Alzheimer disease is a common neurodegenerative disorder that causes losses in memory and cognitive function, and eventually death. Treatments for the disease are limited, in part because the mechanisms that trigger the underlying destruction of brain cells are unknown.
An international collaboration led by Dr. Donald Weaver, Director and Senior Scientist at the Krembil Research Institute, has provided a new explanation for how Alzheimer disease develops.
The explanation revolves around a protein building block called amyloid beta, which accumulates in the brains of people with Alzheimer disease and leads to the death of neurons. Despite a growing understanding of amyloid beta, researchers still do not know what causes it to accumulate, and existing treatments targeting it are neither universally accepted nor suitable for all patients.
“We reframed Alzheimer disease as a disorder of the immune system, wherein amyloid beta triggers an immune response that attacks healthy brain cells,” explains Dr. Weaver. “By viewing the disease as an autoimmune disorder, we have united competing theories of what causes the disease into one compelling picture.”
Through a series of experiments and computer simulations of the interactions between amyloid beta and cells, the research team created a four-step model for the development of the disease:
Step 1. In a manner similar to known immune responses, brain cells release amyloid beta in response to invaders such as bacteria and viruses and to traumatic events such as mechanical injury to nearby cells.
Step 2. The amyloid beta behaves similarly to other agents released by the immune system, inserting itself into the membranes of the invading organisms or damaged cells. This action helps to destabilize the unwanted cells and clear them from the body.
Step 3. The amyloid beta mistakenly acts on healthy brain cells because their membranes share traits with those of bacteria and damaged cells.
Step 4. The attacked brain cells degrade and release more amyloid beta, and the cycle repeats itself.
Dr. Weaver’s team proposes that the repetitive release of amyloid beta fuels a self-perpetuating cycle that ultimately causes the progressive neuron degeneration seen in Alzheimer disease.
With their new model, the team sought to identify targets for drugs that could disrupt the cycle. They screened more than 1,100 molecules that naturally occur in the brain as potential targets.
The researchers discovered that biological products made from the amino acid tryptophan are particularly effective in preventing the accumulation of amyloid beta. They then compiled a library of natural and synthetic compounds that might be good candidates for use in therapy because of their similarities to these biological products.
“By uncovering a new dimension to Alzheimer disease and identifying potential therapeutic compounds, this research could lead to a new treatment that can target the underlying driver of the disease to prevent further cognitive changes,” says Dr. Weaver.
This work was supported by the BrightFocus Foundation, Canadian Institutes of Health Research, Alzheimer’s Society of Canada, Ontario Brain Institute, Canada Foundation for Innovation, Sobey Family and Sobey Foundation, Weston Brain Institute, Michael Albert Garron Foundation, Dalhousie Medical Research Foundation, Atlantic Canada Opportunities Agency, Krembil Foundation and UHN Foundation. Dr. Donald Weaver holds a Tier 1 Canada Research Chair in Drug Design for Protein Misfolding Disorders and is a Professor of Chemistry, Medicine and Pharmaceutical Science at the University of Toronto.
Meier-Stephenson FS, Meier-Stephenson VC, Carter MD, Meek AR, Wang Y, Pan L, Chen Q, Jacobo S, Wu F, Lu E, Simms GA, Fisher L, McGrath AJ, Fermo V, Barden CJ, Clair HDS, Galloway TN, Yadav A, Campágna-Slater V, Hadden M, Reed M, Taylor M, Kelly B, Diez-Cecilia E, Kolaj I, Santos C, Liyanage I, Sweeting B, Stafford P, Boudreau R, Reid GA, Noyce RS, Stevens L, Staniszewski A, Zhang H, Murty MRVS, Lemaire P, Chardonnet S, Richardson CD, Gabelica V, DePauw E, Brown R, Darvesh S, Arancio O, Weaver DF. Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites. Alzheimers Dement (N Y). 2022 Apr 6. doi: 10.1002/trc2.12283.
Congratulations to Krembil Senior Scientist Dr. Nigil Haroon, for receiving the Pravasi Ratna Award from the National Federation of Malayalee Associations in Canada.
Dr. Haroon received the award in recognition of his outstanding contributions to society, as well as being an internationally recognized leader in his field.
