University Health Network

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Donnelly Centre for Cellular & Biomolecular Research

Subheadline

"This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections"

Researchers at the University of Toronto and its hospital partners have developed a method for co-delivering therapeutic RNA and potent drugs directly into cells, potentially leading to a more effective treatment of diseases.

The research, published recently in the journal Advanced Materials, explores how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery.

The team – including Molly Shoichet, the study’s corresponding author and a University Professor in ��ֱ��’s department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – specifically targeted drug-resistant cells with the delivery of a relevant siRNA. The siRNA was discovered study co-author and collaborator David Cescon, a clinician scientist at the Princess Margaret Cancer Centre, University Health Network, and an associate professor in ��ֱ��’s Temerity Faculty of Medicine.

“We found that our co-formulation method not only potently delivered siRNA to cells but also simultaneously delivered active ionizable drugs,” said research lead author Kai Slaughter, a PhD candidate in Shoichet’s lab.

“This could be a game-changer for treating complex conditions where targeting multiple pathways is beneficial, such as cancer and viral infections.”

siRNA is a powerful tool in medicine, capable of silencing specific genes responsible for disease, but delivering these molecules into cells without degradation remains a significant challenge. While recent innovations in ionizable lipid design have led to efficiency improvements, traditional nanoparticle formulations are limited in the amount of small molecule drugs they can carry.

When therapeutic formulations are absorbed by cells, small molecule drugs and siRNA are often trapped in small compartments called endosomes, preventing them from reaching their target destination and reducing their effectiveness.

The research team discovered that combining siRNA with ionizable drugs – compounds that change their charge based on pH levels – enhances the stability and delivery efficiency of siRNA inside cells, helping both the siRNA and drug escape the endosome and more effectively reach their destination. This novel method utilizes the protective properties of lipids to safeguard siRNA during its journey through the body and ensure the release of RNA and the drug together within the target cells.

“One of the biggest hurdles in siRNA therapy has been getting these molecules to where they need to go without losing their potency,” Shoichet says.

“Our approach using ionizable drugs as carriers marks a significant step forward in overcoming this barrier, while also showing how drugs and RNA can be delivered together in the same nanoparticle formulation.”

��ֱ�� researchers integrate crucial immune cells onto heart-on-a-chip platform

Christopher.Sorensen — Fri, 23 Aug 2024 12:56:51 +0000

��ֱ�� researchers integrate crucial immune cells onto heart-on-a-chip platform

Christopher.Sorensen Fri, 08/23/2024 - 08:56

Cutline

L-R: ��ֱ�� post-doctoral fellow Shira Landau, PhD alum Yimu Zhao and Professor Milica Radisic are three of the primary authors of a study that could lead to advancements in the creation of more stable and functional heart tissues (supplied images)

Qin Dai

Topic

Institute of Biomedical Engineering

Toronto General Hospital

Donnelly Centre for Cellular & Biomolecular Research

Subheadline

The immune cells, known as primitive macrophages, were found to enhance heart tissue function and vessel stability

Researchers at the University of Toronto have discovered a novel method for incorporating primitive macrophages – crucial immune cells – into heart-on-a-chip technology, in a potentially transformative step forward in drug testing and heart disease modeling.

In a study published in Cell Stem Cell, an interdisciplinary team of scientists describe how they integrated the macrophages – which were derived from human stem cells and resemble those found in the early stages of heart development – onto the platforms. These macrophages are known to have remarkable abilities in promoting vascularization and enhancing tissue stability.

Corresponding author Milica Radisic, a senior scientist in the University Health Network's Toronto General Hospital Research Institute and professor in the Institute of Biomedical Engineering at ��ֱ��’s Faculty of Applied Science & Engineering, says the approach promises to enhance the functionality and stability of engineered heart tissues.

“We demonstrated here that stable vascularization of a heart tissue in vitro requires contributions from immune cells, specifically macrophages. We followed a biomimetic approach, re-establishing the key constituents of a cardiac niche,” says Radisic, who holds a Canada Research Chair in Functional Cardiovascular Tissue Engineering

“By combining cardiomyocytes, stromal cells, endothelial cells and macrophages, we enabled appropriate cell-to-cell crosstalk such as in the native heart muscle.”

Professor Milica Radisic's research team have worked on developing a miniaturized version of cardiac tissue on heart-on-a-chip platforms for a decade (photo by Nick Iwanyshyn)

A major challenge in creating bioengineered heart tissue is achieving a stable and functional network of blood vessels. Traditional methods have struggled to maintain these vascular networks over extended periods, limiting their effectiveness for long-term studies and applications.

In their study, researchers demonstrated that the primitive macrophages could create stable, perfusable microvascular networks within the cardiac tissue, a feat that had previously been difficult to achieve.

Furthermore, the macrophages helped reduce tissue damage by mitigating cytotoxic effects, thereby improving the overall health and functionality of the engineered tissues.

“The inclusion of primitive macrophages significantly improved the function of cardiac tissues, making them more stable and effective for longer periods,” says Shira Landau, a post-doctoral fellow in Radisic’s lab and one of the study’s lead authors.

The breakthrough has far-reaching implications for the field of cardiac research. By enabling the creation of more stable and functional heart tissues, researchers can better study heart diseases and test new drugs in a controlled environment.

Researchers say this technology could lead to more accurate disease models and more effective treatments for heart conditions.

