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:
● Celebrating Arthritis Research: Researchers from around the world share arthritis discoveries and clinical innovations.
● Seeds of Science: Tune in to UHN’s newest podcast—led by trainees for trainees.
● More than Supporting Cells: Study reveals that astrocytes, a type of non-neuronal brain cell, may play a role in cognition.
● Treating Parkinson Disease: A study examined medication type and the time-to-development of disabling complications.
● A Joint Discovery: Researchers reveal a mechanism for osteoarthritis in an overlooked portion of the joints.
● Moving the Needle: CRISPR gene editing shows potential to treat familial Alzheimer disease in human cells.
Researchers led by Krembil Brain Institute Senior Scientist Dr. Martin Ingelsson have used CRISPR-Cas9 to tackle a gene mutation that causes early-onset Alzheimer disease.
Alzheimer disease is a progressive brain disorder and the leading cause of dementia worldwide. Despite decades of efforts to develop a cure, most available drugs only treat symptoms and do nothing to stop disease progression.
Genomic studies have revealed that early-onset, familial forms of the disease result from changes in numerous genes, including presenilin 1 (PSEN1). This gene and its corresponding protein, PS1, are involved in the production of amyloid beta (Aβ), which builds up and forms amyloid plaques in the brains of people with Alzheimer disease.
Evangelos Konstantinidis, a recent PhD graduate at Uppsala University and the first author of the study, describes PS1 as part of the molecular scissors that produce Aβ from its precursor protein, resulting in Aβ aggregation into plaques. “The precursor protein can get cut in different spots, forming molecules of different sizes. Gene mutations that alter the structure of PS1 can increase the production of a larger and more aggregation-prone form of Aβ—called Aβ42 for its 42 amino acids, compared to the more prevalent Aβ40.”
The research team used the gene editing technology CRISPR-Cas9 to disrupt a particular mutation in the PSEN1 gene. They did this in fibroblasts—the cells that make up human skin and connective tissue.
Although Alzheimer disease is a condition of the brain, the hallmark increase in Aβ42 levels is present in cells throughout the body of people who carry this mutation.
The team tested their gene editing approach in the laboratory, using cells from six people with the mutation, as well as two healthy family members and two healthy unrelated people.
The gene editing led to a reduction in Aβ42 and partially restored the normal Aβ42/40 ratio. It did this by correcting the shape of the abnormal PS1 protein and lowering its levels.
Importantly, the team did not detect any off-target effects of the gene editing.
“Because we are using molecular tools to identify and delete a specific disease-causing gene sequence, it is possible that we might disrupt similar sequences elsewhere in the DNA,” cautions Dr. Ingelsson. “We examined ten sequences that were most likely to be disrupted, and we saw no changes. This tells us that our approach does a good job of distinguishing between sequences, and it could eventually be a safe and effective treatment for people with this mutation.”
This work was supported by the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Åhlén Foundation, the Gamla Tjänarinnor Foundation, the Gun and Bertil Stohne's Foundation, the German Research Foundation, Massachusetts General Hospital, the National Institutes of Health and the UHN Foundation. Dr. Martin Ingelsson is a Scientist at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto.
Konstantinidis E, Molisak A, Perrin F, Streubel-Gallasch L, Fayad S, Kim DY, Petri K, Aryee MJ, Aguilar X, György B, Giedraitis V, Joung JK, Pattanayak V, Essand M, Erlandsson A, Berezovska O, Ingelsson M. CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation. Mol Ther Nucleic Acids. 2022 Mar 28. doi: 10.1016/j.omtn.2022.03.022.
CRISPR-Cas9 gene editing works by precisely cutting DNA at a target location—typically a disease-causing gene sequence—and letting the cell’s natural DNA repair machinery fix the damage.
A research team led by Dr. Mohit Kapoor, Co-Director and a Senior Scientist at the Schroeder Arthritis Institute, has uncovered a new biological mechanism underlying osteoarthritis, an often painful and disabling form of joint deterioration.
The new findings focus on the synovium, the specialized connective tissue that surrounds and lubricates freely movable joints, such as the knee. As osteoarthritis progresses, this tissue becomes inflamed and thickened, contributing to joint stiffness and pain.
