A N U P D AT E F O R PA R T N E R S O F T H E C H I L D R E N ' S D I S C O V E R Y I N S T I T U T E
SUMMER 2016
Featured Research ›
INSIDE THE EPICENTER FOR CELLULAR IMAGING With the October 2015 opening of the Washington University Center for Cellular Imaging (WUCCI), researchers throughout the Washington University School of Medicine campus, including those funded by the Children’s Discovery Institute (CDI), have access to a shared technology resource center where the sole focus is the advancement of imaging technologies in support of their studies. Phyllis Hanson, MD, PhD, cell biology and physiology; and Paul Taghert, PhD, anatomy and neurobiology; are the principal investigators of the CDI grant. Currently, six currently funded CDI investigators, as well as 18 CDI members, have been able to take advantage of this new and illuminating resource. (see page 3).
Team WUCCI (from l-r): Matt Joens, staff scientist; James Fitzpatrick, PhD, WUCCI scientific director; Robyn Roth, staff scientist; Daniel Geanon, undergraduate research assistant; Dennis Oakley, staff scientist
“Our ultimate goal is to build three-dimensional models of healthy versus disease states.”
– continued on next page
– Dr. James Fitzpatrick
CDI RESEARCH GOALS ›
› Understanding Asthma by the Circadian Clock . . . . . . . . . . .
page 4
› Breaking the Blood/Brain Barrier. . . . . . . . . . . . . . . . . . . . .
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ChildrensDiscovery.org
FROM THE SCIENTIFIC DIRECTOR
Join Us for an Inspirational Evening at the Annual CDI Investor Symposium I encourage everyone who has ever supported the CDI to join us on Thursday, Nov. 10, for the CDI Investor Symposium. We have an amazing line-up of presenters and speakers planned. We will not only showcase the research discoveries of the past 10 years, but we will look ahead to the next decade of discovery. Gary Silverman, MD, PhD, the new executive director of the CDI, will open the evening with his vision for how this innovative partnership between St. Louis Children’s Hospital and Washington University School of Medicine will continue to delve deeply for a greater understanding of pediatric disease at the molecular level. He then will introduce two CDI investigators who are applying their expertise in developmental biology and computational genetics to give CDI investigators now and in the future the core technologies they need to advance their research. I am confident that you will leave those presentations with renewed enthusiasm for the undertaking that only philanthropy could have accomplished – understanding the basic biology of pediatric disease. In past symposia, we have offered the audience a chance to have hands-on experiences and individual conversations with CDI investigators. The only difference this year is that even more researchers will have their innovative projects on display. For example, you’ll be able to talk to James Fitzpatrick, PhD, (cover story) about the amazing ways in which CDI investigators are using the Washington University Center for Cellular Imaging (WUCCI) to advance their research. CDI investigators solving for pediatric heart, brain and metabolic diseases also will showcase their work. Invitations will be on their way soon. I hope you can join us for this inspiring evening celebrating not just the researchers of the CDI but you, the investors, who make it all happen.
CELLULAR IMAGING
– continued from page 1
The center is located in a new research building on the School of Medicine campus. James Fitzpatrick, PhD, cell biology and physiology and neuroscience, was recruited from the Salk Institute for Biological Studies in San Diego to serve as the imaging center’s scientific director. He says the new center coalesces imaging technologies to help researchers understand how the structure of a cellular system and the sequence of events within that system dictate its function. “The analogy I like to make is that of building a bridge,” Dr. Fitzpatrick explains. “If it’s a creek you want to be able to cross, you may need just a simple plank. But if it’s the San Francisco Bay, you may want to think about constructing a suspension bridge. Cellular biology works the same way, so that the structure of systems – how cells work together, how they organize and how they differentiate to form different tissues – and in what sequence everything comes together – determine their ultimate function.” A walk through WUCCI with Dr. Fitzpatrick quickly exposes his kid-in-a-candy-store excitement for its technologies and the science carried out there. He points to an image on a computer screen. “That is a mouse spinal cord imaged using infrared microscopy, so we can see all of its motor neurons.” In another room he points to a macrophage eating a dead cell. “Our ultimate goal is to build three-dimensional models of healthy versus disease states,” Dr. Fitzpatrick says. As a center on the leading-edge of multi-scale imaging, WUCCI already has been able to drive innovation. And, Dr. Fitzpatrick says, the CDI has played a major role in the center becoming an institution-wide resource. “Giving its researchers access to the center has been absolutely transformative.” It’s not just the capability to, for example, “localize single fluorescent molecules to build an image that will have the resolution 10-times greater than what a traditional microscope could provide” that’s so valuable. It’s the conversations that happen around it. “The center is a place to intellectually engage with scientists of every discipline,” Dr. Fitzpatrick says. “It’s not uncommon to have a cancer systems biologist and someone studying the nervous system in one of the training courses we provide. This breaking down of departmental silos can spark new ideas and collaborations that will drive biomedical science forward.” ›
“The center is a place to intellectually engage with scientists of every discipline. It’s not uncommon to have a cancer systems biologist and someone studying the nervous system in one of the training courses we
Mary Dinauer, MD, PhD Mary Dinauer, MD, PhD, is the scientific director of the Children’s Discovery Institute. She also is the Fred M. Saigh Distinguished Chair in Pediatric Research at St. Louis Children’s Hospital, professor of pediatrics, and of pathology and immunology at Washington University School of Medicine.