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle — Tue, 20 Aug 2024 16:17:45 +0000

Researchers propose biologically based classification system for Parkinson’s disease

rahul.kalvapalle Tue, 08/20/2024 - 12:17

Cutline

The "SynNeurGe" classification system for Parkinson's disease, proposed by researchers led by Professor Anthony Lang of the University Health Network and ��ֱ��, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Department of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Parkinson's

Subheadline

The classification system could enable advancements in the development of tailored treatments for Parkinson's disease

A team of researchers led by Anthony Lang of the University Health Network and the University of Toronto have proposed a novel classification system for Parkinson’s disease that considers biological features and not just clinical symptoms.

The "SynNeurGe" system, described by Lang and collaborators in a paper published in The Lancet Neurology, classifies Parkinson’s disease based on three biomarkers: presence or absence of misfolded alpha synuclein protein, which is believed to cause or contribute to the underlying neurodegeneration; evidence of neurodegeneration using imaging techniques; and presence of gene variants that increase disease risk.

The researchers argue that such a classification system is necessary to advance the development of tailored treatments for Parkinson’s disease.

Professor Anthony Lang (supplied image)

“This is a complex group of disorders that may cause similar symptoms, but biologically they're very different,” says Lang, a senior scientist and Lily Safra Chair in Movement Disorders at UHN and a professor in the department of medicine and the Tanz Centre for Research in Neurodegenerative Disease at ��ֱ��’s Temerty Faculty of Medicine, where he holds the Jack Clark Chair for Parkinson’s Disease Research

“If we cannot find ways to subdivide patients biologically, then applying a therapy designed to affect one biological pathway may not be effective in another group of patients that doesn't have that same pathway involved – and we won’t really have precision or personalized medicine for Parkinson’s disease.”

Currently, Parkinson’s disease is classified based on clinical presentation and symptoms, but the disease can affect the brain for years, possibly even decades, before symptoms appear. For future therapies to treat the underlying disease rather than just the symptoms, patients will need early intervention and treatments tailored to the biological features of the disease, researchers say.

Similar approaches are being used for other diseases – cancer treatments vary not only by the location of tumors but also their molecular features, and the development of drugs for Alzheimer’s disease is increasingly guided by the specific biological mechanisms involved in the disease.

The SynNeurGe classification system, while based on the three key biomarkers, also considers whether clinical features are present. The different combinations of biomarkers classify the disease into various sub-types.

Lang and co-authors note that such a classification should only be used for research at present, although it will almost certainly have clinical applications.

“Eventually we will see a biological approach influencing clinical care, particularly when we finally have effective disease-modifying therapies,” says Lang. “We currently don’t know how important these biomarkers actually are.

"We need large-scale prospective studies of biomarkers, imaging and clinical features to interpret the results, give patients accurate information about their diagnosis and provide appropriate treatment.”

Lang’s team plans to start conducting such studies of cerebrospinal fluid, skin and blood to look for biomarkers of different sub-types of Parkinson’s disease that will help inform the classification system and the development of tailored therapies.

“Now is the time to think about these diseases not solely based on their clinical manifestations, but to look at the biology and try to separate different biological subtypes so we can ultimately improve treatment for this disease,” Lang says.

Professor Graham Collingridge, director of the Tanz Centre, says Lang and his team’s “landmark paper” is poised to have a significant impact on clinical practice around Parkinson's. “I am delighted that our researchers have played such a key role in this important biological classification,” Collingridge says.

Lang says research by Tanz Centre scholars has contributed significantly to the body of knowledge used to develop the proposed biological classification.

For example, Professor Ekaterina Rogaeva’s research on the genetics and epigenetics of Parkinson’s disease has shown that multiple genes and environments can influence Parkinson’s risk, highlighting the need to tailor therapies based on a patient’s genetic makeup.

Other researchers – including Anurag Tandon, Joel Watts, Martin Ingelsson and Gabor Kovacs – have been studying the role of misfolded alpha synuclein in neurodegeneration as well as cases of Parkinson’s disease where alpha synuclein is absent – which informed how Lang’s team included the protein in the classification.

��ֱ�� community members recognized with Order of Canada

bresgead — Thu, 04 Jul 2024 16:49:13 +0000

��ֱ�� community members recognized with Order of Canada

bresgead Thu, 07/04/2024 - 12:49

Cutline

(photo by Sgt Johanie Maheu, Rideau Hall, OSGG-BSGG)

Adina Bresge

Topic

Our Community

Institute of Health Policy Management and Evaluation

Unity Health

��ֱ��

Chemistry

Dalla Lana School of Public Health

Faculty of Arts & Science

Faculty of Music

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Order of Canada

Political Science

St. Michael's College

University College

Victoria College

Subheadline

"The Order of Canada recognizes individuals who have made positive and lasting impacts on communities here in Canada or who have brought honour to our country abroad"

An innovator in chemical catalyst development. A global leader in cardiac surgery and care. And a public health expert who led the rollout of Canada’s first colon cancer screening program.

These are a few members of the University of Toronto community who were recently honoured with appointments or promotions within the Order of Canada.

The Governor General recently announced 83 new appointments to the Order of Canada, including two promotions within the Order.

They include Doug Stephan, a University Professor of chemistry in the Faculty of Arts & Science; Lee Errett, a professor in the Temerty Faculty of Medicine’s department of surgery, and Linda Rabeneck, a health executive and professor in the Temerty Faculty of Medicine and the Dalla Lana School of Public Health.

