Patricia Donahoe, M.D.
Physician Investigator (NonCl)
Pediatric Surgery, Research Institute
Marshall K. Bartlett Distinguished Professor of Surgery
Harvard Medical School
Pediatric Surgery, Massachusetts General Hospital
Harvard Stem Cell Institute
|MD Columbia University College of Physicians & Surgeons 1964|
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 her colleagues 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 is underway to scale-up rhMIS production in mammalian cells with an industrial partner, for use in preclinical and clinical trials 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 primary and established 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 disruptive single nucleotide polymorphisms and micro-deletions and duplications using whole exomic sequencing and array comparative genomic hybridization (CGH) to select candidate genes contributing to Congenital Diaphragmatic Hernia (CDH).
Dr. 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,, Meaghan Russell, PhD and Frances High, MD, PhD are using next generation whole exomic sequencing, array CGH 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. This entire program is coordinated between the MassGeneral Hospital for Children, Childrens Hospital, Brigham and Women's Hospital, and the Broad Institute.
Transcriptome 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.