Imagine going to a museum where none of the artifacts are labelled. Without any knowledge of the context in which the artifacts were used or where they came from, an exhibit would look like a collection of random objects.
In the past several decades, researchers have amassed large collections of information describing the components of cells and how they work together. However, much of the context has been missing from this information, which has prevented researchers from fully understanding the role of a cell’s components in health and disease.
To help address this, Dr. Igor Jurisica, Senior Scientist at Krembil Research Institute, has been ‘putting labels’ on the interactions between proteins, the cellular machinery that performs much of the essential functions of the cell. In 2005, he created a database of protein interactions that has evolved and expanded over the years. In 2015, it included proteins from humans and five other species, as well as the tissues in which specific interactions occur.
His team recently reported a substantial expansion of their database in the journal Nucleic Acids Research. The new features include protein interactions for 12 more species to support biomedical, veterinary and agricultural research, and three new types of context information: where these protein interactions occur in the cell, the diseases they are associated with, and whether they might respond to a potential drug.
“The Integrated Interactions Database, or IID, is one of the broadest and largest physical interaction databases,” explains Dr. Jurisica. “We’ve also included features that enable researchers to map the networks of protein interactions for each species, identify the key proteins in these networks and determine the conditions under which an interaction network is physiologically important.”
With this additional information, the 4.8 million protein-protein interactions in the database will help researchers better understand the molecular mechanisms behind diseases and treatments, and develop new drugs faster.
This work was supported by the Krembil Foundation, Ontario Research Fund, Natural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation, Canada Research Chairs Program, Toronto General & Western Hospital Foundation and IBM.
Kotlyar M, Pastrello C, Malik Z, Jurisica I. IID 2018 update: context-specific physical protein-protein interactions in human, model organisms and domesticated species. Nucleic Acids Res. 2018 Nov 8. doi: 10.1093/nar/gky1037.
On December 6, 2018, University Health Network (UHN) announced the creation of the McEwen Stem Cell Institute. The sixth institute within its research community, the McEwen Institute is focused on stem cell research and the promise of regenerative medicine and cell therapies.
Formerly the McEwen Centre for Regenerative Medicine, the evolution to the McEwen Stem Cell Institute signals the progress of the research since it was first formed in 2007. In collaboration with research institutions, clinical programs at UHN, and supporters from around the globe, investigators within the new institute will work to harness the potential of stem cell biology to accelerate the development of more effective treatments for conditions such as heart disease, diabetes, liver disease and blood cell diseases.
The McEwen Institute will be led by Dr. Gordon Keller and will launch with an initial focus on developing cell therapies in four areas with significant potential to move quickly from theory to therapy:
Blood: Developing cells in the blood system to replace missing or damaged blood cells and to create potential immune based therapies to treat cancer (Dr. Gordon Keller, PhD)
Diabetes: Developing stem cell therapies to regenerate beta cells to treat diabetes and eliminate the need for insulin injections. (Dr. Cristina Nostro, PhD)
Heart: Developing stem cell therapies to remuscularize and repair the heart (Dr. Michael Laflamme, MD, PhD) and creating stem cell-derived biological pacemakers to eliminate the need for electronic pacemakers (Dr. Stephanie Protze, PhD)
Liver: Creating new liver tissue from pluripotent stem cells to repair damaged livers and reduce the need for transplants (Dr. Gordon Keller, PhD)
“The launch of the McEwen Stem Cell Institute builds on our legacy of innovation in stem cell and regenerative medicine research,” says Dr. Bradly Wouters, Executive Vice President of Science and Research, UHN. “The Institute will help to usher in entirely new forms of cell-based therapies to tackle some of the most important human diseases. It is intensely focused on the creation of new therapies and will become an integral part of the life sciences hub in Toronto that could fuel industry and research for decades to come."
In support of this new initiative, BlueRock Therapeutics announced today significant new funding for engineered cell programs for cardiac disease and the creation of a research chair in regenerative medicine at the McEwen Institute. Additionally, the company stated that it would be doubling its operational space in Toronto to enable potential therapeutic programs and an expanded research collaboration with the new Institute. BlueRock was established in 2016 with a $225 million investment - one of the largest in biotech history. The work of Drs. Gordon Keller and Michael Laflamme, principal investigators at the McEwen Institute, is part of BlueRock's first efforts to commercialize an approach to regenerating heart muscle in patients who have had a heart attack or suffer from chronic heart failure.
