Lisa Willemse

From a woman at the centre of Syria’s revolution to a production designer who teaches students to build their artistic vision – the University of Toronto is full of inspiring people.

Our videographer Lisa Lightbourn has spent the past year bringing these stories to life in ways that will make you laugh, cry – or want to sign up for new courses.

Get comfortable and grab some tissues. Here are our favourite videos of the year:

Noura Al-Jizawi: Syrian revolutionary

“I don’t know why I’m still alive, but I feel like it’s only by chance,” says Noura Al-Jizawi, a master’s student at the Munk School of Global Affairs & Public Policy.

Al-Jizawi was one of the young leaders who kick-started the peaceful revolt in Syria in 2011, which became a deadly civil war. After being detained and tortured, she fled to Turkey where she became the vice-president of the Syrian opposition.

In 2017, she came to ��οthrough the scholars-at-risk program, which offers financial support to graduate students and academics who have fled war or persecution in their homeland.

Jooyoung Lee on gun violence and teaching empathy

Meet Jooyoung Lee, an associate professor in the U of T's department of sociology. He is also a pop-locker, jiu-jitsu master and a pre-eminent expert on gun violence, hip hop, serial homicide and health disparities in the U.S. and Canada.

Lee says he hopes his students come away from his class with a sense of empathy after learning about the mechanisms that reproduce inequality and suffering for people of colour.

“When we allow people to tell their stories, we honour them, we validate their experiences, and we give them the space to begin healing.”

Rose Patten becomes U of T’s 34^thchancellor

Rose Patten was officially installed as the University of Toronto’s 34^th chancellor during fall convocation.

An influential businesswoman and a former chair of U of T’s Governing Council, Patten plans to use her new role to further the university’s mission as one of the world’s top research and academic institutions.

“I get the opportunity to be an advocate for all the university does,” says Patten, who is an Officer of the Order of Canada and has been lauded for her efforts to champion women in leadership roles.

“It's pretty inspirational – pretty exciting.”

Wali Shah says farewell to U of T

Spoken word artist Wali Shah wrote and performed “Thank you U of T,” dedicated to 2018’s graduating class.

Shah, who graduated this year from ��οMississauga, speaks at schools, empowering youth and raising awareness on issues like anti-bullying, mental health and social change. He's currently the poet laureate of Mississauga.

Dr. Toni Zhong reconstructs hope

Dr. Toni Zhong is an assistant professor at University of Toronto’s department of surgery and a plastic surgeon specializing in reconstruction within the University Health Network. Her work has taken her to Bangladesh to help burn victims.

In Toronto, her focus is on working with breast cancer survivors, specializing in breast reconstruction.

“I think hope is all around us and that’s what drives us,” says Zhong.

Jay Pooley on building ideas from the ground up

Jay Pooley has long had a passion for making things.

He was a construction worker and did welding and plumbing before attending architecture school. Now, among his many other hats – architect, production designer and art director – he is also a lecturer in the University of Toronto's John H. Daniels Faculty of Architecture, Landscape, and Design.

At U of T, he co-ordinates first- and fourth-year design studio courses in which he encourages students to work as a team to bring their ideas to life.

“It's absolutely empowering for a student to tell them, to say, that thing you're drawing, you can build that,” he says. “You can absolutely build that. Go make it.”

How the Tasmanian devil inspired Medicine by Design-funded researchers to devise a method to create ‘safe cell’ therapies

noreen.rasbach — Wed, 14 Nov 2018 17:34:42 +0000

How the Tasmanian devil inspired Medicine by Design-funded researchers to devise a method to create ‘safe cell’ therapies

noreen.rasbach Wed, 11/14/2018 - 12:34

Cutline

The Medicine by Design project found inspiration from an unlikely source – the Tasmanian devil population in southern Australia (photo by Arterra/UIG via Getty Images)

Lisa Willemse

Topic

Our Community

Faculty of Medicine

Institute of Medical Science

Medicine by Design

Research & Innovation

Stem Cells

A contagious facial cancer that has ravaged Tasmanian devils in southern Australia isn't the first place one would look to find the key to advancing cell therapies in humans.

