LOS ANGELES, May 3, 2007 (PRIME NEWSWIRE) -- Pediatric surgeon/scientist Patricia Donahoe, M.D., internationally known for her work in understanding the basic mechanisms of human malformations, and whose study of congenital abnormalities eventually may lead to in utero or post-natal therapies to treat such anomalies, was featured in The Saban Distinguished Lecturer Series at The Saban Research Institute of Childrens Hospital Los Angeles on Friday, April 27, 2007. Dr. Donahoe discussed "The Genetics of Congenital Diaphragmatic Hernia: Clues to Future Treatment Strategies."
Dr. Donahoe serves as director of the Pediatric Surgical Research Laboratories and chief emerita of pediatric surgical services at Massachusetts General Hospital, where she has worked for more than three decades. Dr. Donahoe is the Marshall K. Bartlett Professor of Surgery at the Harvard Medical School.
"Dr. Donahoe discovered the molecular sequence of the growth factor gene MIS (Mullerian Inhibiting Substance), which directs the correct formation of the genitalia and urinary tract," said David Warburton, DSc., M.D., FRCP, FRCS, department vice chair and leader of the Developmental Biology Program at The Saban Research Institute at Childrens Hospital Los Angeles, and professor of pediatrics, surgery and craniofacial biology at the Keck School of Medicine of the University of Southern California and the USC School of Dentistry. "Now she is working to discover the molecular basis of another common and devastating anomaly called congenital diaphragmatic hernia (CDH)." In this disease, which has high morbidity and mortality in newborns, diaphragm atresia allows the intestines to herniate or protrude into the chest.
"Dr. Donahoe's work is of particular interest to members of the Developmental Biology and Regenerative Medicine Program at The Saban Research Institute and Childrens Hospital's department of Surgery who are working on related mechanisms of childhood malformation and tissue regeneration," Dr. Warburton said.
Dr. Donahoe has made many contributions to science in her pursuit of the biology of MIS. Early in her career, she noted that many malignancies were of Mullerian duct origin and observed that the male embryo was capable of completely regressing the Mullerian duct. Consequently, she investigated whether natural biologic regressors of Mullerian development could be used to inhibit the growth of malignancies of Mullerian origin.
She developed the biochemical skills to isolate MIS, and, using molecular techniques, she and her colleagues produced recombinant MIS to study its biological properties. Her laboratory developed a radio immune assay (RIA) for MIS, still a standard diagnostic tool in the differential diagnosis of children with ambiguous genitalia and in monitoring malignancies of Mullerian origin. Dr. Donahoe and her collaborators elucidated the transcriptional control mechanism of the MIS gene and the role of MIS in the biology of the developing gonad.
She has received research prizes and honorary degrees for her work on MIS, which is being developed as a therapeutic for ovarian and other reproductive cancers. She hopes to bring understanding to the genetics of congenital abnormalities that will lead to therapies that might be instituted in utero or shortly after birth to alleviate some of these conditions.
Dr. Donahoe presided over one of the busiest pediatric surgical services at Massachusetts General Hospital, focusing her attention on abnormalities of the genitourinary system and ambiguous genitalia, as well as tracheal abnormalities and other urological anomalies. On the basis of these contributions, she became the first female professor of surgery in the history of Harvard Medical School, a member of the National Academy of Sciences, the American Academy of Arts and Sciences and the Institute of Medicine, a fellow of the American Association for the Advancement of Science and a trustee of Boston University.
Dr. Donahoe is an associate member of the Broad Institute of Massachusetts Institute of Technology and Harvard University and a principal faculty member of the Harvard Stem Cell Institute. She is a member of a number of scientific advisory boards, and she has published more than 230 peer-reviewed publications in developmental biology concentrating on MIS as a potential anti-cancer agent against human ovarian carcinomas, the genetics of sex differentiation, and the genetics of other congenital anomalies such as CDH.
Dr. Donahoe has trained a generation of young surgeons and endocrinologists in developmental biology, many now occupying research chairs around the world. She also has sustained competitive National Institutes of Health funding for over 30 years.
