Thirteen world-class UHN scientists have been recognized in Clarivate’s list of Highly Cited Researchers for 2020.
Each year, Clarivate identifies the most influential researchers demonstrated by the publication of multiple highly cited papers that rank in the top one percent by citations for their field and year of publication in the Web of Science.
Congratulations to the following UHN scientists who were included among 6,390 of the most impactful researchers in the world:
• Dr. Andres M. Lozano (Senior Scientist at Krembil and Affiliate Scientist at Techna), an innovator in surgical approaches to treat Parkinson disease, depression and Alzheimer disease
• Dr. Anthony E. Lang (Senior Scientist at Krembil), an influential researcher in the field of movement disorders, most notably Parkinson disease
• Dr. Duminda N. Wijeysundera (Clinician Investigator at Toronto General Hospital Research Institute), a leading anesthesiologist developing methods to prevent post-surgical complications
• Dr. Frances A. Shepherd (Senior Scientist and Clinical Investigator at Princess Margaret Cancer Centre), an instrumental figure in the design and conduct of cancer trials
• Dr. Ming-Sound Tsao (Senior Scientist at Princess Margaret Cancer Centre), a preeminent authority in translational lung cancer research
• Dr. Roger S. McIntyre (Clinician Investigator at Krembil), a leading expert in cognitive impairment associated with mood disorders
• Dr. Sagar V. Parikh (Clinical Investigator at Krembil), an influential researcher investigating interventions for mood disorders at the patient, provider and systems levels
• Dr. Slava Epelman (Scientist at Toronto General Hospital Research Institute), an expert in cardiac tissue injury and regeneration
• Dr. Steven Gallinger (Clinician Scientist at Princess Margaret Cancer Centre), an expert in colorectal and pancreatic cancer genetics
• Dr. Sidney H. Kennedy (Senior Scientist at Krembil), a foremost researcher investigating treatments for major depressive disorder and bipolar disorder
• Dr. Tak W. Mak (Senior Scientist at Princess Margaret Cancer Centre), a pioneer in cancer immunotherapy
• Dr. Theodorus van der Kwast (Clinician Investigator at Princess Margaret Cancer Centre), a leading pathologist uncovering the molecular profile of prostate cancer
• Dr. Trevor Pugh (Senior Scientist at Princess Margaret Cancer Centre), a world-leading cancer genomics researcher and molecular geneticist
This year, Drs. Gallinger, Lozano, Mak, Tsao and van der Kwast were included in the Cross-Field category, demonstrating the interdisciplinary nature of their work and the impact they have made in multiple areas of scientific discovery.
The full list, as well as a detailed explanation of the analysis methodology, is available here.
Krembil researchers, led by Senior Scientist Michael Reber, have constructed the first computational model that describes the molecular and cellular mechanisms of visual connectivity organization in the brain.
The model simulates and predicts the organization of visual connectivity in the brain and how different networks of neurons interact with one another, which is very important for our daily functioning—in particular, for our ability to visualize and comprehend our surroundings.
The model is based a ‘three-step’ map alignment algorithm. The algorithm serves as a set of programming and mathematical instructions for constructing a visual map. The benefit of the three-step approach is that it closely mimics the three steps taken by the brain to process visual information.
The three steps defined in the algorithm and taken in the brain are 1) the formation of a visual map from information sent from the eye to a region of the brain known as the superior colliculus; 2) the incorporation of complementary information from the visual cortex, which is the main area in the brain the processes visual information, and 3) the ‘alignment’ of the visual information so that makes sense to the brain.
Findings from the computational model were compared to those from real-life biological models. The results revealed that errors that arise in certain neurological conditions can be faithfully recreated in the computational model.
Commenting on the new model, Dr. Reber says, “This work is essential for recreating and ultimately predicting what can go wrong in the connections between the eye and brain. Our model has the power to ‘connect the dots’ between how biological parameters—such as the concentration or the function of a particular molecule, or the number of cells—affect visual perception. In the future, our model could reveal what happens to neural connections in diseases such as age-related macular degeneration, glaucoma or diabetic retinopathy—ultimately shedding light on new therapeutic approaches to improve vision.”
This work was supported by The University of Strasbourg Institute for Advanced Study, The French National Centre for Scientific Research (CNRS), the Donald K. Johnson Eye Institute, the Krembil Research Institute, and the Toronto General & Western Hospital Foundation.
