Massachusetts General Hospital

The Pediatric Surgical Research Laboratories were established in 1973 under the directorship of Patricia K. Donahoe, MD, Chief Emeritus of the Pediatric Surgical Services.

The Pediatric Surgical Research Laboratories focus on areas of Developmental Biology which hold promise for clinical application. Patricia Donahoe, MD, and David MacLaughlin, PhD, have purified recombinant human Mullerian Inhibiting Substance (rhMIS), which directs normal male phenotypic development in the fetus by causing regression of the female reproductive duct. This fetal regressor, MIS, is now being developed as a novel treatment for cancers arising in the female reproductive tracts of adults. Work directed by Dr. MacLaughlin is underway to scale-up rhMIS production in mammalian cells with an industrial partner, for use of in preclinical tests against human tumors of Mullerian Duct origin. The first target will be ovarian cancers, followed by endometrial, and cervical cancers.  The laboratory has recently detected a stem cell enriched population in both the normal surface epithelium of the ovary, the site of origin of most human ovarian cancers, and in ovarian cancer cell lines where stem cell enriched population was shown to be remarkably responsive to MIS but paradoxically stimulated by Doxorubin and other chemotherapeutic agents.  Studies are underway to target these cancer stem cells selectively. Stem cell markers and functional studies will be used to select patients for inclusion in clinical trials using recombinant human MIS.

The laboratory also focuses on using array comparative genomic hybridization (aCGH) to elucidate micro-deletions and duplications as a robust genomic technology to select candidate genes contributing to Congenital Diaphragmatic Hernia (CDH).  Drs. Pober and Donahoe and our surgical colleagues at Massachusetts General Hospital and at Children’s Hospital of Boston along with collaborators from this country and abroad have enrolled over 400 patients in the study of the genetics of CDH and have established cell lines from patients, parents, and siblings. Mauro Longoni, MD, and Meaghan Russell, MPH, are using next generation whole exomic sequencing, single-nucleotide polymorphism (SNP) arrays, and embryonic diaphragm expression arrays followed by novel bioinformatics algorithms designed by Kasper Lage, Ph.D. to integrate this data.  In addition, we have employed whole exomic sequencing with Drs. Jonathan and Christine Seidman to detect gene variants shared in patients with have both diaphragm and heart anomalies and will integrate this data with expression arrays followed by bioinformatic analysis. This entire program is coordinated between the MassGeneral Hospital for Children, Children’s Hospital, Brigham and Women's Hospital, and the Broad Institute. Expression arrays have been done in collaboration with the Jackson Laboratory, and developmental studies and analyses have been done in collaboration with the University of Rochester. All of these studies are supported by NICHD.  Using the study of CDH as a template, it is the aim of the laboratory to apply the tools and algorithms devised herein to study the genetics of a number of other congenital abnormalities that affect the infants and children for whom we care in the Pediatric Surgical Department at the MassGeneral Hospital for Children, since here and in other children’s hospitals, children with birth defects fill one third of the hospital beds in the US.

Director: Patricia K. Donahoe, MD
Associate Director: David T. MacLaughlin, PhD
Executive Assistant: Wendy E. Rice
Program Coordinator: Caroline Coletti
Grant Manager: Nina Joshi

Principal Investigators

Allan M. Goldstein, MD
Lizabeth Perkins, PhD
Barbara P. Pober, MD
Cassandra Kelleher, MD
Cristina Ferrone, MD
Jaime Belkind-Gerson, MD
Kasper Lage Hansen, PhD
N. Alex Arango, PhD
Maria Loscertales, PhD

Co-Investigator

Mauro Longoni, MD

Postdoctoral Fellows

David Pepin, PhD
Xialong Wei, MD
Sophia Akbareian, PhD

Research Associate

Martha Reed, PhD

Clinical Investigators

Daniel Doody, MD
David Lawlor, MD
Daniel Ryan, MD
Peter Masiakos, MD    

Surgical Fellows

L. Andrew Benedict, MD
Katia Meirelles, MD
Matteo Ligori, MD
Alberto Pieretti, MD
Lillias Holmes-Maguire, MD

Research Fellows

Xialong Wei, MD
Sophia Akbareian, PhD

Collaborators

Jose Teixeira, PhD
Alessandro Alessandrini, PhD
Mien Hoang, PhD
Lewis Holmes, MD
Jay Wilson, MD
Shyamala Maheswaran, PhD
Charles Lee, PhD
Marcy MacDonald, PhD
Kate Ackerman, MD
Fred Preffer, PhD
Christopher Walsh, MD, PhD
David Dombkowski, PhD
Carol Bult, PhD
Mark Daly,PhD
Russell Jennings, MD
Soren Brunek, PhD
Christine Seidman, MD
Jonathan Seidman, PhD
Cynthia Morton, PhD
Demetrios Vavvas, MD

Lab Associates

Fontini Nicolaou
Casey Steiger
Adam Tracy

Predoctoral Student and Study Coordinators

Meaghan Russell, MPH
Anna Frangulov, BS

Congenital Diaphragmatic Hernia (CDH) Study

For over 10 years, a dedicated team of clinicians at MassGeneral Hospital for Children and Children’s Hospital Boston, scientists, and collaborators world-wide have been working together to better understand the genetic mechanisms underlying congenital diaphragmatic hernia (CDH) and abnormally small lungs (pulmonary hypoplasia). The cornerstones of this project are the individualized assessment of CDH patients, state of the art genetic screening, and integration of data from animal models (i.e. mice, chicks and flies) to identify new genes and molecular pathways necessary for diaphragm and lung development. We hope to harness the benefit of genetic analyses/testing to find potential treatment strategies that may prevent or alleviate CDH and pulmonary hypoplasia in the future.

We are particularly interested in finding a non-invasive pharmacologic approach to enhance maturation of hypoplastic lungs in utero. It is our estimation that even a small improvement of lung function prenatally, would have a profound effect on improving survival and reducing long term complications. 

The CDH study, which is funded by the National Institutes of Health, has recently expanded to include several additional research centers, which have world-renowned expertise in analyses of whole-genomic variation, mutant mouse model development and embryonic characterization, and bioinformatic assessment of complex anomalies. It is with great hope that our strategy will serve as a model for studies of other genetically complex congenital malformations.

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