Toronto General Hospital

U of T researchers integrate crucial immune cells onto heart-on-a-chip platform

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

U of T researchers integrate crucial immune cells onto heart-on-a-chip platform

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

Cutline

L-R: U of T 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

Breaking Research

Institute of Biomedical Engineering

Toronto General Hospital

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Research & Innovation

University Health Network

Subheadline

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

Researchers at the �ؿ�ζSM 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 U of T’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.

UHN and U of T receive $24-million federal grant for transplant research

Christopher.Sorensen — Thu, 13 Jan 2022 18:44:18 +0000

UHN and U of T receive $24-million federal grant for transplant research

Christopher.Sorensen Thu, 01/13/2022 - 13:44

Cutline

Led by Shaf Keshavjee, a research team at UHN and U of T received $24 million from Canada's New Frontiers in Research Fund to advance technology to repair and rebuild organs for transplant (photo by Tim Fraser)

Ana Fernandes

Topic

Breaking Research

Temerty Faculty of Medicine

Toronto General Hospital

Research and Innovation

University Health Network

Researchers at University Health Network (UHN) and the �ؿ�ζSM have received $24 million to advance technology to repair and rebuild organs outside the body for patients in need.

The project, led by Shaf Keshavjee, is one of only seven across Canada selected to receive funding in the Government of Canada New Frontiers in Research Fund (NFRF) – Transformation competition, following an international consultation.

"The Ex Vivo Lung Perfusion (EVLP) system we developed here in Toronto has revolutionized lung transplantation in the past decade. Now, it's been translated around the world to increase lung transplant access and it's being extended to other organs," says Keshavjee, a professor and vice-chair for innovation in the department of surgery in U of T’s Temerty Faculty of Medicine who is surgeon-in-chief at UHN and a senior scientist at Toronto General Hospital Research Institute.

"With this transformative grant, we now have the opportunity to take ex vivo technology to the next level, where we can repair and rebuild organs for transplant."

Atul Humar, director of the Ajmera
Transplant Centre
(photo by Tim Fraser)

Over 4,500 people in Canada are currently waiting for an organ transplant, and more than 270 die each year as the need for transplant greatly exceeds availability.

Ex vivo perfusion systems use specialized machines to maintain, evaluate and treat organs before transplant. They have a huge impact on increasing the number of organs that can be considered for transplant.

The Toronto Lung Transplant Program, led by Keshavjee, has used this technology to double the number of lung transplants performed and lives saved at UHN.

"The New Frontiers grant will allow us to advance applications for lungs and further develop ex vivo systems for other organs, such as liver, kidney, heart and pancreas," says Atul Humar, a co-principal investigator on the project, professor in the department of medicine at U of T and director of the Ajmera Transplant Centre at UHN.

Funding ground-breaking innovation

Brad Wouters, UHN's executive vice president, science and research, notes that this major grant will enable multidisciplinary teams to develop new, cutting-edge approaches to extend the time that donated organs can be used, and also enable treatment and repair of unsuitable organs to allow treatment of more patients.

It will also help the teams refine and improve equitable organ allocation guidelines for all patients, he adds.

“The advancements that this team has made and their continued success is made possible by support from provincial and federal governments, industry partners, external charitable agencies, generous philanthropy from the UHN Foundation and our incredible patient partners,” says Wouters, who is also a professor in the department of radiation oncology at U of T. “This award recognizes the tireless efforts of the team, and this support, which have been key to achieving global impact.”

The New Frontiers Research Fund was designed to support large-scale, Canadian-led interdisciplinary research projects with the potential to realize real and lasting change.

The fund falls under the strategic direction of the Canada Research Coordinating Committee and is administered by the Tri-Agency Institutional Programs Secretariat on behalf of Canada's three research granting agencies: the Social Sciences and Humanities Research Council, the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council.

Personalized medicine for every organ and beyond

Over the course of this project, the team of over 20 researchers at U of T, UHN, national and international partner sites will develop sophisticated ex vivo platforms to:

Increase organ preservation from hours to days
Improve the immune response and organ tolerance for transplant recipients
Advance precision medicine to customize organs to each individual patient's needs

Longer ex vivo preservation prior to transplant will enable many world-first therapeutic applications that will, ultimately, create more organs for clinical transplant.

One example is to use gene therapy to make an organ more like the recipient's cells and help to address the current hurdle of organ rejection by the immune system. Researchers at UHN are also working on changing an organ's blood type so the sickest people can get access to the next available organ, instead of waiting for one that exactly matches their blood – a delay that currently can take several months before a match is found.

Another transformative goal is to use medicines and light therapies in the ex vivo circuit to eliminate viral or bacterial infections that previously prevented an organ to be considered for transplant.

"This grant gives us a unique opportunity to extend personalized medicine to every organ group," says Marcelo Cypel, a professor in the department of surgery at U of T and surgical director of the Ajmera Transplant Centre, who is also a co-principal investigator on the project.

"Not only will it enable longer preservation, this research will let us treat and improve organs. It has the potential to change the paradigm in the field of transplantation."

The change will include several advanced applications, such as the engineering of new organs using stem cells with the goal to make organs available for all in need. Significant progress has already been made in generating new kidneys, lungs and tracheae (windpipe), and their applications will be tested further during the six-year project term.

With the involvement of a multidisciplinary team housed in a world-class centre at UHN, the project will bring personalized medicine to transplant, and go beyond solid organs.