Savier EL, Dunbar J, Cheung K, Reber M. New insights on the modeling of the molecular mechanisms underlying neural maps alignment in the midbrain. Elife. 2020 Sep 30;9:e59754. doi: 10.7554/eLife.59754.
Drs. Alexander Mikryukov and Gordon Keller at McEwen Stem Cell Institute recently discovered how to produce endocardial cells—a type of cell that lines the interior of the heart—from stem cells in the laboratory.
The stem cells that they used are known as human pluripotent stem cells. These cells are capable of giving rise to all of the different cell types found in the human body. Devising ways to coax these stem cells to produce specific types of cells is an area of ongoing research.
“Endocardial cells are formed during one of the earliest stages of heart development and function to stimulate the formation of the first muscle tissue in the heart,” explains Dr. Mikryukov, the lead author of the study. “They also produce cells that are part of the blood vessels and the valves of the heart.”
The human body is made up of roughly 37 trillion cells; all of them originate from a single cell—the fertilized egg. The path of growth from one cell to 37 trillion is highly complex—everything must happen at the right time and in the right place.
In the body, cells use chemical signals to guide the development of new cells so that they have the characteristics needed to perform their role. To identify which chemicals are responsible for giving rise to endocardial cells, the team recreated conditions for early heart development using pluripotent stem cells as an experimental model. They also used advanced gene sequencing approaches that are capable of providing a snapshot of the genes expressed in each individual cell.
These analyses revealed that the protein BMP10 plays a key role in regulating the development of endocardial cells in early heart development. They also showed that the lab-derived endocardial cells had very similar characteristics to embryonic endocardial cells.
“Our results highlight the power of using stem cells as a model to identify the mechanisms behind the formation of the heart tissues during embryonic development,” says Dr. Keller, senior author of the study.
The ability to produce endocardial cells in the laboratory opens new avenues to modelling heart development and disease—and could help to accelerate the development of treatments for heart conditions such as valve diseases.
This work was supported by the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation. G Keller holds a Tier 1 Canada Research Chair in Embryonic Stem Cell Biology.
Mikryukov AA, Mazine A, Wei B, Yang D, Miao Y, Gu M, Keller GM. BMP10 Signaling Promotes the Development of Endocardial Cells from Human Pluripotent Stem Cell-Derived Cardiovascular Progenitors. Cell Stem Cell. 2020 Oct 27. doi: 10.1016/j.stem.2020.10.003.
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:
• Unifying Research, Education & Care: Generous $25 million donation enables creation of the Schroeder Arthritis Institute.
• Immunologist Joins the Krembil Team: New scientist, Dr. Olga Lucia Rojas, studies the link between the gut and neuroinflammation.
• Having it Both Ways: Krembil researchers validate new, highly specific & sensitive criteria for classifying lupus.
• A Case for Research: Study proposes research roadmap to improve knowledge of spontaneous hydrocephalus in adults.
• Well in Hand: Study explores how the brain restores hand function after a hand transplant.
• The Importance of Being Open: Study implicates syntaxin as a gatekeeper of information in the brain and spinal cord.
Dr. Daniel De Carvalho’s laboratory at Princess Margaret Cancer Centre has commenced a collaborative drug discovery research program with Pfizer’s Center for Therapeutic Innovation (CTI). The collaboration will leverage Dr. De Carvalho’s expertise in immunotherapy and aims to screen, identify and optimize potential drug candidates that trigger the body’s own immune system to kill cancer cells.
This research collaboration will match Pfizer’s drug discovery expertise with novel mechanisms of disarming cancer cells against the body’s own immune response by mimicking a viral infection to the cancer cells, which was previously identified by a team of researchers led by Dr. De Carvalho.
“Our prior work provides an exciting foundation for drug development efforts and could lead to the development of a completely new class of drugs that are able to exploit the body’s own genome against cancer,” says Dr. De Carvalho.
UHN’s Technology Development and Commercialization office helped facilitate the collaboration.
