to cancer and a variety of infectious diseases. Some researchers believe that enhancing NKcell function can improve the body’s destruction oftumor cells and may improve the body’s defenseagainst viral disease.

Dr. Orange’s K award allows him to investigate theprocesses that regulate the cytoskeleton, the internalframework that plays a critical role in cellular function. The award supports research on the receptors and signaling molecules involved in the activation and inhibition of cellular function as well asthe cell’s cytoskeleton. A better understanding of NKcells may help physicians prevent tumor growth andinfectious disease in patients.

In addition to receiving a K award from the NIH, Dr. Orange was honored by the American Academy of Allergy, Asthma and Immunology, which chose him as the recipient of the 2005 ERT FacultyDevelopment Award. The award supports one facultymember each year who represents the specialty ofallergy and immunology and shows promise inresearch that will promote the specialty.

Endocrinologist Jake Kushner, M.D., focuses hisresearch effort on gaining a better understanding ofislet cell growth that may reveal new treatmentapproaches or a cure for diabetes, a significant healthproblem for many Americans. Insufficient insulinsecretion affects patients with both type I and type IIdiabetes, but little is understood about the growth ofislet cells, the hormone-producing cells of thepancreas.

With the financial support of a K award, Dr. Kushnerhas been able to hone his cell biology and physiologytechniques as he studies the growth of beta cells andthe signals that trigger activity in these cells.

Dr. Kushner is also the recipient of the prestigiousBasil O’Connor Award from the March of Dimes forhis research on type II and gestational diabetes, whichare highly associated with serious birth defects. Theaward provides funding to young scientists beginningindependent research careers that may provide insightinto preventing birth defects and infant mortality.

Immunity

Diabetes

1999Dr. Beverly Emanuel’s efforts contribute to the complete sequencing of chromosome 22,making it the first human chromosome to befully sequenced. Defects in genes onchromosome 22 are implicated in certainleukemias and other pediatric tumors, mentalretardation, numerous birth defects and the22q11 deletion syndrome.


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Asthma, the most common chronic illness ofchildhood, is at the center of research conducted by emergency physician Joseph Zorc, M.D.Dr. Zorc is devoted to improving the long-termcontrol of asthma for children seen in the EmergencyDepartment. Many inner-city children do notreceive recommended treatments that doctors knoware effective for asthma, which is especially prevalent in metropolitan areas. As a result, many inner-citychildren receive much of their asthma care inemergency departments and never receive long-termpreventative care.

Dr. Zorc’s K award supports his investigation into the impact of an informational video about the benefits of preventive asthma treatment onfollow-up visits to primary care providers and long-term use of asthma medication. Designed forparents of inner-city children who receive asthmatherapy in the emergency department, the videoprovides valuable information about the benefits of follow-up care and addresses misconceptionsabout asthma.

Asthma

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Andrea Kelly, M.D., Division of Endocrinology,“Pediatric obstructive sleep apnea and metabolicsyndrome.”

Ron Keren, M.D., M.P.H., Division of GeneralPediatrics, “Predicting severe neonatalhyperbilirubinemia.”

Jake Kushner, M.D., Division of Endocrinology,“Cyclin D2 regulation of islet growth.”

Richard Levy, M.D., Department ofAnesthesiology and Critical Care Medicine,“Cytochrome oxidase inhibition in septic heart.”

Daniel Licht, M.D., Division of Neurology,“Cerebrovascular physiology of infants withCHD.”

Bradley Marino, M.D., Department ofAnesthesiology and Critical Care Medicine,“Testing the Pediatric Cardiac Quality of Lifeinventory.”

Kathryn Maschhoff, M.D., Division ofNeonatology, “The role of Sox11 in cardiacdevelopment.”

Thornton Mason, M.D., Ph.D., Division ofNeurology, “Periodic limb movements in Williams syndrome.”

Randolph Matthews, M.D., Ph.D., Division ofGastroenterology, Hepatology and Nutrition,“Genetic analysis of zebrafish biliary mutants.”

Yael Mosse, M.D., Division of Oncology,“Genomics of human neuroblastoma.”

Rhonda Boyd, Ph.D., Department of Psychology,“Children of depressed mothers; culture andprevention.”

Valerie Brown, M.D., Division of Oncology,“Role of mTOR inhibitors and IL7 in lymphoidmalignancies.”

Jon Burnham, M.D., Division of Rheumatology,“The functional muscle-bone unit in JRA.”

Josephine Elia, M.D., Department of Psychiatry,“Genetics of ADHD.”

Ricardo Eiraldi, Ph.D., Department ofPsychology, “Understanding ADHD in low-income Latino children.”

Joel Fein, M.D., Division of EmergencyMedicine, “Emergency Department protocol foradolescent suicide.”

Cherie Foster, M.D., Division of Neonatology,“Mechanotransduction in alveolar celldevelopment.”

Joshua Friedman, M.D., Ph.D., Division ofGastroenterology, Hepatology and Nutrition,“Transcriptional control of liver development.”

Adda Grimberg, M.D., Division ofEndocrinology, “Role of IGFBP-3 in mediatingp53-induced apoptosis.”

James Guevara, M.D., M.P.H., Division ofGeneral Pediatrics, “Collaborative care approachfor children with ADHD.”

Fraz Ismat, M.D., Division of Cardiology,“Neurofibromin, ras & NFAT in cardiovasculardevelopment.”

The Hospital has 38 active individual K awards with laboratory and clinical research projects. The recipients and their projects are:


Jordan Orange, M.D., Ph.D., Division of Allergyand Immunology, “Regulation of cytoskeletalactivation of NK cells.”

Susmita Pati, M.D., M.P.H., Division of GeneralPediatrics, “Health care access: maternal child andpolicy factors.”

Brenda Porter, M.D., Ph.D., Division ofNeurology, “Neurogenesis in pediatric temporallobe epilepsy.”

David Rubin, M.D., Division of GeneralPediatrics, “Health and foster care placementstability.”

Sulagna Saitta, M.D., Ph.D., Division of HumanGenetics and Molecular Biology, “Molecularmechanisms of cardiac outflow tractdevelopment.”

Michael Sebert, M.D., Division of InfectiousDiseases, “Molecular mechanisms of pnemococcalcolonization.”

Suresh Shelat, M.D., Department of Pathologyand Laboratory Medicine, “Immunobiology ofheparin-induced thrombocytopenia.”

Nicolas Stettler, M.D., M.S.C.E., Division ofGastroenterology, Hepatology and Nutrition,Mentored patient-oriented research careerdevelopment award, “Energy balance in childrenwith Down syndrome.”

Jason Stoller, M.D., Division of Neonatology,Pediatric Physician Scientist Program Award,“Characterization of the role of Tbx1 inDiGeorge/Velocardiofacial syndrome andpotential interactions with Nkx proteins.”

Rita Valentino, Ph.D., Division ofGastroenterology, Hepatology and Nutrition,“Biogenic amine system, CRF and stress.”

Mei-Lun Wang, M.D., Division ofGastroenterology, Hepatology and Nutrition,“Immune modulation of intestinal goblet cellresponses.”

Theoklis Zaoutis, M.D., Division of InfectiousDiseases, “Risk factors and outcomes ofcandidemia in children.”

Huayan Zhang, M.D., Division of Neonatology,Physician Scientist development Award,“Hyaluronan receptors and alveolization.”

Joseph Zorc, M.D., Division of EmergencyMedicine, “Improving follow-up after anemergency visit for asthma.”

Athena Zuppa, M.D., Department ofAnesthesiology and Critical Care Medicine,“Improving drug development for the critically illchild.”

In addition, Children’s Hospital holds two institutional K awards. One, to Physician-in-Chief Alan Cohen, M.D., provides funding for the Hospital’s Pediatric Scholars Program. The other, to Charles Stanley, M.D., chief, Division of Endocrinology, providescareer development funding in the area of diabetes research.