Established in 1967, the Order of Canada is one of the country’s highest honours, recognizing extraordinary contributions across all sectors of society.

“The Order of Canada recognizes individuals who have made positive and lasting impacts on communities here in Canada or who have brought honour to our country abroad,” Gov. Gen. Mary Simon said in a statement.

Here is a list of ��ֱ�� faculty, alumni and supporters who were appointed to, or promoted within, the Order of Canada in the latest round of honourees.

Current and former faculty

Edward Cole, a staff nephrologist at Toronto General Hospital and professor in the Temerty Faculty of Medicine’s department of medicine, was named a Member of the Order for his dedication to advancing and delivering care to people living with kidney disease, his instrumental role in establishing a globally impactful kidney-paired donation program and his leadership as former physician-in-chief at the University Health Network.

Lee Errett, a professor in the Temerty Faculty of Medicine’s department of surgery, was appointed a Member of the Order for his transformative leadership in cardiac research and care, including his role in establishing St. Michael’s Hospital as a world-class centre for cardiac surgery, his dedication to educating future medical leaders and providing care in underserved areas worldwide.

Franklyn Griffiths, a professor emeritus and George Ignatieff Chair Emeritus of Peace and Conflict Studies in the department of political science in the Faculty of Arts & Science, was appointed a Member of the Order for his scholarship on Russian affairs which has advanced the Western world’s understanding of Soviet politics. An expert in Arctic international relations, Griffiths helped create the Arctic Council and pushed for Indigenous voices to play a central role in the council’s workings.

Beverley Johnston, an internationally renowned percussionist who is an adjunct professor in the Faculty of Music, was appointed an Officer of the Order for her work developing and promoting Canadian music to audiences around the world. Working in a male-dominated field, Johnston’s unconventional performances combine classical transcriptions, contemporary music and an element of theatre.

Daphne Maurer, a professor emeritus of psychology, neuroscience and behaviour at McMaster University who holds a status appointment at ��ֱ��’s Institute of Health Policy Management and Evaluation in the Dalla Lana School of Public Health, was appointed an Officer of the Order for her research on visual and cognitive development in early childhood.

Linda Rabeneck, a gastroenterologist, health executive and professor in the Temerty Faculty of Medicine and the Dalla Lana School of Public Health, was named a Member of the Order for her leadership in colorectal cancer screening and prevention. Formerly the director of the Division of Gastroenterology at ��ֱ��, she led the rollout of ColonCancerCheck, Canada’s first province-wide screening program.

Stephen Randall, who earned his master's degree and doctorate at ��ֱ�� and taught at the university from 1971 to 1974, was named a Member of the Order for his academic contributions and advisory role in international relations. A professor emeritus at the University of Calgary, Randall’s expertise in myriad issues affecting the United States and Latin America, notably Colombia, has informed Canada’s foreign policy.

Bibudhendra Sarkar, senior scientist emeritus at the Research Institute of the Hospital for Sick Children and professor emeritus at ��ֱ��’s department of biochemistry in the Temerty Faculty of Medicine, was named a Member of the Order for his achievements in advancing medical research in Canada and abroad. He discovered a novel treatment for patients with Menkes disease, a rare genetic condition, and led international efforts in South and Southeast Asia to address public health crises from contaminated groundwater.

Jonathan Scott Rose, a professor in the Edward S. Rogers Sr. department of electrical and computer engineering in the Faculty of Applied Science & Engineering, was named a Member of the Order for his pioneering work in architecture and software used in field-programmable gate arrays. Rose served as the chair of the department from 2004 to 2009 and received his PhD degree in electrical engineering from ��ֱ�� in 1986.

Doug Stephan, a University Professor in the department of chemistry in the Faculty of Arts & Science, was named an Officer of the Order in recognition his world-leading research in inorganic and organometallic chemistry. His many achievements include discovering – and commercializing – a new class of catalysts that is now used in one of the largest chemical manufacturing facilities in the world. He also achieved global renown for founding the field of “Frustrated Lewis Pair” chemistry.

��ֱ�� and friends

Sleight-of-hand artist David Ben, who graduated from University College in 1983, was named a Member of the Order for his four decades of dedication to the exploration, development and preservation of magic, including penning several books on the subject and co-founding the Magicana organization.

William Fox, a research fellow and adjunct professor at Trent University who earned his honours bachelor of arts and master of arts in archeology at ��ֱ��, was named a Member of the Order for his distinguished contributions to Canadian archeology, his leadership in the Ontario Archaeological Society, and his steadfast advocacy for the involvement of Indigenous communities in preserving their material heritage.

Martha Friendly, who founded the Childcare Resource and Research Unit at ��ֱ��’s Centre for Urban and Community Studies in the early 1980s, was appointed an Officer of the Order for her work with the now-independent non-profit and her advocacy for accessible, publicly funded early childhood education and care, and women’s equality.

Rosemary Ganley, a writer, activist, teacher and an alumna of St. Michael’s College, was named a Member of the Order for her lifelong advocacy for human rights, gender equity, and social justice, including co-founding Jamaican Self Help, an organization of Canadians working to support the development of healthy Jamaican communities.

Arnie Gelbart, a member of the Chancellors’ Circle of Benefactors, was named a Member of the Order for his decades-long leadership in independent film and television in his role as founder, executive producer and CEO of Galafilm Productions Inc.