But that’s exactly what first inspired a Medicine by Design-funded research team to improve the safety of stem cell-derived treatments by programming the cells to die if they mutate in ways that harm patients. The development of “safe cells,” an advance outlined in a paper published today in Nature, could be a critical step toward the widespread use of cell therapies, which hold the potential to treat and even cure diseases such as heart failure, eye diseases, diabetes and stroke.

“Moving a cell therapy from the lab to the clinic requires answering two important questions: Does it work? And is it safe?” says Andras Nagy, a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health System and a professor in the department of obstetrics and gynecology and the Institute of Medical Science at the University of Toronto. “We believe our ‘safe cells’ help answer the second question and will have a significant impact on the use of stem cells to treat a broad range of diseases.”

Safety in cell therapy involves preventing or mitigating the risk that the cells will develop tumours or unwanted tissues, or trigger an immune response that may jeopardize the health of the patient. It’s a tricky thing to predict, given that cells are living entities.

The development in 2007 of induced pluripotent stem (iPS) cells – adult cells that have been engineered back to a pluripotent stem cell state and have the potential to become any cell type in the body – promised to revolutionize the field by creating an endless supply of stem cells without the ethical baggage of their embryonic counterparts. However, along with embryonic stem cells, iPS cells share a proclivity toward uncontrolled and potentially cancerous growth. This, plus the risk of genetic mutations and current cost of iPS cell production, have hampered their progress to clinical application.

Nagy first became interested in the plight of the Tasmanian devils in previous research that looked at developing “cloaked” cells to enable off-the-shelf cell therapies that would be more cost-effective and timely than personalized treatments using a patient’s own cells. The transmissible cancer, which spread when the highly territorial marsupials bit each other, wiped out 95 per cent of their population between 1996 and 2015. As scientists and conservationists raced to prevent the total demise of the animals, Nagy wondered if the devils might hold the key to overcoming a key hurdle in developing off-the-shelf cell therapies: to prevent the patient’s immune system from attacking the therapeutic cells, immunosuppressive drugs are administered, raising the risk of other, potentially serious, health complications.

“What I found interesting about the Tasmanian devil’s cancer is that the tumour cells were not being recognized by the immune system of the bitten animal, so they were not rejected, and the tumour was able to grow,” explained Nagy. “The transmission between animals was essentially a cell graft and it told us that it was possible to introduce cells that would not be recognized by the host immune system.”

He set out to discover how the cancer cells could evade the immune system. It was no easy task. The immune system is very complex, involving many cell types that are adept at rooting out invaders, which is why instances of transmissible cancer are virtually non-existent. In the case of the Tasmanian devil, the common theory is that the animals are too similar, genetically speaking, and the cancer was able to use that to avoid detection. So how could this apply to more genetically diverse humans? The key was finding the right genes: Nagy and his team identified eight of them that are central to immunity.

From there, he reasoned that just as the devils’ face cancer could avoid detection by turning off the right genetic switches, his iPS cells could similarly become cloaked. Testing in mice showed that the cloaked cells worked. But it led to another problem.

“Cloaked cells could be enormously dangerous because they could develop into cancer cells which are also cloaked. The immune system has an important function to eliminate hotbeds of cells in our body that look weird and could be tumorigenic,” said Nagy (pictured left). “So, we are creating a highly tumour-prone cell type and this is a problem. We have to solve the problem of safety.”

The idea of safe cells – the subject of this week’s Nature paper – emerged from this need to ensure safety, or at the very least the ability to quantify risk. It’s perhaps the biggest barrier in getting iPS cell therapies into patients: Until now, no one could predict the exact likelihood that a batch of cells might be aberrant. In this paper, Nagy and his team have devised a method to increase the safety of a cell graft and a formula to quantify the risk of mutation “unsafeness” so that people can make an informed decision on whether such a risk is acceptable.

At its core, the safe cell calculation revolves around mutation. DNA replication is error-prone and mutation is unavoidable. In cell therapy, mutation is precisely what you don’t want, because it can negatively alter the intended result, say by producing a tumour rather than a remedy for cystic fibrosis, or diabetes, or any other target disease. And the more cells needed for the therapy, the more cell divisions take place, meaning a higher chance mutation will occur.

