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:
● New to Krembil Business Office: Kim Perry joins the Krembil Research Institute as Business Manager.
● Deep Dive Into the Brain: Explore the intricacies of the human brain in a free Gairdner Global Perspectives Panel.
● A New Path to Diagnosis: Study uncovers markers of ankylosing spondylitis by studying cellular packages and their cargo.
● Diversity Builds Resilience: Krembil researchers uncover a protective role of diversity among brain cells.
● Getting Ahead of Arthritis: Subtle changes in DNA could predict the transition from psoriasis to psoriatic arthritis.
● Keeping Cancer at Bay: Study identifies meningeal macrophages as key mediators of anti-cancer signalling in the brain.
What is the best course of action to prevent and treat complications following transplant procedures? Researchers at Toronto General Hospital Research Institute (TGHRI) helped answer this question by identifying the risk factors for kidney dysfunction that can occur after heart transplant as well as the optimal clinical management strategies for this complication.
To investigate this, Dr. S Joseph Kim, Clinician Scientist at the TGHRI worked with students of the Multi Organ Transplant Student Research Training Program (MOTSRTP).
The MOTSRTP, co-directed by Dr. Kim and Mr. Olusegun (Segun) Famure, Research Associate at the TGHRI, is a unique, integrative student program that has been running since 2009. Organized by UHN's Ajmera Transplant Centre, the program trains students in the foundations of clinical research through research-oriented projects.
“Our program allows students from all levels of post-secondary education—undergraduate, graduate or professional—the opportunity to gain exposure to the clinical and research components of organ transplantation” says Mr. Famure.
“Students do hands-on research, write abstracts and manuscripts and present at scientific conferences. Since the program started, our students have been the first-author on 28 publications, co-authors on 20 more and have submitted over 80 conference abstracts.”
In this study, students of MOTSRTP analyzed the risk factors and patient management strategies for chronic kidney disease in 291 Canadian adults following heart transplant.
“Heart transplant patients are at a particular risk of kidney deterioration due to need to take life-long immunosuppressant medications. These medications are necessary to prevent rejection of transplanted tissue but can cause reduced blood flow to the kidney, scarring and other renal tissue damage,” says Dr. Kim.
Recent studies suggest that additional risk factors for kidney disease post-transplant include increasing age, female sex, pre-transplant kidney function, blood pressure and blood sugar.
Chronic kidney disease represents a gradual loss of kidney function which leads to improper excretion of bodily waste and electrolytes. It can progress to kidney failure which often requires dialysis, or even transplant.
“To determine the best way to manage transplant patients and improve outcomes, we wanted to validate the risk factors associated with renal dysfunction in the Canadian population and analyze current clinical management methods,” says Cavizshajan Skanthan, first author of the study and student in the MOTRSTRP.
“We found that the factors associated with moderate to severe kidney dysfunction were female sex, older age, longer time since transplant and low kidney function pre-transplant” says Jonathan Wang, co-author of the study and MOTRSTRP student.
“In addition, prescribing medications called mTOR inhibitors and withholding ones called calcineurin inhibitors were associated with kidney dysfunction,” says Imindu Liyanage, fellow author and student.
However, the research team cautions that further studies are needed to determine the effect of switching from calcineurin to mTOR inhibitors as patients are often switched to the latter when kidney function starts to decline.
“This study also showed that more patients should be referred to a nephrologist,” says Kristiana Xhima, co-author and student. “While referral to a nephrologist can help patients with kidney management and prevent further deterioration, only %19.7 of patients showing signs of moderate-to-severe renal dysfunction were referred.”
The findings from this study will contribute to the knowledge of how to care for heart transplant patients at risk for kidney disease. “Thanks to the students in our MOTRSTRP program, we have been able to provide more evidence of the kidney disease risks and post-transplant practices to the medical community,” concludes Mr. Famure.
This work was supported by the UHN Foundation. Dr. Kim is an Associate Professor in the Department of Medicine at the University of Toronto and the Director of the Kidney Transplant program at UHN.
Skanthan C, Wang J, Liyanage I, Xhima K, Li Y, Kim SJ, Famure O. Renal Dysfunction After Heart Transplant. Transplant Proc. 2023 Jul 19:S0041-1345(23)00382-2.
Kidneys play an important role as a filtration system for your body. They remove waste from your blood and regulate the balance of salt, potassium and other chemicals in the body. Image credit: American Kidney Fund website (kidneyfund.org).
Researchers at UHN’s Donald K. Johnson Eye Institute (DKJEI) have discovered a pivotal role of macrophages—a type of immune cell that destroys invading microorganisms—within the membranes that envelop and protect the brain in anti-cancer cell signalling.