Judy Kent was named a Member of the Order for championing sport as a catalyst for social change, her advocacy for gender equality and inclusion and her leadership in international support. Among her achievements: She was the first woman to serve as both president of Commonwealth Sport Canada and Canada’s chef de mission for the Commonwealth Games, and her paper on sport for international development laid the foundation for the SportWORKS program.

James David Meekison, with a 45-year career spanning investment banking, cable television and private equity, was named a Member of the Order for his extensive philanthropy. The Jim Meekison and Carolyn Keystone Foundation supported ��ֱ��’s Leslie Dan Faculty of Pharmacy’s efforts to launch the Discovery Pharmacy on the St. George campus.

Michael Perley, a ��ֱ�� alumnus who completed a master’s degree in French language and literature, was named a Member of the Order for his lifelong dedication to tackling environmental and health challenges. He has been an advocate for tighter tobacco control laws, reducing second-hand smoke exposure and has led coalitions on acid rain and air pollution.

Dan Poenaru, a pediatric surgeon and professor at McGill University who earned two degrees at ��ֱ��, was named a Member of the Order for his contributions to pediatric surgery in Africa, including establishing a surgical unit and training program in Kenya, co-founding three medical schools and leading initiatives for children's surgery globally.

Vaira Vike-Freiberga, an alumna of Victoria College and the first woman to serve as Latvia’s president, was named an honorary Officer of the Order for her work enriching Canada-Latvia relations and for reflecting Canadian values abroad.

– with files from Mariam Matti and Rahul Kalvapalle

Hospitals with higher ratio of female surgeons, anaesthetists have better patient outcomes: Study

Christopher.Sorensen — Wed, 22 May 2024 14:48:30 +0000

Hospitals with higher ratio of female surgeons, anaesthetists have better patient outcomes: Study

Christopher.Sorensen Wed, 05/22/2024 - 10:48

Cutline

Reaching a critical mass of more than 35 per cent female anesthesiologists and surgeons was linked to lower odds of severe post-operative complications, according to a study from ICES, Sunnybrook Research Institute and ��ֱ�� (photo by Shannon Fagan/Getty Images)

Misty Pratt

Topic

Sunnybrook Health Sciences Centre

Subheadline

"These results are the start of an important shift in understanding the way in which diversity contributes to better quality care around the time of surgery"

Greater sex diversity in hospital anaesthesia-surgery teams is associated with better post-operative outcomes for patients, according to a study from ICES, Sunnybrook Research Institute and the University of Toronto.

The study, published in the British Journal of Surgery, found that teams with more than 35 per cent female anesthesiologists and surgeons were associated with a three per cent reduction in odds of post-operative complications in the three months following surgery.

This is one of the first studies to focus on sex diversity of operating room teams, building on past work that has compared the impact of individual surgeon and anesthesiologist characteristics on patient outcomes.

“We wanted to challenge the binary approach of comparing female and male clinicians and rather highlight the importance of diversity as a team asset or bonus in enhancing quality care,” says lead author Julie Hallet, a scientist with ICES and Sunnybrook Research Institute, and associate professor of surgery at ��ֱ��’s Temerty Faculty of Medicine.

The study includes population-based, health-care data on 709,899 adult patients undergoing major in-patient surgeries in Ontario between 2009 and 2019.

Sex diversity of surgical teams was defined as the percentage of female anesthesiologists and surgeons among all anesthesiologists and surgeons working in the hospital each year. The primary outcome was 90-day major morbidity, which the researchers analyzed with a standardized classification scale to identify severe post-surgical complications.

The findings showed that reaching a critical mass of more than 35 per cent female anesthesiologists and surgeons was linked to lower odds of severe complications.

The association between greater sex diversity and reduced post-surgical complications was even greater for patients treated by female anesthesiologists and female surgeons – which aligns with previous studies comparing outcomes of male to female surgeons.

“These results are the start of an important shift in understanding the way in which diversity contributes to better quality care around the time of surgery,” says Hallet. “Ensuring a critical mass of female anesthesiologists and surgeons in operative teams is crucial to performance. Below a critical mass, female clinicians may withhold their perspectives, such that the benefits of diversity can only be achieved once minimum representation is reached.”

One limitation of the study is that the data did not include gender as a social construct. It is possible that gender roles, behaviours and attitudes would have influenced the strength of the association.

The study’s authors noted further research is also needed to explore diversity based on other sociodemographic variables, including but not limited to race and ethnicity.

Nevertheless, this study is the first to show a robust positive association between team sex diversity, patient outcomes and quality care.

“We hope that these results will encourage hospitals to intentionally foster sex diversity in operating room teams to reduce poor health outcomes, which, in turn, can improve patient satisfaction and promote sustainability of health systems,” says Gianni Lorello, staff anesthesiologist at Toronto Western Hospital, University Health Network and an associate professor in Temerty Medicine’s department of anesthesiology and pain medicine.

“Ensuring sex diversity in operative teams will require intentional effort for recruitment and retainment policies for female physicians, structural interventions such as minimum representation on teams, and monitoring and reporting of teams’ composition to build institutional accountability in existing systems.”

The research was supported by the Sunnybrook Alternate Funding Plan Innovation Fund.

