research HORIZONSA Publication of the Cincinnati Children’s Research Foundation SPRING 2019 Mind Brain Behavior New Collaborative Works to Reconnect Fragmented Science contents SPRING 2019 | Mind Brain Behavior DEPARTMENTS FEATURES 02 New & Noteworthy 12 Rethinking Brain Collaboration >> Circadian | Hogenesch/Ruben/Wu Collaborative seeks to forge stronger research teams across >> Bone marrow transplants | Zheng disciplines. | Glauser, Stark >> Concussion guidelines | Wade >> RNA and obesity | Nakamura 16 Center for Pediatric Neuroscience >> Lab-grown esophagus | Wells Journey begins to explore neural networks and “brain tsunamis.” | Danzer, >> Autism genomics | Lu LaSarge, Skoch, Batie >> Cancer driving protein | Dasgupta/Chhipa >> HLH drug approval | Jordan 20 Alliance for Clinical, Translational Science >> Crohn’s disease prediction | Alenghat Brainstorming over coffee leads to unexpected collaborations. | Kashikar- >> Genomics and pregnancy | Muglia Zuck, Myer >> Immunotherapy limitation | Komurov >> Statins and PAP | Trapnell 24 Teaming Up Against Migraine Pain >> Genetics of PAH | Nichols/Pauciulo Seismic shift in pain science leading to new approaches for managing >> Sickle cell progress | Malik/Ware migraines. | Stark, Glauser, Powers, Hershey, Coghill >> Ebola vaccine | Spearman/Singh >> Asthma risk tool | Hershey/Biagini Myers 28 Honors & Grants Disruptions affecting the gene CHD8 can contribute to white matter damage in the brain, which may help explain why researchers have noted a link between that >> Takebe honored by Japan’s royal family gene and autism spectrum disorders. Read more on page 5. >> Van Ginkel named Great Cincinnatian >> Whitsett receives Trudeau Medal CINCINNATICHILDRENS.ORG/RESEARCH 1 your ethnicity is, your body’s internal clock regulates half your genome.“ Improving the Odds Says Ruben, “Overall this connects thou- Is Now the Time for sands of different drugs, both approved and experimental, to nearly 1,000 cycling genes.” of Bone Marrow Many of these genes code for proteins that help Circadian Medicine? transport or metabolize drugs are themselves Transplants -CASIN drug targets—including genes with well-known connections to the cardiovascular system. The experimental drug CASIN improved the harvest of donor The precise time you take your medicine blood stem cells and lessened toxicity in transplant recipients, could make all the difference in its effective- THE ULTIMATE ‘WEARABLE’? according to two preclinical studies led by our researchers, both ness, say researchers here. Next, first author Gang Wu, PhD, and col- recently published in Leukemia. John Hogenesch, PhD, Director, Center for leagues published findings Oct. 30, 2018, in Both studies were led by senior investigator Yi Zheng, PhD, Chronobiology at Cincinnati Children’s, led a PNAS, concluding that a number of cycling and a team of experts at the Cancer and Blood Diseases Institute. team of several collaborators on two recent genes in the skin function are more effective In June 2018, Zheng’s team reported using CASIN to mimic studies that significantly advance the science biomarkers for measuring an individual’s par- the action of the gene Cdc42, which helps regulate blood stem +CASIN of circadian medicine. The work involved col- ticular internal clock than current methods cells. Tests showed that CASIN effectively mobilized blood- laborators from several divisions at Cincinnati based on genes found in the blood. This study making stem cells and promoted their exit from the bone marrow. Children’s, as well as experts at Vanderbilt, included NIH funding and other sources. Criti- The harvested stem cells also were hardier following transplant the University of Pennsylvania and Procter cal data was provided by Procter & Gamble, than cells harvested with current clinical regimens. John Hogenesch, PhD & Gamble. which also paid for the clinical work involved. Then in September 2018, researchers used CASIN to make Marc Ruben, PhD, was first author for “We showed that human epidermis has the mouse bone marrow more receptive to healthy blood stem findings published Sept. 12, 2018, in Science a stronger clock than blood and developed a cells, lessening the chemotherapy needed prior to transplant. Translational Medicine, that found a surpris- panel of biomarkers that can phase individuals The researchers caution the procedure remains in preclini- A donor stem cell harvested from a mouse treated with CASIN (bottom) is depolar- ing number of genes affected by circadian to within three hours from a single sample,” cal testing and results from such studies may not translate to ized and shows several colorized polarity markers. This cell has better mobilization rhythms. The team developed the CYCLOPS the authors wrote. human