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1999Based on Dr. Katherine High’s groundbreakingstudies on AAV-mediated gene transfer forhemophilia, Dr. Catherine Manno and Dr.Alan Flake perform the first human genetransfer studies for hemophilia B using anAAV vector expressing Factor IX in peoplewith hemophilia.

A fluorescent image of chromosomes from a person with “balanced translocation” that causes Emanuel Syndrome.

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Awards/Recognition

The greatest reward for Children’s Hospital investigators comes in knowing thattheir work — whether in the laboratory, in clinic or in an educational setting —may ultimately improve the health of children throughout the world.

The journey toward that goal may be marked by internal and external honorsfor Children’s Hospital investigators. While all such honors are a testament

to the investigators’ various achievements, they are too numerous to list.The following are highlights of some of the more prestigious honors

and awards bestowed on Children’s Hospital investigatorsduring the fiscal year 2005.


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Genetic Condition Named After Hospital Investigator

Children born with a condition previously referred toas Supernumerary der(22) syndrome (or partialtrisomy 11/22) have an extra chromosome. The extraone is made up of parts of chromosome 22 and a partof chromosome 11, carried by one of the parents as a“balanced translocation,” a condition in which aperson has the right number of chromosomes but twopieces of chromosomes have switched places.

Because of the technical nature and confusionsurrounding the various names for the syndrome, andin recognition of her groundbreaking research, parentsof affected children petitioned to have the conditionrenamed Emanuel Syndrome after Beverly Emanuel,Ph.D., chief of the Division of Human Genetics andMolecular Biology at Children’s Hospital.

Emanuel Syndrome now has an entry in the OnlineMendelian Inheritance in Man, a database of humangenes and genetic disorders developed by the NationalCenter for Biotechnology Information.

The extra chromosome in a child with EmanuelSyndrome can lead to mental, medical and physicalproblems, including cleft palate, heart defects, earanomalies, genital anomalies in males, low muscletone and varying levels of mental deficiency.

Dr. Emanuel and her colleagues have studied the risksof recurrence for Emanuel Syndrome in translocationcarriers.

They also identified the points on chromosomes 22and 11 that lead to the genetic rearrangementinherent in Emanuel syndrome and found anunexpectedly high rate of translocations in the sperm of males not affected with the condition. Therenaming of Supernumerary der(22) syndrome istestament to Dr. Emanuel’s continued achievementsand productivity in genetic research. To further propelher renowned efforts in this area, Dr. Emanuel hasembarked on an extended sabbatical to bring newideas and methods to the next phase of her renownedresearch program on chromosome 22 deletionsyndrome. It is her first sabbatical in more than 25years of service to the Hospital.

Dr. Emanuel anticipates that the skills she hones andinformation she gathers while on leave will aid her indeveloping a sequence-based and microarray platformto detect chromosome 22 abnormalities.

During her sabbatical, Dr. Emanuel will attend arefresher course in molecular cytogentics and DNAmicroarray technology; work with a Holland-basedcompany to develop a better testing kit to detectchromosome 22 abnormalities; and conduct extendedwork with a Yale University collaborator to learn thetricks of imaging chromosomes undergoing meiosis toinvestigate why chromosome 22 behaves poorlyduring meiosis, causing abnormalities.

Emanuel Syndrome

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The cardiology project is an ideal pilot for a numberof reasons. First, the recent Human Genome Projectopened a new frontier in biology and medicine to linkspecific genetic information (genomics) with clinicallyobservable disease descriptions (phenomics). Inaddition, the Hospital’s Cardiac Center has conductedpioneering research over the last decade on theinfluence of genetics on congenital heart disease, andcontributed significantly to the Hospital’s designationas a Specialized Center of Clinically OrientedResearch (SCCOR) in Pediatric Heart Developmentand Disease.

The Institute’s SCCOR program is designed to speedthe process by which advances in basic scientificknowledge are translated into innovative treatmentsfor patients. Drawing on talents of multidisciplinaryteams is an important feature of the SCCOR program; the Children’s Hospital team includescardiologists, cardiac surgeons and geneticists.

The information generated will help physicians andinvestigators better understand diseases and,ultimately, lead to improved diagnosis, treatment andprevention strategies.

Prestigious Pew AwardSupports EmergingBioinformatics Field

The body of data about human disease isgrowing so rapidly in size and complexity thatbroad associations between research findingsand clinical applications are becoming moredifficult to establish. Investigators face thedaunting task of absorbing and applyinginformation from numerous medical journalsand laboratory-generated data. Just 10 yearsago the challenge was to generate sufficientdata for analysis; today the challenge is toanalyze the reams of data that new methods,instrumentation and experiments areproducing.

This issue becomes even more complicatedwhen the desired outcome is to connectresearch findings with patient information.Finding ways to apply biomedical informationis one of the nation’s top healthcare priorities.The emerging field of biomedical informaticsaims to create processes to integrate and usebiological and medical information to assistwith early diagnoses; increase preventivetreatment; produce new and more targetedtreatments; provide a more comprehensiveunderstanding of disease processes; and predictthe likelihood of disease in families.

Recognizing the importance of the field to thefuture of research, the Pew Charitable Trustsgranted Children’s Hospital a $1.3 million,four-year award to launch a pilot program inbioinformatics. The program, led by PeterWhite, Ph.D., focuses on the clinical genomicsof pediatric cardiology.


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Top of the page: Pete White, Ph.D., with researchassistant Haijun Oiu. 1999

The Clinical Trials Office (CTO) is establishedto facilitate clinical research studies conductedat Children’s Hospital.

This team of clinicians and researchers recentlydemonstrated that many children with specific typesof congenital heart disease have a chromosome 22q11deletion. In a pilot study, the investigators evaluatedthe operative course of patients with truncusarteriosus. Some of the patients carried a 22q11deletion and some did not. The preliminary resultsindicate that the operative course of those with thedeletion was notable for a longer period of ventilatorysupport, intensive care unit and hospital stays thanthose without the deletion.

The Pew-supported Clinical Genomics of PediatricCardiology project will use the Cardiac Center’swealth of genomic and phenomic data to develop the systems and tools needed to create an integratedknowledge base. Clinicians and investigators will then be able to browse, query and analyze data fromanywhere in the Hospital’s healthcare network — thelaboratory, an outpatient clinic or a patient’s bedside.

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Leading the Way in an Emerging Field

Katherine High, M.D., a leading hematologyresearcher at Children’s Hospital and a HowardHughes Medical Institute investigator, served as the president of the American Society of GeneTherapy (ASGT).

The ASGT is the largest medical professionalorganization representing researchers and scientistsdedicated to discovering new gene therapies, anapproach focusing on treating disease by deliveringtherapeutic genes directly into a patient’s cells.

Dr. High began serving her yearlong term on June 2, 2004, at ASGT’s annual meeting inMinneapolis. During the meeting, Dr. High alsoreported the preliminary results of a detailed studyof immune responses in a clinical study of a genetherapy approach for treating hemophilia B.

1999Children’s Hospital becomes one of 13academic sites designed by the NIH as aPediatric Pharmacology Research Unit(PPRU). PPRUs are established to conductstudies of drug disposition and action inpediatric patients, and address the lack ofpharmacological information about drugs used in children.


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Stokes Institute awarded one of the project grants toJanis Burkhardt, Ph.D., Department of Pathologyand Laboratory Medicine, who is investigating howphosphorylation, or adding a phosphate and oxygengroup to a protein, affects the protein HS1 — aprotein linked to immunodeficiency andautoimmunity — and the structure and function of a closely related protein called cortactin. Theresearchers are focusing on how this regulation relates to the role of these proteins in cancer andautoimmune disease. In the long run, understandinghow HS1 and cortactin are regulated may allowinvestigators to use them as drug targets for thetreatment of autoimmune disease and cancer.