Siba Haykal (photo by Rob Caruso)

Siba Haykal, plastic and reconstructive surgeon and project co-principal investigator, will lead research involving vascularized composite allotransplantation – the transplant of limbs, face, trachea and composite tissues, such as skin and muscles.

"These are very delicate tissues that can't survive outside the body for very long and are very susceptible to rejection," she explains, adding that the current treatment involves high doses of life-long anti-rejection medication for transplant recipients.

Haykal and the team want to develop a system to preserve limbs and tissues out of the body without blood flow for longer periods. This will enable the application of new cell therapies to ‘adapt’ these tissues to the recipient prior to surgery.

"Whether they have been disfigured by burns or from trauma or cancer, if they've had an amputation and need prosthetic limbs or if they require a new airway, transplantation provides hope for these patients who currently don't have many options," says Haykal, who is an assistant professor in the department of surgery at U of T.

"If we can use techniques that reduce the amount of anti-rejection medication and maybe one day get to a stage where they don't need it anymore, that would have a huge impact on the patient's quality of life."

Humar adds, "I have seen so many people who have literally been at death's door and have been completely turned around by transplant and live a full and healthy life. If we can offer that to more patients, then for me that would be an incredible achievement.

"This funding will also help us disseminate our knowledge, and facilitate other hospitals across Canada and around the world build upon what we're doing at UHN."

This story was originally posted on the University Health Network website.

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen — Fri, 17 Dec 2021 20:40:18 +0000

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen Fri, 12/17/2021 - 15:40

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Juan Carlos Zúñiga-Pflücker and Sarah Crome are among the researchers working on generating pancreatic cells that can be transplanted to diabetes patients without being destroyed by their immune systems (photos courtesy of Medicine by Design)

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Insulin 100

Princess Margaret Cancer Centre

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Toronto General Hospital

Resarch & Innovation

Medicine by Design

Stem Cell

University Health Network

In a person with type 1 diabetes, the body mistakenly attacks pancreatic cells that produce insulin, a hormone responsible for regulating blood sugar.

Without insulin, serious and eventually fatal symptoms will occur. Yet, imagine if, instead of needing daily insulin injections, people with diabetes could have insulin-producing cells placed back into the body, fixing the problem at its source. This is the vision of a Medicine by Design-funded research team.

The approach is not without its challenges.

“Scientists are able to generate pancreatic cells from stem cells in the lab, and they can be transplanted to someone who has lost pancreatic function, but they’ll be reattacked by the immune system,” says Juan-Carlos Zúñiga-Pflücker, senior scientist at Sunnybrook Research Institute and professor of immunology in the Temerty Faculty of Medicine. “What our work is meant to do is enable those transplants to be broadly acceptable so anyone can benefit from transplanted therapies. But the barrier of the immune system is a difficult thing to overcome, and even more so in the context of autoimmunity.”

The cells are attacked because the immune system recognizes them as harmful invaders instead of helpful therapies. It is a complex problem that demands a complex strategy – and that strategy is an emerging area of research called immunoengineering, which uses bioengineering techniques to manipulate the immune system.

The only way to currently suppress the immune system is through drug treatments, but they’re not selective; they suppress the whole immune system and leave people vulnerable to infection and illness.

The team’s strategy aims to be more precise. They want to finely tune the immune system to maintain a healthy system while not rejecting a therapeutic transplant.

Zúñiga-Pflücker says a collaborative effort is important in solving this major challenge to regenerative medicine. “We can optimize cell types and engineer effective tissues in our separate labs. But if we don’t come together to create better tools to engineer the immune system, these therapies will not be usable. It’s something very fundamental.”

The team is one of 12 sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Though the research could be applied broadly across regenerative medicine therapies, type 1 diabetes makes an ideal test case, says Zúñiga-Pflücker, who is also chair of the department of immunology.

“Not only is diabetes an autoimmune disease, where the diabetic’s own immune system attacks and kills insulin producing cells, but attempts to replace the lost cells with transplanted cells are also challenged by other impacts of the disease, as well as the presence of auto-reactive immune cells,” he says. “This makes it a powerful test case for our research since we can test the transplants under multiple immune stresses.”

Zúñiga-Pflücker leads the project, which brings the work of six different labs together.

Two labs, led by the Temerty Faculty of Medicine’s Maria Cristina Nostro, a senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute; and Sara Nunes Vasconcelos, a scientist at UHN’s Toronto General Hospital Research Institute, are using stem cells to generate tissues containing insulin-secreting cells for transplants.

Zúñiga-Pflücker says that this arm of the project is well ahead of schedule. “The Nostro and Vasconcelos labs are defining the right conditions that are necessary for generating insulin-producing cells, which are called islet cells. They’re creating newer and more effective ways to make these tissues.”

Nostro and Vasconcelos are also associate professors at U of T in the department of physiology and Institute of Biomedical Engineering, respectively.

The tissues created in their labs will be used to test the work of the other four labs involved in the project, which are concerned with engineering the immune reaction. And here, each of these labs is bringing a piece of the puzzle.

Read about research into therapeutic cell “cloaking”

Zúñiga-Pflücker and Naoto Hirano, a senior scientist at Princess Margaret Cancer Centre and a professor of immunology at U of T, work on producing regulatory T cells (Tregs). These cells can supress immune response and play a role in preventing autoimmune diseases like diabetes.