patients. potential than the untreated stem cell in the top image. algorithm (CYCLic Ordering by Periodic Struc- The researchers emphasize that addi- ture) to analyze thousands of human tissue tional studies are needed before the findings samples to measure the timing of gene-to- can be applied to clinical practice. But the tissue interactions in 13 tissue types. findings suggest that a practical method may soon become available to allow doctors to Evidence-based OUR BODIES HAVE MANY CLOCKS instruct patients more precisely on when to “We identified rhythms in gene expression take medications at peak times for maximum Marc Ruben, PhD Guidelines Emerge across the body in a large and diverse group effectiveness, or at trough times to minimize of people,” Hogenesch says. “It doesn’t matter side effect risks. if you’re male, female, young or old, or what for Concussion Healthcare providers now have consistent, evidence- based guidance for diagnosing and managing mild traumatic brain injury, or concussion. Shari Wade, PhD, Director of Research, Division of Re- habilitation Medicine, was one of the clinical experts who worked with the Centers for Disease Control and Preven- tion (CDC) to develop 19 clinical recommendations that cover diagnosis, prognosis, management and treatment. The Gang Wu, PhD guidelines were published Sept. 4, 2018, in JAMA Pediatrics. The recommendations include several key, practice- changing guidelines, says Wade, including identifying risk factors that might contribute to slower recovery; advice on avoiding routine neuroimaging for diagnosis; and optimizing recovery by allowing children to return to non-sports activi- ties within days, rather than weeks, of injury. The CDC followed a rigorous process guided by the Left: This heat map of clock gene expression in skin from 239 donors shows robust population-based clock function in humans. Red American Academy of Neurology, and the 2010 National means correlated; blue indicates anti-correlated. Right: This CYCLOPS display shows conservation in timing of clock gene expression Academy of Sciences’ methodologies for developing evi- in mice and humans. Moving clockwise from 0 (~10PM), the outer circle shows when human genes peak, while the inner circle dence-based guidelines. The guideline authors also reviewed Shari Wade, PhD depicts mouse genes. 25 years of scientific research. 2 RESEARCH HORIZONS / SPRING 2019 CINCINNATICHILDRENS.ORG/RESEARCH 3 Deleting an RNA-Silencing Protein Findings Explain Speaks Volumes About Obesity Gene’s Role in Researchers here say that blocking an RNA-silencing protein in the Autism livers of mice keeps the animals from getting fat and developing diabetic Scientists here have clarified how mutations in the gene conditions. Findings appeared Sept. 10, 2018, in Nature Communications. CHD8 harm the brain and contribute to autism spectrum disorders. Takahisa Nakamura, PhD, and colleagues genetically deleted a They reported their findings June 18, 2018, in Developmental Cell. protein called Argonaute 2 (Ago2) from the livers of mice. Ago2 slows Previous studies had linked CHD8 mutations to autism and energy metabolism and the liver’s ability to process a high-fat diet. When abnormalities in the brain’s white matter, but the underlying biol- the scientists deleted the protein, it stabilized energy metabolism, staved ogy has been a mystery. off obesity and prevented the mice from developing diabetes and fatty This study showed that disruption of CHD8 hinders production liver disease. and maintenance of nerve insulation, harming the brain’s neuro- “Although this is still basic science, our findings may have important nal connections and contributing to white matter damage. Mice translational implications for metabolic disorders like diabetes, fatty engineered to lack CHD8 protein in the oligodendrocytes—cells liver diseases, and other obesity-associated illnesses,” says Nakamura, that produce the protective nerve sheath—exhibited behavioral a member of the Division of Endocrinology. “This allows us to explore anomalies and seizures, according to lead investigator Q. Richard the potential of finding a novel therapeutic approach that alters energy Lu, PhD, Division of Experimental Hematology and Cancer Biology. balance in obesity and modulates the associated diseases.” Although study results are early, Lu says the work could lead Takahisa Nakamura, PhD to treatments that restore function to faulty CHD8-dependent processes. This micrograph shows the presence of basic myelin protein and normal oligodendrocyte Scientists Grow First cell differentiation in the brain of a mouse. The cells form a protective sheath of Human Esophagus insulation around nerves in the outer layers of the brain. in Lab Researchers here have grown a human esophageal