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Cracking the code of cellular reprogramming

December 10, 2014

Dr. Peter Tongue, Dr. Ian Rogers, Dr. Samer Hussein, Dr. Andras Nagy, Dr. Mira Puri
An international consortium, led by Dr. Andras Nagy's laboratory at Mount Sinai Hospital's Lunenfeld-Tanenbaum Research Institute has conducted the first high resolution characterization of molecular events required for the formation of stem cells from specialized cells, a process called cellular reprogramming. The team also identified a new type of stem cell called F-class that has unique properties compared to the previously known stem cell types. This discovery has importance by opening new avenues for generating useful "designer" cells, which might not necessarily exist in the body or during development but could be safer and more efficient when used for therapy.
The importance and anticipated impact of this research is supported by the unprecedented coordinated publication of 5 scientific articles in the highly respected journals, Nature and Nature Communications on December 11, 2014.
The extremely in-depth analysis of the process of reprogramming specialized cells to stem cells focused on learning how to control the path to either the new F-class stem cell versus "traditional", embryonic-like stem cells. Comparing the two cell types revealed that the new class of stem cells is easier, less expensive and faster to grow compared with the embryonic-like stem cells. Because of these properties, the new F-class stem cells can be produced more economically in very large quantities, which will speed up drug screening efforts, disease modeling and eventually the development of treatments for different illnesses.
The Nagy Laboratory at Mount Sinai Hospital's Lunenfeld-Tanenbaum Research Institute is historically a stem cell laboratory. The team joined research on reprogramming shortly after Dr. Shinya Yamanaka's discovery of induced pluripotent stem (iPS) cells, for which he received the Nobel Prize in 2012.
Dr. Andras Nagy's laboratory was the first to report a method of producing stem cells without the need for viruses that could harm the genetic material. This work was published in 2009, also in the journal Nature. For this discovery Dr. Nagy was selected for the first annual Scientific American Top 10 Honor Roll in 2009, which he shared with U.S. President Barack Obama, Bill Gates, Michael Bloomberg and others.
In 2010, Dr. Nagy received financial support from the Ministry of Science and Innovation of Ontario, from his industry partner Pfizer, from the Canadian Institutes of Health Research and McEwen Centre for Regenerative Medicine to carry out the research that resulted in the current 5 publications. This support allowed his group to engage with other stem cell research experts from laboratories in Australia, South Korea and The Netherlands. The resulting consortium generated and analyzed an unprecedented dataset, uncovering the molecular events underlying biological processes of cell fate change toward stem cells.
"It was an enormously enlightening feeling that a single scientific question was able to transcend geographical distances, time zones, international borders and cultural differences. Each of the close to 50 scientists with unique expertise contributed to a unified product which none of us as individuals could even get close to," said Dr. Andras Nagy, the senior author of the two Nature Articles.
"We are incredibly proud of Dr. Nagy's leadership of this extraordinary team. Every one of the researchers involved in this historic effort is driven by their desire to improve therapies for patients. These papers reinforce how strategic investment in the best scientific research can truly transform our understanding and lead to new therapeutic possibilities," says Dr. Jim Woodgett, Director, Lunenfeld-Tanenbaum Research Institute.
"This is an incredibly exciting announcement, and it's a fine example of the groundbreaking research that takes place here in Ontario," says Hon. Eric Hoskins, MPP (St. Paul's), Ontario's Minister of Health and Long-Term Care. "Stem cell research was pioneered here in the province, and I am proud that we continue to make world-class breakthroughs in this life-saving area of research."
"Ontario is proud to support the work of Dr. Nagy and the Lunenfeld-Tanenbaum Research Institute," says Hon. Reza Moridi, Ontario's Minister of Research and Innovation. "This discovery has the potential to lead to improved disease treatments not only for millions of Ontarians, but people worldwide, and demonstrates Ontario's ongoing leadership in the field of stem cell research."
Other quotes:
"This project has been a real adventure for us into integrative biology in a new era of global science," says Dr. Albert Heck, Scientific Director of the Netherlands Proteomics Center, and also affiliated with the Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University. "Our group determined the faith of every protein during this process, picking up many known and novel markers for transitions to iPS cells and the new F-class stem cells." 