Outside his lab, Dr. Haroon contributes to multiple health-related outreach initiatives around the world. For example, in 2018, multiple floods occurred in Kerala, India, where Dr. Haroon grew up and completed his medical education. Floods frequently cause major outbreaks of water-borne diseases due to disruptions in clean water supplies. To help to reduce these outbreaks, Dr. Haroon worked with the humanitarian aid organization GlobalMedic and the local government administration to provide water filtration kits. These kits supplied clean drinking water to nearly 40,000 people in three different towns that were most affected.
Dr. Haroon continued this volunteerism during the COVID-19 pandemic, which quickly overwhelmed India’s hospital capacity. Dr. Haroon spearheaded a multi-institutional effort to collect and deliver $4.5 million-worth of medical supplies, including masks. He also partnered with the Indian Medical Association (IMA) to develop a local home-care program in Kerala to reduce hospital burden.
“Many patients with COVID-19 can be effectively managed at home, but they worry about what will happen to them if they worsen outside a hospital,” explains Dr. Haroon. “We set up a system in which each person being treated at home gets connected with a local healthcare worker who they can call if they have issues. By enabling patients to be safely cared for in their homes, we freed up ICU beds for patients who require advanced care.”
To facilitate at-home patient monitoring, Dr. Haroon also worked with the IMA and the Association of Kerala Medical Graduates to increase the availability of pulse oximeters. The team set up a centralized system for identifying and loaning pulse oximeters to nearby patients in need. Dr. Haroon also oversaw the collection and delivery of over 2000 pulse oximeters to launch the program.
Many of Dr. Haroon’s colleagues from across UHN have generously donated to each of these activities, delivering on UHN’s vision of A Healthier World. “Each of these projects was a massive team effort,” he explains. “Their success has been due to the many driven individuals, from all walks of life, who have come together with a shared goal of helping others.”
Dr. Jennifer Campos, a Senior Scientist at UHN's KITE Research Institute, has received the prestigious NSERC Award for Science Promotion for her work supporting science education, youth outreach and advocacy for equity, diversity and inclusion in STEM.
In addition to her role as the Associate Academic Director at KITE, Campos is a Tier 2 Canada Research Chair in Multisensory Integration and Aging; an Associate Professor in the Department of Psychology at the University of Toronto; Chief Scientist of the Challenging Environments Assessment Laboratory; and the Associate Scientific Director of AGE-WELL, Canada’s aging and technology network.
The award, which is presented by the Natural Sciences and Engineering Research Council of Canada (NSERC), recognizes individuals and groups who have demonstrated incredible impact promoting science to the general public.
“Science promotion is perhaps more important now than ever,” said Campos. “Communicating one’s science is not only critical for generating broad public interest and sharing new knowledge, but it is valuable for scientists themselves to hone their ideas and achieve clarity in their thinking.”
Campos has been an enthusiastic and dedicated champion of science promotion for more than 20 years. Her support for outreach and science promotion includes spearheading the KITE Young Innovators (kYI) program, which has introduced the world of science to more than 35,000 youth through lab tours, design competitions, researcher panels, career seminars and hands-on activities since 2009.
“Enhancing science literacy and generating excitement about science at a very early age provides a solid foundation for our future thinkers, innovators and citizens. As such, some of my most valued science promotion activities have been with youth, who I hope become inspired, but who also provide inspiration,” added Campos.
Under her leadership, kYI has encouraged underrepresented and equity-deserving youth to pursue careers in the fields of science, technology, engineering and mathematics (STEM). And these efforts are being amplified through UHN’s IDEA (Inclusion, Diversity, Equity, Accessibility) sub-committee for youth outreach, which Campos chairs.
“Campos has demonstrated ongoing innovation and creativity that has delivered a lasting influence on students,” said KITE Director Dr. Milos R. Popovic. “The success of her youth outreach efforts at UHN is a testament to Campos’ vision and leadership and we are thrilled that she is being recognized with this award.”
Dr. Campos will receive $10,000 in funding from the NSERC to support her outstanding outreach initiatives.
For more information, see the NSERC award page.
On World Neurofibromatosis Day, May 17, UHN celebrated an anonymous donation of $11 million to support neurofibromatosis research and patient care at the Krembil Brain Institute.
Neurofibromatoses are a group of genetic disorders that cause tumours to form in the nervous system. These disorders can cause numerous complications such as vision and hearing loss, skeletal problems, increased risk of cancer and various neurological disorders.