“Our relationship with BlueRock has been critical in helping us accelerate our work,” said Dr. Gordon Keller, Director, McEwen Stem Cell Institute. “This most recent investment underscores their commitment to our work and will allow us to move more rapidly to test these therapies in patients.”
BlueRock Therapeutics, LP, an engineered cell therapy company leveraging its novel Cell+Gene platform to develop regenerative medicines for intractable diseases, announced today the strengthening of its ongoing strategic collaboration with the McEwen Stem Cell Institute at the University Health Network (UHN) in Toronto.
“Toronto is an incredible scientific ecosystem, and a world-renowned center for stem cell biology and regenerative medicine,” said Emile Nuwaysir, PhD, Chief Executive Officer of BlueRock Therapeutics. “The McEwen Stem Cell Institute at UHN is the epicenter of that ecosystem, and we have been very pleased with our relationship to date. The expansion of that partnership deepens the relationship, broadens our access to that foundational science and accelerates the development of our therapeutic programs.”
The partnership encompasses an operations and infrastructure expansion. BlueRock will be moving into an additional 14,000 square feet within UHN in Toronto’s MaRS Discovery District, co-located with the McEwen Institute. The new lab will be in close proximity to the already established 7,000 square foot faculty housing BlueRock process development and manufacturing teams as well as the new pilot Good Manufacturing Practices (GMP) facility, which will open in early 2019.
The strengthened partnership will also provide funding to support a BlueRock-endowed research chair in regenerative medicine for Dr. Stephanie Protze, PhD, principal investigator, McEwen Stem Cell Institute. While a post-doctoral fellow in Dr. Gordon Keller’s lab, Dr. Protze successfully transformed human stem cells into functional pacemaker cardiac cells; these cells were able to elicit a rodent’s heartbeat. Today her work is focused on further validating if these pacemaker cells can function as biological pacemaker using additional models and developmental biology-based approaches to establish strategies to guide the differentiation of hPSCs into the second type of pacemaker cell found in the heart.
“The collaboration between BlueRock and the McEwen Institute at UHN will continue to greatly enrich and expedite the development of regenerative therapy approaches for cardiovascular disease,” said Dr. Protze. “I am thrilled to have the opportunity to develop BlueRock’s unique Cell+Gene therapy platform and translate its capabilities to new treatments.”
Additionally, BlueRock will increase the amount of funding and the breadth of sponsored research programs with Dr. Gordon Keller, PhD, Director, McEwen Stem Cell Institute; Dr. Protze; and Dr. Michael Laflamme, MD, PhD, Principal Investigator. This funding will enable BlueRock to advance native and engineered cell programs in cardiac indications as well as additional areas.
A new study from the Krembil Research Institute suggests there could be more to coffee than a boost in energy and attention. It may also protect you against developing both Alzheimer and Parkinson disease.
"Coffee consumption does seem to have some correlation to a decreased risk of developing Alzheimer disease and Parkinson disease," says Dr. Donald Weaver, Krembil Research Director.
"But we wanted to investigate why that is – which compounds are involved and how they may impact age-related cognitive decline."
Dr. Weaver enlisted Dr. Ross Mancini, a research fellow in medicinal chemistry, and Yanfei Wang, a lab technician, to help. The team chose to investigate three different types of coffee – light roast, dark roast, and decaffeinated dark roast.
"The caffeinated and de-caffeinated dark roast both had identical potencies in our initial experimental tests," says Dr. Mancini. "So we observed early on that its protective effect could not be due to caffeine."
Dr. Mancini then identified a group of compounds known as phenylindanes, which emerge as a result of the roasting process for coffee beans. Phenylindanes are unique in that they are the only compound investigated in the study that prevent beta amyloid and tau, two protein fragments common in Alzheimer and Parkinson disease, from clumping.
As roasting leads to higher quantities of phenylindanes, dark roasted coffee appears to be more protective than light roasted coffee.
"It's the first time anybody's investigated how phenylindanes interact with the proteins that are responsible for Alzheimer and Parkinson disease," says Dr. Mancini. "The next step would be to investigate how beneficial these compounds are, and whether they have the ability to enter the bloodstream, or cross the blood-brain barrier."
The fact that it's a natural compound versus synthetic is also a major advantage, says Dr. Weaver.
"Mother Nature is a much better chemist than we are. If you have a complicated compound, it's easier to grow it in a crop, harvest the crop, grind the crop out and extract it than try to make it."
But, he admits, there is much more research needed before these findings can be translated into potential therapeutic options.