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen — Wed, 08 May 2024 14:03:08 +0000

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen Wed, 05/08/2024 - 10:03

Cutline

From left to right: researchers Mia Stanić, Razqallah Hakem, Mitra Shokrollahi, Karim Mekhail and Anisha Hundal (photo by Erin Howe)

Erin Howe

Topic

Princess Margaret Cancer Centre

Laboratory Medicine and Pathobiology

Resarch & Innovation

Cancer

Institutional Strategic Initiatives

Subheadline

“It’s exciting to think about where these findings will lead us next”

Researchers at the University of Toronto and partner hospitals have discovered a DNA repair mechanism that advances understanding of how human cells stay healthy – a finding that could lead to new treatments for cancer and premature aging.

The study, published in the journal Nature Structural and Molecular Biology, also sheds light on the mechanism of action of some existing chemotherapy drugs.

“We think this research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells,” said Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology in ��ֱ��’s Temerty Faculty of Medicine.

“It also makes many previously published discoveries in other organisms applicable in the context of human DNA repair, which should help science move even faster.”

DNA double-strand breaks arise when cells are exposed to radiation and chemicals, and through internal processes such as DNA replication. They are one of the most serious types of DNA damage because they can stall cell growth or put it in overdrive, promoting aging and cancer.

The new discovery, made in human cells and in collaboration with Razqallah Hakem – a senior scientist at UHN’s Princess Margaret Cancer Centre, University Health Network, and a professor in Temerty Medicine’s department of medical biophysics and department of laboratory medicine and pathobiology – extends prior research on DNA damage in yeast by Mekhail and other scientists.

In 2015, Mekhail and collaborators showed how motor proteins deep inside the nucleus of yeast cells transport double-strand breaks to “DNA hospital-like” protein complexes embedded in the nuclear envelope at the edge of the nucleus.

Other studies uncovered related mechanisms during DNA repair in flies and other organisms. However, scientists exploring similar mechanisms in human and other mammalian cells reported little to no DNA mobility for most breaks.

“We knew that nuclear envelope proteins were important for DNA repair across most of these organisms, so we wondered how to explain the limited mobility of damaged DNA in mammalian cells,” Mekhail says.

The answer is both surprising and elegant.

When DNA inside the nucleus of a human cell is damaged, a specific network of microtubule filaments forms in the cytoplasm around the nucleus and pushes on the nuclear envelope. This prompts the formation of tiny tubes, or tubules, which reach into the nucleus and catch most double-strand breaks.

“It’s like fingers pushing on a balloon,” says Mekhail. “When you squeeze a balloon, your fingers form tunnels in its structure, which forces some parts of the balloon’s exterior inside itself.”

Further research by the study authors detailed several aspects of this process. Enzymes called DNA damage response kinases and tubulin acetyltransferase are the master regulators of the process, and promote the formation of the tubules.

Enzymes deposit a chemical mark on a specific part of the microtubule filaments, which causes them to recruit tiny motor proteins and push on the nuclear envelope. Consequently, the repair-promoting protein complexes push the envelope deep into the nucleus, creating bridges to the DNA breaks.

“This ensures that the nucleus undergoes a form of reversible metamorphosis, allowing the envelope to temporarily infiltrate DNA throughout the nucleus, capturing and reconnecting broken DNA,” says Mekhail.

The findings have significant implications for some cancer treatments.

Normal cells use the nuclear envelope tubules to repair DNA, but cancer cells appear to need them more. To explore the mechanism's potential impact, the team analyzed data representing over 8,500 patients with various cancers. The need was visible in several cancers, including triple-negative breast cancer, which is highly aggressive.

“There is a huge effort to identify new therapeutic avenues for cancer patients, and this discovery is a big step forward,” says Hakem.

“Until now, scientists were unclear as to the relative impact of the nuclear envelope in the repair of damaged DNA in human cells. Our collaboration revealed that targeting factors that modulate the nuclear envelope for damaged DNA repair effectively restrains breast cancer development,” Hakem says.

In the aggressive triple-negative breast cancer, there are elevated levels of the tubules – likely because they have more DNA damage than normal cells. When the researchers knocked out the genes needed to control the tubules, cancer cells were less able to form tumours.

One medication used to treat triple-negative breast cancer is a class of drugs called PARP inhibitors. PARP is an enzyme that binds to damaged DNA and helps repair it. PARP inhibitors block the enzyme from performing repair, preventing the ends of a DNA double-strand break in cancer cells from reconnecting to one another.

The cancer cells end up joining two broken ends that are not part of the same pair. As more mismatched pairs are created, the resulting DNA structures become impossible for cells to copy and divide.

“Our study shows that the drug’s ability to trigger these mismatches relies on the tubules. When fewer tubules are present, cancer cells are more resistant to PARP inhibitors,” says Hakem.

Mekhail says the work underscores the importance of cross-disciplinary collaboration.

“The brain power behind every project is crucial. Every team member counts. Also, every right collaborator added to the research project is akin to earning another doctorate in a new specialty – it’s powerful,” he says.

Mekhail notes the discovery is also relevant to premature aging conditions like progeria. The rare genetic condition causes rapid aging within the first two decades of life, commonly leading to early death.

Progeria is linked to a gene coding for lamin A. Mutations in this gene reduce the rigidity of the nuclear envelope. The team found that expression of mutant lamin A is sufficient to induce the tubules, which DNA damaging agents further boosted. The team thinks that even weak pressure on the nuclear envelope spurs the creation of tubules in premature aging cells.