It is commonly believed that gene mutations within precancerous cells are sufficient to trigger uncontrollable tumour growth and metastasis—but this is not the case.
It fact, it is quite difficult for tumours to form and grow. This challenge results from biological roadblocks that either exist within precancerous cells (e.g., molecular pathways that turn off cell division) or come from nearby healthy cells, such as immune cells.
For cancer cells to flourish, they need to co-operate with healthy cells in their environment. This process is a constant push-pull, with tumours continually receiving chemical signals that promote or inhibit their growth.
In a recent study published in Developmental Cell, a team of UHN scientists has brought to light a key cell population and chemical signalling pathway that inhibit the development of brain tumours.
According to Dr. Valerie Wallace, Co-Director and Senior Scientist at DKJEI and the lead author of the study, we can think of a developing cancer like a smoldering fire. “Early stage tumours are akin to embers that fail to cause fires because they are smothered by factors in their environment,” she explains. “This smothering often succeeds in extinguishing the embers, but they can burst into flames if sufficient fuel becomes available.”
The cells and processes that smother early tumours are clinically relevant for cancer screening and treatment. Screening tests such as colonoscopies are aimed at detecting precancerous lesions so they can be removed before they progress, and drugs that mimic or bolster natural anti-tumour processes can help prevent or treat cancers.
“Because we cannot biopsy brains to screen for early stage cancers the way we do elsewhere in the body, there are a lot of unknowns related to anti-cancer cell signalling in this tissue,” says Dr. Nenad Pokrajac, a postdoctoral researcher in Dr. Wallace’s lab and the first author of the study.
To overcome this limitation, the team used an experimental model of medulloblastoma—the most common type of cancerous brain tumour in children—to study how non-tumour cells affect tumour formation in a particular brain region called the cerebellum.
“From previous studies, we knew that blood vessels in the cerebellum can have anti-tumour effects, but these vessels interact with many partners,” says Dr. Pokrajac. “Our goal was to pinpoint the cells that work with blood vessels to inhibit tumour growth.”
The sophisticated experimental model enabled the team to track the division of cancer cells in response to changes in cell signalling.
The team discovered that the meninges—the tissues that line the surface of the brain and spinal cord—are powerful cancer fighters.
Of the many cell types present in the meninges, macrophages stood out as key players in the fight against tumour development. When the researchers removed these cells or inhibited their activity, tumours grew faster.
“We also discovered that macrophages attack early tumours by releasing a protein called CXCL4, which inhibits a powerful growth-promoting protein called CXCL12,” explains Dr. Pokrajac. “Based on these findings, blood vessels instruct macrophages that reside in the meninges to release CXCL4 to smother tumours by depriving them of fuel.”
Importantly, because macrophages can be found throughout the meninges, their protective role is likely not specific to the cerebellum, or even to a particular type of tumour.
More research is needed to confirm whether this is the case, but the team’s findings raise the possibility that these cells play a general, widespread role in the development of brain tumours.
“This is an exciting step forward for understanding how brain tumours form and how we can leverage the body’s natural cancer-fighting processes to treat them,” concludes Dr. Wallace. “In many tissues, it can take years for tumours to develop. If we can identify the processes that keep tumours at bay, and how they can go awry, we can intervene early and improve patient outcomes.”
The work was supported by the Cancer Research Society, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Ontario Institute for Regenerative Medicine, the Government of Ontario, the University of Toronto-UHN Vision Science Research Program, Medicine by Design-University of Toronto, Foundation Fighting Blindness and the UHN Foundation. Dr. Valerie Wallace is DKJEI Co-Director and Senior Scientist and a Professor in the Department of Ophthalmology & Vision Science at the University of Toronto. She holds the Donald K. Johnson Chair in Vision Research at UHN and a Tier 1 Canada Research in Retina Regeneration at the University of Toronto.
Pokrajac NT, Tokarew NJA, Gurdita A, Martinez AO, Wallace VA. Meningeal macrophages inhibit chemokine signalling in pre-tumour cells to suppress mouse 1 medulloblastoma initiation. Developmental Cell. 2023 Sept 28. doi: 10.1016/j.devcel.2023.08.033.
UHN’s Office of Research Trainees and the podcast production team are excited to announce the launch of the second season of the Seeds of Science podcast.
Hosted by Dr. Emily Mills and Rima El-Sayed, trainees with Dr. Karen Davis at the Krembil Brain Institute, the Seeds of Science podcast offers a platform to showcase the unique academic journeys, scientific discoveries and personal growth of the trainees at UHN. Follow along as they detail the achievements of these junior researchers, obstacles they have faced and life outside of research.