PA

Aw

Aw

PA

Normal lung

Congenital diaphragmatic hernia with pulmonary hypertension

Abbrev. - PA: pulmonary artery, Aw: Airway

YFP control YFP-HS1-WT YFPHS1-2YF

YFP

F-actin

Merge

Marcus Davey, Ph.D., Department of Surgery,received a new investigator grant for his project ontreatment strategies of pulmonary hypertension insevere lung hypoplasia. The project examines theeffects of different drugs on lung blood flow incongenital diaphragmatic hernia, a devastating diseasein which the diaphragm fails to form completely andallows abdominal organs to invade the chest cavityand compress the developing lungs. Dr. Davey hopesthe research will identify optimal drug therapies forpatients with CDH.

Internal Awards

Through its internal awards programs, the StokesInstitute provides support and recognition toinvestigators with innovative research ideas and tonew investigators embarking on their research careers.

Among these internal awards are the Ethel BrownFoerderer Fund for Excellence and the Florence R.C.Murray Awards, each of which provide one year ofsupport for basic or clinical research projects.

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2001Dr. Beverly Lange and associates devise astrategy that has about a 70 percent salvagerate for recurring acute lymphoblasticleukemia. This has been successful in gettingchildren into remission until another therapy(e.g., bone marrow transplant) is available.

Robert Levy, M.D., Division of Cardiology, receivedthe Foerderer-Murray Innovation Award for hisproject on cartilage prepared with triglycidyl amine.Dr. Levy hopes to create an artificial cartilageimplant to treat knee injuries in children and adults.The key to this strategy involves a novel reagentcalled TGA, which Dr. Levy and investigators in hislaboratory discovered and patented

Dr. Levy and his colleagues originally created TGAfor preparing artificial heart valves and are stillinvestigating the use of the reagent for that purpose.If beneficial for preparing artificial knee cartilage, thechemical compound may aid in the development ofimplants that will restore function and last longerthan the therapies currently used to treat kneeinjuries.

Knee cartilage replacement using triglycidylamine (TGA)-Treated Prosthesis


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2001Dr. Scott Adzick, in collaboration with Drs.Charles Stanley and Robin Kaye, performs apartial pancreatectomy, a procedure to curenewborns of focal congenital hyperinsulinismwithout causing diabetes.

Project GrantsTerri Finkel, M.D., Ph.D., Division of Rheumatology, “Lentiviral therapy for acquiredand congenital immunodeficiency disease.”

Wenzhe Ho, M.D., Division of Allergy and Immunology, “Establishment of infectious hepatitis C virus cell model.”

Michael Hogarty, M.D., Division of Oncology, “Global tumor proteomics-applied neuroblastoma.”

Weidong Xiao, Ph.D., Division of Hematology, “Gene therapy of hemophiliausing split Factor VIII gene.”

X. Long Zheng, M.D., Ph.D., Department of Pathology, “ADAMTS13 protease and liver fibrosis.”

New Investigator AwardsCraig Bassing, Ph.D., Department of Pathology, “The consequences of combinedH2AX and ATM inactivation.”

Ilia Fishbein, M.D., Ph.D., Division of Cardiology, “Chemically modified adenoviralvectors to bypass receptor-mediated cell uptakefor cardiovascular gene therapy.”

Stefania Gallucci, M.D., Division of Rheumatology, “Function of CD40 in lupusdendritic cells.”

John Germiller, M.D., Ph.D., Department ofSurgery, “Analyzing the neurotrophic activity ofthe early embryonic inner ear.”

Adda Grimberg, M.D., Division of Endocrinology, “Factors influencing shortstature referrals.”

2005 Foerderer-Murray Awardees

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Celebrating Postdoctoral Fellows and Students

As part of its continuous support for training young scientists, Children’s Hospital held its 15th annual Children’s Hospital/Stokes Institute Fellows’ Research Poster Day in February. During the daylong event, graduate students and postdoctoral and clinical fellows showcased their basic, translational and clinical research.

Poster Day attendees review fellows’ presentations.

More than 130 abstracts were presented during theevent, which was organized by William Fox, M.D.,Division of Neonatology, Helen Korchak, Ph.D.,Division of Allergy and Immunology, and RogerWood, director of Research Operations.

The Stokes Institute recognized 19 posters asparticularly outstanding. These posters received anaward in one of nine categories — clinical,translational and basic research by clinical staff,postdoctoral fellows and predoctoral candidates.

These awards were made possible thanks to anendowment created by Mrs. Mary Hummeler, wife ofthe late Dr. Klaus Hummeler, the first director of theStokes Institute.


Fellows’ Poster Day Awardees

The awardees and their poster topics were:

Obinna Adibe, M.D., Department of Surgery,“Retrospective comparison of outcomes followingopen versus laproscopic pyloromyotomy.”

Majed Aljamali, Ph.D., Division of Hematology,“Hemostatic effects of long-term expression ofactivated murine FVII in normal and hemophilicmice.”

Pinaki Banerjee, Ph.D., Division of Allergy andImmunology, “Cdc42 interacting protein 4 is apotential link between actin and microtubules atthe natural killer cell immunological synapse.”

Elsa Bianchini, Ph.D., Division of Hematology,“Ratcheting between two distinct conformationsof substrate drives the sequential cleavage ofprothrombin by prothrombinase.”

Angela Breidenstine, Ph.D., Department ofPsychology, “Protective factors in the lives ofchildren experiencing the risks of poverty andmaternal depression.”

Jin-Wen Chen, Ph.D., Division of InfectiousDiseases, “Normal heart development requirescardiomyocyte-specific expression ofcoxsackievirus and adenovirus receptor.”

Michael Chorny, Ph.D., Division of Cardiology,“Injectable adenovirus-polylactide nanoparticlecomposites for efficient gene transfer to smoothmuscle cells (A10) and cardiomyocytes (HL-1).”

Julie Davis, M.D., Division of Cardiology,“Longitudinal assessment of cardiovascularexercise performance after pediatric hearttransplantation.”

Daniel Delaney, M.S., Division of Urology,“Molecular analysis of the HOX!9 gene in cryptorchidism.”

Marco Gonzalez, Ph.D., Division of ChildDevelopment and Rehabilitation Medicine,“Regulation of the neuronal glutamatetransporter, Eaac1/Eaat3, by caveolae/lipid rafts.”

Lisa Meltzer, Ph.D., Department of Psychology,“Sleep and functioning in caregivers of ventilator-dependent children.”

Karna Murthy, M.D., Division of Neonatology,“Cathepsin H (CTSH) and Napsin A (NapA)expression during human lung development.”

Emily Rowell, B.A., Department of Pathologyand Laboratory Medicine, “Opposing roles for thecyclin-depenent kinase inhibitors p18ink4c andp27kip1 in allograft tolerance induced bycostimulatory blockade.”

Diana Shellmer, Ph.D., Department ofPsychology, “Pediatric HIV: effects of adjustment,social support, and disclosure on cognitive andpsychosocial functioning.”

Amanda Shillingford, M.D., Division ofCardiology, “Inattention and hyperactivity arecommon 6-11 years after neonatal cardiacsurgery.”

Jason Stoller, M.D., Division of Neonatology,“Mechanisms of DiGeorge syndrome:characterization of human TBX1 mutations.”

David Teachey, M.D., Divisions of Hematologyand Oncology, “Unmasking Evans syndrome: Tcell phenotype and apoptotic response revealautoimmune lymphoproliferative syndrome(ALPS).”

Zhi Wang, Ph.D., Division of Neonatology,“Zinc protophophyrin IX inhibits cellproliferation via suppression of cyclin D1 proteinsynthesis in hepatoma cells.”

Mingce Zhang, Ph.D., Division of Rheumatology, “C-maf cooperates with NFAT1 to augment HIV-1 transcription in T-helper-2 CD4 T cells.”

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Addressing the Needs of Faculty, Trainees and Staff

Whether working in the laboratory or clinic or crunching data in an office, conductingresearch is a complicated matter, extending far beyond generating a research question,developing a plan to answer that question or mastering a specific technique.