In earlier Medicine by Design-funded research, Zúñiga-Pflücker and Hirano came up with a method for producing T cells in a defined way. Some of the key breakthroughs developed as part of this research helped lay the foundation for Notch Therapeutics, a company co-founded by Zúñiga-Pflücker, which closed an $85-million (U.S.) Series A financing earlier this year.

Now, in the current research project, the two labs are crafting methods for producing Tregs and investigating how harnessing the power of other types of immune cells to work alongside the Tregs can induce the immune system to tolerate transplanted therapies.

The third investigator is Tracy McGaha, whose lab is looking at the role of macrophages, a type of white blood cell that that typically helps to attack foreign substances but can also play a role in repairing damaged tissues. McGaha is a senior scientist at Princess Margaret Cancer Centre, UHN, and a professor in the department of immunology in the Temerty Faculty of Medicine.

A fourth lab, led by Sarah Crome, is investigating a family of immune cells called innate lymphoid cells (ILCs), which act within tissues to help induce and modulate immune responses.

“We know several immune cell populations we individually study can protect from harmful immune responses and promote immune tolerance,” says Crome, who is a scientist at the Toronto General Hospital Research Institute, UHN, and an assistant professor of immunology at U of T. “The trouble is when you get into a situation that combines an autoimmune disease with rejection that can occur following islet transplantation, it’s a real challenge shutting down multiple harmful and sustained immune responses.”

Crome says that there are many different types of ILCs, so her work focuses on narrowing down which types of ILCs are best to use along with the Tregs.

Right now, each of the four labs working with immune cells are optimizing their cell types and techniques, and then, Crome says they will bring all their “best players” together.

“We’re really looking at harnessing whole networks of cells, instead of just looking at one cell population at a time. It’s bringing all of our collective expertise together into one project that makes this a powerful approach.”

Zúñiga-Pflücker says Medicine by Design has been instrumental in uniting this team of experts.

“Thanks to Medicine by Design’s support of our immunoenigneering program, we’re able to bring together multiple research sites within the �ؿ�ζSM and affiliated research institutes; UHN’s Princess Margaret Cancer Centre, Toronto General Hospital Research Institute and McEwen Stem Cell Institute; and Sunnybrook Research Institute.”

Insulin 100: Parks Canada unveils commemorative bronze plaque at U of T

rahul.kalvapalle — Fri, 12 Nov 2021 20:15:21 +0000

Insulin 100: Parks Canada unveils commemorative bronze plaque at U of T

rahul.kalvapalle Fri, 11/12/2021 - 15:15

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Christine Allen, U of T’s associate vice-president and vice-provost, strategic initiatives, and Christine Loth-Brown, vice-president, Indigenous Affairs and Cultural Heritage, Parks Canada, unveil the plaque (Photo by Johnny Guatto)

Topic

Temerty Faculty of Medicine

Toronto General Hospital

Myhal Centre for Engineering Innovation & Entrepreneurship

Research & Innovation

One hundred years ago this month, scientists at the �ؿ�ζSM and its partner hospitals carried out the first studies that demonstrated the ability of insulin to lower blood sugar levels in animals and prevent their death from diabetes.

Three months later, insulin was successfully administered to a person with type 1 diabetes at Toronto General Hospital. His life would become the first of millions around the world to be saved by insulin – one of the landmark medical discoveries of the 20^th century.

On Friday, the historical significance of the discovery was marked by the unveiling of a commemorative bronze plaque at a ceremony hosted by Parks Canada and the Historic Sites and Monuments Board of Canada (HSMBC) at the Myhal Centre for Engineering Innovation & Entrepreneurship on U of T’s St. George campus.

The event was attended by government dignitaries including Sonia Sidhu, member of parliament for Brampton South. The final location of the plaque, which is inscribed by bilingual text, will be determined at a later date.

“The story of insulin is a brilliant example of the power of collaboration – in this case, how a university, its hospital partners and a pharmaceutical company could work together and change the world,” said Christine Allen, U of T’s associate vice-president and vice-provost, strategic initiatives.

“On this illustrious foundation, U of T and its hospital and industry partners built a culture of discovery, innovation and collaboration that has transformed health care and continues to have a ripple effect worldwide.

From left: Patricia Brubaker, Richard Alway, Sonia Sidhu, Christine Allen, Christine Loth-Brown and Lynn Wilson (photo by Johnny Guatto)

The ceremony marked the culmination of Insulin 100, a year-long campaign to mark the centenary of insulin’s discovery and celebrate a legacy of health innovation that continues to be advanced by U of T and its partner hospitals, research institutes and industry partners.

“The Parks Canada plaque not only serves as a fitting reminder of the critical research discoveries made here at U of T – it will also inspire future trainees and researchers whose work will be pivotal in the health research discoveries made over the next hundred years,” Allen said.

Patricia Brubaker, a professor in the departments of physiology and medicine at the Temerty Faculty of Medicine and member of the faculty’s Banting & Best Diabetes Centre, described the key areas of diabetes research being investigated by U of T faculty and students today.

“Our interests cover the spectrum of diabetes research, including not only type 1 diabetes, but also type 2 diabetes, which is now reaching epidemic levels, affecting one in six Canadians, as well as gestational diabetes or diabetes during pregnancy,” said Brubaker, who has been conducting diabetes research for four decades.