“UHN trainees and post-docs are the future of health research. So, we created this podcast to enable trainees to share and learn from one another,” says Dr. Mills. “As they continue to grow in their scientific field, trainees truly are the seeds of science.”
Episode one features Dr. Emma Bell, a postdoctoral researcher in Dr. Daniel De Carvalho’s lab at the Princess Margaret Cancer Centre. This episode follows Emma from their beginnings as a wet-lab researcher to discovering their true passion for bioinformatics and coding. Listen to the episode to find out how Emma has turned failures into learning opportunities, learn about important advancements in the field of liquid biopsies, and hear more about their beloved corgi, Sophie.
“Whether you are a trainee, a budding researcher or simply curious about the wonders of science and the scientific journey, Seeds of Science highlights the incredible research and real-life experience of those in academia,” adds Rima. “Tune in to be inspired and connect with others at UHN.”
For a glimpse into the second season of Seeds of Science listen to short promotion clip here.
Diversity is a hallmark of life. Variation among species and cell types within a single organism is key for supporting the myriad functions and adaptations needed to survive. A new study from the Krembil Brain Institute has explored the importance of brain cell diversity for brain function and health.
“In previous studies, we found that individuals with epilepsy have lower cell diversity in a brain region that is responsible for the generation of seizures,” says Dr. Taufik Valiante, co-senior author of the study. “We also demonstrated that when neurons behave too much like one another, neuronal networks become unstable.”
“We wanted to expand on this work and understand more generally why there are so many distinct neurons within the same regions of the healthy human brain,” explains co-senior author Dr. Jérémie Lefebvre. “While scientists have previously suggested that brain cell diversity is just noise, our research into epilepsy suggested that it protects against the development of seizures.”
To explore this possibility, the team applied computational tools to model neuronal networks—complex webs of interconnected neurons.
“We applied mathematical tools that were developed in the field of ecology and have been traditionally used to study ecosystems, but rather than using them to study food webs, we used them to study neuronal networks,” explains Dr. Hutt, first author of the study. “The specific type of diversity that we explored was that related to neuron excitability—how easily a neuron will send a signal after receiving a stimulus.”
The researchers exposed their neural networks to a slowly changing signal that mimics what a neuron might experience in the environment. They found that the networks were less stable when their neurons were not diverse. This instability manifested as sudden shifts in neuron activity levels.
“Our models revealed that cellular diversity bolsters the brain’s resiliency, making it better able to maintain functions in the face of ageing, disease and injury,” says Dr. Valiante.
The team suggests that a deeper understanding of the diversity among brain cells could improve our understanding of various neuropsychiatric disorders and how to treat them.
“Our findings may explain why drugs that are used to treat epilepsy fail in so many patients. By shedding light on the underlying mechanisms of the disease, this research could pave the way for improved therapies,” says Dr. Valiante. “Importantly, changes in cell diversity are likely not limited to epilepsy, but also play a role in various neurodevelopmental and neurodegenerative conditions.”
These findings serve as a striking reminder of the fundamental role that diversity plays in the resilience of natural systems in the face of change. This truth applies not only to neural circuits but also to humans, communities and other complex systems.
This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Krembil Foundation and the UHN Foundation. Dr. Valiante is an Associate Professor in the Department of Surgery at the University of Toronto. Dr. Jérémie Lefebvre is an Associate Professor in the Department Mathematics at the University of Toronto and an Associate Professor of Biology at the University of Ottawa. Dr. Axel Hutt is Research Director at the National Institute for Research in Digital Science and Technology in France.
Hutt A, Rich S, Valiante TA, Lefebvre J. Intrinsic neural diversity quenches the dynamic volatility of neural networks. Proc Natl Acad Sci U S A. 2023 Jul 11;120(28):e2218841120.
Neurons communicate with each other to form complex networks. Researchers can assess diversity within neural networks by measuring how individual cells respond to excitatory and inhibitory inputs.
When a patient is diagnosed with cancer, the family physician is often the first line of support that plays many vital roles in the patient’s care journey. However, many family physicians feel ill-prepared due to inadequate oncology education and care training, according to a recent study from The Institute for Education Research (TIER) at UHN.
Dr. Marissa Sherwood, first author on the study and a radiation oncology resident at the Princess Margaret Cancer Centre, interviewed 13 family physicians and asked them to reflect on their sense of preparation for cancer diagnosis and care, supplemental learning and previous cancer patient care experiences. Through these interviews, the researchers uncovered three main themes relating to the training needs and perceptions of the participants: lack of defined roles, inadequate oncology knowledge and education and the importance of palliative care experience.
Reflecting on the journey from diagnosis to treatment, participants expressed difficulty navigating the complex cancer care system often due to a lack of connections with specialists and other care providers. This challenge left them feeling uncertain about their roles and ability to contribute to patient care.