The findings suggest that in progeria, DNA repair may be compromised by the presence of too many or poorly regulated tubules. The study results also have implications for many other clinical conditions, Mekhail says.

“It’s exciting to think about where these findings will lead us next,” says Mekhail. “We have excellent colleagues and incredible trainees here at Temerty Medicine and in our partner hospitals. We’re already working toward following this discovery and using our work to create novel therapeutics.”

The research was supported by the Canadian Institutes of Health Research, Royal Society of Canada, ��ֱ�� and Princess Margaret Hospital.

��ֱ��, hospitals launch pilot program to boost commercialization of medical innovations

rahul.kalvapalle — Wed, 24 Apr 2024 14:19:19 +0000

��ֱ��, hospitals launch pilot program to boost commercialization of medical innovations

rahul.kalvapalle Wed, 04/24/2024 - 10:19

Cutline

(photo by Daria Perevezentsev)

Rahul Kalvapalle

Topic

Our Community

Acceleration Consortium

Sunnybrook Health Sciences Centre

Artificial Intelligence

Department of Chemistry

Department of Computer Science

Entrepreneurship

Faculty of Art & Science

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Startups

The University of Toronto is collaborating with the University Health Network, the Hospital for Sick Children and Sunnybrook Research Institute on a new program that aims to leverage the expertise of entrepreneurs and business leaders to advance commercialization of emerging medical technologies and regenerative medicine research.

Funded by the Government of Ontario, the Entrepreneur-In-Residence program will support projects that display high potential for clinical impact and spin-off company formation, spanning areas ranging from regenerative therapies and medical devices to AI-powered clinical tools and apps for patient care.

The one-year pilot program is being launched with the help of a $300,000 grant from Intellectual Property Ontario (IPON), a provincial agency that was established in 2022 to provide IP resources and supports to researchers and businesses.

“The Entrepreneur-in-Residence program will help take medical innovations developed in academic and hospital environments and translate them into the commercial arena, generating economic opportunity for the region and expanding clinical impact globally,” said Leah Cowen, ��ֱ��’s vice-president, research and innovation, and strategic initiatives.

“The University of Toronto is grateful to IPON for its support of this initiative, which stands to strengthen existing networks of knowledge exchange and collaboration between the university and its partner hospitals.”

Jill Dunlop, left,Ontario’s minister of colleges and universities, said post-secondary institutions are critical incubators of innovation and commercialization (photo courtesy of IPON)

The program will see Entrepreneurs-in-Residence – individuals with a track record of launching science-based ventures and shepherding projects from proof-of-concept to incubation, acceleration and seed funding – liaise with ��ֱ��’s Innovations & Partnerships Office and IPON to generate and protect IP. It is designed to add capacity and scope to ��ֱ��’s thriving entrepreneurship and commercialization ecosystem, including existing Entrepreneur-in-Residence initiatives such as those offered by the Temerty Faculty of Medicine and Medicine By Design, an institutional strategic initiative (ISI).

“In today’s global knowledge-based economy, Ontario’s post-secondary institutions are critical – not just as centres of learning, but as incubators for innovation and commercialization,” said Jill Dunlop, minister of colleges and universities, in a recent announcement of new IPON-funded initiatives.

“Through the province’s support of IPON, our government is ensuring the social and economic benefits of publicly funded research stay in our province, so that Ontarians and the Ontario economy benefit from these new discoveries and innovations.”

Dunlop also spoke at an April 8 event with Christine Allen, a professor in ��ֱ��’s Leslie Dan Faculty of Pharmacy who has an extensive track record of translating and commercializing lab discoveries.

Christine Allen, far right, is a professor in the Leslie Dan Faculty of Pharmacy and the founder and CEO of Intrepid Labs (photo courtesy of IPON)

At the event, Allen highlighted the growth of her startup, Intrepid Labs Inc., which she co-founded with Alán Aspuru-Guzik, a professor in the departments of chemistry and computer science in ��ֱ��’s Faculty of Arts & Science and director of the Acceleration Consortium. The company marries Allen’s prowess in drug formulation and development with Aspuru-Guzik’s expertise in AI and advanced computing in order to accelerate the development of next-generation medicines. In the fall, the company closed a pre-seed round of US$4 million.

“The availability of top-notch talent in AI and life sciences made Toronto a great place to launch our company,” says Allen, who is Intrepid’s CEO, noting all four of the startup’s co-founders are from ��ֱ��.

She added that ��ֱ�� is a powerhouse for entrepreneurship and intellectual property, ranked second in North America for university-based startups, and that companies with founders or co-founders from ��ֱ�� make up a significant percentage of some of the fastest-growing companies in Ontario.

“This is the beauty of being at the University of Toronto and having the MaRS Discovery District across the street and all the hospitals around us. It’s such a rich environment,” she says.

“We can do this in Toronto.”

Allen stressed that a thriving lab-to-market ecosystem is critical to inspire the next generation of entrepreneurs.

“Students are increasingly seeking out roles in the private sector,” she says. “For them to see other students and faculty members [found startups] helps them realize that it’s possible for them to start companies, too.”

