Welcome to the latest issue of Research Spotlight.
As Canada’s largest research hospital, UHN is a national and international source for discovery, education and patient care. This newsletter highlights top research advancements across UHN and from over 1000 researchers appointed at our institutes.
Stories in this month’s issue:
● Treating COVID-19 Outpatients: Antiviral drug shows promise for COVID-19 outpatients in a phase II clinical trial.
● Self-Driving Towards the Future: Study shows that age and driving style affect older adults’ acceptance of automated vehicles.
● Surviving the Test of Time: Cancer cells are able to survive chemotherapy and targeted agents by entering a dormant state.
● COVID-19 in Health Care Workers: Study shows how many asymptomatic hospital staff were infected with SARS-CoV-2.
Sickle cell disease is the world’s most common inherited blood disorder. The majority of the 5,000 to 6,000 people in Canada affected by this disorder are of African ancestry.
A multidisciplinary research team at Toronto General Hospital’s Red Blood Cell Disorders Program aims to change the lives of people living with sickle cell disease. The team is co-led by Princess Margaret Cancer Centre Clinician Investigators Dr. Kevin Kuo (research lead) and Dr. Richard Ward (clinical lead).
“Our patients are from communities that have historically been marginalized within our society and medical research,” explains Dr. Kuo. “Through close collaboration with our patients as partners, this research is leading to new therapies and models of care for sickle cell disease.”
“Our clinical trials are not only important for advancing research, but also for building meaningful relationships with our study participants,” says Pearl Onugha, Registered Nurse and Clinical Coordinator for the team. “As research health care providers, we find joy in knowing that we are offering novel therapies that can help improve our patients’ care and experience.”
Sickle cell disease is an inherited disorder that causes crescent-shaped red blood cells, which can block blood flow and prevent oxygen from reaching vital organs. Obstructed blood vessels cause immense pain, and over time, patients experience complications such as anemia, stroke and early death. Despite the impact sickle cell disease has on an individual’s quality of life, few reliable treatments are available.
The research group is conducting close to 20 different clinical trials. Combined, these trials touch on the entire health care and treatment journey. Below are some examples of the ongoing projects addressing sickle cell disease:
“I want to live longer and experience no pain,” says Omar Nelson, an individual with sickle cell disease who is participating in his fifth clinical trial. “I’ve been through a lot and I don’t want anyone to have to go through what I’ve been through. I like to be a part of research studies so they can learn from my experience and help people after me.”
By expanding our understanding of diseases that disproportionately impact people of colour, these projects are a critical step towards providing compassionate care and comprehensive treatments to all.
Support for the crizanlizumab trial comes from Novartis Pharmaceuticals. Support for the BENEFiTS trial comes from National Heart, Lung, and Blood Institute/National Institutes of Health grant 1R33HL147845-01A1. Support for the transition navigator study comes from Toronto General Hospital Foundation, SickKids Foundation, Novartis and ApoPharma. Support for the neurocognitive screening trial comes from Pfizer Inc.
Dr. Kuo is a member of a committee at Bioverativ and Agios Pharmaceuticals; a consultant for Agios Pharmaceuticals, Alexion Pharmaceuticals Inc., Celgene/BMS, Novartis, Bluebird Bio, Pfizer and Apellis; receives honoraria from Alexion Pharmaceuticals and Novartis; is a scientific collaborator with Abfero and Phoenicia Biosciences; and receives research funding from Pfizer.
Effective learning is crucial in the training of future health care professionals. At UHN, researchers at The Institute for Education Research (TIER) are investigating ways to improve learning outcomes.
One of the most effective teaching strategies is known as productive failure. This is when learners are asked to invent a solution by themselves before they are provided a solution. An example of this strategy would be to ask students to invent an equation to that describes a straight line before providing them with the solution (i.e., y=mx+b). Productive failure is particularly useful for improving how we learn, so that we become more creative and flexible problem-solvers.
“Class activities based on productive failure are often more difficult to design; furthermore, such activities are tough for students because they are being asked to work on a task that they will likely ultimately fail,” says Naomi Steenhof, Education Investigator at TIER.
“Naturally we wondered: Is it really worth the effort? And is it necessary to put the learners through this?”