For example, a project like targeting genetherapy to the fetus to treat genetic disordersinvolves complex regulatory, legal and ethicalissues surrounding the conduct of research.Those issues include laboratory safety,confidentiality of specimens and data, thesafety of human subjects, publication practices,collaboration, authorship, mentoring andintellectual property.

Success, therefore, means not only gettinginteresting research results throughexperimental dexterity, but also managinga research group, mentoring, maintainingrelationships with colleagues, andunderstanding and abiding by the rules forhandling data and publishing study results.

Few young investigators receive training in these types of “survival skills,” yet failure to understand and comply with government requirements and theexpectations of the scientific community canultimately jeopardize an investigator’s career as well as an institution’s entire research program. Highlytrained, responsible investigators and research staff are imperative to the long-term success of individualinvestigators and the research institution as a whole.

Rather than pursuing information or training on an individual basis, investigators and clinical andpostdoctoral fellows can now participate in acomprehensive program aimed at fortifying theirknowledge and understanding of the ethical issuesaccompanying research.


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Page 74 Jodi Leckrone, M.Ed., assistant director, Research Education Page 75 Research Education Director Wendy Williams, Ph.D.

2002The first tandem transplantation of peripheralstem cells performed in a pediatric oncologycenter.

The Responsible Conduct of Research (RCR) trainingprogram teaches and promotes ethical researchpractices based on regulatory standards. A programfor training grant-supported trainees and career awardrecipients, the RCR program fulfills an NIH trainingrequirement and is offered to all postdoctoral andmedical fellows at Children’s Hospital.

The RCR program, administered by the Departmentof Research Education, aims to prevent outrightresearch misconduct, like fabrication of data andplagiarism, as well as questionable behaviors — likethe refusal to collaborate — and authorship issues.The Hospital’s RCR program, encompassing 10 areasof instruction, is tailored to the Stokes Institute’senvironment and pediatric research.

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Initiative Takes Aim at Study-Coordinator Certification

Conducting clinical research is a complex endeavorthat involves more than recruiting subjects oradministering a questionnaire or experimentaltreatment. After principal investigators, studycoordinators bear the brunt of responsibility for theproper handling of projects that involve humansubjects and may be regulated by the FDA. Studycoordinators’ duties include project initiation,administration responsibilities and budgeting,among others.

However, despite the wide range of responsibilities,formal training for clinical study coordinators hasbeen historically limited to that received on the jobor through one-on-one mentoring. Although thefederal government does not require training andcertification, many institutions — includingChildren’s Hospital — are implementing formaltraining programs for employees working in clinicalresearch.

The Hospital’s Research Compliance OversightCommittee instituted a policy requiring training forall clinical research staff. As a result, the Hospitaldeveloped a training and certification programthrough the Department of Research Education.

Those working on clinical studies now complete theseven-module Clinical Research CoordinatorCertification Program, which addresses theregulatory and ethical issues governing researchinvolving human subjects; how to prepare for anaudit or monitor a visit; how to initiate and close astudy; how to budget a study and how to addressregulatory issues that may arise during the course ofa study.

The Web-based, interactive program coversinstitutional policies and procedures and federalregulations. More specifically, the modules —developed by a team of leading study coordinatorsin conjunction with Research Education, facultyand other staff — address topics such as pre-studyactivities, clinical and administrative responsibility,and working with the Hospital’s InstitutionalReview Board.

Advanced training modules address InvestigationalNew Drugs and Investigational Device Exemptions,with future modules covering topics such as researchethics and budget development.

Completion of the program ensures that studycoordinators successfully manage the many facets ofclinical research while protecting the Hospital’s mostcherished resource — its patients and their families.


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2002 Dr. Katherine High is named the Hospital’sfirst Howard Hughes Medical InstituteInvestigator based on her leadership of researchin the area of gene therapy for hemophilia.

Stokes is home to a large number of trainees, amongthem, undergraduates conducting independentresearch studies or graduate students conductingthesis research with Hospital investigators. Othersare clinical fellows who are receiving training inresearch as part of their subspecialty programs andare the physician-scientists of the future.

Another important group of trainees is theHospital’s postdoctoral fellows. These trainees, whohave completed their Ph.D.s, will spend as long asfive years conducting mentored research withinvestigators at the Stokes Institute before takingpermanent positions as faculty or researchers atChildren’s Hospital or elsewhere. Postdoctoralfellows do not apply for admission to a program;rather, they apply directly to investigators

conducting research or using techniques ofparticular interest to them. This puts postdoctoralfellows in a unique position that requires specializedattention.

The particular needs of the Hospital’s expansivepostdoctoral fellow community are addressedthrough the Office of Postdoctoral Affairs. Here,mentors receive specialized support for theHospital’s more than 100 postdoctoral fellows, mostof whom are from outside the U.S. and encounterimmigration-related issues and other hurdlesbecause of their international status.

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Enhancing Collegiality, Building a Community

With the rapid growth of the Stokes Institute, flourishing research programs and the continuous recruitment of new investigators, it can be difficult for researchersto stay informed about the work of their colleagues. To remedy this situation, Stokes provides special events to give researchers the opportunity to interact andlearn about each other’s research.

The annual Stokes Scientific Symposium highlightsthe breadth of the research programs at the StokesInstitute and continues to strengthen the Institute’ssense of community. The daylong, off-campus eventincluded 13 presentations from investigators in basic,translational and clinical research, and featured akeynote address by Nobel Prize winner MichaelBrown, M.D. In cooperation with Joseph L.Goldstein, M.D., Dr. Brown discovered the low-density lipoprotein (LDL) receptor that controls thelevel of cholesterol in blood and cells.

The presentations were chosen to stimulate dialogueamong investigators. The event also included extendedbreaks, a group luncheon and a reception toencourage investigators to learn about one another’sresearch and to open the door to greater cross-collaboration.

In addition to the scientific presentations, the StokesCore Facilities provided displays and presentations topromote their services, new technologies andcapabilities available to support and enhance theresearch efforts of Stokes investigators.

Nobel Prize winner Michael Brown, M.D., deliversthe keynote address at the 2005 Scientific Symposium.

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Participants discuss clinical research during theHospital’s first Clinical Research Week.

Celebrating Clinical Research

Thanks to the efforts of dedicated volunteers, Clinical Research Week in 2005 recognizedthe efforts of those involved in clinical research and their many achievements. The weekserved as an opportunity for all members of the clinical research community — studycoordinators, physicians, nurses and psychologists — to share their research and itspotential impact on clinical care.

Richard Behrman, M.D., chair of the Institute ofMedicine’s Committee on Clinical Research InvolvingChildren, gave the week’s keynote address, titled “TheThreat to Clinical Research from the Cult ofIrrationality.”

Events during the week were designed to encourageclinical research, promote careers in the field, andeducate the community on topics such as privacyregulations, the essentials to successfully launching aclinical research study, and nursing research. Posterpresentations highlighted the results of clinicalinterventions, changes to standard of care based onresearch, and descriptions or evaluations of researchprograms.

The success of both the Stokes Scientific Symposiumand the Clinical Research Week ensures that theStokes Institute will continue to hold such events toenhance the experience of its investigators and toprovide a sense of community among its researchers.


Administrative Enhancements

Changes to Support Our Growing Research Enterprise

The Hospital embarked on a new initiative aimed at streamlining procedures forresearch subjects participating in research studies.


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The Clinical Research Processes and Systems Improvement Project aims to ensure all clinicalresearch business processes comply with “bestpractices,” to improve the experiences ofprincipal investigators working in clinicalresearch, and to enhance the quality of serviceto research subjects and their families.

Improvements made under this pilot projectcenter on several clinical trial elements: correctbudget preparation, proper registration ofsubjects in Hospital systems, appropriateidentification of procedures as “research” ratherthan standard of care, and billing of proceduresand account reconciliation.

When fully implemented, streamlining andcoordinating clinical research business willenable the responsibility for administrativeaspects of studies to be placed on theappropriate Hospital departments. This, in turn, will enhance the experience of patientsand allow investigators to conduct researchrather than manage administrative steps.