“Most of the research into osteoarthritis has focused on what is going on in the joint cartilage and bone. Changes to the synovium have been traditionally thought of as secondary effects,” says Dr. Kapoor. “We now know that the synovium is actively involved in osteoarthritis, but we still do not know exactly how.”
Dr. Kapoor’s lab previously discovered that a particular microRNA—a molecule that regulates the production of proteins from genes—is elevated in the synovial fluid of patients with knee osteoarthritis. This finding spurred the team to investigate whether this microRNA—miR-27b-3p—affects disease progression.
Using lab models of osteoarthritis and samples of knee synovia from patients with varying degrees of disease severity, the researchers discovered that elevated levels of miR-27b-3p coincide with more severe changes in the synovium, such as a build-up of collagen—a structural protein that makes up connective tissues.
Next, the research team showed that they could control the production of collagen and other key structural proteins by manipulating the levels of miR-27b-3p in experimental models. By doing this, they could even induce an osteoarthritis-like state in healthy synovial tissue.
To explore how the microRNA affects joints, the team searched for the genetic targets of miR-27b-3p. They found that numerous genes are under the molecule’s influence, including some key genes that are most closely associated with collagen regulation and osteoarthritis.
In particular, they discovered that miR-27b-3p consistently affects one gene that leads to the production of proteins that make up the scaffolding outside cells (i.e., the extracellular matrix). They also identified a way to counter this effect: a drug called rosiglitazone reduces the ability of the microRNA to regulate this gene.
“This study shines a light on a less appreciated part of the joint—the synovium—and shows how microRNA can affect collagen production in the synovium and even drive progression of this debilitating form of arthritis,” says Dr. Ghazaleh Tavallaee, co-lead author of the study and a PhD graduate of Dr. Kapoor’s lab.
“We have also uncovered mechanisms that could lead to new treatment approaches, ones that may be able to prevent the build-up of extracellular materials that thicken and stiffen joints in osteoarthritis,” adds the second co-lead author, Dr. Starlee Lively, a Scientific Associate in Dr. Kapoor’s lab.
This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the Ontario Research Fund, Arthritis Society Canada, IBM, the Ian Lawson van Toch Fund, the Krembil Research Institute, the Schroeder Arthritis Institute and the UHN Foundation. Dr. Mohit Kapoor is a Professor in the Departments of Surgery and Laboratory Medicine & Pathobiology at the University of Toronto, and a Tier 1 Canada Research Chair in Mechanisms of Joint Degeneration.
Tavallaee G#, Lively S#, Rockel JS, Ali SA, Im M, Sarda C, Mitchell GM, Rossomacha E, Nakamura S, Potla P, Gabrial S, Matelski J, Ratneswaran A, Perry K, Hinz B, Gandhi R, Jurisica I, Kapoor M. Contribution of microRNA-27b-3p to synovial fibrotic responses in knee osteoarthritis. Arthritis Rheumatol. 2022 Jul 6. doi: 10.1002/art.42285. #These authors contributed equally.
Researchers at The Institute for Education Research (TIER) are using artificial intelligence (AI) to improve virtual cancer care and patient well-being.
A cancer diagnosis can have a profoundly harmful effect on an individual’s mental health. Virtual care platforms, such as online support groups, are a convenient and cost-effective tool for reducing emotional distress.
UHN’s de Souza Institute offers CancerChatCanada, a therapist-led, text-based support group for cancer patients that features an AI-based co-facilitator (AICF). This tool processes the language that participants use in session chats to provide customized online resources that are tailored to their particular needs.
Dr. Yvonne Leung, a TIER Education Investigator, explains that her team developed the AICF to quickly identify participants who are at increased risk of emotional distress and to automatically share online resources with them following each session.
“The AICF scans session chats in real-time to monitor patients’ engagement and to detect keywords that signal emotional distress. If the system detects a participant at risk, it alerts the therapist,” says Dr. Leung. “The system also creates profiles for each participant following the sessions to help the therapist assess their emotional trajectories and psychosocial health.”
Developing the AICF was a complex, multi-step process. The group started by training the AI on a collection of chat sessions—approximately 80,000 messages in total. They then taught the system a list of common keywords related to psychosocial concern, such as ‘anxiety’ and ‘depression’. The AI used this information to identify related words and expressions, building a large vocabulary list that it could use to detect psychosocial distress. Once the AICF identifies a user that is at risk of psychological harm, the system uses a concern-response algorithm to determine the most appropriate resource from a curated bank of online tools and websites.
