Donnelly Centre

A startup born from the lab of renowned �ؿ�ζSM researcher Molly Shoichet has received $10.3 million from investors to begin human safety trials on an injectable gel that can improve post-surgery pain treatment, the Globe and Mail reports.

AmacaThera is built on a gel technology developed by Shoichet, a University Professor in chemical engineering and applied chemistry and biomaterials and biomedical engineering, and her team. She co-founded AmacaThera with Mike Cooke, who was a post-doctoral researcher in her lab.

The gel dramatically extends the duration of anesthetics injected at the site of a surgical incision, potentially eliminating the need to give patients the powerful post-surgery painkillers that frequently lead to opioid addiction.

The Globe and Mail reported that the financing was led by Toronto’s Lumia Ventures and backed by investors in Canada, the United States and Europe, including Viva BioInnovator, BDC Capital Women in Technology Venture Fund and Inveready.

“The work out of that lab is truly transformative and she’s a leader in the space,” Lumira Ventures Managing General Partner Peter van der Velden told the Globe and Mail.

AmacaThera raised $3.25 million in its first round of financing in 2019. It received support from UTEST and the Creative Destruction Lab, two of U of T’s entrepreneurship hubs.

Researchers at U of T use stem cells to grow functional blood vessel cells found in liver

Christopher.Sorensen — Thu, 09 Jul 2020 15:26:35 +0000

Researchers at U of T use stem cells to grow functional blood vessel cells found in liver

Christopher.Sorensen Thu, 07/09/2020 - 11:26

Cutline

Blair Gage is a post-doctoral researcher at the McEwen Stem Cell Institute at UHN and lead author of the study, which could lead to new therapies to treat hemophilia A (photo courtesy Blair Gage)

Topic

Laboratory Medicine and Pathobiology

Medicine by Design

Molecular Genetics

Research and Innovation

University Health Network

An inter-disciplinary team of researchers, funded by the �ؿ�ζSM’s Medicine by Design, has generated functional blood vessel cells found in the liver from stem cells – a discovery that offers an opportunity to study the role the cells play in liver development and disease progression, and which could lead to new therapies to treat hemophilia A.

The study, titled “Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem Cell-Derived Venous Angioblasts,” was published this week in Cell Stem Cell. It represents a collaborative effort between basic and clinical researchers at U of T and the University Health Network (UHN) with expertise in stem cell and computational biology, human liver physiology and function and liver transplantation.

It also draws on previous Medicine by Design-funded research that led to the creation in 2018 of the first single-cell “map” of the human liver.

“By combining insights from developmental biology and liver anatomy with the cell atlas of the human liver, we were able to generate and validate functional human liver vasculature from stem cells,” says Blair Gage, a post-doctoral researcher at the McEwen Stem Cell Institute at UHN and lead author of the study. “Now we can move forward to use these liver endothelial cells to better understand their role in liver function and to develop new therapies to treat disorders such as hemophilia A.”

The interdisciplinary research team also includes: Jeff Liu, research associate at U of T’s Donnelly Centre for Cellular and Biomolecular Research; Brendan Innes, a PhD candidate at the Donnelly Centre and in the department of molecular genetics in the Faculty of Medicine; Sonya MacParland, scientist in the multi-organ transplant program at the Toronto General Hospital Research Institute and an assistant professor in U of T’s departments of immunology and laboratory medicine and pathobiology; Ian McGilvray, senior scientist at the multi-organ transplant program at the Toronto General Hospital Research Institute and a professor in U of T’s department of surgery; Gary Bader, professor at the Donnelly Centre and the department of molecular genetics; and Gordon Keller, director and senior scientist at the McEwen Stem Cell Institute at UHN and professor in U of T’s department of medical biophysics.

Researchers in the Keller lab had the goal of generating a functional liver vasculature cell type known as liver sinusoidal cells (LSECs) from human pluripotent stem cells (hPSCs) – cells that can self-renew and have the potential to turn into any other cell type in the human body. LSECs are essential for normal liver function and represent the main source of factor VIII, a blood-clotting protein that is missing or defective in patients with hemophilia A.

However, the team had to demonstrate that the cells they had made in the lab had the same specialized genetic and functional features as those in the human liver. So they turned to the work of MacParland, Bader and McGilvray, who in the first phase of Medicine by Design’s team project funding described a molecular map of the cell types in the adult liver. That research has contributed to the Human Cell Atlas – an international effort to create comprehensive reference maps of all human cells – and last year attracted follow-on funding from the Chan Zuckerberg Initiative.

“This paper uses our human liver map as a guide to know if the cells being generated are the right ones through collaboration with Gary Bader’s group,” says MacParland. “The work really highlights the strength of Medicine by Design in bringing together researchers from multiple institutions to focus on a common goal.”

With Bader and Liu’s help, Keller lab researchers were able to use the MacParland human liver map to show that the hPSC-derived endothelial cells they had generated shared many of the features found in normal liver vasculature. The Keller lab team then brought Innes on board to format the data from the hPSC-derived LSECs for the research community to easily explore the molecular profile of these cells.

This research was supported by Medicine by Design, which receives funding from the federal government’s Canada First Research Excellence Fund and by the Canadian Institutes of Health Research.