2004Dr. Ian Krantz leads a team that identifies thegene that causes Cornelia de Lange syndrome,(CdLs) which leads to a genetic test. CdLssymptoms include mental retardation, growthfailure, hearing loss, and physical defectsaffecting the limbs, face, heart, intestines andother structures.


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Above: Judith Argon, vice presidentof Research Administration.

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Above: Director of Research Finance Steve Wiley.Page 83 (left to right): Director of Sponsored Projects

Sara Dubberly and Mary Tomlinson, vice president ofResearch Finance and Sponsored Projects.

Administrative Changes Lead to Heightened Services

To enhance efficiency and customer service forinvestigators and research staff, the Stokes Instituteconsolidated all sponsored projects under a singlepoint of leadership and created a newadministrative position to manage these tasks.

As a result, Mary Tomlinson, who distinguishedherself as the director of Research Finance, wasnamed as the first vice president of Research Finance and Sponsored Projects.

In her new position, Mary is responsible for pre- and post-award grant management functions,electronic research administration and businessmanagement functions related to researchaccounts.

Stokes also united Research Services, including the offices of Grants Preparation and GrantsManagement, and Research Finance, which includes the Research Business Office, into a single administrative unit.

Steven Wiley, who served as the manager forResearch Accounting for 11 years, now serves as the director of Research Finance. Sara Dubberly,who previously served as the manager of theResearch Business Office, serves as director ofSponsored Programs.

2005 Supernumerary der(22) syndrome (or PartialTrisomy 11/22) — a genetic conditioncharacterized by an extra chromosome made up of parts of chromosome 22 and a part ofchromosome 11 — is renamed EmanuelSyndrome in honor of Beverly Emanuel,Ph.D., chief, Division of Human Genetics andMolecular Biology, who spearheaded researchefforts into the syndrome.


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Financial/Award Information

For the FY Ended June 30, 2005

As a world leader in pediatric research, Children’s Hospital is dedicated todeliberate and controlled growth, designed to strategically expand the Institute’scommitment to pioneering research.

FY 2005 is an excellent example of this impressive growth. Grant awards from theNIH exceeded the growth of the NIH extramural budget, the number of researchstaff increased by 50 percent and research space continues to expand to meet thegrowing needs of researchers.

This growth reflects the Institute’s past successes and fuels the pioneering spiritthat will help Children’s Hospital continue to be a world leader in pediatric

research.


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$0

$20

$40

$60

$80

$100

$120

Grant & Contract Expenditures*$

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ion

s)

2001 2002 2003 2004 2005

*Total Costs (direct and indirect)

2005Dr. Vivian Cheung identifies genomic regionsthat contain the transcriptional regulators forabout 1,000 genes. These results provide abetter understanding of transcriptionalregulation in human cells and may beapplicable for discovering the genetic basis ofother complex human traits and diseases.

Financial /Award Information

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0

200

400

600

800

1000

1200

Nu

mb

er o

f R

esea

rch

Sta

ff

2001 2002 2003 2004 2005

Number of Research Staff

Dedicated Research Space (net sq. ft.)

Pre ARC 1996 1999 2001 2002 2003 2004 2005

0

100

200

300

400

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600

Th

ou

san

ds

Research Lab Space

Leased Lab Space

Animal Facility

Clinical Research Space

Stokes Administration

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$1,000,000 or more Anonymous (1)State Farm Insurance Companies

$100,000 — $999,999Anonymous (2)The W. W. Smith Charitable TrustThe Pew Charitable TrustsFriends of Trisomy 21 CenterMuscular Dystrophy Association, Inc.The Philadelphia FoundationCraig-Dalsimer FundAlex’s Lemonade Stand Fund of

The Philadelphia FoundationGenzyme CorporationJuvenile Diabetes Research FoundationFoundation for AnesthesiaAmerican Society of Clinical OncologyAmerican Heart AssociationAmylotrophic Lateral Sclerosis AssociationEpilepsy FoundationNational Multiple Sclerosis SocietyMr. and Mrs. Robert J. Edmunds

$25,000 — $99,999American Cancer Society, Inc.Child Neurology FoundationEastern States HyundaiPhiladelphia Insurance CompaniesHeineman FoundationThe Valerie FundMadelyn Bucksbaum Adamson and Allen AdamsonAmerican Diabetes AssociationAmerican Epilepsy SocietyAmerican Liver FoundationLola Ervien Douglass Fund of

The Philadelphia Foundation Louis Callmann GoldschmidtThe Childhood Brain Tumor FoundationPhRMA FoundationAmerican College of SurgeonsNational Sleep FoundationComprehensive Consulting SolutionsCooley’s Anemia FoundationFirst Hospital FoundationHope Street Kids

Mr. and Mrs. John C. HaasCaesars Atlantic CityCaitlin Robb FoundationCitizens United for Reseach in EpilepsyDaniel Patrick Sullivan Foundation at Fidelity

Charitable Gift FundMr. Duane D. DeanerF. and B. Berman Family Foundation Inc.Goldman Philanthropic PartnershipsR & B Inc.The Schulman Foundation

$10,000 — $24,999Lincoln Financial GroupKayla’s Hope for KidsNational Neurofibromatosis Foundation Inc.Friedreich’s Ataxia Research AllianceWawa Inc.Eagles Fly for Leukemia Inc.Safe Kids Coalition of Southeastern PAThe Evan T.J. Dunbar Neuro-Blastoma FoundationUniversity of PennsylvaniaMerck Partnership for Giving CampaignAlexander Graham Bell AssociationCapita FoundationGoerlich Family Foundation Inc.L.I. Maternal Fetal Medicine P.C.National Organization for

Hearing Research FoundationCornelia de Lange Syndrome Foundation Inc.Philadelphia Chapter of Credit UnionsThe William Penn FoundationUnited Way of Kitsap CountyTo Our Children’s Future With HealthDavis Cup Golf TournamentUnited Way of Tri-State Inc.Indian Valley Middle SchoolA.L.M. Lubrications Inc.Advanta FoundationAmerican Academy of OtolaryngologyDr. and Mrs. Toshio AsakuraCommerce BankMr. and Mrs. Harry G. Hayman IIIIrwin Homer Breslow, M.D.

Nursing Scholarship FundMs. Judy JamisonPediatric Endocrinology Nursing SocietyThe Starner Spitalny Memorial

Gifts and Awards for Research from Private Sources


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$5,000 — $9,999H & R Auto Radio Service, Inc.Ballard Spahr Andrews & Ingersoll, LLPNational Hemophilia FoundationPrudential Fox & Roach RealtorsFriends of VinnieJulieDance Inc.Orthopaedic Research and Education FoundationPhoebe W. Haas Charitable Trust “A”Ms. Kathy BuckwalterOrder of the Golden Chain Charity FoundationBuild A Bear Workshop Foundation, Inc.Mr. and Mrs. Kevin D. ScarboroughBayer HealthcareMr. and Mrs. M. T. PiotrowiczBlank Rome Comisky & McCaule, LLPAmerican Society for ParenteralMr. and Mrs. Daniel AustinMr. and Mrs. Louis BucksbaumMr. and Mrs. Dominic J. CarusoGreatworld Inc.Mr. and Mrs. Thomas J. HughesKristin & William Loomis FoundationMs. Carol LevittMarch of Dimes Philadelphia ChapterRosario’s RestaurantThe Harold Wetterberg FoundationWPVI-TVMs. Ellen C. Wolf and Mr. Richard A. Harris

$1,000 — $4,999Ms. Elaine BreslowUnited Way Miami-Dade IncChristine’s KidsKane Builder’s Inc.RBC Dain RauscherVentiv Health U.S. SalesPhiladelphia Main Line Alumnae ChapterMrs. Herbert SarvetnickMr. and Mrs. John M. StrotbeckCarlson Shared ServicesMr. and Mrs. William G. CraneD’Ignazio’s Towne HouseFormedic Communications Ltd.Health Resource Publishing CompanyPhiladelphia Coca Cola Bottling Co.Q.E.D. Communications Inc.

