Solving the Mystery of Disease Through Research

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Department of Pediatrics Annual Report – 2023

Molecular Genetics

Banner graphic for the Department of Pediatrics Annual Report for 2023

The primary mission of the Division of Molecular Genetics is research. The division operates across several scientific and administrative areas of the university, with studies focusing on the physiology and genetics of body weight homeostasis and diabetes and the molecular physiology of DNA replication. The laboratory is also the location of the Molecular Biology/Molecular Genetics Core laboratory of the New York Nutrition and Obesity Research Center and the Columbia Diabetes Research Center (both NIH centers).

The division has nationally recognized clinical and research programs, including:

  • Russell Berrie Foundation Programs
    • Berrie Program in Cellular Therapies of Diabetes: Evaluates the molecular basis for the development and function of insulin-producing cells in the pancreas and hypothalamic cells of the brain
    • Russell Berrie Foundation Obesity Research Initiative: Promotes transformative research in the neuroscience of ingestive behavior and body weight regulation
  • New York Nutrition and Obesity Research Center (NYNORC)
    • NYNORC focuses on the etiology, pathophysiology, and complications of obesity; treatment strategies; the physiology of weight regulation; and new tools and strategies for the study of nutrition and obesity.
  • Columbia Diabetes Research Center
    • The center provides research support for investigators pursuing research on diabetes and metabolic disorders.
    • Screening for Monogenic Forms of Diabetes and Obesity:
      • We receive samples from around the world including for genetic evaluation of neonatal diabetes, isolated familial diabetes, MODY, Wolfram syndrome, and obesity.

Faculty Research Areas of Expertise

  • Michael Rosenbaum, MD: Regulation and responses of behavioral, metabolic, neurological, neuroendocrine, and autonomic system to changes in body weight.
  • Vidhu Thaker, MD: Genetic determinants of severe early childhood obesity and its clinical consequences for children from minority populations; the impact of maternal metabolism on fetal development related to obesity.
  • Yiying Zhang, PhD: Metabolism of obesity and leptin biology; molecular physiology of the Prader Willi Syndrome.
  • Wendy K. Chung, MD, PhD: Performs human genetic research of monogenic and complex traits, including congenital heart disease, pulmonary hypertension, breast cancer, pancreatic cancer, obesity, diabetes, and autism. Maps and clones human genes. Dr. Chung became the Chair of Pediatrics at Boston Children's Hospital/Harvard Medical School in July 2023.
  • Claudia Doege, MD: Elucidates the neuro-molecular mechanisms of human obesity to gain insights into the molecular neurophysiology of body weight regulation in humans.
  • Dietrich M. Egli, PhD: Studies genome stability and the cell cycle in early embryonic development, during somatic cell reprogramming and cell differentiation. Uses stem cell-derived human islets to understand molecular physiology of diabetes.
  • Charles LeDuc, PhD: Focuses on the molecular neurophysiology of the regulation of mammalian energy homeostasis.
  • Lori Zeltser, PhD: Explores how development and environment impacts body weight regulation and influence later susceptibility to obesity and eating disorders.
  •  Rudolph Leibel, MD: The genetics of obesity and non-insulin-dependent diabetes (diabetes mellitus type 2); uses cells derived from human stem cells to understand the biology of body weight regulation and diabetes. Role of the cerebellum in body weight homeostasis.

Education

The Division of Molecular Genetics provides opportunities for graduate students to receive training and mentorships leading to a doctorate degree. Interested students who have been accepted into the Columbia University Graduate School of Arts and Sciences can rotate through our laboratories before deciding whether to pursue their research projects in our labs under the mentorship of our faculty.

