Monthly Archives: July 2015

Dr. Elaine Petrof

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Recurrent C. difficile infection (CDI) is an increasing problem in hospitals, and treatment options for recurrent CDI are limited. FMT (fecal microbial transplantation, or stool transplant) has proven effective for recurrent CDI, likely due to re-establishment of a healthy gut microbial ecosystem that restores colonization resistance against CDI. Using the same principles of colonization resistance, we sought to improve on FMT by developing a defined microbial ecosystem to accomplish this task.

RePoopulate: first studies of defined human microbiome therapy to treat disease. An ecosystem of 33 strains of commensal gut microbes was isolated from a healthy human donor, grown in the laboratory, and tested for antimicrobial susceptibility and “ecosystem robustness” using a continuous culture chemostat apparatus that mimics the conditions of the distal human gut. The bacterial ecosystem mixture was then administered by colonic infusion to two patients with recurrent C. difficile infections that had failed all standard-of-care therapies. We were able to show that, not only was this successful and feasible to do, but the patient microbiota in both cases remodeled to a composite of the original patient microbiota and the defined microbial community that we had administered. This study was a first-in-the-world proof of concept study that used a defined microbial ecosystem as human microbiome therapy to cure human disease.

By using a defined bacterial ecosystem grown in the lab under reproducible conditions, our study demonstrated the feasibility of using an alternative to fecal transplant that still employs the same concept of utilizing a microbial ecosystem to cure recurrent CDI. This approach would have many potential advantages over the use of stool transplant, including reproducibility, stability, and patient safety (as the absence of viruses and other pathogens can be ensured).

PSI was willing to take a chance on funding a highly translational and innovative, but “out-of-the-box” idea, that the traditional funding agencies viewed as too “high risk”/“high chance of failure” and would not support. Thanks to PSI, we were able to pursue our proof-of-concept study that went on to receive much attention internationally, both in the scientific press (Nature News) and lay media (BBC, CTV, NPR, Maclean’s, National Geographic, etc.). Had it not been for the support of PSI, this study would never have gotten off the ground.

Dr. Petrof is a clinician scientist in Infectious Diseases with a special interest in Clostridium difficile and other gastrointestinal infections. She completed her MD at the University of Toronto, and her clinical and research training at the University of Chicago. She is currently an Associate Professor in the Department of Medicine at Queen’s University. Dr. Petrof’s research interests focus on the microbiome, microbial-epithelial cell interactions in the gut, and the effects of intestinal bacteria on inflammation. Her team also studies commensal bacteria, probiotics and the gut microbiome under conditions of health and disease. Through a better understanding of mechanisms of action, these investigations will ultimately lead to a better understanding of the protective role of commensal gut microbiota during infection and inflammation, and lead to novel microbiome-based therapies for diseases such as Clostridium difficile infection.

Dr. John Kingdom

KINGDOM HeadshotI moved to Mount Sinai Hospital, University of Toronto from University College London, U.K. in 1998 to embark on a career combining basic research in placental complications of pregnancy with a clinical practice in high-risk pregnancy care (maternal-fetal medicine). The following year I started the “Placenta Clinic”, perhaps the first worldwide to offer comprehensive assessment of pregnancies at risk of “placental diseases” – and got my first grant – from PSI.

That initial work allowed me to recruit a talented molecular biologist, Ms. Dora Baczyk, who has remained with me ever since as my research associate. Together we were able to move this research program forwards. Following a successful PSI renewal in 2001, we were able to secure funding by CIHR in 2003. Since then I have maintained CIHR funding, with a 3rd successful renewal of the research program in 2014.

In parallel, we started to take an interest in how the anticoagulant drug heparin may improve pregnancy outcomes in women with placental dysfunction, receiving funding from PSI in 2007 to conduct a novel pilot randomized control trial where we assessed the drug’s target organ, namely the placenta. PSI continued to support our work in this area at the bench level, such that we developed the hypothesis that heparin may exert favorable actions on the placenta via non-anticoagulant mechanisms. This work too has now transitioned to CIHR funding to allow expansion of our translational medicine research, between maternal-fetal medicine, cardiology and pharmacology at UofT.

I am ever grateful to PSI for nurturing my research career here in Toronto; I have been fortunate to be able to combine a career in science aligned to my clinical practice in high-risk pregnancy care and in doing so, to be able to offer research training opportunities to all types of trainees.

John Kingdom graduated from Trinity College Dublin Medical School in 1984 and undertook Residency Training Programs in Paediatrics and Obstetrics-Gynaecology in Glasgow. He developed his research interests in the placenta during a Medical Research Council (UK) Research Fellowship. He did his Maternal-Fetal Medicine Fellowship at University College Hospital, London, followed by three years as Assistant Professor. In 1998 he was recruited to his current position as a Clinician-Scientist in Maternal-Fetal Medicine at Mount Sinai Hospital in Toronto. He established the Placenta Clinic with his colleague Dr. Rory Windrim in the Maternal-Fetal Medicine Division in 1999. His basic and clinical research interests in Placental Development and Pathology are currently funded by the Canadian Institutes of Health Research and a variety of donors; he has previously been funded also by the Ontario Physicians’ Services Incorporated Foundation and the Alternate Funding Plan Innovation Fund of Mount Sinai Hospital-University Health Network. He has held the Rose Torno Chair at Mount Sinai Hospital since 2005. He directed the University of Toronto Maternal-Fetal Medicine Fellowship Program for ten years until 2009. In 2011 he was President of the US-based Perinatal Research Society. In 2012 he was appointed Head of the Division of Maternal-Fetal Medicine at the University of Toronto and more recently was elected to the Chair of Obstetrics & Gynaecology at the University of Toronto, effective July 2013. John has published over 240 original peer review publications and supervises a wide range of Clinical and Basic Science Trainees.

His current research focuses on improving clinical outcomes in women at risk of “placental insufficiency”, advanced imaging methods in IUGR pregnancies and the non-anticoagulant actions of heparin in-vitro and in-vivo.