In 2015, UHN established the Elisabeth Raab Neurofibromatosis Clinic—the first-in-Canada multidisciplinary clinic for adults with neurofibromatoses—with sites at Toronto Western Hospital and Toronto General Hospital.
A portion of this generous donation will go towards establishing the Elisabeth Raab Early Career Research Chair in Neurofibromatosis, which will enable the recruitment of a neurosurgeon-scientist specialized in neurofibromatosis research and patient care.
“Currently there is a shortage of medical and scientific experts in the neurofibromatosis field,” says Dr. Gelareh Zadeh, Medical Director of the Krembil Brain Institute and co-Director of UHN’s Neurofibromatosis Program. “This gift will help to promote research and development excellence in neurofibromatosis care. Most importantly, it will strengthen our collaborative work with other leading neurofibromatosis-related programs globally.”
This gift will also support basic research that will spur the development of improved approaches for managing neurofibromatoses. For example, this investment will boost ongoing research into how benign tumours become cancerous.
“Current treatment options are limited, so this research is essential to help identify more targets for therapeutic intervention,” says Dr. Vera Bril, co-Director of the Neurofibromatosis Program and a Clinician Investigator at the Toronto General Hospital Research Institute.
“Our team is so grateful for this gift, one of the largest ever in support of neurofibromatosis research,” Dr. Zadeh.
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A collaborative team of Canadian researchers used a database of over 10,000 drugs and an artificial intelligence system to find compounds that may be effective against coronaviruses, including SARS-CoV-2. The team included researchers at UHN, the University of Toronto, St. Michael’s Hospital and the Vector Institute for Artificial Intelligence.
As we have seen, viruses can quickly adapt and give rise to new variants. While developing treatments is key, it can take years for a new drug to be approved. That is why it is so important to find existing drugs that can be repurposed and quickly deployed.
“Identifying drugs strictly using their known functions, such as their ability to treat other viral diseases, is limiting. Instead, we expanded the search by developing a data-driven computational approach,” says Techna Scientist Dr. Bo Wang, who co-led the research team.
The strategy used by the team is called a “multiscale interactome approach”, where the relationships between diseases, proteins, biological pathways and other data are used to predict new interactions. Machine-learning tools are used to predict how drugs and the proteins that they target interact, and this information is used to identify useful interactions that may interrupt the infection process.
The researchers included 26 proteins from SARS-CoV-2, the virus behind the COVID-19 pandemic, in their models. The 26 virus proteins interact with 332 proteins in the human body. These human proteins represented a valuable resource in the search for antivirals. This is because drugs that are known to interact with them would be expected to affect the infection process.
Applying the artificial intelligence approach, the team identified 26 drugs that had the potential to treat Covid-19. They then tested several in single-cell experimental infections, and found that capmatinib, an anticancer drug, was able to neutralize the ability of SARS-CoV-2 to infect cells at doses that were likely safe for human use. The team then tested capmatinib against other coronaviruses and found that it had broad antiviral activity.
The study also identified a pair of related proteins—IRAK1 and IRAK4—as being necessary for SARS-CoV-2 to infect human cells. How viruses interact with these proteins is poorly understood, but they are present in bronchial cells, which are found in the airways. Furthermore, several of the drugs identified in the study worked by targeting IRAK1/IRAK4.
“Our method represents a new and powerful approach to rapidly identify new therapies using existing drugs. To our knowledge, our study is among the early attempts to demonstrate that this anticancer drug also has antiviral activity against coronaviruses—making it particularly promising as a therapy against SARS-CoV-2. Our screen also identified drugs that have already been shown to inhibit coronavirus infection, which validates our approach,” concludes Dr. Wang.
This work was supported by the Canadian Institute for Advanced Research, the Natural Sciences and Engineering Research Council of Canada, Mitacs, the EU Horizon 2020 program, the Government of Ontario, the Ryerson University Faculty of Science and the UHN Foundation. Dr. Roberto Botelho holds a Tier 2 Canada Research Chair in Biomedical Sciences and Technologies, Dr. Jean-Philippe Julien holds a Tier 2 Canada Research Chair in Structural Immunology. Dr. Bo Wang is an Assistant Professor in the Department of Medical Biophysics at the University of Toronto.