provide. This breaking down of departmental silos can spark new ideas and collaborations that will drive biomedical science forward.” – Dr. James Fitzpatrick
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Featured Research ›
DISCOVERY AT THE
MOLECULAR LEVEL Through a CDI-funded large-core initiative, CDI researchers have jumped at the promise of advanced cellular imaging technologies available at the WUCCI. Here are a few examples: Steven Brody, MD, medicine, is using the center as part of his lab’s investigation of the assembly of cilia for ciliary function, and how the assembly is affected in genetic and acquired disease. The aim is to identify the function of known and novel lung disease proteins in cilia and identify their role in the assembly of cilia and, in turn, how that function is disrupted in disease. Cilia are the microscopic, hair-like structures that extend outward from the surface of many animal cells. In the lung, their function is to sweep airways clean of mucus. Abdinav Diwan, MD, medicine, studies lysosomes, ubiquitous organelles that play a role in the breakdown of lipids, proteins and carbohydrates. Dr. Diwan is using CDI funding to study how exactly lysosome dysfunction impairs metabolism, causing reduced fat stores and resulting in significant energy deficit. He brought a unique C. elegans (roundworm) system of lysosome storage disease to the WUCCI to help expose how lysosome dysfunction causes a deficiency in lipid metabolism. Phyllis Hanson, MD, PhD, cell biology and physiology, looks at lysosome storage disease, as well as other pediatric diseases, from another angle. In the WUCCI, she takes advantage of the center’s electron microscopy and confocal and superresolution imaging to study a variety of fixed and live cell models depleted of some essential proteins that run the operation of lipid degradation. Kory Lavine, MD, PhD, medicine, uses the center’s transmission and scanning electron microscopy to study a zebrafish model of pediatric cardiomyopathy (heart failure). In addition, three-dimensional electron microscopy will be used to precisely quantify abnormalities in the size and geometric structure of mechanistic elements that contribute to the disease. S. Celeste Morley, MD, PhD, pediatrics, uses the WUCCI’s live cell imaging to help identify molecular pathways that control immune response to pneumococcal respiratory infection, a major driver of pediatric illness and mortality worldwide. Rodney Newberry, MD, medicine, studies the rising incidence of food allergies. He is using WUCCI technology to gain insight into how dietary antigens are crossing the stomach lining to be delivered into the immune system. Dr. Newberry hopes to identify alterations in feeding practices and the gut microbiota in infancy that predispose to food allergies. ›
“Giving its researchers access to the center has been absolutely transformative.” – Dr. James Fitzpatrick
Dr. Kory Lavine
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Featured Research ›
ASTHMA
CLOCKING
Ask asthma sufferers when their symptoms seem to get
worse and most will say in the middle of the night. Asthma’s severity also varies by season and, in children, by age. But it’s the time-of-day variable that most intrigues researchers interested in circadian rhythms, those 24-hour cycles of physiological processes that affect every living being.
One such researcher is Jeffrey Haspel, MD, PhD, medicine. In September of 2014 Nature Communications published his research revealing a connection between time of day and immune function in the lungs. A little over a year later, Dr. Haspel received CDI funding to extend his research to children. “We know that kids who are hospitalized with viral infections, such as respiratory syncytial virus (RSV), have an increased risk of later developing asthma,” Dr. Haspel says. “My lab is interested in how differences in circadian clock rhythms can make these kids sicker and more likely to develop asthma.”