“We are studying the causes of diabetes through research into obesity, a major risk factor for type 2 diabetes; we are interrogating new approaches to the treatment of diabetes, including stem cell replacement therapy and new pharmacologic treatments; and our researchers are exploring the fundamental mechanisms that underlie the normal regulation of glucose and fat metabolism and how this is disrupted in diabetes, leading to long-term complications such as kidney and cardiovascular disease.”

Brubaker also reflected on the impact of insulin and diabetes research on her own life. As a person living with type 1 diabetes, she noted she is “one of legions who would not be alive today without the discovery of insulin.”

In addition to saving countless lives, the discovery of insulin helped establish U of T, its partner hospitals and Toronto more generally as a vanguard of diabetes research and treatment.

In April, some of the latest developments in the field were discussed at the Insulin100 conference, a two-day virtual symposium that drew over 6,000 attendees from around the world.

Also in April, U of T’s Banting & Best Diabetes Centre and Diabetes Action Canada hosted “100 Years of Insulin – Celebrating its Impact on our Lives,” a public celebration and forum featuring an array of topics of interest to people living with diabetes.

It was at this public celebration that Canada Post unveiled a special stamp to commemorate the discovery of insulin. The stamp, which depicts a vial of insulin resting on an excerpt from Banting’s unpublished memoirs, was unveiled from the Banting House National Historic Site of Canada in London, Ont. – in the very room where Banting first got the idea that eventually led to the discovery of insulin. Brubaker and Scott Heximer, chair of the department of physiology at the Temerty Faculty of Medicine and a principal investigator at the Ted Rogers Centre for Heart Research, worked with Canada Post and Banting House to ensure the stamp’s historical accuracy and help source archival material.

The stamp would be the first of several commemorations to mark the place of insulin in the cultural tapestry of Canada’s heritage.

In May, Historica Canada released a Heritage Minutes segment paying tribute to the discovery. The segment depicts the plight of 13-year-old diabetes patient Leonard Thompson, and the efforts of Banting and Best to formulate and refine the insulin treatment that ultimately saves Thompson’s life. Again, experts from U of T – including science and medicine librarian Alexandra Carter, archivist Natalya Rattan and medical historian Christopher Rutty – were consulted on the project to ensure historical accuracy.

In July, the Royal Canadian Mint issued its own commemoration in the form of a two-dollar coin depicting a monomer (a building block of the insulin molecule), insulin cells, blood cells, glucose and the scientific instruments used in early formulations of insulin.

The importance of insulin was recognized almost immediately after its initial discovery. In 1923, the Nobel Prize in Physiology or Medicine was awarded to Frederick Banting and James McLeod, who isolated insulin in U of T’s department of physiology. The prize was shared with physiology and biochemistry student Charles Best and biochemist James Collip.

U of T researchers continue to be recognized for their stellar work in advancing diabetes research.

Brubaker was honoured last year with a Lifetime Achievement Award from Diabetes Canada, a recognition of her longstanding contribution to diabetes research and the Canadian diabetes community. And, earlier this year, Daniel Drucker, professor of medicine in the Temerty Faculty of Medicine and a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, was awarded a Canada Gairdner International Award for research on glucagon-like peptides that has helped revolutionize treatments for type 2 diabetes – an honour he shared with collaborators at Harvard University and the University of Copenhagen.

U of T researchers lead effort to understand short- and long-term effects of COVID-19 on patients, caregivers

Christopher.Sorensen — Fri, 05 Nov 2021 19:34:59 +0000

U of T researchers lead effort to understand short- and long-term effects of COVID-19 on patients, caregivers

Christopher.Sorensen Fri, 11/05/2021 - 15:34

Cutline

The Canadian COVID-19 Prospective Cohort study, led by U of T researchers, looks at how genomics, demographics, social factors and other variables influence disease progression and severity (photo by Marko Geber/Getty Images)

Topic

Temerty Faculty of Medicine

Toronto General Hospital

Occupational Therapy

Research and Innovation

University Health Network

Many people who contract COVID-19 get better on their own at home, but more serious cases can involve hospitalization and months of recovery – or more.

Angela Cheung and Margaret Herridge, both professors in the �ؿ�ζSM's department of medicine in the Temerty Faculty of Medicine, are co-leading an interdisciplinary team of more than 100 researchers who are studying short- and long-term outcomes for COVID-19 patients. The Canadian COVID-19 Prospective Cohort study (CanCOV) looks at how genomics, demographics, social factors and other variables influence disease progression and severity.

Angela Cheung (photo by Jessica Chang)

Several factors influence COVID-19 patient recovery, including age, general health and pre-existing medical conditions. Ventilation, sedative drugs and other interventions in the intensive care unit may be crucial and life-saving, but can also have consequences.

“The majority of patients who require mechanical ventilation for a week or more are unable to walk at the time of their ICU discharge, and it may take them months or up to one year or longer to recover,” says Herridge, a professor in the department of medicine and the Institute of Medical Science in the Temerty Faculty of Medicine.

Critically ill patients may require mechanical ventilation weeks or months, which may lead to lung injury and compromise respiratory muscles. Rapid muscle breakdown and immobility may further aggravate muscle loss and cause profound weakness.

These changes can result in functional dependency and compromise a person’s ability to carry out regular daily activities or return to work. “Many patients are left with life-long functional disability, cognitive and mood disorders,” says Herridge, who is also a senior scientist at Toronto General Hospital Research Institute (TGHRI) and a respiratory and critical care physician at University Health Network.