Sugiyama MG, Cui H, Redka DS, Karimzadeh M, Rujas E, Maan H, Hayat S, Cheung K, Misra R, McPhee JB, Viirre RD, Haller A, Botelho RJ, Karshafian R, Sabatinos SA, Fairn GD, Madani Tonekaboni SA, Windemuth A, Julien JP, Shahani V, MacKinnon SS, Wang B, Antonescu CN. Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease. Sci Rep. 2021 Dec 2;11(1):23315. doi: 10.1038/s41598-021-02432-7.
Scientists at the Krembil Research Institute’s Centre for Medicinal Chemistry and Drug Discovery (CMCDD) report a new total synthesis of natural product lipoxin B4 (LXB4), a molecule with neuroprotective properties.
LXB4 is a small lipid molecule that dampens inflammation. Krembil Senior Scientist Dr. Jeremy Sivak and his team found that this molecule is produced in the retina and protects retinal neurons against the damaging effects of increased eye pressure and inflammation in experimental models of glaucoma—one of the leading causes of blindness in people over the age of 60.
“We have been exploring whether we can stimulate the body to produce more LXB4 or deliver a synthetic version of the molecule directly into the retina to treat glaucoma,” says Dr. Sivak.
After discovering LXB4’s key roles in retinal disease, Dr. Sivak’s team focused on strategies to reproduce the molecule in the lab so that they could study its biological effects. To do this, they partnered with medicinal chemist Dr. Mark Reed, a Staff Scientist at the Krembil Research Institute and Director of CMDD.
Starting with readily accessible chemical building blocks, Dr. Reed’s team used a series of medicinal chemistry methods to create the complex molecule from scratch. The team confirmed the molecule’s precise chemical structure for the first time and demonstrated that it has significant neuroprotective activity in a test of retinal neuron survival.
Dr. Reed says, “Our team has shown that LXB4 can be produced in large quantities synthetically and can easily be modified to change its activity. This opens the door to studies that explore how LXB4 functions, which will ultimately shed light on how to enhance its action to treat inflammatory and neurodegenerative diseases.”
In addition to the molecule serving as a potential treatment for glaucoma, a deeper understanding of LXB4 could unlock new treatments for a host of diseases in which inflammation is a contributing factor, such as lupus, asthma, cancer and Alzheimer disease.
“Drug development is a complex undertaking—it often takes over 10 years to bring a new drug to market,” says Dr. Reed. “The close collaboration between scientists and in-house medicinal chemists at Krembil is enabling us to accelerate this process and translate discoveries into life-changing therapies.”
This work was supported by a LAB150 grant administered through Toronto Innovation Acceleration Partners, the Krembil Foundation and the UHN Foundation. Nuclear magnetic resonance (NMR) spectrometers were funded by the Canada Foundation for Innovation and the Princess Margaret NMR Core Facility was supported by the Princess Margaret Cancer Foundation. J Sivak holds the Graham Trope Chair in Glaucoma Research. D Weaver holds a Tier I Canada Research Chair in Drug Design for Protein Misfolding Disorders.
Lee CF, Brown CE, Nielsen AJ, Kim C, Livne-Bar I, Parsons PJ, Boldron C, Autelitano F, Weaver DF, Sivak JM, Reed MA. A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation. Chemistry. 2022 May 1. doi: 10.1002/chem.202200360.
The Stem Cell Network has announced its largest single investment in stem cell research in Canada—a total of $19.5M across 32 projects. Of these, seven projects will be led by researchers at University Health Network, infusing $4.75M into research that advances innovative regenerative medicine therapies.
The projects, outlined below, explore cutting-edge approaches, including nanoparticle-based therapies, gene therapy, cell-based therapies and three-dimensionally printed organ tissues (i.e., bioprinted tissues). The projects will move us closer to addressing unmet clinical needs for blood cancers, liver disease, heart disease, genetic brain disorders and organ transplantation.
“These investments build on a strong legacy of innovation in stem cell and regenerative medicine research in Canada and at UHN,” says Dr. Bradly Wouters, Executive Vice President of Science and Research, UHN.
“The projects demonstrate a high degree of creativity and collaboration. Given the complexity of the health issues being addressed, this willingness to share ideas, expertise and resources will be key to success. As Canada’s leading research hospital, much of our research is driven by a desire to improve the lives of patients, a goal that these projects place first and foremost.”
Congratulations to the following researchers and their teams!