Sol Goldman Charitable TrustMr. and Mrs. Robert TallonTargetRx Inc.Mr. and Mrs. Thomas J. ConroySpringfield Township Hockey LeagueKanoski & AssociatesPublic Financial Management, Inc.Callan, Koster, Brady & Brennan, LLPDr. and Mrs. Timothy K. HartMr. and Mrs. Peter KorneffelPhiladelphia College Basketball Officals AssociationPretzel & Stouffer CharteredSubaru of America Foundation Inc.Atlantic City Hockey, LLCPenn’s Town PropertiesMr. and Mrs. John W. PollardKiss Cycles Honda Rider’s ClubDr. and Mrs. Joel GoldweinMr. and Mrs. Mark D. ArianGenentech Inc.Mr. Duncan A. HaasInterboro High SchoolMr. Edward D. OhlbaumPhillies CharitiesRadian Guaranty Inc.SHS North AmericaThe Craigmyle FoundationThe Ryan Foundation Inc.US Airways Pilots Union and FamiliesThe Philadelphia FlyersDance for the KidsMontgomery County Intermediate UnitThe Prudential Foundation Matching Gifts ProgramHamilton High School WestUnited Way of Camden CountyBessie Garber - Philadelphia Link 33Mr. Robert J. BlinkCross Atlantic Capital PartnerDr. Jeffrey A. Fine Associates, P.C.Embassy Suites Hotel and EmployeesFranklin Homeowners Assurance CompanyMerrill Lynch Pierce Fenner & Smith Inc.Orleans CorporationPepper Hamilton, LLPPremiere ConferencingRoss Family FundThe Coca-Cola Bottlers’ FoundationMr. and Mrs. William C. Davis

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$1,000 — $4,999Physicians Pharmaceuticals Inc.American Academy of PediatricsMr. and Mrs. Marc BartolomeiDelta Delta Delta Sorority, Psi ChapterMr. and Mrs. Paul K. BrantleyThe Baldwin School21 DownMr. and Mrs. David AltmanBJNB FoundationMs. Cathleen M. BanniganMs. Laura B. BarnessMr. and Mrs. F. Becattini Jr.Ms. Melissa BhatnagarMs. Kathryn I. BuckleyBurns Pontiac/GMCCallahan, McCune & WillisCarousel Toyota/Hyundai/SuzukiCastle DealershipsColonial Cadillac/SterlingColonial HyundaiDodge Chrysler CityFred Beans Ford/Lincoln/Mercury/IsuzuHyundai of SpringfieldHyundai of TurnersvilleMr. and Mrs. Ronald S. KierpaLadies Philoptochos SocietyLehigh Valley HondaLewis Brisbois BisgaardDr. and Mrs. Stuart LichtMr. and Mrs. Donald M. MaclayMr. and Mrs. James J. Maguire Jr.Mr. And Mrs. James J. Maguire Sr.Marshall, Conway & Wright, P.C.McCafferty Ford Sales Inc.Mr. and Mrs. Keith Morgan

Mr. and Mrs. Francis X. MullenMs. Christopher MulloyMr. and Mrs. Michael W. NeffNortheast Auto Outlet Inc.Mr. and Mrs. Jay OchrochPacifico HyundaiMr. and Mrs. J. G. Popper Jr.Porter Chevrolet/HyundaiQuality Mercury/Hyundai, Inc.Raymond James Charitable Endowment FundMr. and Mrs. Peter A. RohrMr. Carlo RondinaSaul & Eleanor Lerner Foundation Inc.Savage Hyundai Inc.Secrest, Wardle, Lynch, HamptonShaddox, Compere, WalravenMr. Henry D. SmithSport Hyundai/DodgeSusanna Delaurentis Charitable FoundationSussman HondaMr. and Mrs. Joseph TarditiThe Citizens National BankThe William J. & Dorothy K. O’Neill FoundationWilliam Guy Forbeck Research FoundationWilmington Trust of PennsylvaniaWinner Hyundai

Gifts and Awards for Research from Private Sources


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Joseph Stokes Jr. ResearchInstitute LeadershipPhilip R. Johnson Jr., M.D.Chief Scientific Officer andSenior Vice President, Director ofThe Joseph Stokes Jr. Research Institute

Virginia A. Stallings, M.D.Deputy Director, Clinical Research

Judith ArgonVice President, Research Administration

Mary TomlinsonVice President, Research Finance and Sponsored Projects

Joseph Stokes Jr. Research Institute Board CommitteeTristram C. Colket Jr., ChairN. Scott Adzick, M.D.Steven M. Altschuler, M.D.Richard M. Armstrong Jr. Robert Berkowitz, M.D.Aminta Hawkins Breaux, Ph.D.Richard R. CarrAlan Cohen, M.D.James DiganWilliam J. Greeley, M.D., M.B.A.Philip R. Johnson Jr., M.D.Richard I. Markowitz, M.D.R. Anderson PewPhillip S. Schein, M.D.Salem D. SchuchmanJames M. Steven, M.D.Frank E. Weise III

Research OperationsPhilip Johnson Jr., M.D., ChairPeter Adamson, M.D.N. Scott Adzick, M.D.Steven M. Altschuler, M.D.Judith ArgonRobert Berkowitz, M.D.Alan Cohen, M.D.Charles EnicksWilliam J. Greeley, M.D., M.B.A.Diego Jaramillo, M.D., M.P.H.Meg JonesGavin KerrVirginia Stallings, M.D.James M. Steven, M.D.Thomas J. Todorow, C.P.A., M.B.A.Mary TomlinsonBryan Wolf, M.D., Ph.D.

Research Affinity Group CouncilJudith ArgonYair Argon, Ph.D.Jeffrey Barrett, Ph.D.Louis Bell, M.D.Steven Douglas, M.D.Carolyn Felix, M.D.Terri Finkel, M.D., Ph.D.Alan Flake, M.D.Jeffrey Golden, M.D.Katherine High, M.D.Philip Johnson Jr., M.D.John Maris, M.D.Paul Offit, M.D.Mortimer Poncz, M.D.Michael Robinson, Ph.D.Jeffrey H. Silber, M.D., Ph.D.Rebecca Simmons, M.D.Nancy Spinner, Ph.D.Virginia Stallings, M.D.Mary TomlinsonFlaura Winston, M.D., Ph.D.Babette Zemel, Ph.D.

Who’s Who at Stokes in 2005


Institutional Review BoardCommittee AJeffrey Merrill, M.D., ChairJanine Beal, B.S.Lynn Bevan, CIPBetsy Bickert, Pharm.D. Nancy Bunin, M.D. Kim Davis, M.A.James Guevara, M.D., M.P.H.Brian Hanna, M.D., Ph.D. Richard Hodinka, Ph.D.Thomas Innes, J.D.Laureen Kotzer, Pharm.D.Stephen Leff, Ph.D.Jennifer Long, M.S, M.J.Roger Marsh, Ph.D.Oscar Mayer, M.D.Jerilynn Radcliffe, Ph.D.Ann O’Sullivan, Ph.D., F.A.A.N., C.R.N.P.George Reath Jr., Esq. Linda Rosenthal, R.Ph.Mark Schreiner, M.D.Chuck Scott, Ph.D.Jennifer Smith, M.D.Tyra Bryant-Stephens, M.D.Babette Zemel, Ph.D.Committee BBernard J. Clark, M.D., ChairJulian Allen, M.D.Janine BealLynn Bevan, CIP Betsy Bickert, Pharm.D.Leonard S. Buchoff, Ph.D.Shirley Bonnem Avital Cnaan, Ph.D.Kim Davis, M.A.Jacquelyn Evans, M.D.Michael Fisher, M.D.Janice Prodell-Glisson, R.N.Adda Grimberg, M.D.Jean Hassler Ellaria Lee, Pharm.D.Jennifer Long, M.S., M.J.Anna Meadows, M.D.Pierre Russo, M.D.Erin Simon, M.D.Mark Schreiner, M.D.Elaine SkypalaJoseph Zorc, M.D.

