The notion of reproducibility is fundamental to good science.
If a finding cannot be reproduced by independent research groups, its relevance is very limited, regardless of its validity. It is therefore imperative that scientists describe their experiments in sufficient detail so that they can be reproduced, challenged and built upon.
However, due to recent technological advances in the biological and computational sciences, experimental protocols, data analysis and interpretation have become increasingly complex. This has made reproducing research findings more challenging.
As the number of high-profile cancer studies that cannot be reproduced continues to grow (see eLife Reproducibility Project), some researchers have suggested that the biomedical sciences are experiencing a “reproducibility crisis”.
To address this important issue, the US Food and Drug Administration (FDA) led the MicroArray and SEquencing Quality Control (MAQC/SEQC) projects to assess the reproducibility of the new high-throughput biotechnologies used in cancer research for diagnosis and prognosis. Recognizing that new technologies and analytical approaches are being developed at a rapid pace, members of the MAQC/SEQC consortium decided to form a new international society, the Massive Analysis and Quality Control (MAQC) Society, whose mission is to promote the best research practices for enhanced reproducibility.
As described in a letter published in Nature Biotechnology, the initial focus of the new society will be on data analysis. “While it is obvious that assays used in biomedical studies must be robust, the reproducibility of computational analyses is a relatively new concept that is yet to be fully adopted by the scientific community,” says Dr. Benjamin Haibe-Kains, Scientist at the Princess Margaret (PM) Cancer Centre and co-founder of the MAQC Society.
Given the complexity and diversity of the computational analyses used in biomedical research, the society will select examples of fully reproducible studies, which will be collectively analyzed in order to draft practical guidelines for future studies. “This is an ambitious initiative that will only be possible with the support of the society members who will directly benefit from the resulting guidelines,” adds Dr. Haibe-Kains.
To foster collaborations and the active involvement of the community, Carl Virtanen, Director and Research Lead of UHN Digital and head of the Bioinformatics and HPC Core, created the MAQC Society website. “I followed with great interest the previous efforts led by the FDA to assess the reproducibility of cutting-edge technologies used in cancer research and was involved in similar initiatives back in the era of microarrays. Because the Bioinformatics Core also runs clinical software pipelines for genetic testing at UHN which are, by law, mandated to be fully reproducible, I was eager to get involved and help build a web-resource for the new MAQC Society,” says Mr. Virtanen. “Data analysis is a critical part of all cancer studies, and we must ensure that the studies’ findings are fully reproducible. This initiative is vital and will help to ensure that the massive investments in cancer research deliver benefits to patients and the health system in the long-term.”
This initiative was supported by The Princess Margaret Cancer Foundation.
The international MAQC Society launches to enhance reproducibility of high-throughput technologies. Shi L , Kusko R, Wolfinger RD, Haibe-Kains B , Fischer M, Sansone SA, Mason CE, Furlanello C , Jones WD, Ning B, Tong W. Nature Biotechnology, Volume 35, Number 12, December 2017.
TGHRI researchers won three of the Canadian Society of Transplantation’s awards for 2017. The Canadian Society of Transplantation is the professional organization for physicians, surgeons, scientists and allied health professionals working in the field of transplantation; it has more than 600 clinical and research members from across Canada, covering all transplant fields.
Dr. Gary Levy (TGHRI Senior Scientist) won the Society’s prestigious Lifetime Achievement Award for his “internationally recognized work in the field of transplantation and participation in the development of transplantation activities in Canada.” Dr. Levy helped established the UHN Multi-Organ Transplant Program in 1990 and has since continued to make advances in transplantation research in his thriving lab.
Dr. Joseph Kim (TGHRI Clinical Researcher) received the Society’s Research Excellence Award for his body of research achievement and excellence in the field of transplantation. He is the Co-Director of the Kidney Transplant Program at UHN.
Dr. Nazia Selzner (TGHRI Scientist) received the Astellas Clinical Research Grant to investigate a novel approach to improve the outcome of liver transplantation.
UHN’s Multi-Organ Transplant Program is Canada's largest organ transplant program. Home to many transplant firsts and a world leader in transplant research innovation, it performs more than 500 transplantation procedures each year—representing one quarter of all transplants in Canada—and provides follow-up care to over 5,000 transplant recipients.
PM researchers have spent the past few months receiving prestigious awards. The following researchers add to the institute’s ever-growing list of recognitions for world-class cancer research and innovation.
Dr. Eleftherios Diamandis (PM Clinical Researcher and TGHRI Clinical Researcher) was presented with the 2017 Lifetime Achievement Award from the Ontario Society of Clinical Chemists. The award recognizes “an individual who has devoted their professional life to providing exemplary service and improving the field of Clinical Biochemistry”. An internationally renowned leader in clinical biochemistry, Dr. Diamandis has made many significant contributions to clinical research throughout his career, such as the development of predictive tests for cancer.