“A critical element of training any AI system is providing feedback—telling the AI what it is doing right and what needs to change,” explains Dr. Leung. “We went through multiple rounds of human evaluation and feedback to improve the AICF’s performance before we tested it in live support group sessions.”
Across five sessions involving 48 participants, the AICF did an excellent job of detecting at-risk patients and recommending suitable resources. Over 50% of patients accessed at least one of the resources that the AICF recommended to them, and 75% of these patients found the resources useful.
“We have shown that our AICF can personalize online support and improve care for cancer patients without increasing therapists’ workload,” says Dr. Leung.
Beyond demonstrating the usefulness of the AICF, this study identified strengths and weaknesses of the system, which will help the team to optimize it for future applications. According to Dr. Leung, “Cancer care is just the start—AI systems could enhance online support for all sorts of patient populations. We have incredible technological resources at our disposal, and we are ready to use them to provide holistic care our patients, wherever they are.”
Next steps for this research include using an interactive chatbot to provide patient education as an on-demand support. Patients can ask specific questions related to their cancer and an AI-based recommender system will bring them to a relevant online resource.
This work was supported by the Ontario Institute for Cancer Research - Cancer Care Ontario Health Services Research Network and the UHN Foundation. Dr. Yvonne Leung is an Adjunct Lecturer in the Department of Psychiatry at the University of Toronto.
Leung YW, Park B, Heo R, Adikari A, Chackochan S, Wong J, Alie E, Gancarz M, Kacala M, Hirst G, de Silva D, French L, Bender J, Mishna F, Gratzer D, Alahakoon D, Esplen MJ. Providing Care Beyond Therapy Sessions With a Natural Language Processing-Based Recommender System That Identifies Cancer Patients Who Experience Psychosocial Challenges and Provides Self-care Support: Pilot Study. JMIR Cancer. 2022 Jul 29. doi: 10.2196/35893.
The Government of Canada has announced the latest round of Canada Research Chair (CRC) funding.
The CRC program provides funding to attract and retain Canada’s most accomplished and promising researchers. Chairholders aim to achieve research excellence, improve our depth of knowledge and quality of life, strengthen Canada's international competitiveness and help to train the next generation of highly skilled professionals.
In this latest round of funding, the CRC program invested more than $139 million to support 176 new and renewed Chairs across 46 Canadian research institutions.
“This program is a catalyst for discoveries and innovations that directly benefit Canadians,” says Dr. Brad Wouters, Executive Vice-President of Science and Research at UHN. “The Chairs announced this round highlight the rich diversity of Canadian scholars and will strengthen our leadership across a broad spectrum of disciplines. Congratulations to all our researchers on this wonderful achievement.”
Read below to learn more about the five UHN researchers that received CRC funding:
● Dr. Myron Cybulsky, Tier 1 CRC in Arterial Wall Biology and Atherogenesis (renewal). Dr. Cybulsky is a Senior Scientist at the Toronto General Hospital Research Institute and a world leader in the mechanisms of atherosclerosis, a contributing factor to heart disease and stroke. This Chair will help to advance Dr. Cybulsky’s research into the formation of arterial plaques, which will help doctors treat heart disease before it becomes fatal.
● Dr. Courtney Jones, Tier 2 CRC in Leukemia Stem Cell Metabolism (new). Dr. Jones is a Scientist at the Princess Margaret Cancer Centre and an emerging international leader in leukemic stem cell (LSC) metabolism. Funding from this Chair will enable Dr. Jones’ group to study how LSCs use energy differently from normal cells and how healthy blood-forming stem cells become cancerous and cause acute myeloid leukemia. This research will help to develop strategies that target LSC metabolism to prevent cancer relapse and improve patient outcomes.
● Dr. Sushant Kumar, Tier 2 CRC in Genomic Medicine (new). Dr. Kumar is a Scientist at the Princess Margaret Cancer Centre with expertise in bioinformatics and the analysis of large-scale cancer data. This Chair will enable his team to develop computational methods to integrate and analyze cancer data sets from gene sequencing, functional genomics, protein structure and pharmacogenomics studies. This research will contribute to precision oncology efforts by yielding novel tools for studying tumour evolution and heterogeneity and identifying clinically actionable disease biomarkers.