mice do, in fact, get much sicker. Without bmal1 telling the lungs to coordinate a defense, the mice often die. Dr. Haspel also is tapping into mucosal samples from babies hospitalized for RSV. These samples have already proven helpful to CDI researchers studying why some children with severe RSV develop asthma and some don’t. In Haspel’s lab, researchers looked at the circadian clock gene in each sample to verify that bmal1 expression went awry in those patients. The children who were enrolled in that earlier study happen to be turning 6 now and are due for followup testing. As they come in, Dr. Haspel’s team will
be sending them home with a Fitbit-like activity tracker to wear for a week. “By watching them move and sleep, we can infer the organization of their circadian clock rhythms,” he says. “Because circadian clock genes are designed to be accessed by the outside world, it isn’t a stretch to imagine there might be a way to improve a child’s resistance to viruses that lead to the development of asthma through some kind of behavioral intervention.” Whether the most effective intervention is behavioral or pharmaceutical, it’s just a matter of time for this leading circadian clock researcher to find it. ›
With his CDI grant, Dr. Haspel will study bmal1, the “clock” gene responsible for the lung’s circadian rhythm. “The genetics behind circadian rhythms were identified just a few years ago,” Dr. Haspel says. “We’ve learned that our biological clocks are run by a relatively small number of genes and those genes are expressed in virtually every cell in our bodies, meaning that every cell, and every organ where they reside, has the capacity to keep time when those genes are expressed.” It makes sense, he points out, for the brain to have a circadian rhythm. It evolved out of the human need to sleep at night in order to avoid encounters with predators. It also makes sense for our digestive organs to be governed by a clock. Feeling hunger at certain times of the day keeps us nourished. But why the lungs? To solve that mystery, Dr. Haspel’s lab started looking into the molecular biology of the lung. “Turns out the lung clock is specialized for immunology,” he says. Because the amount of exposure to potentially harmful agents varies throughout the day, the lungs must be able to mount an immune response. Dr. Haspel hopes to determine the extent to which bmal1 regulates the lung’s response to common respiratory viruses. In addition, he seeks to understand how a child’s age modifies the impact of bmal1 on lung anti-viral responses and asthmalike airway disease. To do that, Dr. Haspel’s lab will perform a mix of basic and translational experiments, including giving viruses to mice whose clock genes are insufficiently expressed and verifying that those 4|
“Because circadian clock genes are designed to be accessed by the outside world, it isn’t a stretch to imagine there might be a way to improve a child’s resistance to viruses that lead to the development of asthma through some kind of behavioral intervention.” – Dr. Jeffrey Haspel
“Moved by Brett’s unusual Make-a-Wish Foundation wish to be a priest for a day, the St. Louis Archdiocese sent him to Philadelphia to meet Pope Francis.” – Dr. David Limbrick
BRETT GETS HIS WISH Children’s neurosurgeon-in-chief David Limbrick, MD, PhD, and Karen Gauvain, MD, pediatrics, need only to witness the incredible strength and resilience of the patients they treat for brain tumors to put everything they have into their work. But, if they needed inspiration, Brett Haubrich could provide. When the Make-a-Wish Foundation asked Brett what he wanted, his response wasn’t Disney World or the Super Bowl. It was to have the opportunity to be a priest for a day. And Drs. Limbrick and Gauvain made sure he did. The two physician-researchers are collaborating on a CDI study to investigate the efficacy of using non-invasive lasers to treat kids with brain tumors. After using lasers to treat adults with brain tumors, Dr. Eric Leuthardt, a School of Medicine professor of neurosurgery, was able to demonstrate the four-week breakdown of the blood-brain barrier. The blood-brain barrier shields the brain from harmful toxins but also blocks potentially helpful drugs, such as chemotherapy.
The purpose of this CDI study is to examine the outcomes of pediatric patients with newly diagnosed and recurrent brain tumors who are treated with lasers and chemotherapy. The study will test whether the non-invasive laser treatment works as well for children as it does for adults at enhancing the infiltration of chemotherapy drugs as a result of blood-brain barrier disruption.
