Bench to Bedside | March 2016

Seeing the Impact of a Decade of Genomics Discoveries

When The Children’s Hospital of Philadelphia established the Center for Applied Genomics (CAG) in 2006 with a $40 million commitment, it was one of the largest single investments in a research program at the hospital’s history. The ambitious idea spearheaded by CAG’s founder and director, Hakon Hakonarson, MD, PhD, was to establish the world’s largest pediatric genomics biobank and to use that vast quantity of genetic data to discover the causes of disease and disability hidden within a population’s genes.

Success was by no means assured. But today, as CAG approaches its 10th anniversary, its influence is evident across the research landscape. That impact is poised to grow as more of the center’s genomic discoveries move toward clinical applications.

Biobank Powered by Family Participation Powers CAG’s Success

“This is by far the biggest pediatric biobank in the world,” Dr. Hakonarson said. “No one has anything remotely close to what we have built here at CHOP.”

This enormous collection now totaling DNA samples from more than 400,000 people, including about 100,000 CHOP patients and their family members, is housed at CHOP and used for a vast range of research discoveries. It would not have grown into the world’s largest pediatric biobank if not for early success with recruiting large numbers of patients and families at CHOP.

From the earliest days after CAG was established, well over 100 CHOP investigators were eager to participate. Together with members of the CAG staff, many of whom have been with the program since its inception in 2006, they have contributed to patient recruitment, phenotyping and sample collections from the participating families. The CAG staff has been exceptional, according to Dr. Hakonarson, and their collaborative work on the biobank has subsequently led to many groundbreaking discoveries.

“One of the most remarkable things about the biobank is that more than 80 percent of the patient-families we ask to donate samples to it say yes,” CHOP’s CEO Madeline Bell wrote in a recent message to CHOP employees. She highlighted the biobank as a “CHOP treasure” and cited the appreciation of the value of such research among families who chose to participate.

With such a large number of samples, CHOP investigators have great statistical power to detect genetic variations underlying diseases in the population. In addition, CAG investigators and their collaborators have helped hundreds of families to resolve the underlying genetic causes of their extremely rare diseases.

What makes the biobank even more powerful and unique is the complementary data associated with each biological sample. Each one is linked to a patient’s continuously updated electronic health record — giving researchers a deeper insight into later diagnosed conditions even after the time when participants enroll. Plus, many participants who contributed to the biobank signed an innovative consent form that allows researchers to contact their families again to request additional information, such as information about environmental exposures, family history that was not already part of their record, or even samples from additional family members. The informed consent and information about the CAG operation can be found at www.caglab.org

“This was very, very unique,” Dr. Hakonarson said. “No one was doing this type of consent at the time we started the project.”

The volume and statistical power of the biobank has also positioned CHOP as a hub for pediatric genomics research. As a result, CHOP’s initial investment in developing CAG and the biobank has evolved into a self-sustaining enterprise, funded by major research grants and contracts for research services.

Decade of Discoveries and Impact on Research

The volume of samples in CAG’s biobank combined with the scientific prowess of researchers at CHOP has allowed the discovery of links between genetic underpinnings and the disease phenotypes in patient populations. Based on analyses of biobank samples, CHOP researchers have published more than 450 papers in scientific journals, many of them in the top-tier ones such as Nature and Cell. They have made landmark discoveries in the gene variations and genetic pathways involved in a wide range of conditions, including asthma, autism spectrum disorder, cancers, schizophrenia, and Type 1 diabetes.

“That has led to huge visibility to CHOP as a mecca of pediatric genomics today,” Dr. Hakonarson said. “These efforts have really transformed genomics research at CHOP.”

 Dr. Hakonarson was recently recognized by Thomson Reuters as one of the most highly cited researchers across all disciplines. The “highly cited” status can be seen as an independent verification of his program’s research impact; not only is the CAG team publishing papers in well-regarded journals, but other researchers build on that work often enough that they cite those papers with exceptionally high frequency.

Emerging Impact on Clinical Care

The impact goes beyond research. CHOP researchers have begun to translate more and more of CAG’s genomic discoveries into therapies.

One of the earliest such successes stems from a 2008 discovery by a team led by CHOP pediatric oncologist and Penn Assistant Professor Yael Mossé, MD. They found that a mutation in the gene ALK was a driver of most cases of rare, inherited neuroblastoma, a pediatric nervous system cancer. The pharmaceutical company Pfizer had been working on an ALK-inhibitor drug, crizotinib, which had been approved for adults with lung cancer.

“It was about seven months after making this discovery that patients at CHOP were receiving this drug,” Dr. Hakonarson said.

Dr. Mossé and colleagues have continued to build on this work as well, identifying more effective ALK inhibitors to help patients whose tumors were less responsive to crizotinib. She is working to launch a clinical trial for a new drug this year.

Looking beyond rare cancers, Dr. Hakonarson is excited about a broad-scale population impact of more recent CAG discoveries of mutations in multiple genes that are part of a neurotransmitter signaling pathway regulating memory, attention, cognition, learning, behavior, among other biological processes. They found these mutations to be associated with several neuropsychiatric conditions in children including attention deficit hyperactivity disorder (ADHD) and have already completed the first proof of concept clinical trial in ADHD. These findings could rapidly lead to clinical therapies, as an investigational drug that targets this pathway is already in use in clinical trials for ADHD led by Medgenics Inc. (Medgenics licenses certain CAG assets and funds some of Dr. Hakonarson’s research.)*

“This discovery alone may have a huge impact on millions of kids down the road,” Dr. Hakonarson said. “It would never have been discovered if not for the CHOP biobank we built.”

*In addition, Dr. Hakonarson indirectly owns stock in Medgenics and CHOP and Dr. Hakonarson could benefit financially from their relationships with Medgenics.


www.research.chop.edu

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

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