"What this study does is demonstrate that there are indeed components within coffee that may ward off cognitive decline. It's interesting but are we suggesting that coffee is a cure? Absolutely not."
This work was supported by the Krembil Foundation and the Toronto General & Western Hospital Foundation. D Weaver is a Tier I Canada Research Chair in Protein Misfolding Diseases.
Mancini RS, Wang Y, Weaver DF. Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation. Front Neurosci. 2018 Oct 12;12:735. doi: 10.3389/fnins.2018.00735.
This story was adapted from a press release prepared by UHN Public Affairs. The original text can be found here.
Six University Health Network (UHN) researchers have been named Highly Cited Researchers 2018 by Clarivate Analytics.
The list, which was introduced in 2014, identifies scientists and social scientists who have demonstrated significant influence in their fields. To be included, researchers had to have published multiple exceptional papers that rank in the top 1% by citations for their field and publication year between 2006 and 2016.
The elite researchers from UHN who were included among the 6,078 scientists worldwide are as follows:
For the first time, the list this year also includes a new Cross-Field category to identify researchers with substantial influence across several fields. Approximately one third of the Highly Cited Researchers belong to this category, demonstrating significant influence across more than one discipline.
Canada placed seventh in the world for the number of Highly Cited Researchers, with 166 scientists across all research fields based at Canadian institutions—representing 2.7% of the worldwide total. Of these individuals, 33 are from Toronto.
The full list, as well as a detailed explanation of the analysis methodology, is available here.
Congratulations to UHN’s Highly Cited Researchers for their exceptional research performance and influence.
The human body is made of trillions of cells, but not just cells. The extracellular matrix (ECM) is the material that surrounds and supports our cells, and it has an important role to play in the outcomes of different types of cancer and the success of different therapies.
Though not a part of a cancer cell itself, the ECM can be an important factor in how aggressively a cancer can spread. To help better understand how the ECM contributes to cancer, a research team led by Dr. Dan De Carvalho examined how genes involved in the ECM are changed in cancer.
The researchers used data from The Cancer Genome Atlas, a resource from the US National Institutes of Health that contains information on genetic changes in tumours from over 11,000 patients.
Using a ‘big data’ approach, the team examined thousands of patient samples in the Atlas to identify ECM genes associated with worse treatment outcomes. The analysis enabled creation of a gene signature—a set of conditions that can be used to predict outcomes for immunotherapy. Immunotherapies are emerging as a powerful anticancer strategy—they work by helping a patient’s immune system to target and kill cancer. The signature out-performed other molecular markers in predicting whether immunotherapy would work.
While there are many complex reasons ways the various genes in the signature could influence the ECM and treatment resistance, many of the findings pointed to the TGF-β signalling molecule—which is secreted by many cell types can regulate the ECM—as a key player.
Further research into ECM regulation in cancer may uncover new therapeutic approaches. "The ultimate goal is to find a biomarker that can help the clinician decide if a patient should receive immunotherapy or not. For those who will not respond, the answer could be the patient would first receive a drug to target the ECM, and then be able to respond to immunotherapy," Dr. Carvalho concludes.
This work was supported by The Princess Margaret Cancer Foundation, the Cancer Research Society, the Canadian Cancer Society, the Natural Sciences and Engineering Research Council, the Ontario Institute for Cancer Research, J.P. Bickell Foundation, the University of Calgary and the Canadian Institutes of Health Research. D. De Carvalho holds a Tier 2 Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy.
Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Comm. 2018 Nov 08.
Welcome to the latest issue of The Krembil.
The Krembil is the official newsletter of the Krembil Research Institute (formerly the Toronto Western Research Institute). Research at Krembil is focused on finding innovative treatments and cures for chronic debilitating disorders, including arthritis and diseases of the brain and eyes.
Stories in this month’s issue include:
● KREMBIL’S NEW COMMUNICATIONS TEAM: Meet the two new communications specialists who will help our researchers share their work.
● SHARING OUR STORIES: Two newly released publications showcase Krembil’s research and achievements.
● GIVING OLD DRUGS A NEW LIFE: Researchers show that two drugs for fungal infections could help treat brain cancer.
● A HARBINGER OF SEVERE DISEASE: Back X-rays could help rheumatologists identify patients with severe psoriatic arthritis.
● BREATHING A SIGH OF RELIEF: Distinct group of nerve cells promote breathing after spinal cord injury.
● INTERCEPTING THE MESSENGER: Potential new treatment for osteoarthritis could stop knee and spine joint destruction.
Read these stories and more online here. To read previous issues, see the newsletter archive.
