One Hundred Years of CHOP Research

By Jill Rose Lim

In Philadelphia 1922, the city trembles with growth. Urban planners widen Market Street at 32nd, architects envision university campuses free of urban congestion, and in the basement of Children’s Hospital of Philadelphia, newly appointed clinician and investigator Joseph Stokes Jr., MD, starts testing hypotheses in a 14-by-16 foot room with a single centrifuge.

“When CHOP established its first research lab in the basement of the hospital, Joseph Stokes Jr., MD, and other CHOP researchers were focused on addressing the major public health challenges of the time, including infectious diseases and infant mortality,” said Susan Furth, MD, PhD, Executive Vice President and Chief Scientific Officer of CHOP Research Institute. “Because of their work and the work of many other scientists, we have made great strides in curing and treating childhood illnesses over the past 100 years.”

Discoveries take shape around every corner of the Research Institute and beyond, from basic science at the bench to children’s health policies in communities. And they span every age group, from fetal surgeons who repair birth defects in the womb, to teen driving safety researchers who developed and validated a laboratory-based driving assessment.

“Because of their work and the work of many other scientists, we have made great strides in curing and treating childhood illnesses over the past 100 years.” - Susan Furth, MD, PhD

“Our physician-scientists’ curiosity, drive, and need to know has always driven the Research Institute,” said Howard Eck, director of Research Resources at CHOP, who has witnessed three decades of CHOP’s evolution. “We call research a pillar of CHOP today, but truly it’s always been a pillar — it’s a foundational aspect of who we are and what we do. The phrase “bench to bedside” didn’t exist 40 or more years ago, but I think that’s really what it’s always been about.”

CHOP’s Earliest Pioneers

From its early days, CHOP scientists established themselves as leaders and collaborators, particularly in the field of virology, immunology, and bacteriology. Between the 1940s and 1960s, husband-and-wife team Werner and Gertrude Henle, MD, discovered vaccines for influenza and mumps, demonstrated gamma globulin as an effective therapy for Hepatitis A, and connected the Epstein-Barr virus with the development of Burkitt’s lymphoma.

They worked alongside Dr. Stokes and Klaus Hummeler, PhD, who would later become the first director of the Research Institute. Dr. Hummeler, along with Dr. Mary Crawford, identified over 20 viruses and their related diseases. In total at this time, CHOP employed 65 scientific investigators working on 20 projects.

As the years went on, subsequent discoveries followed: In 1963, Stanley Plotkin, MD, developed a vaccine for rubella. In 1965, cardiologist William Rashkind created the balloon catheter, a lifesaving, nonsurgical procedure for infants with a type of congenital heart disease. And in 1968, Douglas Wilmore, MD, and Stanley Dubrick, MD, described the first method to provide intravenous nutrition to a critically ill infant in the Journal of the American Medical Association. These discoveries and more solidified CHOP’s early reputation as a pioneer in pediatric science.

Square Footage for Science

As breakthrough followed breakthrough, the research department’s square footage grew. In 1954, CHOP built a six-story research building next to the hospital at 18th and Bainbridge Street. The building, known formally as the “Rheumatic Fever and Virus Research Building” was more commonly called the “Research Building” and cost the hospital $843,000 to build and equip.

“Research programs have grown and developed to address the needs experienced by our patients.” - Howard Eck

In 1974, when CHOP moved to its current location at 34th and Civic Center Boulevard, its design included research laboratories and facilities. And with the 1989 construction of the Wood Center, the hospital’s first dedicated outpatient facility, CHOP devoted one floor to the Division of Human Genetics and the Division of Hematology. It was here that Beverly Emanuel, PhD, former Chief of Human Genetics, began work on chromosome 22 as part of the Human Genome Project.

In 1995 came the Leonard and Madlyn Abramson Pediatric Research Center, where the Research Institute expanded much-needed wet bench research space and, for the first time, dedicated one floor to dry research. The hospital emphasized its commitment to research with the creation of its Centers of Emphasis (COEs). These COEs promoted collaboration and integration within the Research Institute to enhance productivity, growth, and home in on specific research areas in child health.

“What we’ve done is we’ve kept pace with the development of science,” Eck said. “As issues in pediatrics have come up over the course of time, we’ve addressed them with our Centers and buildings. For example, we developed the Center for Autism Research (CAR) because autism became such a prominent issue, and we wanted to be able to investigate that. Research programs have grown and developed to address the needs experienced by our patients.”