For the study, CanCOV researchers planned to recruit 2,000 patients and 500 family caregivers from the four hardest hit provinces: Quebec, Ontario, Alberta and B.C. The research team includes experts in respiratory medicine, physical medicine and rehabilitation, critical care, occupational therapy, genetics and basic sciences.

“We see patients and caregivers as a dyad. How people recover from illness is often tied to how they’re cared for,” says Cheung, who is also the KY and Betty Ho Chair of Integrative Medicine, and is a senior scientist at TGHRI and the Schroeder Arthritis Institute.

Margaret Herridge and Jill Cameron

“And we’ve learned from other conditions, including acute respiratory distress syndrome and SARS, that caregivers may acquire new mood disorders including anxiety, depression and post-traumatic stress disorder,” Cheung says.

In the first 14 months of the pandemic, there were more than 42,000 hospital stays averaging two weeks each for people with a COVID-19 diagnosis, according to the Canadian Institute for Health Information. Of that group, roughly 8,400 were admitted to intensive care.

A recent publication by the Ontario Science Table suggests as many as 78,000 people in this province may have had or currently live with “long COVID,” a condition that can include fatigue, joint pain, brain fog, muscle and chest pain, and shortness of breath.

Kelly O'Brien, a physiotherapist and U of T associate professor in the department of physical therapy and the Rehabilitation Sciences Institute, sees parallels between long COVID and her previous work on disability related to HIV/AIDS.

Kelly O'Brien

O’Brien recently co-authored a commentary in BMJ Global Health on conceptualizing long COVID as an episodic condition.

“Health-related challenges or symptoms experienced by adults living with long COVID can overlap, relapse, remit and change over time,” says O'Brien, who holds a Canada Research Chair in Episodic Disability and Rehabilitation. “These characteristics resemble episodic disability, a concept derived from the context of HIV, where health challenges are multidimensional in nature affecting physical, cognitive, mental and social health domains.”

Those challenges can fluctuate – sometimes unpredictably – daily or over longer periods of time, O’Brien says.

She is also part of a team working on a Canadian Institutes of Health Research-funded study, which will establish a patient-reported outcome measure to capture the nature and extent of episodic disability in people living with long COVID. The work will help guide access to rehabilitation, evaluate interventions and inform workplace policies.

In addition to her research, O’Brien is a member of Long COVID Physio, an international patient-led association of physiotherapists who live with long COVID and allies, which collaborated with World Physiotherapy to develop a briefing paper on rehabilitation approaches, including physical activity.

Jill Cameron, an associate professor in the department of occupational science and occupational therapy, studies caregiving and its impact on family members who assume this critical role.

She says the impact of COVID-19 on caregivers will prove to be intense, based what she and her colleagues have learned in the context of other conditions like dementia and stroke.

“Caregivers have to do more with less support,” says Cameron, who is also involved in the CanCOV study. “Throughout the pandemic, friends and family members haven’t been as able to come help as they might have prior to COVID.”

Professional services that would typically provide home visits have been limited, Cameron notes. “Public health measures have reduced the number of visits, and factors like cleaning protocols result in longer turnaround time between visits, which means workers can’t see the same caseloads,” Cameron says.

Early data from other studies and jurisdictions show increased caregiver stress and poorer mental health outcomes during the pandemic, as well as more restrictions on caregivers’ other work, leisure activities and care for other family members.

These impacts on caregivers are also likely to affect the well-being of COVID-19 patients. Research into these consequences is an emerging field, Cameron says, but she notes that, in the context of stroke, there is a connection between caregiver depression and patients who are more likely to be hospitalized in the year following their stroke.

Cameron says she is pleased to be contributing to research that may shed light on the impact of the ongoing pandemic.

“We’re doing great things, and we’re learning a lot here,” she says.

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj — Fri, 08 Oct 2021 10:57:51 +0000

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj Fri, 10/08/2021 - 06:57

Cutline

Andras Nagy (Photo provided by Sinai Health Foundation)

Paul Fraumeni

Topic

Breaking Research

Institute of Biomedical Engineering

Institutional Strategic Initiatives

Insulin 100

Temerty Faculty of Medicine

Toronto General Hospital

Diabetes

Medicine by Design

Mount Sinai Hospital

Research & Innovation

Stem Cells

University Health Network

Stem cell pioneer Andras Nagy has a way of describing the work of your immune system: “It’s surveillance inside our body.”

That surveillance does us good when harmful bacteria or viruses enter our body. The immune system releases fighter cells to kill the invaders.

But regenerative medicine therapies often involve transplanting tissues or cells into a person. When new heart or pancreatic cells are transplanted, for example, the immune system will see these good things as enemies and reject them. Drug treatment can be used to suppress this immune response, but it can leave the person open to serious infection.

Nagy, a professor in the department of obstetrics and gynaecology at the �ؿ�ζSM's Temerty Faculty of Medicine and a senior investigator at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute, and his research team have been experimenting with a process called “cloaking,” which he believes could be used to hide therapeutic cells from the immune surveillance system and allow them to do their good work.

Though this research will one day be applicable to all cell therapies, Nagy’s team is currently testing the cloaking technology with insulin-secreting pancreatic cells that are made from stem cells and could be a powerful cell therapy for type 1 diabetes.

Stem cells are cells that can be reprogrammed and turned into an unlimited source of any type of human cell needed for treatment. Nagy notes that the first years of stem cell research were at the basic science level, as scientists worked to understand the nature of stem cells. He says about 10 years ago, there was a notable shift to what he calls “translational” research. His work is part of this wave of applied science; in fact, in 2015 he co-founded a biotech company, panCELLa Inc., to make his cell technologies widely available.