To determine whether experiencing failure helps health care professionals to learn better, Ms. Steenhof and her colleagues tested two teaching methods with a group of pharmacy students.
For the same learning activity, half of the group was asked to come up with a solution prior to being taught the answer—i.e., the productive failure strategy. The other half was asked to contrast the correct solution with incorrect ones from past students—a strategy that the researchers referred to as indirect failure.
The two groups showed similar performance when they were tested on the concepts that they had just learned. However, when asked to learn a new related concept, students in the productive failure group performed better than those in the indirect failure group. “The struggle that they had experienced in the learning activity had improved their ability to learn,” says Ms. Steenhof.
Quizzes and exams are designed to evaluate how well the students understand the concepts taught in class. However, students often memorize the course material then forget the knowledge soon after.
“Good performance on a test does not always translate to learning, and poor performance does not mean that learning has not occurred,” cautions Ms. Steenhof. “Performance and learning are not the same, and we should focus more on learning when evaluating overall learner success.”
This work was supported by the Toronto General & Western Hospital Foundation.
Steenhof N, Woods NN, Mylopoulos M. Exploring why we learn from productive failure: insights from the cognitive and learning sciences. Adv Health Sci Educ Theory Pract. 2020 Dec. doi: 10.1007/s10459-020-10013-y.
Acute myeloid leukemia (AML) is a cancer of the blood cells. Almost three out of four of adults with AML die within five years of being diagnosed with the disease, so there is a great need for new ways to treat it.
One emerging approach is to use a subset of cells from the immune system called DNT cells to target and kill the mal-formed blood cells produced by the disease. The DNT cells can be extracted from patients or from healthy donors, multiplied outside the body, and given to patients with AML as a therapy. Early results with this DNT cell-based therapy have been promising, however some cancer cells from AML patients are not successfully targeted by the DNT cell therapy.
A team led by Senior Scientists Dr. Housheng Hansen He at Princess Margaret and Dr. Li Zhang at Toronto General Hospital looked for genetic differences that would explain why some patients don’t respond to DNT cell therapy.
Their study used a powerful tool called CRISPR to edit the genes in AML cell samples. In an experimental model, they made changes to 1,000 genes at a time, and then tested whether the therapeutic T-cells were able to target the cancer.
Using this approach, the team identified a group of genes—which are components of the SAGA deubiquitinating complex—as important for enabling AML cells resistance to T-cell therapy. These genes have many functions, but their ability to make changes to proteins that bind to a cell’s DNA may be important for treatment resistance.
The team was also able to identify genes that can serve as markers for whether the cancer would respond to DNT cell therapy. “We found that when a protein known as the CD64 was expressed on the cancer cells, they were effectively targeted and killed by DNT cells. Likewise, when CD64 was absent, the cancer was resistant to the therapy,” says Dr. Zhang.
These findings provide important first steps towards optimizing DNT cell therapy and for predicting whether the therapy will help individual patients. Future clinical trials will test whether CD64 can be used to identify the individuals with AML that are most likely to benefit from DNT cell therapy, while basic research studies are needed to explore the role of the SAGA complex in therapy resistance and how to target it.
This work was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Ministry of Colleges and Universities, and The Princess Margaret Cancer Foundation. Dr. He holds the Joey and Toby Tanenbaum Brazilian Ball Chair in Prostate Cancer.
Fraser Soares, Branson Chen, Jong Bok Lee, Musaddeque Ahmed, Dalam Ly, Enoch Tin, Hyeonjeong Kang, Yong Zeng, Nayeema Akhtar, Mark D Minden, Housheng Hansen He, Li Zhang. CRISPR screen identifies genes that sensitize AML cells to double negative T cell therapy. Blood. 2020 Dec 3. doi: 10.1182/blood.2019004108
Driving can serve as a lifeline for older adults, enabling them to run errands, attend medical appointments and maintain social connections. This independence can be jeopardized as mental capacity and mobility decline, making driving unsafe.
While fully automated vehicles are a potential solution to help older adults maintain their independence, the success of this strategy depends on whether older adults accept and use the technology.
A team of researchers at the KITE Research Institute, the research arm of the Toronto Rehabilitation Institute, sought to understand how age, driving style, driving conditions and exposure to automated vehicle technology impacts older adults' acceptance of automated vehicles.