In 2010, CHOP constructed the Ruth and Tristram Colket Jr. Center, a 730,000-square-foot translational research facility, and in 2017, the Roberts Center for Pediatric Research opened its doors on the other side of the Schuylkill River. These new buildings reflected the speedy pace and cutting-edge nature of the Research Institute’s work, with state-of-the-art laboratory facilities.

At the Research Institute, our infrastructure is designed to foster new ideas, technologies, and applications. Access the video transcript

To stay on the cutting-edge of clinical treatment, CHOP also created the Frontier Programs — a trailblazing set of research initiatives that expedite research from the bench to the bedside. While the hospital began with just four Frontier Programs, CHOP now counts 20. Out of these Frontier programs came discoveries that scientists in 1922 could only dream of: immunotherapy that harnesses a child’s own cells to fight cancer, the discovery of genes related to epilepsy that pave the way for precision medicine, a lifesaving treatment based on novel discoveries about the body’s lymphatic system, and more.

One hundred years after Dr. Stokes set up his first lab, CHOP’s research campus forms a distinct part of West Philadelphia’s skyline, spanning approximately 608,000 square feet of wet and dry lab space, and 1,050 investigators. CHOP continues to invest in research infrastructure to be positioned to recruit the best and the brightest scientists who are on the cutting edge of solving health problems for children.

“What I love to see is when an investigator here at CHOP is giving me a tour of their lab and telling me about what they’re doing and trying to achieve,” said Madeline Bell, President and Chief Executive Officer of CHOP. “The animation on their face and the excitement and pride in their lab and the people that work there gives me new energy and gets me excited to help them to realize their goals.”

The Leukodystrophy Program is an example of a lab that has grown into a dynamic research infrastructure. Access the video transcript

Omics Science Opens Opportunities

Two of pediatric science’s revolutionary fields today, omics and gene therapy, are prime examples of the Research Institute’s readiness and agility to pursue new approaches to scientific discovery.

The field of omics continues to advance at a tremendous pace. When Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics (CAG) joined CHOP to study asthma genetics in 1992, today’s advanced sequencing tools did not exist. In fact, studying genes was “more like a guessing game,” according to Dr. Hakonarson.

After working on a large-scale genomics project in Iceland, Dr. Hakonarson returned to CHOP in 2006 to establish CAG, which capitalized on the then-new technology of single nucleotide polymorphism (SNP) arrays. Through SNP arrays, CAG scientists were able to conduct genome-wide association studies that involved looking at the entire genome in one experiment. Over the last decade, they have gained a greater understanding of the genetic basis for autism, attention-deficit/hyperactivity disorder, asthma, obesity, diabetes, inflammatory bowel disease, and cancer, among others.

“CAG published its first paper in Nature, discovering a new type 1 diabetes gene, and our first asthma paper in the New England Journal of Medicine, describing a major asthma gene as an excellent therapeutic candidate,” Dr. Hakonarson said. “And through the years, we have published over 950 papers using these new technologies.”

In 2016, CAG was the first program on the East Coast to implement the next phase of genomics technology: sequencing genes at the RNA level in a single cell.

“RNA sequencing allows us to figure out if genes are expressed in any cell or any tissue and then assess whether that sub-cell type might be the key disease-driving cells in the body,” Dr. Hakonarson said. “This has fundamentally changed the landscape of coming up with new therapies and how we administer these new therapies.”

In 2018, Yi Xing, PhD, joined CHOP to establish the Center for Computational and Genomics Medicine, which uses big data and cutting-edge genomics technologies to study these complexities in RNA biology, and potentially how they cause disease.

The next challenge is for researchers to better understand the epigenetics that underlie these diseases, as well as in the sequencing of proteins — a field called proteomics.

“We are moving away from DNA and RNA and now sequencing the proteins, those functional units that basically regulate all biological functions in the human body,” Dr. Hakonarson said. “Proteomics is going to get us a better understanding of how we use gene-editing technologies. And once we start using these technologies to cure diabetes or rheumatoid arthritis or multiple sclerosis, that’s when we need to precisely target only the cell responsible for triggering and initiating the disease event. That is how a multi-omics approach drives a new therapy with the least side effects.”

Cell and Gene Therapy Transforming Care

Beverly Davidson, PhD, Chief Scientific Strategy Officer for the Research Institute, marks the genesis of gene therapy research at CHOP with the recruitment of Katherine High, MD, in 1992. At that time, gene therapy did not have the support or star power it carries today. But believing in the potential for gene therapy to change children’s lives, Dr. High received support from CHOP leadership and established a facility to make clinical-grade vectors within the hospital.