Knowing this, Nagy’s team found a way to predict the odds of obtaining potentially dangerous therapeutic cells and ameliorate these odds through gene-editing. The edited cells have a suicide gene spliced into the DNA, directly connected to a gene necessary for cell division and survival. In addition, if a harmful mutation is detected, the application of a small drug can prevent those cells from dividing and causing harm. They’re also cloaked, removing the need for immunosuppression.

“We have an absolute external control on a safe cell,” said Nagy. “There is the possibility that mutations could kill the suicide gene but leave the cell-division gene unharmed. But we can calculate the probability of this mutation happening, and this is how the safe cell level is generated.”

Read the research in Nature

The safe cell level measurement itself is based on the probability of getting a batch containing mutated cells. In this case the higher the number, the greater the safety. A safe cell level of 100 means the odds of getting a mutated batch of cells are one in 100; a safe cell level of 1,000,000 represents odds of one in 1,000,000.

“What’s important here,” Nagy qualified, “is that the patient can decide what level is acceptable. So, if someone has a life-threatening illness and their chance of survival is only 10 per cent, a lower safe cell level might be acceptable, versus a patient who has a non-life-threatening illness.”

“And if that risk is low, then it becomes like many other activities we do, such as riding a bike, getting in a car, taking a flight. Everything we do in life, when we step out of the house, is a risk-benefit decision. That’s what this is. What is needed in cell therapy is good knowledge of the risk we are taking which is enough to allow us to make informed decisions.”

Nagy is optimistic, based on feedback thus far, that they are moving in the right direction. His next steps are to conduct more tests in animal models and he has initiated talks with Health Canada to move to human clinical trials. He has also created a new company, panCELLa, to help with these efforts. If the safe cell method can be implemented into all iPS cell manufacturing, it could well become a standard for cell therapy safety that will provide a measure of confidence and predictability and allow a rapid progression of gene-edited iPS cells into clinical trials and clinical approval.

This research is one of 19 team projects funded by Medicine by Design, a regenerative medicine research initiative at ��οthat aims to accelerate discoveries and translate them into new treatments for common diseases. It is made possible thanks in part to a $114-million grant from the Canada First Research Excellence Fund, the single-largest research award in U of T’s history. The project was also funded by the Canadian Institutes of Health Research and The Foundation Fighting Blindness.

��οresearchers tackle type 1 diabetes with regenerative medicine technologies

Christopher.Sorensen — Tue, 10 Jul 2018 14:30:32 +0000

��οresearchers tackle type 1 diabetes with regenerative medicine technologies

Christopher.Sorensen Tue, 07/10/2018 - 10:30

Cutline

��οresearchers Cristina Nostro (centre), Sara Vasconcelos (right) and post-doctoral fellow Yasaman Aghazadeh (left) are collaborating to find alternatives to donor islets as a transplant option for patients with type 1 diabetes

Topic

Regenerative Medicine

Research & Innovation

University Health Network

Subheadline

Projects funded by multidisciplinary Medicine by Design initiative

Nearly 20 years ago, Canadian researchers developed the Edmonton Protocol, a revolutionary treatment for type 1 diabetes in which insulin-producing islet tissue from a donor pancreas is transplanted into a patient to restore their ability to regulate sugar in the blood.

Since then, more than 2,000 islet transplants have been performed worldwide, but the shortage of donor pancreata means the procedure is not available to most patients who could benefit from it.

“The procedure is overall very successful, but tissue scarcity is a real problem,” says Yasaman Aghazadeh, a post-doctoral researcher at the University of Toronto who is working in the laboratories of Cristina Nostro and Sara Vasconcelos at the Toronto General Hospital Research Institute, part of University Health Network (UHN).

That’s not the only challenge. “Right now, the majority of these donor islets die within the first few days after transplantation because they don’t have enough support in the form of nutrients or oxygen,” explains Aghazadeh, who was the recipient of a 2017 post-doctoral fellowship award from U of T's Medicine by Design regenerative medicine initiative. “As a result, one patient may need tissue from up to three different donors, so fewer than 0.001 per cent of patients can obtain a tissue transplant.”