Learn More About Our Division

Major Grants

  • New York Nutrition-Obesity Research Center studies the etiology, treatment strategies and the physiology of weight. NIH/NIDDK (P30DK26687-43). Principal Investigator: Rudolph Leibel, MD; Co-Investigators: Wendy Chung, MD, PhD, Claudia Doege, MD, Dieter Egli, PhD, Vidhu Thaker, MD, Yiying Zhang, PhD, and Charles LeDuc, PhD.
  • Diabetes & Endocrinology Research Center to promote interactions among research groups in diabetes, obesity, lipid metabolism, structural biology, immunology and beta cell transplantation. NIH/NIDDK (P30DK63608-22). Principal Investigators: Domenico Accili, MD and Rudolph Leibel, MD.
  • The GUARDIAN (Genomic Uniform screening Against Rare Diseases In All Newborns) is a pilot research study using genome sequencing and analysis of 250 conditions to screen newborns for treatable genetic conditions using the dried blood spot collected already for screening. Wendy Chung and Rudy Leibel
  • Center for identification and study of individuals with atypical diabetes mellitus. NIH/NIDDK (U54DK118612-05). Principal Investigators: Louis Philipson, MD, PhD and Rudolph Leibel, MD.
  • Predictors of recidivism to obesity in weight-reduced individuals. NIH/NIDDK (4UH3 DK128302-02). Principal Investigators: Rudolph Leibel, MD, Dympna Gallagher, EdD, Laurel Mayer, MD, and Michael Rosenbaum, MD.
  • SNORD109a expression across the human hypothalamus and cerebellum. The Foundation for Prader-Willi Research. PI: Claudia Doege, MD.
  • Virtual systemic identification of drug targets of obesity candidate genes. NIH/NIDDK (R01DK135938-01). PI: Lu, Yingchang / CU: Claudia Doege, MD
  • Neuroanatomic and functional characterization of cerebellar circuits mediating ingestive behaviors. NIH/NIDDK (R01DK131086-03). Principal Investigators: Nathaniel Sawtell, PhD and Rudolph Leibel, MD.
  • Establishing the role of OCRL as a novel ciliary gene in weight regulation in human and murine models. NIDDK (1R21DK129893-01A1). Principal Investigator: Vidhu Thaker, MD; Co-Investigator: George Stratigopoulos, PhD.
  • CTSA. NIH UL1 TR00040. Co-Investigator Associate Program Director: Michael Rosenbaum, MD (PI-Reilly)
  • Metabolic impact of antiretroviral therapy regimens on people living with HIV. NIH (R01 DK131503-01). Co-Investigator: Michael Rosenbaum, MD (PI Shivakoti).
  • Maternal glycemia and early childhood outcomes (MAGNET) study: pilot study Irving Institute Collaborative and Multidisciplinary Pilot Research – Integrating Special Populations. (CaMPR-ISP) pilot. PI: Vidhu Thaker, MD
  • Dissemination and Outreach Core, Prospective Genetic Risk Evaluation and Assessment (PROGRESS) in Autism. NIH/NICHD (1P50HD109879-01). Principal Investigators: Jeremy Veenstra-VanderWeele, MD and Wendy Chung, MD, PhD
  • Developmental Mechanisms of Trachea-Esophageal Birth Defects. NIH/NICHD (P01HD093363-06). Principal Investigators: Aaron Zorn, PhD, and Wendy Chung, MD, PhD. Co-Investigator: Yufeng Shen. PhD.
  • Gene mutation and rescue in human diaphragmatic hernia. NIH/NICHD (5P01HD068250). Principal Investigators: Patricia Donahoe, MD, Wendy Chung, MD, PhD., Yufeng Shen, PhD.
  • Role of the Kinesin KIF1A in Neurological Disease. NIH/NINDS (5R01NS114636-04). Principal Investigators: Richard Bert Vallee, PhD and Wendy Chung, MD, PhD.
  • Identifying and applying genetic variation relevant to clinical outcomes for individuals with congenital heart disease. NIH/NHLBI (5U01HL153009-04). Principal Investigators: Wendy Chung, MD, PhD, Bruce D. Gelb, MD, and Yufeng Shen, PhD.
  • COVID Recovery Corps. Chan Zuckerberg Initiative Foundation. Principal Investigator: Wendy Chung, MD. PhD. Co-Investigator: Charles Leduc, PhD, Steve Spitalnik, PhD.
  • Jordan’s Guardian Angels - Clinical Characterization of PPP2R5D Mutations. University of California, Davis. Principal Investigator: Wendy Chung, MD, PhD.
  • Ovid Research Collaboration for the development of treatments for patients with neurogenetic disorders. Ovid Therapeutics. Principal Investigator: Wendy Chung, MD, PhD; Co-Investigator: Charles Leduc, PhD
  • A Combination Retrospective and Prospective Natural History Study of Patients with Sanfilippo Syndrome Type D (MPS IIID) Disease as amended from time to time and incorporated herein by reference. Phoenix Nest Inc. Principal Investigators: Wendy Chung, MD, PhD, Morales Corado, Jose Andres, MD.
  • In vivo analysis of human islet graft infiltration and its immunomodulation by antigen-specific therapy. Juvenile Diabetes Research Foundation. JDRF 2-SRA-2022-1220-S-B. Principal Investigators: Remi Creusot, MD, and Dieter Egli, PhD.
  • Thymic selection abnormalities in Type 1 Diabetes. NIH (R01AI177872-01). Principal Investigators: Sykes, Megan (Contact PI); Winchester, Robert J. (MPI) Co-Investigator: Dieter Egli, PhD.
  • DNA repair pathway choice mediates somatic cell reprogramming. NIH/NIGMS (R01GM132604). Principal Investigator: Dieter Egli, PhD.
  • Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk. NIH/NIDDK (5R01DK127778). Principal Investigator: Dieter Egli, PhD.
  • The essentialome of the early differentiation and disease modeling using genome-wide screening in haploid human pluripotent stem cells. US-Israel Binational Science Foundation. Principal Investigator: Nissim Benvenisty, MD, PhD; Co-Principal Investigator: Dietrich Egli, PhD.
  • Preventing genome instability and developmental failure in human fertility treatments. TRx/ACT Pilot Award. Principal Investigator: Dieter Egli, PhD.
  • DNA replication dynamics and genome fragility in pancreatic beta cells. The CSCI and the Seed Fund Award. Principal Investigator: Dieter Egli, PhD.
  • CFTR function in human beta cells in a stem cell model of CFRD. Dartmouth College P&F award. Principal Investigator: Dieter Egli, PhD.