“We are thrilled to enter into this new collaboration with Pfizer,” says Mark Taylor, Director, Technology Development and Commercialization at UHN. “This new relationship pairs Dr. De Carvalho’ s deep know-how with Pfizer’s drug-discovery engine, to accelerate the possibility of a new treatment to patients, sooner,” he said. “Our collaboration with Pfizer illustrates our commitment to research partnerships that allow access to the latest technology to enrich possibilities for patients world-wide.”
The brain is bathed in a protective fluid called cerebrospinal fluid. In a condition known as hydrocephalus, the fluid fails to drain properly from cavities in the brain called ventricles and puts pressure on the surrounding tissue.
The type of hydrocephalus that is most commonly seen in adults—normal pressure hydrocephalus—can be caused by an infection, tumour or head trauma. However, the condition is often deemed idiopathic, which means that the cause of the fluid accumulation is unknown.
To shed light on this elusive form of hydrocephalus, a research team led by Krembil Clinical Investigator Dr. Alfonso Fasano highlighted the current knowledge gaps in diagnosis and treatment, and proposed a research roadmap to address them.
“There are currently no standardized diagnostic criteria for normal pressure hydrocephalus and it often goes misdiagnosed because the symptoms can be similar to neurodegenerative conditions such as Parkinson disease,” explains Dr. Fasano. “We must take a research-oriented approach to defining diagnostic guidelines and understanding treatment outcomes.”
The researchers highlighted the actions needed to advance our understanding of the condition, which are listed below:
● Develop unified international diagnostic criteria
● Conduct population-based studies to reveal how the disease develops and progresses in a variety of individuals
● Build international biobanks where samples from diverse patient populations can be stored and shared
The roadmap also emphasizes the need for better ways to assess how normal pressure hydrocephalus is treated. Currently, the condition is treated through shunting—a procedure in which a small tube is inserted into the brain to drain excess fluid. A key problem is that the test used to decide whether shunting should be used is unreliable. To address this, the roadmap calls for rigorous clinical trials (ie, randomized controlled trials) that involve a variety of different patients. These trials will help to reveal more effective ways to decide which patients should receive the procedure.
“In order to better treat those affected by this disorder, we need a stronger understanding of the underlying factors,” says Dr. Fasano. “A unified approach is the best way forward. By working together, the research community is uncovering the molecular and biological mechanisms at play so we can improve the quality of life for patients living with this condition.”
Fasano A, Espay AJ, Tang-Wai DF, Wikkelsö C, Krauss JK. Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus [published online ahead of print, 2020 Sep 22]. Mov Disord. 2020;10.1002/mds.28251. doi:10.1002/mds.28251
Researchers at the Krembil Research Institute have revealed that a protein—known as syntaxin—could hold the key for new therapies for a variety of neurological disorders.
Syntaxin plays a key role in how neurons—specialized cells in the brain and nervous system—transmit information throughout the body. Neurons communicate with other cells at narrow gaps known as synapses, where neurotransmitters are released. These neurotransmitters serve to ‘bridge the gap’ between the cells by passing on the signal.
The release of neurotransmitters is key to the process known as synaptic transmission, which enables the flow of electrical information between the brain, spinal cord and body.
At the molecular level, syntaxin serves as a switch and changes shape from a ‘closed’ to an ‘open’ state. Once in the ‘open’ state, syntaxin acts in concert with other proteins to enable the release of the neurotransmitters. When syntaxin or other proteins involved in this process are defective, certain neurological disorders can arise.
“Using an experimental model, we introduced a version of syntaxin that was locked in the ‘open’ state. This version of syntaxin was able to overcome losses in proteins that are implicated in a wide spectrum of childhood epilepsy and autism spectrum disorders,” says Dr. Sugita.
These findings position syntaxin as a key player in synaptic transmission, and suggest that drugs, and other small molecules, could be developed to push syntaxin to the ‘open’ state as part of a strategy to treat certain neurological diseases.
This work was supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, The Welch Foundation, National Natural Science Foundation of China, the United States National Institute of Neurological Disorders and Stroke, the Dengfeng Initiative of the Global Talents Recruitment Program, and the Toronto General & Western Hospital Foundation.
Tien CW, Yu B, Huang M, Stepien KP, Sugita K, Xie X, Han L, Monnier PP, Zhen M, Rizo J, Gao S, Sugita S. Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans. Nat Commun. 2020 Nov 2;11(1):5516. doi: 10.1038/s41467-020-19178-x.
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