She represents a modern paradigm of an able physician/surgeon, an outstanding teacher and mentor, a superb scholar and an innovative investigator for more than three decades at Massachusetts General. There, she also served on the institution's general executive committee, chief's council, and on the executive committee on research, which she has chaired for three years. She received the Koch award of the Endocrine Society in 2004.
Dr. Donahoe told the Saban Research Institute audience that she had great admiration for the work being done at Childrens Hospital Los Angeles. "It's a pleasure to be here and to have watched pediatric surgery and developmental biology grow and develop here. I would venture to say that at this time you have become one of the most in-depth surgical and developmental biology programs of any institution in the country."
She focused her remarks on the genetics of congenital anomalies, particularly the genetics of CDH. "Using a combination of genome-wide Single Nucleotide Polymorphic (SNP) analysis and array-based Comparative Genomic Hybridization, we were able to detect a mutation that causes CDH," she said.
Yet, identifying the genetic culprits responsible for causing these anomalies was only the beginning for Dr. Donahoe and her colleagues. "The next step is to test this mutation in the larger cohort of CDH patients," she said.
And the Holy Grail?
"The next challenge will be to use this finding to develop an in-utero or post-natal treatment strategy to ameliorate the severity of CDH and thus improve the outcome of this severe congenital anomaly.
"Furthermore, we must apply the methodology used here as proof of principle, to attack other severe congenital anomalies that afflict our pediatric population, as these account for at least one-third of our hospital beds in pediatric hospitals across the nation."
Dr. Donahoe said there has been a radical change in the way research is being done. Just as today's scientists have more tools at their disposal than ever before to investigate developmental biology, there has been a paradigm shift in the way those investigations are handled. Instead of researchers working individually, large groups of investigators from different disciplines now pool their knowledge to explore and resolve a specific question.
She predicts that the cost of genetic sequencing should be reduced dramatically in the next year or so, and as it does, tertiary hospitals should begin to establish cell lines routinely on all new patients with congenital anomalies.
Such information could greatly expedite the work of researchers, and enable them to find solutions to help avert or cure the heartbreaking congenital anomalies that put enormous emotional and economic strain on patients, their families and the health care system. "We really firmly believe this should be done at institutions like Childrens Hospital Los Angeles," she said.
Dr. Warburton, who has worked at Childrens Hospital for nearly 30 years, said he shared Dr. Donahoe's optimism that cures for devastating congenital anomalies now seem promisingly close.
"I can't tell you how exciting this is to see that we can now understand the molecular and genetic basis for complex anomalies that we deal with every day," Dr. Warburton said.
Founded in 1901, Childrens Hospital Los Angeles has been treating the most seriously ill and injured children in Los Angeles for more than a century, and it is acknowledged throughout the United States and around the world for its leadership in pediatric and adolescent health.
Childrens Hospital is one of America's premier teaching hospitals, affiliated with the Keck School of Medicine of the University of Southern California for more than 75 years. It is a national leader in pediatric research.
Today, physician-scientists at Childrens Hospital Los Angeles address the most vexing pediatric medical problems and discover important new therapies for children everywhere, including advances in cancer care, gene transfer, stem cell and organ transplantation and diabetes. The Saban Research Institute is among the largest and most productive pediatric research facilities in the United States, with 93 investigators at work on 200 laboratory studies, clinical trials and community-based research and health services. It is one of the few free-standing research centers in the nation to combine scientific laboratory inquiry with patient clinical care -- dedicated exclusively to children -- and its base of knowledge is widely considered to be among the best in pediatric medicine.
Programs and initiatives at The Saban Research Institute include the Cancer Program, the Cardiovascular Research Program, the Community, Health Outcomes and Intervention Research Program; the Developmental Biology Program; the Gene, Immune and Stem Cell Therapy Program; the Childrens Imaging Research Program; the Neuroscience Program/Childrens Brain Center; and the Microbial Pathogens Initiative.
Clinical research is conducted under the auspices of the Center for Endocrinology, Diabetes and Metabolism; the Childrens Center for Cancer and Blood Diseases; the Childrens Clinical Investigation Center; The Heart Institute; the Childrens Orthopaedic Center; and the USC-CHLA Institute for Pediatric Clinical Research.
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