Thirty-six participants ranging in age from 65 to 90 completed driving scenarios in the KITE Research Institute’s state-of-the-art DriverLab simulator. Three driving scenarios were replicated: heavy rain, high traffic and clear daytime. For each of these scenarios, two driving sessions were completed: one that was controlled by the participant; and one controlled by the computer to simulate a self-driving car.
Before and after each session, participants filled out questionnaires that assessed their comfort with, and acceptance of automated vehicles.
The researchers also assessed differences in the driving style—such as braking and accelerating—between the participant and the automated vehicle. The results showed that greater differences in driving styles (especially for deceleration), were associated with more negative attitudes towards self-driving vehicles in participants. Additionally, participants over the age of 80 had lower expectations of the reliability of automated vehicles.
“It is projected that age-related frailties will be the leading cause of fatal road accidents by 2025,” says Dr. Mihailidis. “While fully automated vehicles could potentially help older adults maintain their independence while keeping our roads safe, our findings suggest we need to customize the automated driving experience to the user to help build trust in this technology.”
This work was supported by Canadian Institutes of Health Research, AGE-WELL NCE Inc., UBER Canada, the Schwartz Reisman Institute for Technology at the University of Toronto and Toronto Rehab Foundation.
Haghzare S, Campos JL, Bak K, Mihailidis A. Older adults' acceptance of fully automated vehicles: Effects of exposure, driving style, age, and driving conditions. Accid Anal Prev. 2021 Feb;150:105919. doi: 10.1016/j.aap.2020.105919. Epub 2020 Dec 10.
The UHN Office of Research Trainees (ORT) is proud to announce the release of the latest issue of The ORT Times!
It is bittersweet for us to announce that this month's edition of the UHN ORT Times will be our last. With every end comes a new beginning, and we are excited about this new chapter where the ORT will focus on more timely and rapid communications, including bi-weekly email updates and utilizing social media. Using these platforms, we will continue to share helpful content including career development workshops, research training opportunities within and outside of UHN, and trainee and alumni spotlights.
We look forward to connecting with you on Twitter and LinkedIn or by email at email@example.com.
Since our inaugural edition of the ORT Times in November 2011, the ORT Times has served as a monthly email e-newsletter for UHN trainees and the research community as a whole. To view past issues of the ORT Times, please visit uhntrainees.ca.
Read and download the full issue now!
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Princess Margaret Cancer Centre’s Dr. Tak Mak and Stanford University’s Dr. Mark Davis have been awarded the 2021 Szent-Györgyi Prize for Progress in Cancer Research. Drs. Mak and Davis received the award for their discovery of the structure of the T-cell receptor (TCR) and their research into the underlying mechanisms of T-cell function and development.
Their discoveries have laid the foundation for a novel T-cell-based immunotherapy approach, known as CAR (chimeric antigen receptor) T-cell therapy, which has been approved for the treatment of several types of blood cancer.
The award, presented by the National Foundation for Cancer Research (NFCR), honours scientists who have made discoveries that have led to advances in cancer prevention, diagnosis or treatment. The prize was established in 2006 in honour of NFCR’s cofounder, Dr. Albert Szent-Györgyi, who received the 1937 Nobel Prize in Physiology or Medicine.
“We would like to see more and continued support to basic cancer research that is the true driving force for the development of novel cancer therapies,” stated Sujuan Ba, Ph.D., co-chair of the 2021 Prize selection committee and president and CEO of NFCR. “What Mak and Davis have achieved is an outstanding example of how the discoveries made from basic cancer research can lay a solid foundation for the further development of life-saving clinical applications.”
This pioneering research was set in motion by Dr. Mak in 1984, who successfully cloned the human TCR β gene, and at the same time by Dr. Davis, who cloned the murine TCR gene. Based on these and other complementary discoveries in T-cell biology, scientists were able to finally engineer T-cells that recognize and destroy cancer.
Drs. Mak and Davis will be presented the award in Washington D.C. at a ceremony that is tentatively scheduled in October 2021, depending on the status of the COVID-19 pandemic.
Congratulations to Drs. Mak and Davis for this prestigious honour and for their life-changing contributions to cancer research and our understanding of the immune system.
Source: NFCR press release.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
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