Committee CRonald Rubenstein, M.D., Ph.D., ChairRoberto Accorsi, Ph.D.Richard Aplenc, M.D.Arthur BenedictLynn Bevan, CIPJaclyn Biegel, Ph.D.Avital Cnaan, Ph.D.Kim Davis, M.A. Kevin Franck, Ph.D.Beth Goldberg, R.N., M.S.N., C.R.N.P.Judith Kathleen Goodman, M.D. Marta Guttenberg, M.D.Tom Kolon, M.D.Janet Kwiatkowski, M.D.Ellaria Lee, Pharm.D.Richard Lin, M.D.Jennifer Long, M.S., M.J.Jeanne Manson, Ph.D.Robert Mullen, Pharm.D.Allison Muller, Pharm.D.John L. Rodgers, D.Min.Mark Schreiner, M.D.Baird M. StandishRabbi Murray SilbermanDonna Sylvester, R.N., B.S.N.

Institutional Animal Care and Use CommitteeMichael Robinson, Ph.D., ChairLynn Bevan, Director of Research Regulatory AffairsAdele ButtonPamela S. Caudill Rodolfo I. Godinez, M.D., Ph.D., Deputy ChairJudith Grinspan, Ph.D.Stephan Grupp, M.D., Ph.D., Deputy ChairWayne Hancock, M.D., Ph.D.Richard Knauff, D.V.M.Kenro Kusumi, Ph.D.Jane MaehlCarol Schneider, Ph.D. Rebecca Simmons, M.D.Gwen Talham, D.V.M.Mitchell Weiss, M.D., Ph.D.


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Institutional Biological Safety CommitteeKatherine High, M.D., ChairMortimer Poncz, M.D.Jeffrey Bergelson, M.D.H. Fred Clark, D.V.M., Ph.D.Jacqueline Wagner

Research Compliance and Oversight CommitteeJudith Argon, ChairDouglas Coulter, Ph.D.Richard Dashefsky, J.D.Sara DubberlyPhilip Johnson, M.D.Jeffrey KahnJohn MatthewsMichael Robinson, Ph.D.Carol SazamaMark Schreiner, M.D.Kurt Schwinghammer, Ph.D.Virginia Stallings, M.D.Mary TomlinsonShifra Vega, Ph.D.Jacqueline WagnerWendy Williams, Ph.D.

Postdoctoral Affairs CommitteeJudith ArgonBrant Burkhardt, Ph.D. Chunxia Chen, Ph.D.Carolyn Felix, M.D.Evelyn FrancisJane KimIan Krantz, M.D.Sriram Krishnaswamy, Ph.D.Jeanne Manson, Ph.D., M.S.C.E.Denise OutlawJerilyn Radcliffe, Ph.D.Michael Robinson, Ph.D.Wendy Williams, Ph.D.Babette Zemel, Ph.D.

Research Affinity GroupsCardiovascular ResearchGroup Leader: Mortimer Poncz, M.D.

Cell and Gene Therapy Group Leader: Katherine High, M.D.

Child Health ServicesGroup Leaders: Louis Bell, M.D., and Jeffrey H. Silber, M.D., Ph.D.

Defective Proteins and DiseaseGroup Leader: Yair Argon, Ph.D.

Developmental Biology and Pediatric DisordersGroup Leader: Jeffrey Golden, M.D.

Fetal ResearchGroup Leader: Alan Flake, M.D.

Genes, Genomics and Pediatric DiseaseGroup Leaders: Nancy Spinner, Ph.D., and John Maris, M.D.

Metabolism, Nutrition and Physical DevelopmentGroup Leaders: Babette Zemel, Ph.D., and Rebecca Simmons, M.D.

Mind Brain Research Center Group Leader: Michael Robinson, Ph.D.

Normal and Malignant Hematopoiesis Group Leader: Carolyn Felix, M.D.

Pediatric Injury ResearchGroup Leader: Flaura Winston, M.D., Ph.D.

Pharmacologic Basis of Pediatric TherapeuticsGroup Leader: Jeffrey Barrett, Ph.D.

Vaccines and ImmunotherapiesGroup Leader: Terri Finkel, M.D., Ph.D.; Co-leaders:Steven Douglas, M.D., and Paul Offit, M.D.

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Administrative Units and DirectorsResearch EducationWendy Williams, Ph.D., Director Jodi Leckrone, M.Ed., Co-director

Research FinanceSteven Wiley, DirectorLuz Arrison, Accounting ManagerSara Dubberly, Manager, Business officeBethann Kurek, Accounting Manager

Research Human ResourcesDenise Outlaw, Manager

Research OperationsRoger Wood, Director

Research Acquisitions and ContractingKimberly C. Gossin, Contract Manager

Technology Transfer Kurt Schwinghammer, Ph.D., Director

Research ServicesRobert DeNight and Lawrence Pavlik, Co-directors

Research Regulatory AffairsLynn Bevan, Director

Research StaffDepartment of Anesthesia and Critical Care Medicine

Anesthesia ResearchSheryl Beck, Ph.D.Li Wei Chao, M.D., Ph.D.Kathryn Commons, Ph.D.Yuelin Li, Ph.D.Rita Valentino, Ph.D.

Critical Care MedicineMaria Luiza Albuquerque, M.D.Rodolfo Godinez, M.D., Ph.D.Bradley Marino, M.D.Robert Nelson, M.D., Ph.D.Joel Portnoy, M.D.Athena Zuppa, M.D.

General AnesthesiaGiovanni Cucchiaro, M.D.Sarah Hoehn, M.D.Ronald Litman, D.O.Mark Schreiner, M.D.

Department of Pathology and Laboratory Medicine

Cell PathologyYair Argon, Ph.D.Craig Bassing, Ph.D.Janis Burkhardt, Ph.D.

Developmental BiologyJeffrey Golden, M.D.

Laboratory MedicineJohn Kim Choi, M.D., Ph.D.Ruth Muschel, M.D., Ph.D.Suresh Shelat, M.D., Ph.D.Long Zheng, M.D., Ph.D.

Department of PediatricsAdolescent MedicineYair Argon, Ph.D.Craig Bassing, Ph.D.Janis Burkhardt, Ph.D.

Biostatistics and EpidemiologyAvital Cnaan, Ph.D.Abbas Jawad, Ph.D.David Shera, Sc.D.

CardiologyIvan Alferiev, Ph.D.Alvin Chin, M.D.Bernard Clark, M.D.Mark Fogel, M.D.Elizabeth Goldmuntz, M.D.Maryanne Kichuk-Chrisant, M.D.Robert Levy, M.D.Jonathan Rome, M.D.Kenneth Ryan, Ph.D.Jack Rychik, M.D.Victoria Vetter, M.D.Gilberto Wernovsky, M.D.

Child Development and RehabilitationIvan Alferiev, Ph.D.Nathan Blum, M.D.Paige Kaplan, M.B.B.Ch.Stephen Leff, Ph.D.Itzhak Nissim, Ph.D.Thomas Power, Ph.D.Jerilynn Radcliffe, Ph.D.Michael Robinson, Ph.D.Stanton Segal, M.D.Marc Yudkoff, M.D.



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Clinical PharmacologyPeter Adamson, M.D.Jeffrey Barrett, Ph.D.

Emergency MedicineEvaline Alessandrini, M.D.Elizabeth Alpern, M.D.Kristy Arbogast, Ph.D.Dennis Durbin, M.D., M.S.C.E.Joel Fein, M.D.Joseph Zorc, M.D.

EndocrinologyDiva DeLeon, M.D.Adda Grimberg, M.D.Lorraine Katz, M.D.Andrea Kelly, M.D.Jake Kushner, M.D.Thomas Moshang, M.D.Charles Stanley, M.D.Steve Willi, M.D.