Dr. David Limbrick
“For Brett, who we enrolled in the study, the non-invasive laser treatment worked well enough for him to participate in his school play,” says Dr. Limbrick. “Moved by Brett’s unusual Make-a-Wish Foundation wish, the St. Louis Archdiocese sent him to Philadelphia to meet Pope Francis.” ›
Dr. Karen Gauvain
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CDI News ›
NEW CDI STUDIES
UNDERWAY The Children’s Discovery Institute recently allocated $2.8 million toward comprehensive genome analysis to improve the ability to diagnosis birth defects, toward work that will seek to identify biomarkers of cognitive dysfunction in survivors of pediatric brain tumors and more. The CDI also will fund the creation of the Zebrafish Models for Pediatric Research Cooperative under the direction of Lilianna Solnica-Krezel, PhD; and Kelly Monk, PhD, developmental biology. Zebrafish make for great model organisms for genetic dissection of development and the regeneration and modeling of human birth defects and diseases. These little swimmers can be put through gene disruption, gene editing and transgenesis, epigenetic profiling and pilot chemical screens for a relatively low cost. The cooperative will enable new projects that use zebrafish to understand, diagnose and develop treatments for birth defects and pediatric disease. This funding cycle also launched a study by two School of Medicine leaders in the worldwide malnutrition battle: Indi Trehan, MD, PhD, and Mark Manary, MD, pediatrics. Severe acute malnutrition afflicts 20 million children worldwide at any given time. Through the years, different types of ready-to-use therapeutic foods have helped children with malnutrition but have not addressed the cognitive deficits that often result from it. The CDI researchers will use their funding to test two improved ready-to-use therapeutic food formulas to see which is better at solving for both healthier nutritional status and improved neurocognitive development. In addition, McDonnell Pediatric Cancer Center researcher, Joshua Rubin, MD, PhD, pediatrics, teams up with Bradley Schlaggar, MD, PhD,
pediatrics and neurology, to discover ways to avoid creating cognitive deficits while treating children with brain tumors. Cutting-edge neuroimaging and advanced computational analysis will help the researchers more precisely pinpoint and validate biomarkers for cognitive deficits. This will lay the groundwork for more sensitive and truly personalized metrics for improving cognitive outcomes for the ever-growing population of pediatric brain tumor survivors. F. Sessions Cole, MD, pediatrics, and a multidisciplinary team will work with investigators and the McDonnell Genome Institute to conduct a comprehensive genome analysis of infants born with birth defects. The goal is to accelerate the state of the art of precision medicine strategies in infants with birth defects; improve diagnostic success; and define genome-directed disease categorization, prognosis, therapeutic strategies and future genetic risk. “The board’s support of these new projects is advancing the CDI’s vision of applying precision medicine to childhood disease,” says Gary Silverman, MD, PhD, pediatrician-in-chief at Children’s Hospital and CDI executive director. “The CDI will have a major focus in the next 10 years on developing genomics-based personalized treatments for children with common disease, such as asthma and childhood infections, as well as those with rare and neglected disease, birth defects or neurological and neurobehavioral disorders.” ›
Dr. Trehan has made the eradication of diseases of poverty his life’s work.
“The board’s support of these new projects is advancing the CDI’s vision of applying precision medicine to childhood disease. The CDI will have a major focus in the next 10 years on developing genomics-
CDI principal investigators and School of Medicine developmental biologists Lilianna Solnica-Krezel and Kelly Monk are seeing to it that other CDI researchers have access to the illuminating zebrafish models.
based personalized treatments for children with common disease, such as asthma and childhood infections, as well as those with rare and neglected disease, birth defects or neurological and neurobehavioral disorders.” – Dr. Gary Silverman
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CDI News ›
RIDING FOR
The St. Louis Children’s Hospital
VIVIAN Pedal the Cause Ride for a Child Ambassador
Vivian Keith is a feisty,
sometimes stubborn 3-year-old with curly-cue hair and a twin brother named Lane. Her mom, Ginger, always knew Vivian was a determined little girl but she didn’t realize the depth of that determination until Vivian had to battle cancer. Ginger could sense something wasn’t right when bruises started appearing on Vivian’s shins, knees and forearms. Two weeks later, tests revealed cancer cells in her blood. The news of leukemia that turned the Keiths’ world up-side-down came around 7 p.m. that evening. “I never in a million years thought I would have a child with cancer,” Ginger says. “It tore our family to pieces for a while.” Thanks to pediatric cancer research, the prognosis of children Vivian’s age with leukemia is good and improving all the time. And now that Vivian has fought through the worst part of chemotherapy and has moved onto maintenance treatment, the Keiths can breathe a little easier and have the emotional space needed to wonder how they can join the fight to end childhood cancer.