The Canadian Cancer Research Alliance presented Dr. Michael Jewett (PM Clinical Researcher and Techna Affiliated Faculty) with the 2017 award for Exceptional Leadership in Patient Involvement in Cancer Research. Dr. Jewett was recognized for his “long-standing commitment to and advocacy for greater patient involvement in clinical research prioritization, research proposals, funding decisions, research design, and patient-relevant outcome measures.” His efforts have given patients a voice in helping to shape priorities for cancer research and care.
Dr. Wey-Liang Leong (PM Clinical Researcher) received a grant to develop a biodegradable scaffold that helps tissues regenerate following surgery for breast cancer. Called ReFilx, the technology aims to improve patients’ quality of life and reduce the need for further surgeries. The funds were awarded by the Canadian Medical Association company, Joule, and Dr. Leong’s project received $25,000 as part of the Early Stage Initiatives program.
(November 30, 2017) - A study led by Dr. Thomas Waddell at the Toronto General Hospital Research Institute (TGHRI) and Dr. Andras Nagy at the Samuel Lunenfeld Research Institute describes a new method for producing high yields of cells that could be used in cell therapies.
The approach is a modified version of the induced pluripotent stem (iPS) cell technology, which was discovered by Dr. Shinya Yamanaka in 2006 at Kyoto University in Japan and won him a Nobel Prize in 2012.
The discovery of iPS cells was hailed as the beginning of medical revolution. This is because iPS cells can be used to make an array of patient-specific therapeutic cells: for example, using the technology, patient skin cells can be ‘reprogrammed’ into iPS cells that can then be used to create photoreceptors to treat vision loss. An added benefit of this approach is that the transplanted cells are not rejected by the patient’s immune system because they were made from the same patient’s skin cells.
However, to date, the use of these cells in the clinic has been limited, with only one therapy for age-related macular degeneration currently in clinical trials. Part of the reason for this is that it is difficult to use iPS cells to grow large quantities of pure cells. Also, there is the danger that iPS cells might be contaminated with stem-cell-like cells that could eventually grow into tumours.
To address this issue, the research team led Drs. Waddell and Nagy refined the iPS technology using ‘interrupted reprogramming’. This approach has enabled them to convert adult mouse cells into induced-progenitor-like (iPL) cells.
“Unlike iPS cells, which behave like stem cells and can become a wide variety of cells, the iPL cells that we created can only become a restricted number of cell types. The types of cells that they can become depends on which type of adult cells we start with, which makes it quicker and easier to purify target cells,” says Dr. Waddell.
To explore the potential use of iPL cells to treat respiratory diseases, Dr. Waddell’s team focused on a cell type—known as a Club cell—that lines the inner surface of the lungs. Club cells were converted into iPL cells using the ‘interrupted reprograming’ method, which involved genetically modifying the Club cells then exposing them to a drug. These iPL cells could then be coaxed into producing other cell types in the lung: goblet and ciliated cells, as well as other Club cells. Once the drug was removed, the iPL cells reverted back into Club cells.
These findings show that the method can be used to expand a subset of cell types, in a tightly controlled manner. In the lungs, this could translate into new therapies to speed up the healing process after lung injury, or to repair donor lungs before transplantation.
“These findings reveal an important shortcut for cell manufacturing—rather than converting adult cells into iPS cells, which then need to be converted to pluripotent cells to make the cells of interest, we can use adult cells to create iPL cells to rapidly produce relatively pure populations of the desired cell type,” says Li Guo, the graduate student who worked with Dr. Waddell on this project.
This new approach could be used to create new models of disease, quickly screen investigational drugs for efficacy or regenerate damaged tissues. However, Dr. Waddell cautions, “These are preliminary findings. Future work will test this approach in other cell types and in human cells. If we’ve learned anything in the past 10 years since the discovery of iPS cells, it is that there will be much work to be done before iPL cells can be used safely and effectively in humans.”
This work was supported by the Hospital for Sick Children Transplant and Regenerative Medicine Program, the Canadian Institutes of Health Research, the Ontario Research Fund, and the Toronto General & Western Hospital Foundation. TK Waddell holds the Pearson-Ginsberg Chair in Thoracic Surgery and the Thomson Family Chair in Translational Research. A Nagy holds a Tier 1 Canada Research Chair in Stem Cells and Regeneration.
Li Guo, Golnaz Karoubi, Pascal Duchesneau, Maria V. Shutova, Hoon-Ki Sung, Peter Tonge, Christine Bear, Ian Rogers, Andras Nagy and Thomas K Waddell. Generation of Induced Progenitor-Like Cells from Mature Epithelial Cells Using 1 Interrupted Reprogramming. Stem Cell Reports. Nov 2017.