“Regenerative medicine is at a point now where we can translate our research into therapies that can help all humankind,” he says.

The Canada Research Chair in Stem Cells and Regeneration, Nagy says that researchers have long known that transplanted cells and tissues can be attacked by the immune system.

“We wondered if there was a way to hide or ‘cloak’ these good cells, so the immune response wouldn’t destroy them,” says Nagy. “But before we could move into that we had to deal with a significant hurdle – the safety of the implanted cells.”

Nagy points out that when these new cells are created, there is a chance they could mutate and become cancerous. The more cells needed for a therapy, the more cell divisions that take place, meaning a higher chance of mutation and cancer.

In earlier research, partially funded by a previous Medicine by Design team projects award, Nagy published a paper in Nature that described a “fail safe” cell technology that he and his team devised that can increase the safety of a cell graft and has a formula to quantify the risk of mutation so that people can make an informed decision on whether such a risk is acceptable to them.

The fail-safe system is a switch that eliminates potentially dangerous cells during cell therapy. The switch is introduced into stem cells, which are then turned into the therapeutic cells. The switch is turned on by a drug that can be added to the cell graft or applied directly into the body after transplant.

Nagy says the killer switch is fail safe because it is composed of two genes, one required for division and one that can trigger cell suicide, stitched together. If a mutated gene begins dividing, the drug is there to activate the kill switch and kill the cell. And if the cell loses the switch, it also loses the ability to multiply.

With the important first step of creating the fail safe switch done, Nagy turned to the cloaking, work that is supported by his team’s current Medicine by Design team projects award.

Nagy’s team is one of 12 sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is an institutional strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

“Medicine by Design has been really important in supporting scientists in bringing the possibilities of regenerative medicine to patients. I’m grateful to Medicine by Design for funding the high-risk and high impact projects that many other funding agencies often say are just too ambitious.”

The cloaking technology involves turning off certain genetic switches in the cells created from stem cells to avoid detection by the immune system. This work was supported by findings from a devastating cancer found in Tasmanian devils, the marsupial native to the Australian state of Tasmania.

Between 1996 and 2015, 95 per cent of the Tasmanian devil population was wiped out as a result of contagious facial cancer cells transmitted when the devils bit each other. Nagy’s research found that the cancer had a way of cloaking itself from the devils’ immune system, which backed up his theory that cells could be hidden from the immune system.

Nagy identified eight genes that are central to immunity. He reasoned that just as the Tasmanian devils’ facial cancer could avoid detection by turning off the right genetic switches, his stem cell-derived cells could similarly become cloaked. Scientists in Nagy lab have been testing the cloaking in mice with encouraging results.

Sara Vasconcelos

Working with Nagy are Maria Cristina Nostro, senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute and associate professor, department of physiology at U of T; and Sara Vasconcelos, scientist at the UHN’s Toronto General Hospital Research Institute and associate professor at U of T’s Institute of Biomedical Engineering.

The Nostro lab’s focus is to generate insulin-secreting pancreatic cells from stem cells. These cells could one day have the potential to treat patients with type 1 diabetes. Nostro works closely with Vasconcelos, whose lab focuses on helping to keep the transplanted cells alive once they enter the body. Cells need oxygen and other nutrients, which are delivered through the blood vessels.

Together, the team is testing ways to integrate Nagy’s technologies into Nostro’s functional pancreatic cells. Vasconcelos’s aim is for these therapies to survive in the body.

“When you just transplant the cells, they don’t have blood vessels, so they’ll die, independent of whether the immune system kills them or not. If they die, we’ll never know if it was the immune system or lack of oxygen,” Vasconcelos says. The Vasconcelos lab team repurposes small vessels, which exist in fat. They then use the vessels as units to increase blood flow and allow the cells to engraft and survive after they have been transplanted.

Nagy says the combination of the fail safe and cloaking technologies will make for a powerful therapy. “On the one hand, we can now introduce good cells into recipient’s body that can be hidden from the immune response and do the work they were intended to do. And that means doctors won’t have to use immunosuppression drugs. Finally, if one of the newly created cells is cancerous to the patient, our safe-cell technology can kill it or at least give us information on risk that we can communicate to the patient.”

When stem cell-derived therapies are created for individual patients, Nagy says, it is expensive, costing hundreds of thousands of dollars per patient. Nagy envisions turning his cells that combine fail safe and immune cloaking technologies into “off-the-shelf” products that can be used by anyone and are inexpensive.

Nagy has been building a notable research career in regenerative medicine since he came to Canada from Hungary in 1989, initially joining the lab of renowned researcher and University Professor Janet Rossant at the Samuel Lunenfeld Research Institute (now the Lunenfeld-Tannenbaum Research Institute) at Mount Sinai Hospital.

Sunscreen, shade and covering up: U of T dermatologist Cheryl Rosen offers sun safety tips

Christopher.Sorensen — Fri, 06 Aug 2021 15:15:09 +0000

Sunscreen, shade and covering up: U of T dermatologist Cheryl Rosen offers sun safety tips

Christopher.Sorensen Fri, 08/06/2021 - 11:15

Cutline

(photo by d3sign via Getty Images)

Blake Eligh

Topic

Our Community

Temerty Faculty of Medicine

Toronto General Hospital

Cancer

Princess Margaret Hospital

University Health Network

Dermatologist Cheryl Rosen is so serious about sun protection that she sometimes carries her own shade – a parasol.