He will then tap into a CDI-funded core of noncancer cells to generate stem cells with a genetic background of each patient. These cells will help explain the role of normal and variant MLL3 during normal (and abnormal) blood development. He also will use several methods to characterize the developmental toxicity following chemotherapy exposure to patient-derived and engineered cell lines. These experiments will provide pre-clinical data on novel therapeutic agents and lead to new
strategies for engineering blood stem cells that could be transplanted into IL patients, ultimately improving their clinical outcomes. Reflecting on her family’s participation in this year’s Pedal the Cause event, Ginger says, “We are so close to finding cures that we just need to keep pushing to get there. I just know the funds from Pedal the Cause will get everyone fighting cancer across the finish line.” ›
They got their answer when St. Louis Children’s Hospital asked if Vivian would serve as co-captain of its Pedal the Cause team. “This is year seven of the Pedal the Cause ride to end cancer,” says Lee Fetter, president of the St. Louis Children’s Hospital Foundation and the hospital’s team captain. “The day of the ride is always packed with the kind of emotion that comes from so many people coming out for such an important cause.” Last year, the event raised nearly $1 million for pediatric cancer research. That money has been put to good use in the Children’s Discovery Institute (CDI) McDonnell Pediatric Cancer Center research labs on the Washington University School of Medicine campus in St. Louis. While medical science has come a long way in developing treatments for leukemia in children Vivian’s age and older, it still has a long way to go to successfully treat infant leukemia (IL). The deadliest of all pediatric leukemias, IL arises before a child is even born. Pediatric oncologist and CDI researcher Todd Druley, MD, PhD, pediatrics, has found that, while parents of children with IL do not get cancer, the infants inherit a significant enrichment of rare and damaging genetic variants in leukemia-associated genes. In particular, every infant with acute myeloid leukemia (AML) inherits two damaged copies of MLL3, one from each parent, suggesting that AML requires the dysfunction of MLL3. Dr. Druley is now sequencing all the genes from non-cancer DNA of 150 IL patients and their parents.
“The day of the ride is always packed with the kind of emotion that comes from so many people coming out for such an important cause.” – Lee Fetter, president |7 Children’s Hospital Foundation
Children’s Discovery Institute ›
BOARD OF MANAGERS Chair: Raymond R. Van de Riet Jr. President, Aero Charter Inc.
Keith S. Harbison Managing Partner, Alitus Partners, LLC
Andrew E. Newman Chairman, Hackett Security, Inc.
Dale L. Cammon Chairman and Co-Chief Executive Director, Bryant Group, Inc.
Jennifer Lodge, PhD Professor, Molecular Microbiology Associate Dean for Research, Washington University School of Medicine Vice Chancellor for Research, Washington University
David H. Perlmutter, MD (Ex-officio) Executive Vice Chancellor for Medical Affairs and Dean, Washington University School of Medicine
Lee F. Fetter Group President, BJC HealthCare President, St. Louis Children’s Hospital Foundation Daniel Getman, PhD Retired President, Kansas City Area Life Sciences Institute Former Vice President, Pfizer R&D Director, St. Louis Laboratories Jeffrey I. Gordon, MD Dr. Robert J. Glaser Distinguished University Professor Director, Center for Genome Sciences and Systems Biology Washington University School of Medicine
Joan Magruder (Ex-officio) President, St. Louis Children’s Hospital Richard J. Mahoney Retired Chairman and CEO, Monsanto Company Distinguished Executive in Residence at the Weidenbaum Center on the Economy, Government and Public Policy, Washington University
Gary A. Silverman, MD, PhD Executive Director, Children’s Discovery Institute Chairman, Department of Pediatrics The Harriet B. Spoehrer Professor of Pediatrics, Washington University School of Medicine Pediatrician-in-Chief, St. Louis Children’s Hospital Kelvin R. Westbrook President and Chief Executive Officer, KRW Advisors, LLC
James S. McDonnell III Retired Corporate Vice President, McDonnell Douglas Corporation
St. Louis Children’s Hospital Foundation One Children’s Place St. Louis, MO 63110 A N U P D AT E F O R PA R T N E R S O F T H E C H I L D R E N ' S D I S C O V E R Y I N S T I T U T E
INSIDE
THIS ISSUE›
Inside the Epicenter for Cellular Imaging . . . . . . . . . . . . . . . . . . . . . . . . cover Clocking Asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 4 Brett Gets His Wish. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 5 New CDI Studies Underway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 6 Riding for Vivian. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . page 7
The Children’s Discovery Institute is a multidisciplinary, innovation-based research partnership between St. Louis Children’s Hospital and Washington University School of Medicine. Founded in 2006, the Institute has awarded more than $50 million in scientific grants for pediatric research projects aimed at some of the most devastating childhood diseases and disorders. ›
› Visit our website for
ongoing research updates.
› ChildrensDiscovery.org
This newsletter shares the accomplishments of the Children’s Discovery Institute with our stakeholders, particularly those whose generosity supports the research carried on by Institute investigators.
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If you have comments or questions about Pathways, please contact: Janice Bailey, Vice President, St. Louis Children’s Hospital Foundation 314.286.0971 / 888.559.9699 | jbailey@bjc.org SLC24970 8/16