"In a nutshell, this international consortium contributed to make a thorough roadmap of epigenomic changes during reprogramming to pluripotency." says Dr. Jeong-Sun Seo, Professor in the Department of Biochemistry at Seoul National University, College of Medicine, South Korea. "Our results reveal the crucial role that DNA methylation plays in the epigenetic switch that drives somatic cells to pluripotency."
"When the consortium met in Seoul in October 2012 to discuss each other's findings, there were two things that stood out for me," says Dr. Thomas Preiss, Professor at The John Curtin School of Medical Research in Canberra, Australia. "First, I was struck by the depth of data that was available across multiple "omic" levels. Second, it became clear to me that we had described the existence of distinct, experimentally accessible states of cellular pluripotency, with profound implications for future patient-derived stem cell therapy."
"The role of the group was to help the researchers have access to the vast information the Project Grandiose generated. Our platform is designed to let non-specialists view the genes involved and the many ways they are regulated," says Dr. Christine Wells, Associate Professor at the University of Queensland's Australian Institute for Bioengineering and Nanotechnology.
The research project, spearheaded by Dr. Andras Nagy at Mount Sinai Hospital's Lunenfeld-Tanenbaum Research Institute, involved close to 50 researchers in Canada, The Netherlands, South Korea, and Australia, over four years. The team has catalogued the major biological stages of the reprogramming process, identifying which combination of genes and proteins are associated with each step. The comprehensive dataset generated from this work acts as a detailed multi-dimensional map that will be used world-wide for even more discovery by hundreds of labs working on reprogramming, stem cells, cancer, fetal development and regenerative medicine.
Clinical Implications:
Stem cells hold enormous promise for future medicine aiming to treat and cure currently incurable and frequently devastating diseases such as blindness, Parkinson's, Alzheimer's, spinal cord injury, stroke, diabetes, blood and kidney diseases, and many others which are associated with tissue damage and cell loss. The molecular changes that lead to stem cells during reprogramming, are starting to be uncovered. The detailed analyses of the data generated and now reported in the five papers will help to better understand this process which is critical to generating safe and highly efficient sources for therapeutic cell production.
About the Lead Researcher:
Dr. Andras Nagy, a renowned stem cell researcher and the Canada Research Chair in Stem Cells and Regeneration, has been working out of Mount Sinai's Lunenfeld-Tanenbaum Research Institute for 25 years. He is a Professor at the University of Toronto's Department of Obstetrics & Gynaecology and at the Institute of Medical Sciences.
About the key principal investigators:
Dr. Jeong-Sun Seo is a Professor in the Department of Biochemistry at Seoul National University, College of Medicine. He is focusing on understanding how genomic and epigenetic variations affect pathological changes. He presently leads the ILCHUN Genomic Medicine Institute, Seoul National University (GMI-SNU) as a Director since 1997.
Dr. Albert Heck is a Professor of Biomolecular Mass Spectrometry and Proteomics at Utrecht University since 1998. Since 2003, he has been the scientific director of the Netherlands Proteomics Centre. Dr. Heck was awarded the HUPO Discovery Award in 2013 and EuPA's Proteomics Pioneer Award 2014.
 Dr. Thomas Preiss is a Professor of RNA Biology at The John Curtin School of Medical Research, The Australian National University in Canberra. Dr Preiss is well known for his research into the patterns and mechanisms of gene regulation at the RNA level with an international profile as one of Australia's foremost experts in this area. He was awarded the 2014 Julian Wells Medal for his contribution to the advancement of genome science in Australia.
Dr. Christine Wells is an Associate Professor at University of Queensland's Australian Institute for Bioengineering and Nanotechnology. She leads the Australian Stemformatics contingent, which is based at and built as the collaboration platform for Stem Cells Australia.
Dr. Peter Zandstra is a Professor at the University of Toronto, Institute of Biomaterials and Engineering, Department of Chemical Engineering and Applied Chemistry. He is the CSO of the Centre for Commercialization of Regenerative Medicine.
The Funders:
The Ontario Ministry of Research and Innovation's Global Leadership Round 2 in Genomics & Life Sciences Competition Program for enhancing genome and stem cell research in Ontario; Canadian Institutes for Health Research; McEwen Centre postdoctoral fellowship; and Pfizer.

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