Those odds are better than getting struck by lightning or winning the lottery, but not by much. For the remaining 300,000-plus type 1 diabetes patients in Canada, insulin injections remain the only option. Despite advances in insulin formulations, delivery and monitoring, many people with type 1 diabetes continue to suffer devastating complications from the disease, including kidney disease, amputations and blindness.

That’s why two cross-disciplinary teams funded by U of T’s Medicine by Design are working on novel regenerative medicine approaches they hope will lead to new solutions and better outcomes for people with type 1 diabetes. The projects are two of 19 team projects Medicine by Design is funding as part of its mandate to accelerate regenerative medicine breakthroughs, and translate them into new treatments for common diseases. Medicine by Design is made possible thanks in part to a $114-million grant from the Canada First Research Excellence Fund – the largest single research award in U of T’s history.

Tricking the faulty immune system into beta cell tolerance

Type 1 diabetes is, first and foremost, an autoimmune disease in which a person’s immune system begins to attack and kill insulin-producing beta cells, leaving them incapable of regulating blood sugar. With an immune system constantly on high alert for new beta cells to attack, a treatment will not be as simple as merely delivering replacement cells. Since we don’t know what triggers the immune system to launch an attack on healthy beta cells, researchers are working to outwit the autoimmune response using a number of different strategies. Juan Carlos Zúñiga-Pflücker (left), a professor and chair of U of T’s department of Immunology and a senior scientist at Sunnybrook Research Institute, is leading one Medicine by Design team that is pursuing two intersecting strategies. One seeks to suppress the immune response, while the other is developing a “cloaked” beta cell capable of evading an immune attack.

The immune suppression approach involves careful control of the body’s immune cells, most of which are found in the bloodstream.

“We thought the best way to do this is to use the immune system to create a state of tissue tolerance to the graft,” explains Zúñiga-Pflücker.

To suppress the immune response, the team is manipulating T-cells, a type of white blood cell that responds to various cues to attack abnormal cells such as those that have been invaded by a virus or are cancerous. But T-cells don’t always get it right. In the case of an autoimmune attack, they incorrectly respond and kill healthy cells. One of the project team members, Naoto Hirano, a senior scientist at the Princess Margaret Cancer Centre at UHN and an associate professor in U of T’s Department of Immunology, is working to suppress these misdirected T-cells. He aims to convert them into regulatory T-cells (or T-regs), another type of T-cell that acts as a suppressor, allowing the body to tolerate certain cues that would otherwise lead to an autoimmune attack.

Our blood normally has some T-regs lurking about, ready to pounce if called upon. Unfortunately, probably due to their relative scarcity in the blood, they cannot launch an adequate attack against the faulty T-cells in autoimmune disease.

It would make sense, therefore, to increase the number of T-regs in a patient’s blood so they can protect the body’s vulnerable cells and organs from autoimmune attack. But, Hirano says, “It’s not so simple. T-regs are just so very rare and not easy to expand.” To overcome this, Hirano began looking elsewhere. He showed that when the protein FOXP3 was added to the more abundant T-cell populations, they could be converted to T-regs. So far, the team is pleased with the immune suppression they can achieve with the T-regs they have generated to date.

“I’m always optimistic, but science is science,” says Hirano. “We have very important data on how FOXP3 degradation is controlled that will make a very good paper. But there’s more work still to be done.” Next, they will study whether these T-regs can stop autoimmune attacks in diabetic mice.

The second approach that Zúñiga-Pflücker’s team is exploring centres on modifying beta cells, which are the target of the autoimmune attack in diabetic patients. For this work, he turned to Nostro and Andras Nagy, a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health System and a professor at U of T’s department of obstetrics and gynaecology and Institute of Medical Science.