Rosen is a professor in the department of medicine in the �ؿ�ζSM’s Temerty Faculty of Medicine, and head of the dermatology division at Toronto Western Hospital, Toronto General Hospital and Princess Margaret Hospital. Her research interests include public education for skin cancer prevention.

Each year 85,000 Canadians will be diagnosed with skin cancer and one in six Canadians will be diagnosed in their lifetime. As a member of the Canadian Dermatology Association’s (CDA) sun awareness working group, Rosen hopes public education about the need for sun protection will change those numbers.

A spokesperson for skin cancer prevention and part of a group whose advocacy helped introduce a provincial law prohibiting people 18 and under from using tanning beds, Rosen says practising good sun safety is the best way to avoid skin cancers that are caused by sun exposure.

Writer Blake Eligh recently asked Rosen to share her sun safety tips as Canadians take to the outdoors during another pandemic summer, including common sunscreen mistakes and her trick to eliminate the pesky white cast left by mineral sunscreens.

What are the basic steps for staying safe in the sun?

Everyone spends time outside in the summer, but particularly now because of the pandemic and the need for social distancing. As dermatologists, we say go outside and have a wonderful time, but be aware of the sun. Wear sunscreen, seek shade and cover up.

Find a broad spectrum sunscreen with an SPF (sun protection factor) of 50 or higher to protect against both ultraviolet B and ultraviolet A (UVB and UVA) radiation. Put sunscreen right beside your toothpaste to make it an automatic part of your morning routine. Put it on every day in the warmer weather — you never know when you might have the chance to have lunch on an outdoor patio.

There are clothes that offer UV protection, with a UPF label, but you don’t really need them if you choose clothes with tightly woven fabrics. Don’t forget to wear a hat and sunglasses.

Plan your outdoor activities wisely and, if you can, schedule activities like tennis for earlier or later in the day.

Seek shade wherever possible. Look for natural shade from trees and outdoor patios with umbrellas. You may choose to use a parasol or umbrella – carrying your own shade around with you is a good idea.

What is the role of sunscreen in skin protection?

Years ago, we didn’t know about the damage the sun could cause.

Sunscreens help prevent sunburns, but they also prevent DNA damage in skin cells and decrease your risk of developing certain skin cancers – squamous cell carcinoma and melanoma. A sunscreen may also decrease signs of photoaging, wrinkles and fine lines.

There are so many sunscreens on the market. How do we choose the right one?

The best sunscreen is one that you don’t mind putting on, so it’s important to find a product that works for you.

Find a sunscreen with an SPF of 50 or 60. The SPF tells you about protection against UVB radiation.

Look for the words “broad spectrum” on the label. That indicates protection against both UVA radiation and UVB radiation, which play a role in developing skin cancer and in photoaging.

Also look for the symbol of recognition by the CDA, or the letters “UVA” within a circle, which indicates the sunscreen has met the European Union standards for UVA protection.

Are there new developments in sunscreen formulas?

Iron oxide is the next big thing in sunscreen. There’s recent research that shows visible light – daylight, not just ultraviolet radiation – can increase pigmentation in the skin. Iron oxide can help protect our skin from this visible light. Some sunscreens include it as an inactive ingredient, but it hasn’t yet been approved by Health Canada as a sunscreen active ingredient.

What are some common mistakes that people make with sunscreens?

We know people put on way less sunscreen than is actually used in testing, so that’s a great reason to use a sunscreen with a high SPF value. If you’re putting on half as much as the test quantity, you’re actually getting half the SPF.

One common mistake is missing parts of the body during application. People do a poor job of putting it on the first time. There are examples of tests where fluorescent dye is added to the sunscreen. A special light reveals whole areas that people missed in application.

People forget to put sunscreen on their ears or the back of their neck.

If you’re using a spray, you have to rub it in, or you might end up with lines of protected and unprotected skin.

Forgetting to reapply is another issue. The FDA and Health Canada both advise reapplying sunscreen every two hours. Other research shows that the best time to reapply is 20 minutes after the first time to make up for the mistakes and missed spots during the first application.

When should we take extra precautions?

Medical conditions are one reason to take extra precautions. Solid organ transplant patients have a markedly higher rate of skin cancer because they take medication that suppresses the immune system. They should be careful in the sun, as should people with systemic lupus erythematosus, or those who are taking certain drugs that cause photosensitivity to UVA.

People with melasma develop darker patches on the face. These people need to use sunscreen during the day to prevent further darkening of the melasma, and may use a medicated cream at night which can help fade the patches. If you’ve had a facial procedure that’s healing, such as laser therapy, you also should avoid the sun or you’ll be left with darker areas.

How does the sun affect people with darker skin?

For people with skin of colour, the risk of skin cancer caused by the sun is very low because melanin, the pigment that gives skin its colour, is a very good source of protection. What can be an issue is increased pigmentation from the sun, such as patches of darker colour. Sun protection can help with that.

Mineral sunscreens can leave a white cast. One trick I’ve learned is to add a little bit of foundation to your sunscreen and really blend it in, so it’s closer to your skin tone.

Should we be worried about chemicals in sunscreen formulations?

Some studies have reported concerns about particular sunscreen ingredients, such as benzophenone. There are reports of benzophenone being an endocrine disruptor, but another study found that reproductive hormone levels were normal in humans using sunscreen on a regular basis.