Selected Publications

  • Thaker VV, Kwee LC, Chen H, Bahnson J, Ilkayeva O, Muehlbauer MJ, Wolfe B, Purnell JQ, Pi-Sunyer X, Newgard CB, Shah SH, Laferrère B; Look AHEAD Research Group. Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions. Obesity (Silver Spring). 2023 Nov 14. Epub ahead of print. PMID: 37962326.
  • Guo K, Carolan D, Leibel RL, Zhang Y. Assessing Dgkk as a Snord116 target in the pathogenesis of PWS. Oral Presentation at 2023 Annual Symposium, Foundation for Prader-Willi Research, Denver, CO, Oct 4-6, 2023 (Abstract).
  • Herb BR, Glover HJ, Bhaduri A, Colantuoni C, Bale TL, Siletti K, Hodge R, Lein E, Kriegstein AR, Doege CA, Ament SA. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus. Science Advances, 2023;9(45)
  • Sui L, Du Q, Romer A, Su Q, Chabossau P, Xin Y, Kim J, Kleiner S, Rutter G, Egli D. 2023. ZnT8 loss of function mutation increases resistance of human embryonic stem cell derived beta cells to apoptosis in low zinc condition. Cells. doi: 10.3390/cells12060903. PMID: 36980244
  • Skowronski AA, Leibel RL, LeDuc CA. Neurodevelopmental programming of adiposity: contributions to obesity risk. Endocr Rev. 2023 Oct 31:bnad031. doi: 10.1210/endrev/bnad031. Epub ahead of print. PMID: 37971140
  •  Zhang Y, Sui L, Du Q, Haataja L, Yin Y, Viola R, Xu S, Nielsson CU, Leibel RL, Barbetti F, Arvan P, Egli D. Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identitybioRxiv. 2023 Sep 15:2023.09.01.555839. doi: 10.1101/2023.09.01.555839.PMID: 37745320
  • Rosenbaum M, G Foster. Novel concepts to investigate and promote weight loss vs. weight loss maintenance. Nat. Metabolism, 5: 1266-74:2023.
  • Zhu N, LeDuc CA, Fennoy I, Laferrère B, Doege CA, Shen Y, Chung WK, Leibel L. Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity. NPJ Genom Med. 2023 Oct 21;8(1):33. doi: 10.1038/s41525-023-00376-7. PMID: 37865656; PMCID: PMC10590409
  • Solomon BD, Chung, WK. Artificial Intelligence and the Impact on Medical Genetics. Am J Med Genet C Semin Med Genet. 2023 Sep;193(3):e32060. doi: 10.1002/ajmg.c.32060. Epub 2023 Aug 10. PMID: 37565625.
  • Lewis M, Hsieh A, Qiao L, Tan R, Kazzi B, Channing A, Griffin E, Jobanputra V, Su J, Chowdhury S, Kochilas L, Gaynor JW, Lee T, Goldmuntz E, Russell M, Mital S, Firouzi MT, Bruekner M, Newburger J, Shen Y, Chung WK. Association of Predicted Damaging De Novo Variants on Ventricular Function in Individuals with Congenital Heart Disease. Circ Genom Precis Med. 2023 Apr;16(2):e003900. doi: 10.1161/CIRCGEN.122.003900. PMID: 36866680. PMCID: PMC10121832 (available on 2024-04-01).
  • Flex E, Albadri S, Radio FC, Cecchetti S, Lauri A, Priolo M, Kissopoulos M, Carpentieri G, Fasano Venditti M, Bellacchio E, Welch CL, Colombo PC, Kochav SM, Chang R, Bressi R, Trivisano M, Micalizzi A, Maglicocca V, Mancini C, Pizzi S, De Santis F, Rosello M, Specchio N, Compagnucci C, McWalter K, Chung WK, Del Bene F, Tartaglia M. Dominantly acting KIF5B variants with pleiotropic cellular consequences cause variable clinical phenotypes. Hum Mol Genet. 2023 Jan 13;32(3):473-488. PMID: 36018820. PMCID: PMC9851748.

Highlights

Father-Daughter Super Duo Inspires on Father’s Day

Father-daughter team Drs. Natasha and Rudolph Leibel work in parallel at the forefront of science and medicine to improve the treatment of patients with diabetes and obesity.

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