For several years, Nostro has been successfully working to improve the quality of beta cell populations grown in her lab. It’s a competitive field of research, and she is among the world’s best. Nagy, meantime, is a leader in the development of induced pluripotent stem cells and in engineering them to display desirable characteristics. In this project, Nagy and Nostro have teamed up to create a population of stem cells that could then be grown into replacement beta cells carrying the same cloaking gene. These cloaked cells would be able to evade an immune attack by becoming undetectable to the immune system. A year and a half into the project, the team is making progress in mice and is beginning to see how it could be applied to humans.

“Because the immune system is able to recognize an infinite number of different things, and in an environment where a person has already had an autoimmune response, we always felt that even the best cloaked cell may still be recognized. The immune system always finds a way,” says Zúñiga-Pflücker. “That’s why we wanted to combine the two approaches [immune suppression and cell cloaking], as an extra level of security so the tissue would not be rejected. We hope this research gives us the ability to ask whether it is sufficient to prevent a response.”

If the answer is yes, this approach could be applied as an off-the-shelf solution for a much broader range of immune challenges, such as tissue or organ transplants in which rejection carries immense risk, or other forms of autoimmune disease.

The complicated business of cell survival

Even with a modulated immune system, beta cell transplantation still has challenges that have yet to be fully overcome. Since donor islets are in short supply, researchers have turned to lab-grown beta cells as a possible source of the quantity of cells that will be needed.

In a second Medicine by Design-funded project, Nostro is looking at whether pancreatic progenitor cells grown in the lab could be a viable alternative to donor islets as a transplant option for patients. Pancreatic progenitor cells are a type of stem cell that can produce all the cells in the pancreas, including the beta cells that reside in the islet and produce insulin. These cells have already been tested in clinical trials in Canada and elsewhere with some success, but improving their survival after transplantation will be key to delivering an optimal therapeutic product.

For any cell, survival depends on obtaining the right nutrients. In the lab, this is relatively easy since cells in a petri dish are essentially swimming in all the nutrients they need. In the body, however, delivering nutrients to cells in the middle of solid tissue requires a network of blood vessels. Therefore, establishing a blood supply to newly transplanted cells or tissues is critical to their long-term survival and is currently a major bottleneck in the production of large tissues.

For beta cells, connection to a blood supply is especially important. “Because of their function, beta cells need to be in close contact with the blood system. In fact, it is speculated that every beta cell is either connected with a vessel or, at most, is just two cells away from a vessel,” says Nostro, who, in addition to her role as a scientist at UHN, is also an assistant professor in U of T's department of physiology.

“This close connection allows the beta cell to constantly monitor and regulate blood sugar,” Nostro continues. “Unfortunately, when we make beta cells in the lab they lack this interface.”

So Nostro teamed up with Vasconcelos, who is also an assistant professor at U of T’s Institute of Biomaterials & Biomedical Engineering, an expert in engineering tissues with functional blood vessels (also referred to as vascularized tissue). Together, they are working to overcome the current limitation in pancreatic progenitor transplantation by generating a highly vascularized islet. Nostro and Vasconcelos are enthusiastic about the progress seen in initial, as yet unpublished, experiments.

Nostro and others are convinced that finding a way to integrate transplanted cells with a supportive network of blood vessels will be critical to achieving a successful cell-based diabetes treatment. Effectively combining their efforts with cell cloaking and immune suppression may be a significant and long-awaited advance in type 1 diabetes management.

Lisa Willemse

Amazing journeys and lyrical goodbyes: Here are U of T’s top 6 videos of 2018

Noura Al-Jizawi: Syrian revolutionary

Jooyoung Lee on gun violence and teaching empathy

Rose Patten becomes U of T’s 34th chancellor

Wali Shah says farewell to U of T

Dr. Toni Zhong reconstructs hope

Jay Pooley on building ideas from the ground up

How the Tasmanian devil inspired Medicine by Design-funded researchers to devise a method to create ‘safe cell’ therapies

Read the research in Nature

��������οresearchers tackle type 1 diabetes with regenerative medicine technologies

Tricking the faulty immune system into beta cell tolerance

The complicated business of cell survival

Rose Patten becomes U of T’s 34^thchancellor

��οresearchers tackle type 1 diabetes with regenerative medicine technologies