● Dr. Gregory Schwartz, Tier 2 CRC in Bioinformatics and Computational Biology (new). Dr. Schwartz is a Scientist at the Princess Margaret Cancer Centre and an expert in computational biology and the analysis of single-cell data sets. His research team is developing computational tools to analyze multi-omic, single-cell data sets to uncover cell-cell communication networks in cancer. Understanding how cells communicate in cancer will provide insights into disease progression and drug resistance, and will enable the development of innovative diagnostic tools and strategies to overcome resistance.
● Dr. Anastasia Tikhonova, Tier 2 CRC in Stem Cell Niche Biology (new). Dr. Tikhonova is a Scientist at the Princess Margaret Cancer Centre and an emerging leader in the fields of hematopoiesis and stem cell biology. Her research focuses on how communication between blood stem cells and the bone marrow environment changes during cancer. Funding from this Chair will enable her group to define the role of the bone marrow microenvironment in malignant hematopoiesis and identify microenvironmental cues that promote the development of acute lymphoblastic leukemia.
These latest funding results were announced by the Honourable François-Philippe Champagne, Minister of Innovation, Science and Industry, on November 16, 2022. To read more, see the official press release.
Congratulations to the fourteen UHN researchers who have made the 2022 list of Highly Cited Researchers from Clarivate—a global leader in bibliometrics and analytics. Only 6,938 researchers from 69 countries were awarded the distinction.
A citation (i.e., when a scientific article references a previously published article) is an objective measure of how influential a publication is within a particular field. The Clarivate Highly Cited Researcher list recognizes individuals who published highly cited papers that rank in the top 1% by citations for field and publication year in the Web of Science citation index over the past decade. Seven UHN researchers on the list received the added distinction of being included in the ‘Cross-Field’ category, reflecting their interdisciplinary excellence and impact in multiple research fields.
Dr. Brad Wouters, Executive Vice-President of Science and Research at UHN, comments, “These highly cited researchers represent exceptional leaders. Through their research, they are making waves within the international scientific and medical communities. Their discoveries are also leading to new and improved therapies that are making our vision of A Healthier World a reality. We are proud of them, and it is an honour to celebrate their achievements.”
The list of UHN researchers and the categories in which they received their distinction are listed below. To read more, see the Clarivate press release.
Cheryl Arrowsmith | Cross-Field
Senior Scientist, Princess Margaret Cancer Centre
Research focus: cancer-related structural biology, chemical biology and epigenetics.
Gary Bader | Biology and Biochemistry
Affiliate Scientist, Princess Margaret Cancer Centre
Research focus: bridging molecular and clinical datasets to identify clinically relevant targets of cancer and regenerative wound healing processes.
Eddy Fan | Clinical Medicine
Scientist, Toronto General Hospital Research Institute
Research focus: advanced life support for acute respiratory failure and patient outcomes from critical illness.
Slava Epelman | Immunology
Senior Scientist, Toronto General Hospital Research Institute
Research focus: the contribution of immune cells to cardiac tissue injury and repair.
Steven Gallinger | Cross-Field
Clinician Scientist, Princess Margaret Cancer Centre
Research focus: cancer genetics, including gastrointestinal, colorectal and pancratic cancers.
Gordon Keller | Cross-Field
Senior Scientist, McEwen Stem Cell Institute and Princess Margaret Cancer Centre
Research focus: the application of developmental biology-guided principles to the differentiation of pluripotent stem cells into therapeutically relevant cells, such as cardiomyocytes, hematopoietic cells and liver cells.
Sidney Kennedy | Psychiatry and Psychology
Senior Scientist, Krembil Brain Institute
Research focus: the application of deep brain stimulation to treatment-resistant depression, including clinical trials and the development of treatment guidelines.
Anthony Lang | Neuroscience and Behavior
Senior Scientist, Krembil Brain Institute
Research focus: the etiology and pathogenesis of Parkinson disease and related movement disorders, as well as related novel diagnostics, and disease-modifying and symptomatic therapies.
Natasha Leighl | Cross-Field
Clinician Investigator, Princess Margaret Cancer Centre
Research focus: novel therapeutics and diagnostics for thoracic cancers, including early phase trials.