“Dr. High recruited individuals who were technically advanced in the cell and gene therapy space, and it all coalesced in 2004 into what became the Raymond G. Perelman Center for Cellular and Molecular Therapeutics,” Dr. Davidson said. “That in itself recruited a lot of interest in the gene therapy and hematology space, and then it grew tentacles out from there.”

With Dr. Davidson’s own recruitment to CHOP in 2015, research accelerated in the neurology side of gene therapy, and collaborating with the University of Pennsylvania, scientists were studying gene therapy for difficult-to-treat cancers. Almost a decade later, CHOP researchers have pioneered Food and Drug Administration-approved gene therapies for inherited blindness and acute lymphoblastic leukemia and continue to make discoveries in immunotherapies for hemophilia and solid cancers such as neuroblastoma. Emily Whitehead, the first pediatric patient to receive CAR T-cell therapy, celebrated 10 cancer-free years in 2022.

Beverly Davidson, PhD, shares that "the energy here is palpable, and that it’s a really good feeling when you walk to work." Access the video transcript

Scientists are also refining the methods and mechanisms of gene therapy delivery itself. In 2021, Dr. Davidson and her team engineered a delivery system to fine-tune levels of gene therapy expression. Researchers in the Maris Lab used a multi-omics approach to develop a novel type of CAR T-cell that opens the door to treating a wider range of cancers through immunotherapy, including neuroblastoma. Through the Cell and Gene Therapy Collaborative, researchers from different departments across CHOP, from Oncology to Pathology, Genomics, and Fetal Research, work together to advance the future of disease therapies.

“In the cell and gene therapy space, we’re finding new targets and developing new drugs, and we have the capabilities to advance that here at CHOP,” Dr. Davidson said. “CHOP’s breakthroughs are fueled by residents and fellows who work with basic scientists on how best to advance the technologies. With support from the Research Institute, we’ve been able to draw in a cadre of new investigators into this space who are applying cell and gene therapy methodologies to their particular fields of focus, which definitely broadens the scope of what we can accomplish at CHOP.”

‘Change Takes Time’

The growth of the Research Institute’s most valuable asset — its approximately 2,720 staff, administrators, faculty, scientists, and trainees — cannot go unnoticed. Just as the world has changed in 100 years, so too has the diversity of the Research Institute’s population. Seeing the value of a research community that includes scientists from all walks of life, CHOP began multiple pipelines for attracting diverse talent in STEM fields, and in 2021 created the Diversity, Equity, and Inclusion (DEI) council.

“Scientific progress depends on people learning about new things and studying existing things in new ways,” said Paulette McRae, PhD, associate director of Specialty Programs and Diversity. “Having racial, ethnic, gender, religious, economic people included means bringing different lenses, different experiences, different questions, different passions — and getting better results. By being more inclusive, the likelihood of scientific success is higher, promoting economic growth and competitiveness.”

Dr. McRae first joined CHOP as a postdoctoral fellow in 2007 and has witnessed much change in the Research Institute’s diversity of population.

“During my training, there were not many near peer or faculty members that looked like me or shared similar life experience,” Dr. McRae said. “That is changing with intentional efforts to not only increase diversity but to promote a culture of belonging for historically marginalized groups.”

The DEI’s most significant initiatives have thus far included the development of summer research internship programs to support STEM-M education for historically disadvantaged youth, the Postdoctoral Research Fellowship for Academic Diversity, the Gateway to Pediatric Research recruitment events, and most recently, the CHOP BEST (Building Excellence in STEM Together) Awards.

“Change takes time, but we are starting to see more representation across the Research Institute,” Dr. McRae said. “We are excited about what the future holds for the Research Institute and CHOP.”

Commitment from leadership has been essential to moving diversity initiatives forward at CHOP Research Institute. Access the video transcript

Innovation and the Future

As the Research Institute recruits top research talent and increases grant funding from the National Institutes of Health and other organizations, CHOP broke ground on another research facility, the Morgan Center for Research and Innovation in October 2022. The building’s design reflects the expansive and flexible nature of scientific discovery. The space will be adaptable to different needs, with demountable partitions that can be put up or taken down with ease. Like in years past, the new 14-story building will follow the science.

“We’ve always approached it from the perspective of we don’t necessarily know what’s coming next, but we know something is, and we want to be able to be in a position to meet that need and address it,” Eck said. “Science has moved on, and we’ve moved with it. So, you can’t really predict what’s coming, but that’s what’s exciting. It’s always interesting, and it’s always exciting.”

Dr. Stokes, known to maintain what he called “a proper balance between laboratory investigation and clinical care,” may very well agree.