On November 24, 2017, UHN welcomed The Honourable Kirsty Duncan, Canada’s Minister of Science, to tour its research facilities. The 90-minute visit highlighted selected research focusing on personalized cancer medicine happening at two sites: Princess Margaret Cancer Centre (PM) and the Princess Margaret Cancer Research Tower.
Hosted by senior leaders—Dr. Brad Wouters (Executive Vice President, Science and Research, UHN), Dr. Mary Gospodarowicz (Medical Director, PM), Dr. Rama Khokha (Interim Research Director, PM), Gill Howard (Vice President, Public Affairs and Communications, UHN) and Laura Syron (Vice President, Community Programs, The Princess Margaret Cancer Foundation)—the visit provided researchers with an opportunity to showcase innovative research and state-of-the-art facilities:
Minister Duncan’s visit also provided the ideal opportunity to show UHN’s full support for Canada’s Fundamental Science Review, Investing in Canada’s Future: Strengthening the Foundations of Canadian Research. Commissioned by Minister Duncan and released in early 2017, the report states that “by various measures, Canada’s research competitiveness has eroded in recent years when compared with international peers” and provides a series of recommendations to restore federal funding for research—the implementation of which would ensure that Canada continues to attract and retain some of the world’s best and brightest research talent.
After the tour, the Minister sat down with for a lively roundtable discussion, which was joined by Dr. Michael Hoffman and Dr. Marianne Koritzinsky. The conversation focused on a number of key issues, including the unique funding challenges faced by research hospitals in Canada; the need for more stable funding to support and encourage early career researchers; and implementation of the recommendations outlined in Canada’s Fundamental Science Review. The roundtable was also an opportunity for researchers to learn about Minister Duncan’s background, including her experience leading a research team to the Norwegian Arctic to search for the origins of the 1918 flu pandemic, as well as her teaching at Royal Roads University in British Colombia and at the University of Toronto, where she is appointed as an Adjunct Professor.
UHN thanks Minister Duncan for taking the time to visit.
In the classic 1980s film Fatal Attraction, a man and a woman enter into a relationship that heads down a dark path. It is safe to say that they were better off apart.
Similarly, genetic mutations can sometimes cause two separate genes to fuse together. Once fused, these genes can create abnormal molecules, known as fusion proteins, with similarly harmful consequences.
One such genetic fusion, known as MLL-AF6, is found in people that often develop leukemia, a cancer of the blood; however, it is not known exactly how the resulting fusion protein promotes the disease.
To address this gap in knowledge, Dr. Mitsu Ikura (PM Senior Scientist) and Dr. Matthew Smith (a former research associate in Dr. Ikura’s lab and now a faculty member of Université de Montréal’s Institute for Research in Immunology and Cancer) used NMR spectroscopy—a technology that uses powerful magnets to study the properties of molecules—to determine how the structure of the MLL-AF6 fusion protein influences its function.
Their research team found that the MLL-AF6 fusion protein had an abnormal structure: portions of the MLL and AF6 proteins that were normally hidden deep within the molecules were exposed on the surface of the MLL-AF6 fusion. These portions, known as hydrophobic regions, are attracted to other hydrophobic regions and cause one MLL-AF6 fusion protein to stick to another MLL-AF6 fusion protein—creating a pair.
The researchers found that the ability of one MLL-AF6 protein to pair with another was key to its role in promoting cancer: pairs of MLL-AF6 fusion proteins bound to DNA and turned on a set of genes that promote leukemia. When the researchers prevented the fusion proteins from pairing in an experimental model, the development of disease was halted.
“Our study takes us one step closer to revealing how cancer develops: our results identify the exact ways that gene fusions can change the shape and function of proteins in the cell,” explains Dr. Ikura. “We’ve revealed two promising strategies—targeting the abnormally exposed portions of the protein and preventing the proteins from pairing—to develop new anti-leukemia drugs."
This work was supported by the Cancer Research Society; the Canadian Cancer Society Research Institute; the Canadian Institutes of Health Research; the Leukemia & Lymphoma Society Canada; the Natural Sciences and Engineering Research Council of Canada; Ministère de l'Éducation et de l'Enseignement supérieur Québec; Fonds de recherche du Québec - Nature et technologies; Fonds de recherche du Québec- Santé; Deutsche Forschungsgemeinschaft; the Canada Foundation for Innovation; and The Princess Margaret Cancer Foundation. M Ikura is a Tier 1 Canada Research Chair in Cancer Structural Biology, AC Gingras is a Tier 1 Canada Research Chair in Functional Proteomics and MJ Smith is a Tier 2 Canada Research Chair in Cancer Signalling and Structural Biology.
Smith MJ, Ottoni E, Ishiyama N, Goudreault M, Haman A, Meyer C, Tucholska M, Gasmi-Seabrook G, Menezes S, Laister RC, Minden MD, Marschalek R, Gingras AC, Hoang T, Ikura M. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia. Nat Commun. 2017 Oct 23. doi: 10.1038/s41467-017-01326-5.