Andres Lozano | Cross-Field
Senior Scientist, Krembil Brain Institute
Research focus: brain mapping, deep brain stimulation (DBS) and focused ultrasound (FUS) in patients and experimental models of brain diseases.
Tak Mak | Cross-Field
Senior Scientist, Princess Margaret Cancer Centre
Research focus: the mechanisms underlying immune responses, the pathogenesis and tumorigenesis of cancer.
Roger McIntyre | Psychiatry and Psychology
Clinician Investigator, Krembil Brain Institute
Research focus: the effects of mood disorders on cognitive function, related health conditions and workplace functioning.
Frances Shepherd | Clinical Medicine
Senior Scientist, Princess Margaret Cancer Centre
Research focus: the design and conduct of research studies evaluating the new targeted agents and anti-angiogenesis agents in lung cancer.
Ming-Sound Tsao | Cross-Field
Senior Scientist, Princess Margaret Cancer Centre
Research focus: the mechanisms of non-small cell lung cancer, including how it metastasizes (i.e., its ability to spread throughout the body), its resistance to therapy and the small subpopulations of tumour cells that can evade treatments.
A recent study from the Princess Margaret Cancer Centre found that a protein called interferon regulatory factor 2 (IRF2) drives exhaustion of the immune system during immunotherapy. The findings suggest that targeting IRF2 might be key to overcoming treatment failure.
Immunotherapies exist for breast, lung, colorectal and skin cancers. Their effectiveness depends on a key component of the immune system: killer T cells. These killer cells can be activated to fight cancer by a class of proteins referred to as type I and type II interferons.
“While interferon signalling can enhance the effectiveness of anti-cancer therapies, when this signalling is prolonged, T cells become exhausted and lose their ability to fight tumours,” says Dr. David Brooks, Senior Scientist at Princess Margaret Cancer Centre and co-corresponding author of the study. “This switch to suppression is particularly devastating because it underlies the failure of multiple types of otherwise highly effective therapies.”
Currently it is poorly understood how interferons switch between roles—from maintaining the activity of killer T cells, to mediating their exhaustion.
Commenting on the team’s approach to solving this mystery, Dr. Sabelo Lukhele, a postdoctoral fellow in Dr. Brooks’ lab, explains “We looked at immune cells in tumors and noticed that levels of the IRF2 protein spike in response to sustained interferon signaling. We decided to zero in on IRF2 to see if it was causing the switch from beneficial interferon signaling towards T cell exhaustion.”
The researchers found that deletion of IRF2 in T cells overcame exhaustion and led to sustained anti-tumour activity.
Next, the team tested whether the deletion of IRF2 in T cells enhanced the effectiveness of different immunotherapies. To do this, they treated experimental models of breast and colorectal cancer with two different types of immunotherapies: anti-PD1 blockade or adoptive cell transfer therapy. In both cases, they found that the IRF2-deleted T cells greatly impeded tumour growth and markedly improved the effectiveness of both therapies.
“Based on our findings, IRF2 represents a promising new anti-cancer target. Shutting down IRF2 could give the immune system a boost—right when it starts to lag in the fight against cancer. By preventing the loss of function that normally occurs and enabling the cells to maintain anti-tumour activity, we revealed a new strategy that could help stop cancer in its tracks,” says Dr. Brooks.
“We are now deleting IRF2 from human T cells and testing these in pre-clinical models of adoptive cell therapy with the goal of moving this into human clinical trials. This work has the potential to improve existing cell therapies, while expanding treatment options for currently untreatable cancers.”
This work was supported by the Canadian Institutes of Health Research, the National Institutes of Health, a Scotiabank Research Chair and The Princess Margaret Cancer Foundation. Dr. Brooks is a Professor of Immunology at the University of Toronto.
Lukhele S, Abd-Rabbo D, Guo M, Shen J, Elsaesser HJ, Quevedo R, Carew M, Gadalla R, Snell LM, Mahesh L, Ciudad MT, Snow BE, You-Ten A, Haight J, Wakeham A, Ohashi PS, Mak TW, Cui W, McGaha TL, Brooks DG. The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity. 2022 Nov 11. doi: 10.1016/j.immuni.2022.10.020.
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