Gastroenterology, Hepatology and NutritionRobert Baldassano, M.D.Margarita de la Llera-Moya, Ph.D.Joshua Friedman, M.D., Ph.D.Barbara Haber, M.D.Chris Liacouras, M.D.Kathleen Loomes, M.D.Sissel Lund-Katz, Ph.D.Asim Maqbool, M.D.Jonathan Markowitz, M.D.Michael Phillips, Ph.D., D.Sc.George Rothblat, Ph.D.Virginia Stallings, M.D.Nicolas Stettler, M.D., M.S.C.E.Babette Zemel, Ph.D.

General PediatricsLouis Bell, M.D.Tyra Bryant-Stephens, M.D.Cindy Christian, M.D.Ricardo Eiraldi, Ph.D.John Feudtner, M.D., Ph.D.James Guevara, M.D., M.P.H.Trude Haecker, M.D.Nancy Kassam-Adams, Ph.D.Ronald Keren, M.D., M.P.H.Janet Kwiatkowski, M.D.Daniel Licht, M.D.Rajiv Menon, Ph.D.

Susmita Pati, M.D., M.P.H.David Rubin, M.D.Richard Rutstein, M.D.Flaura Winston, M.D., Ph.D.

HematologyKazuhiko Adachi, Ph.D.Valder Arruda, M.D., Ph.D.Toshio Asakura, M.D., Ph.D.Gerd Blobel, M.D., Ph.D.Rodney Camire, Ph.D.Alan Cohen, M.D.Katherine High, M.D., HHMISriram Krishnaswamy, Ph.D.Catherine Manno, M.D.Kwaku Ohene-Frempong, M.D.Mortimer Poncz, M.D.Leslie Raffini, M.D.Kim Smith-Whitley, M.D.Mitchell Weiss, M.D., Ph.D.Weidong Xiao, Ph.D.

Human Genetics and Molecular BiologyJaclyn Biegel, Ph.D.Beverly Emanuel, Ph.D.Ian Krantz, M.D.Kenro Kusumi, Ph.D.Jeanne Manson, Ph.D., M.S.C.E.Sulagna Saitta, M.D., Ph.D.Tamim Shaikh, Ph.D.Nancy Spinner, Ph.D.

Allergy and ImmunologyDonald Campbell, Ph.D.Steven Douglas, M.D.Wen-Zhe Ho, M.D.Laurie Kilpatrick, Ph.D.Helen Korchak, Ph.D.Dimitrios Monos, Ph.D.Jordan Orange, M.D., Ph.D.Jonathan Spergel, M.D., Ph.D.Kathleen Sullivan, M.D., Ph.D.

Infectious DiseasesJeffrey Bergelson, M.D.Fred Clark, D.V.M., Ph.D.Philip Johnson Jr., M.D.Paul Offit, M.D.Michael Sebert, M.D.Theoklis Zaoutis, M.D.

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NeonatologyPhilip Ballard, M.D., Ph.D.Roberta Ballard, M.D.Phyllis Dennery, M.D.Cherie Foster, M.D.Andrew Gow, Ph.D.Susan Guttentag, M.D.Hallam Hurt, M.D.Harry Ischiropoulos, Ph.D.Scott Lorch, M.D., M.S.C.E.Kathy Maschhoff, M.D.Rashmin Savani, M.D.Rebecca Simmons, M.D.

NephrologyJohn Hoyer, M.D.Mary Leonard, M.D., M.S.C.E.Kevin Meyers, M.D.Nataliya Zelikovsky, Ph.D.

NeurologyPeter Bannerman, Ph.D.Christina Bergqvist, M.D.Carsten Bonneman, M.D.Amy Brooks-Kayal, M.D.Lawrence Brown, M.D.Vivian Cheung, M.D.Robert Clancy, M.D.Akiva Cohen, Ph.D.Douglas Coulter, Ph.D.Richard Finkel, M.D.Judy Grinspan, Ph.D.Takayuki Itoh, Ph.D.Robert Kalb, M.D.David Lynch, M.D., Ph.D.Peter Phillips, M.D.Brenda Porter, M.D., Ph.D.Gihan Tennekoon, M.D.John Wolfe, V.M.D., Ph.D.

OncologyMelissa Alderfer, Ph.D.Richard Aplenc, M.D.Jean Belasco, M.D.Garrett Brodeur, M.D.Valerie Brown, M.D.Greta Bunin, Ph.D.Nancy Bunin, M.D.Carolyn Felix, M.D.Jill Ginsberg, M.D.Stephan Grupp, M.D., Ph.D.Michael Hogarty, M.D.Anne Kazak, Ph.D.Beverly Lange, M.D.John Maris, M.D.Anna Meadows, M.D.Kim Nichols, M.D.Susan Rheingold, M.D.Jeffrey Silber, M.D., Ph.D.Peter White, Ph.D.Richard Womer, M.D.

Pulmonary MedicineJulian Allen, M.D.Michael Grunstein, M.D., Ph.D.Carole Marcus, M.B.B.Ch.Ronald Rubenstein, M.D., Ph.D.Laurence Suaud, Ph.D.

RheumatologySandy Burnham, M.D.Randall Cron, M.D., Ph.D.Terri Finkel, M.D., Ph.D.Stefania Gallucci, M.D.David Sherry, M.D.

Department of PsychiatryRobert Berkowitz, M.D.Guy Diamond, Ph.D.Josephine Elia, M.D.Annie Steinberg, M.D.Elizabeth Weller, M.D.

Department of RadiologyRoberto Accorsi, Ph.D.Diego Jarmillo, M.D., M.P.H.D.J. Wang, Ph.D.Robert Zimmerman, M.D.



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Department of SurgeryCT Surgery J. William Gaynor, M.D.Peter Gruber, M.D.Thomas Spray, M.D

General SurgeryN. Scott Adzick, M.D.Marcus Davey, Ph.D.Alan Flake, M.D.Holly Hedrick, M.D.Michael Nance, M.D.

OphthalmologyEric Pierce, M.D., Ph.D.Graham Quinn, M.D.Terri Young, M.D.

OrthopaedicsJohn Dormans, M.D.Denis Drummond, M.D.Lawrence Wells, M.D.

OtolaryngologyBryan Crenshaw III, Ph.D.Jim Davis, Ph.D.Ian Jacobs, M.D.Roger Marsh, Ph.D.

Plastic and Reconstructive SurgeryRichard Kirschner, M.D.Linton Whitaker, M.D.

UrologyDouglas Canning, M.D.Stephen Zderic, M.D.

The 2005 Research Annual Report is produced by the Joseph Stokes Jr. Research Institute of

The Children’s Hospital of Philadelphia

Steven M. Altschuler, M.D.President and Chief Executive Officer

Philip R. Johnson Jr., M.D.Chief Scientific OfficerDirector and Senior Vice President, Joseph Stokes Jr. Research Institute

Judith ArgonVice PresidentResearch Administration

Jennifer LongSenior Medical/Science Writer

Sarah ReedyMedical Writer

Evan KatzManager, Stokes Studio

Angela KnottGraphic Designer

Melissa LaVigneProduction Assistant

Robert NeroniPrincipal Photographer

Merck & Co.Rotavirus vaccine, RotaTeq®,and delivery system on page 29Rotavirus image on page 49

Eric Niederhoffer, Ph.D.Biochemistry and Molecular BiologySouthern Illinois University School of MedicinePhotography credit for GATA-1 image on page 23

Apple PressPrinting

Founded in 1855, The Children’s Hospital ofPhiladelphia is the birthplace of pediatric medicine in America. Throughout its rich history, a passionate spirit of innovation has driven this renowned institution to pursue scientific discovery, establish the highest standards of patient care and train future leaders in pediatrics. For a century and a half, Children’s Hospital hasserved as a haven of hope for countless children and families worldwide.

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