COVID-19 virus disrupts protein production, study finds

Christopher.Sorensen — Tue, 23 Apr 2024 20:58:38 +0000

COVID-19 virus disrupts protein production, study finds

Christopher.Sorensen Tue, 04/23/2024 - 16:58

Cutline

This transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. (photo by NIAID)

Jenni Bozec

Topic

COVID-19

Laboratory Medicine and Pathobiology

Subheadline

Post-doctoral researcher Talya Yerlici calls SARS-CoV-2 "a clever saboteur inside our cells, making sure its own needs are met while disrupting our cells’ ability to defend themselves"

Despite huge advances in our understanding of COVID-19 over the past four years, the disease is still very much among us – and there remains a lot to learn.

One thing we do know: Following infection, it’s critical that our cells make new proteins to defend against the virus.

(photo supplied)

But Talya Yerlici, a post-doctoral researcher at the University of Toronto’s Temerty Faculty of Medicine, recently showed how SARS-CoV-2 disrupts the manufacture of proteins.

She is the first author of a paper detailing the process that was published recently in the journal Cell Reports.

Writer Jenni Bozec recently spoke with Yerlici – who is based in the lab of Professor Karim Mekhail in the department of laboratory medicine and pathobiology – about the findings.

What have you discovered about how COVID-19 uses proteins?

One way SARS-CoV-2 makes us sick is by using a strategy called “host shutoff.” This means that while the virus makes copies of itself, it also slows the production of vital components within our cells. As a result, our bodies take longer to respond to the infection.

When SARS-CoV-2 enters our cells, it disrupts the process of making proteins, which are essential for our cells to work correctly. A particular SARS-CoV-2 protein called Nsp1 has a crucial role in this process. It stops ribosomes, the machinery that makes proteins, from doing their job effectively. The virus is like a clever saboteur inside our cells, making sure its own needs are met while disrupting our cells’ ability to defend themselves.

We found that Nsp1 is good at blocking ribosomes from making new proteins, but also interferes with the production of new ribosomes. In effect, it shuts down the machinery output and the ability to make the machinery itself – a serious double hit.

It does this by blocking the maturation or processing of specialized RNA molecules needed to build ribosomes. This adds a new layer of complexity to our understanding of SARS-CoV-2's interference with the host cell.

How could this discovery impact treatment for those with COVID-19?

Building on our published research, it will be crucial to understand how Nsp1 works to stop different types of human cells, tissues and organs from making proteins when infected with different variants of SARS-CoV-2 and related coronaviruses.

Scientists have been working to find precision medicines that can counteract Nsp1 and help fight against the continually evolving SARS-CoV-2 virus. These drugs aim to help infected cells keep producing proteins and build a robust immune response when dealing with infection. Ongoing research on such drugs should now benefit from testing whether they can block Nsp1 from interfering with both the production and function of ribosomes, and this should help find more effective precision medicines.

What drew you to this line of research?

This project started because of circumstances during the COVID lockdown. We wanted to help in the fight against the pandemic. However, since I couldn't physically work in the lab, we took the opportunity to analyze next-generation sequencing datasets computationally from home.

Looking at published RNA-sequencing datasets, we realized that cells infected with SARS-CoV-2, compared to uninfected cells, may have difficulty processing the RNA molecules needed to build ribosomes. Through this analysis, together with Dr. Mekhail, we developed hypotheses and designed the project.

I had the privilege of collaborating closely with the talented members of the Mekhail lab, including Alexander Palazzo’s group from the department of biochemistry at Temerty Medicine and Brian Raught and Razqallah Hakem’s labs at the Princess Margaret Cancer Centre (University Health Network). This work wouldn't have been possible without the collective efforts of our team and collaborators, and I’m grateful for their contributions. My responsibilities included conducting numerous hands-on experiments and bioinformatics analyses, analyzing the results and preparing the paper for peer review and publication.

What were the most challenging and rewarding aspects of this project?

The most challenging part was conducting research during a global pandemic, which presented many logistical hurdles – from disrupted lab routines to limitations on collecting and using samples infected with SARS-CoV-2.

On the other hand, the opportunity to contribute to our understanding of SARS-CoV-2 viral mechanisms and shed light on potential therapeutic targets was incredibly fulfilling. Seeing our research culminate in a published paper and knowing it could inform future strategies for combating coronaviruses is deeply gratifying.

What are your longer-term goals as a scientist?

As an independent investigator in my future lab, I want to study how the complex processes of making ribosomes affect the body's natural defense against viruses. It's an area I find compelling and presents ample opportunities for further exploration. One approach I’m particularly interested in is integrating RNA-sequencing with genetic CRISPR and small-molecule chemical screens, targeting distinct stages of ribosome biogenesis across diverse infection or infection-mimicking conditions. Such integrated approaches hold promise for uncovering novel mechanisms underlying the regulation of antiviral responses and should help us find innovative and impactful ways to fight viral infections.

This research was supported by the Canadian Institutes of Health Research.

Heart-on-a-chip model used to glean insights into COVID-19-induced heart inflammation

Christopher.Sorensen — Mon, 08 Apr 2024 19:06:23 +0000

Heart-on-a-chip model used to glean insights into COVID-19-induced heart inflammation

Christopher.Sorensen Mon, 04/08/2024 - 15:06

Cutline

Researchers worked in the Toronto High Containment Facility at ��ֱ�� to examine the effects of COVID-19 on heart inflammation (photo by Lisa Lightbourn)

Betty Zou

Topic

Institute of Biomedical Engineering

Unity Health

��ֱ��

Leslie Dan Faculty of Pharmacy

Emerging and Pandemic Infections Consortium

Subheadline

Researcher dedicates study to her late grandmother, who died from COVID-19-induced heart failure

Researchers at the University of Toronto and its partner hospitals have created a unique heart-on-a-chip model that is helping untangle the causes of COVID-19-induced heart inflammation and uncover strategies to reduce its impact.