Participants also expressed frustration because they found that their existing medical training and knowledge of cancer care lacked relevancy and applicability in their daily practice. This disconnect can hinder a family physician’s ability to provide accurate and effective care to patients.
Further, it was revealed that a physician’s experience in palliative care was a potential opportunity for learning cancer care pathways, developing oncology skills and connecting with oncology specialists.
“As the field of cancer care continues to evolve, it’s essential that we adapt the education and support we provide to family physicians,” concludes Dr. Sherwood “By reshaping oncology education, we can empower family physicians to provide more optimal care for cancer patients and improve patient outcomes.”
This work was supported by UHN Foundation. Dr. Meredith Giuliani is an Associate Professor within the Department of Radiation Oncology at the University of Toronto and is also the Associate Dean of Postgraduate Medical Education.
Dr. Meredith Giuliani has served on ad boards at AstraZeneca and Bristol Myers Squibb. Marissa Sherwood was awarded a READS grant from the American Association of Cancer Education.
Sherwood M, Papadakos J, Kulasegaram K, Martimianakis MA, Kucharski E, Giuliani M. Exploring Family Physician Training Needs to Improve Cancer Patient Care. J Cancer Educ. 2023 Jul 14. doi: 10.1007/s13187-023-02339-z. Epub ahead of print.
UHN has appointed Dr. Bo Wang, Scientist at Toronto General Hospital Research Institute, as Chief Artificial Intelligence (AI) Scientist. Dr. Wang, whose primary research areas are machine learning, computational biology and computer vision, will take on the pioneering role that is a first for a Canadian hospital.
His appointment builds upon the launch earlier this year of UHN’s AI Hub, a UHN Collaborative Centre for AI and Data Science and another first-of-its-kind initiative in the Canadian health care landscape.
Designed to augment human intelligence through AI health care innovation, the UHN AI Hub brings together scientists and clinicians from across UHN working in AI, including those in cancer, cardiovascular disease, neuroscience, transplant and rehabilitation.
“Health care is becoming increasingly data-driven and AI plays a pivotal role in extracting valuable insights from large datasets,” says Dr. Wang, who is also co-lead of the UHN AI Hub with Dr. Shaf Keshavjee, Chief of Clinical Innovation at UHN and Director of the Toronto Lung Transplant Program.
“AI has the potential to revolutionize health care by improving patient outcomes, increasing efficiency and reducing costs,” says Dr. Wang, who has been Lead AI Scientist at UHN’s Peter Munk Cardiac Centre since 2019. “This role offers an opportunity to drive innovation and advance patient care."
Dr. Brad Wouters, UHN’s Executive Vice President of Science and Research, says Dr. Wang’s appointment “represents the long-term commitment we’re making in AI in health care at UHN and the important role it will play in achieving the organization’s goals in research, innovation and clinical care.”
Dr. Wouters says UHN is in a good position to lead this work due to the uniqueness of the vast amounts of data available here. UHN sees patients with some of the most complex cases in Canada and being located in Toronto – one of the most multicultural cities in the world – means great patient diversity.
Many UHN clinicians and researchers have already begun using forms of AI to enhance patient care. In addition to the UHN AI Hub, the Temerty Centre for AI Research and Education in Medicine at the University Toronto (U of T) is also committed to AI in health care.
“We’re well positioned to create a new leadership role like this at UHN and tap into the other expertise and investments going on in Toronto,” Dr. Wouters says. “We very much want Bo’s leadership and the new UHN AI Hub Collaborative Centre to strengthen the partnerships across Toronto, across Canada and around the world.”
Dr. Wang graduated with a PhD from the Department of Computer Science at Stanford University before he was recruited to UHN. He now holds a CIFAR AI Chair at Vector Institute and is also an inaugural Temerty Professor in AI Research and Education in Medicine, and assistant professor at U of T.
Dr. Barry Rubin, Program Medical Director of the Peter Munk Cardiac Centre, had a vision to integrate machine learning, or AI, into research, education and clinical work, and with the support of the Peter and Melanie Munk Charitable Foundation created an AI team in 2019 with Dr. Wang as Lead AI Scientist.
“For us, the secret sauce was integrating computer scientists, software engineers, data scientists and clinician researchers,” Dr. Rubin says. “From a technical point of view, they don’t speak the same language and have different areas of expertise, but we saw potential for them to be complementary.
In his new role, Dr. Wang hopes to explore some of the following AI applications:
“These are just a few examples and I’m eager to collaborate with experts across UHN to explore and implement AI solutions that improve patient care and health care operations,” Dr. Wang says.
To read more, see this story in the Canadian Press.
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