HORIZON AWARD
UHN will lead one of three national Horizon Awards. This funding represents a new multi-year program for the Stem Cell Network, and each award is valued at $3 million—the largest award offered in the past decade. The funds support research, technology development and made-in-Canada intellectual property that will lead to health and economic benefits in the coming decade.
Sara Vasconcelos, Scientist, Toronto General Hospital Research Institute (TGHRI), UHN
Advancing microvessel-based cardiac regeneration into a large pre-clinical model
● Collaborators: Gregory Korbutt (University of Alberta), Michael Laflamme (UHN), Nilesh Ghugre (Sunnybrook Research Institute)
FUELING BIOTECHNOLOGY PARTNERSHIPS
UHN will lead one of the Fueling Biotechnology Partnerships, which serve as catalysts for the translation of stem cell research into the market and clinic. The program provides $400,000 to strengthen partnerships between Canadian academics and emerging Canadian regenerative medicine biotech companies.
Shinichiro Ogawa, Affiliate Scientist, McEwen Stem Cell Institute, UHN
Developing functional 3D bioprinted liver tissues with sustained immune evasion
● Biotech Partner: Aspect Biosystems
● Collaborators and co-investors: Gordon Keller (UHN), Ian McGilvray (UHN), Rafal Witek (Aspect Biosystems), Sam Wadsworth (Aspect Biosystems), Sonya MacParland (UHN)
EARLY CAREER RESEARCHER JUMP-START AWARDS
The Stem Cell Network granted twelve Early Career Researcher Jump-Start Awards at $300,000 each. The funds support early-career researchers who are developing research programs focused on regenerative medicine.
Mamatha Bhat, Scientist, TGHRI, UHN
A Nanoparticle-based Strategy to Therapeutically Restore Regenerative Capacity in Cirrhotic Livers
● Co-investors and collaborators: Gang Zheng (UHN), Jeff Wrana (Sinai Health System)
Anastasia Tikhonova, Scientist, Princess Margaret Cancer Centre, UHN
Targeting the bone marrow microenvironment to promote hematopoietic regeneration
● Co-investors and collaborators: Courtney Jones (UHN), Dennis Kim (UHN), Gary Bader (University of Toronto, UHN)
Bo Wang is serving as a co-investigator on an Early Career Researcher Jump-Start Award being led by Amy Wong at the Hospital for Sick Children (Project title: Deciphering cell competition during iPSC differentiation towards lung epithelia).
IMPACT AWARDS
Impact Awards support proof-of-principle research to test novel technologies, approaches and therapies that will push the boundaries of regenerative medicine. Three of these awards, valued up to $250,000 per award, will be led by UHN researchers.
Gordon Keller, Senior Scientist and Director, McEwen Stem Cell Institute, UHN
Novel human pluripotent stem cell-derived hematopoietic cell therapy
● Collaborator: Juan Carlos Zuniga-Pflucker (Sunnybrook Health Sciences Centre)
Milica Radisic, Senior Scientist, TGHRI, UHN
Stem cell-derived resident cardiac macrophages in designer polymers for cardiac repair and regeneration
● Collaborators and co-investors: Gordana Vunjak-Novakovic (The Trustees of Columbia University in the City of New York), Gordon Keller (UHN), Michael Laflamme (UHN), Slava Epelman (UHN)
Karun Singh, Senior Scientist, Krembil Research Institute, UHN
Gene therapy to restore neural connectivity in neurodevelopmental disorders associated with a CNV microdeletion
● Collaborator: Sarah Wootton (University of Guelph)
The announcement was made on Thursday May 12, 2022 at an in-person event in Ottawa and streamed on the Stem Cell Network’s Twitter account. Parliamentary Secretary Mr. Andy Fillmore made the announcement on behalf of the Minister of Innovation, Science and Industry. These awards represent the Stem Cell Network’s largest investment in stem cell and regenerative medicine research over the agency’s 20-year history.
Of the funding, the Honourable François-Philippe Champagne, Minister of Innovation, Science and Industry commented, “Stem cell and regenerative medicine is a made-in-Canada success story that drives innovation and saves the lives of Canadians and countless others around the world. Through the Stem Cell Network, we are proud to invest in our world-class researchers and scientists and support their ground-breaking work to tackle some of the most serious illnesses we face today. When we invest in science, we invest in better, healthier lives for everyone.”
To see all the funded projects and for additional information, visit the Stem Cell Network’s competition results page.
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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