Sunscreens have been used for years and have not shown any signal that they cause a problem. As dermatologists, we have to keep looking at the studies reported in the literature.

What tips can you share on coping with a sunburn?

Typically, people don’t come to see me about sunburns. The pain and redness will fade in a few days. There may be some skin damage, such as DNA damage in the skin cells. A cool compress or a moisturizer that’s been in the fridge can be soothing. A non-steroidal anti-inflammatory medication might help ease the pain.

Prescription retinoids, such as tretinoin, may reverse some sun damage. It can be applied as a cream to an area that might eventually show fine lines and wrinkles, or to try to reverse these changes once they have appeared.

Heritage Minute showcases life-saving impact of U of T’s insulin discovery

lanthierj — Mon, 17 May 2021 19:35:42 +0000

Heritage Minute showcases life-saving impact of U of T’s insulin discovery lanthierj Mon, 05/17/2021 - 15:35

Yanan Wang

Topic

Our Community

Insulin 100

Temerty Faculty of Medicine

Toronto General Hospital

Dalla Lana School of Public Health

Physiology

Research & Innovation

Thomas Fisher Rare Book Library

U of T Libraries

University Health Network

Christopher Rutty
(photo by Alie Rutty)

After decades studying the 100-yea

r-old discovery of insulin and its later development, Christopher Rutty faced a daunting task: select the most compelling details to be showcased in just 60 seconds.

A medical historian, he was one of three historical consultants on the team that created a new Heritage Minutes segment that pays tribute to the discovery of insulin at the �ؿ�ζSM’s department of physiology in 1921.

The segment follows the patient journey of a young and emaciated-looking Leonard Thompson, who would become the first diabetes patient to be successfully treated with the life-saving extract. Working away in their laboratory, scientists Frederick Banting and Charles Best offer an extract that they believe may save the child, who receives the treatment at Toronto General Hospital. In the evening, however, they receive a knock on the door from collaborators J.J.R. Macleod and James Collip, who says the extract is not pure enough.

“So, we try again,” Banting responds with defiance. “And again. And again.”

The decision to highlight the story of a single patient stemmed from a desire to emphasize the human element of the Nobel Prize-winning scientific discovery, according to Rutty, an adjunct professor at U of T’s Dalla Lana School of Public Health.

“If you’re going to reduce it down to a 60-second story, that’s a key moment,” Rutty says. “It shows the drama of the impact of insulin, which was that it practically resurrected the dead.”

A self-described stickler for details, Rutty says he felt a sense of responsibility to portray the story accurately because of the memory of his late PhD thesis adviser, U of T University Professor Emeritus Michael Bliss, who wrote the acclaimed book The Discovery of Insulin.

Rutty is also the lead historian for Defining Moments Canada’s Insulin 100 website, which features a series of articles authored by Rutty that recount the historical events leading up to and following insulin’s discovery – including the story of Thompson’s treatment.

He says he drew on Bliss’s work, original documents and newspaper reports from the period to help the Heritage Minutes team develop a full historical reconstruction of what took place. The short films are released by Historica Canada, a Toronto-based non-profit that seeks to generate awareness of Canadian history.

In a nod to Bliss’s conclusion that all four scientists in the team were critical to the discovery, Rutty felt it was important that Banting, Best, Macleod and Collip all be depicted and named.

“It was critical to make sure what the Heritage Minute was saying was true,” says Rutty. “Heritage Minutes are a record. They have a reputation of being well-done and historically responsible, and they are often an entry into the story for students and the general public.”

Alexandra Carter

Alexandra Carter, science and medicine librarian at U of T’s Thomas Fisher Rare Book Library, says she was struck by the historical accuracy of the visual details in the Heritage Minutes segment.

“We have photos of the lab; it’s this shoddy-looking, cluttered space where this amazing discovery took place,” Carter says. “I love that they put that in. I was also impressed by the attention to detail with Banting’s round glasses and their outfits – I could tell right away who was who.

“Banting was known to be a bit dramatic, so they got that right as well with the voiceover.”

Natalya Rattan

Carter and Natalya Rattan, an archivist at the rare book library, have curated an online exhibition in celebration of the 100th anniversary of the breakthrough. Drawing from U of T’s extensive archives, as well as a 1996 article by Bliss, the exhibition chronicles the team’s tribulations and eventual triumph. The story is told through original handwritten notes and notebooks from the scientists themselves, patient charts, newspaper articles, letters and other historical documents.

The Thomas Fisher Rare Book Library also recently contributed to the creation of a new commemorative Canada Post stamp, which features the image of an excerpt from Banting’s unpublished memoir and an original insulin bottle with a red cap.

As for Thompson, there are few archival materials despite his reputation as the first patient to be treated with the extract, Rattan says.

Patient records from Toronto General Hospital indicate that he was 13 years old and weighed just 65 pounds. He received an injection of the first extract on Jan. 11, 1922, followed by the second version of the extract on Jan. 23. The latter shot proved dramatically successful, as Thompson’s blood sugar dropped to normal in one day.

The Heritage Minute ends with a close-up shot of Thompson, whose previously listless face blossoms into a smile as the insulin takes effect.

“When people come to see the records – they are sometimes diabetics themselves, or doctors with direct connections to patients – they are always really drawn to the patient stories,” Rattan says.

“The patient narratives within the archives are at the heart of the discovery.”