While COVID-19 is primarily a respiratory infection, clinicians and researchers are increasingly aware of the virus’s effects on other organs – including the heart. Data from the U.S. Centers for Disease Control and Prevention shows patients hospitalized with COVID-19 between March 2020 and January 2021 had 15 times higher risk for developing myocarditis, or inflammation of the heart muscle, compared to patients without COVID-19.

But the biology behind the association between SARS-CoV-2 infection and heart inflammation had remained unclear – in part because there have not been good models with which to study infection-related heart inflammation.

“Conventionally, people grow heart cells in a 2D setting and then expose it to SARS-CoV-2 to see how the virus damages the heart. But that’s not actually what happens in our body,” says Rick Lu, a PhD graduate from ��ֱ��’s Institute for Biomedical Engineering who is currently a postdoctoral researcher at ��ֱ��’s Leslie Dan Faculty of Pharmacy.

Lu is the first author of a new study published in Science Advances that describes a miniature 3D heart-on-a-chip model that more accurately captures the impact of SARS-CoV-2 infection and its associated immune response on cardiac dysfunction.

The first-of-its-kind model builds on previous work led by Milica Radisic, Lu’s PhD adviser, a senior scientist at University Health Network and a ��ֱ�� professor of biomedical engineering. The approach uses a lab-made network of blood vessels surrounded by heart tissues grown from stem cells to mimic a real human heart with its tangle of vessels going in and out.

From left to right: Researchers Milica Radisic, Rick Lu and Claudia dos Santos (supplied images)

To examine the effects of COVID-19 on heart inflammation, Lu and his colleagues first had to adapt their model to work in the Toronto High Containment Facility, a specialized lab that allows researchers to study high-risk pathogens like SARS-CoV-2 in a safe and secure way.

“This work would simply not be possible without the Toronto High Containment Facility,” says Radisic, who holds the Canada Research Chair in Organ-on-a-Chip Engineering.

In the high containment lab, the researchers added live virus and immune cells to the blood vessels and allowed them to flow through their mini hearts-on-a-chip, replicating the immune response that happens after a SARS-CoV-2 infection. They found that the combination of SARS-CoV-2 and immune cells reduced the heart’s ability to contract and pump. To understand why, the researchers turned to mitochondria, the tiny energy storehouses that power the muscle’s beating movements. They showed that SARS-CoV-2 infection led to loss of mitochondria and a release of mitochondrial DNA from the heart cells into the nutrient broth used to grow the organoids.

Working with Claudia dos Santos, a scientist and critical care doctor at Unity Health Toronto, associate professor of medicine and Pitts Research Chair in Acute Care and Emergency Medicine at ��ֱ��’s Temerty Faculty of Medicine, the researchers then asked whether the presence of freely circulating mitochondrial DNA is also seen in patients experiencing COVID-19-induced heart complications.

They analyzed blood samples from patients with and without COVID-19 and found nearly two-and-a-half times higher levels of mitochondrial DNA in patients who were COVID-19-positive. Their findings point to mitochondrial DNA levels as a powerful predictor of a person’s risk of experiencing cardiac problems after SARS-CoV-2 infection.

The team also showed that a new type of cell-based therapy called exosomes – little cargo vessels that bubble off cells – could reduce inflammation and mitochondria loss, as well as improve heart function, after SARS-CoV-2 infection, highlighting their potential to repair COVID-19-associated heart damage.

By integrating blood vessels and immune cells, Lu hopes that the innovative heart-on-a-chip model can help researchers and clinicians understand and identify treatment strategies for other infection-related heart conditions.

“The good thing about our system is that it’s readily adaptable to any kind of infectious disease,” says Lu. “The other benefit is that we don’t have to rely as much on animal models. Since we’re already using human-derived cells, the clinical translatability is much higher.”

As a next step, Radisic’s group plans to use the miniature organs to uncover why males are more likely than females to experience COVID-19-associated heart complications and to examine the cardiac issues commonly seen in people with long COVID-19.

Radisic says the motivation for this work was deeply personal. She dedicated the study to her late grandmother who died from COVID-19-induced heart failure after six weeks in the intensive care unit.

“The feeling of helplessness is rather profound when a loved one is dying,” she says. “As scientists, we can take small steps toward new cures so that other people do not meet the same fate. For me, this work meant overcoming the feeling of helplessness.”

The work was supported by investments from the Canada Foundation for Innovation and the creation of the ��ֱ�� COVID-19 biobank and the Precision Medicine in Critical Care (PREDICT) Biobank at Unity Health Toronto – and by the contributions of patients and families that donated biological samples, making significant advances in research possible.

��ֱ�� receives $10 million from Ontario government for modernization of high containment facility

Christopher.Sorensen — Mon, 18 Mar 2024 18:15:01 +0000

��ֱ�� receives $10 million from Ontario government for modernization of high containment facility

Christopher.Sorensen Mon, 03/18/2024 - 14:15

Cutline

(photo by Julia Soudat)

Betty Zou

Topic

Our Community

Institutional Strategic Initiatives

Sinai Health

Sunnybrook Health Sciences Centre

Hospital for Sick Children

Unity Health

Health