Autophagy in Development and Disease

BCRP residents and physician-scientist couple Darius Ebrahimi-Fakari and Lara Walster

Autophagy is an intercellular pathway that is essential to the development and function of all major organs. Disorders of this pathway offer a unique opportunity to understand the importance in health and disease – a concept that current residents Lara Wahlster and her husband, Darius Ebrahimi-Fakhari, explore on a clinical, genetic and molecular level. While Lara’s work has focused on congenital anemias and hematopoiesis, Darius is interested in neurogenetic diseases and movement disorders. Their scientific paths often cross around autophagy.

Working with George Daley at Children’s Lara generated hematopoietic progenitor cells from induced pleuripotent stem cells of patients with Diamond-Blackfan anemia (DBA). Using an unbiased chemical screening she helped identify SMER28, a small molecule inducer of autophagy that enhances erythropoiesis in a range of in vitro and in vivo models of DBA
(Nat Cell Biol). These findings point to autophagy as a therapeutic pathway in DBA (Sci Transl Med). As a resident in the accelerated research pathway, Lara is working with her mentor and former BCRP graduate Vijay Sankaran to identify genetic variants that affect engraftment and clinical outcomes after stem cell transplantation.

As a student in the lab of Pamela McLean at MGH, Dari-us became interested in the role of autophagy in neurons, when he found that the Parkinson’s disease associated protein α- synuclein is targeted by this pathway (J Neurosci, Autophagy). In Mustafa Sahin’s laboratory at Children’s, he used Tuberous Sclerosis Complex (TSC) as a genetically tractable model of mTORC1-dependent autophagy in neurons (Cell Rep). For this work, Darius was awarded the Outstanding Junior Member Award from the Child Neurology Society and the Outstanding Investigator Award from the German Society for Pediatric Neurology. In addition, Darius has led several clinical research projects aimed at understanding rare genetic movement disorders associated with PRRT2 mutations (Neurology, Brain) and more recently hereditary spastic paraplegia type SPG47, a disorder again linked to deficits in autophagy. Most of his work is inspired by patients and families that he cared for as a medical student and as a resident at Children’s.

In other studies, Lara and Darius collaborate on diseases that share both hematologic and neurological problems, such as the lysosomal storage disorders (Hum Mol Gen). Following their research and clinical interests, Lara is going to fasttrack into a Hematology and Oncology Fellowship and Darius will join the Child Neurology Program after graduating from the BCRP.

Health Outcomes

BCRP resident Emily Bucholz

As an MD/PhD student at Yale, resident Emily Bucholz studied socio-demographic disparities in health outcomes and quantified the long-term impact of quality metrics on patient life expectancy. She has continued her work in quality measurement as a pediatric resident in the Integrated Research Pathway (IRP) studying pediatric readmissions under the mentorship of Dr. Mark Schuster and Dr. Jay Berry. Her work focuses on characterizing the timing and causes of pediatric readmissions as well as the association of pediatric and adult readmissions and trends over time. The goal of this research is to better understand when children are at greatest risk of readmission, how patterns of readmission vary by index diagnoses and causes of readmission, and whether large-scale readmission efforts in adult populations have had an effect on pediatric readmissions. In addition, she has continued to investigate sociodemographic disparities in health outcomes among children with single ventricle heart disease and disparities in cardiovascular risk factor awareness among young adults. She has been awarded young investigator awards by both the American Heart Association and the American College of Cardiology; and more recently, her work evaluating the relationship between hospital performance and patient life expectancy (N Engl J Med) was awarded one of the Top 10 Clinical Research Achievement Awards of 2017 by the Clinical Research Forum.

Emily will be staying at Boston Children’s for fellowship in pediatric cardiology.

Dark Matter of the Cancer Genome

Recent BCRP resident John Prensner

After completing undergraduate degrees in English literature and history, recent resident John Prensner embarked on a career shift towards the sciences. He took a research position at the then newly minted Broad Institute of Harvard and MIT and became absorbed in the study of cancer genomics. He followed this by enrolling in the MD/PhD program at the University of Michigan in Ann Arbor, where he completed his dissertation work under the mentorship of Arul Chinnaiyan. For his research, John delved into the “dark matter” of the cancer genome—the 98% which is not known to produce proteins and has few described func-tions. John’s work pioneered the use of next generation sequencing in human cancer research and used human prostate cancer samples to delineate an unknown network of long non-coding RNAs (lncRNAs). He discovered PCAT1 as a lncRNA that controls cell proliferation (Nat Biotechnol), functioning as a sponge that interferes with the ability of one microRNA to degrade the cMYC onco-gene (Neoplasia). He further found a separate function of PCAT1 as a regulator of genome maintenance through antagonism of the BRCA2 tumor suppressor gene (Ca Resch). He then defined the SChLAP1 lncRNA as a central mediator of cancer cell invasion and metastasis, functioning by blocking the SWI/SNF epigenetic complex and altering cell gene expression globally (Nat Genet). He also showed that SChLAP1 expression is one of the single best clinical predictors of prostate cancer relapse, metastasis, and death (Lancet Oncol). He was able to translate these findings into two patents with one commercial biomarker assay developed. As a BCRP resident, John has continued his research efforts back at the Broad Institute, under the mentorship of Todd Golub, where he has been working to characterize a class of unknown proteins, termed micropeptides, and how these micropeptides offer new clinical and therapeutic angles for translational cancer science. In other studies, John has been a collaborator on efforts to translate genomics to pediatric clinical medicine (JAMA) and is studying pediatric cancer patients who have had their genomes sequenced (Pediat Blood Cancer). John is currently an incoming pediatric hematology/oncology fellow at Boston Children’s/Dana-Farber Cancer Institute.