The work continues in a current Medicine by Design-funded team project led by Keller that aims to make other key liver cell types and put together the pieces to get functional tissues with the goal of developing new cell-based therapies for liver-related diseases. That project is part of a new $20-million round of team project funding that Medicine by Design announced late last year.

Medicine by Design brings together investigators from different disciplines at U of T and its affiliated hospitals to advance new discoveries in regenerative medicine and accelerate them toward clinical impact. Medicine by Design will host a meeting of the Human Cell Atlas’s Development and Pediatric Atlas in July 2021 in Toronto.

U of T researchers involved in first map of human liver cells at the molecular level

noreen.rasbach — Tue, 23 Oct 2018 04:00:00 +0000

U of T researchers involved in first map of human liver cells at the molecular level

noreen.rasbach Tue, 10/23/2018 - 00:00

Cutline

From left, Sonya MacParland, Ian McGilvray and Gary Bader are part of the collaborative research team that created the first map of human liver cells at the molecular level (photo courtesy of UHN)

Topic

Research & Innovation

A map of the cells in the human liver has been created by �ؿ�ζSM researchers and the University Health Network transplant program, revealing for the first time differences between individual cells at the molecular level that can have a profound impact on their behaviour in tissue, tumours and disease.

The researchers, led by Assistant Professor Sonya MacParland, of immunology and laboratory medicine and pathobiology in the Faculty of Medicine; Associate Professor Ian McGilvray of surgery; and Professor Gary Bader, of the Donnelly Centre for Cellular & Biomolecular Research, mapped out the cellular landscape of 8,444 individual cells obtained from the tissues of healthy deceased donor human livers.

“For the past 20 years, we have studied the liver as a soup of cells as opposed to its individual components. This makes it difficult to target individual cells that are driving liver disease,” says lead author MacParland, who is also a scientist at the Toronto General Hospital Research Institute.

By examining the gene expression profiles of each of these cells – about 1,500 active genes per cell – the researchers found 20 distinct cell populations made up of hepatocytes, endothelial cells, cholangiocytes and various immune cells such as B cells, T cells and Natural Killer (NK) cells.

“These evaluations reveal new aspects of the immunobiology of the liver, such as the presence of two surprisingly distinct populations of liver resident macrophages (“big-eaters” of cellular debris) with inflammatory and non-inflammatory functions,” write the authors in their paper published Monday in Nature Communications.

“We present a comprehensive view of the liver at single cell resolution that outlines new characteristics of resident cells in the liver, and in particular provides a new map of the human hepatic immune microenvironment,” note the authors.

The authors will also make their research available to the Human Cell Atlas Project, an international, open-access, collaborative effort to map all human cells, to help scientists understand how genetic variation impacts disease risk and influences health. Because it is an open, free resource for any researchers in the world, it will accelerate discoveries that will in turn inform new treatments and drug development.

Bader says the creation of the liver map was made possible because of Medicine by Design, a regenerative medicine research initiative at U of T with a mandate to accelerate discoveries and translate them into new treatments for common diseases.

“The liver project came together serendipitously via the Medicine by Design community, and it would not have happened without Medicine by Design,” says Bader, who is also a member of the organizing committee of the Human Cell Atlas Project.

Learn more about single-cell genomics in this Research2Reality video

In creating the liver map, the team had to overcome several challenges.

First, the project could only have been possible with a multidisciplinary team consisting of transplant surgeons, immunologists, hepatologists, computer scientists and genomics researchers from different institutions to develop the first-ever map of a solid organ.

Another major problem in studying the human liver is difficulty in accessing fresh tissue. Samples in the study were collected from deceased donor livers deemed acceptable for liver transplantation, with consent and ethics approvals. This makes it unique in the world, in contrast to the standard method of studying the liver from biopsy samples.

A third challenge is isolating single cells from liver tissue. Liver cells such as hepatocytes and others are delicate and often do not survive standard tissue extraction, which may involve chopping, separating and filtering of tissue into smaller parts. During this process, cells often die.

But with the experience gained in transplantation and painstaking trial and error work of many years, the researchers were able to develop the best protocols using enzyme mixtures to gently dislodge cells embedded in the spider web-like net of connective tissue of the liver, without actually harming the fragile cells themselves.

Only then could the team begin studying the molecular make-up of each cell individually. This step is absolutely essential in gaining a deeper understanding of how a small but critical change in a cell can precipitate a disease state within a complex mix of many other cells.

The latest technological advances helped the team to overcome the limitations of previous techniques such as genomics. Although it can analyze many cell types simultaneously “in bulk”, it cannot tease out the critical differences between cells or do so in combination with multiple other data.

The team reached out to colleagues in the Princess Margaret Genomics Centre with their 10X Genomics Chromium system which excels at the analysis of complex tissues and heterogeneous collections of cells, and to the Donnelly Centre’s Bader, who developed the state-of-the art data analysis pipeline and custom pathway analysis software for the project. They were then able to map out the genetic and molecular function of each cell and how each one contributes to overall liver function.

“We found some very cool things about the human liver that we did not expect,” says McGilvray. “Until this study, very little was known about what the liver macrophage – the ‘tank’ of the immune system that destroys foreign substances and co-ordinates the immune response – actually is. We found that there are two distinct populations of macrophages in the human liver, one which is pro-inflammatory and the other anti-inflammatory.”

This new understanding can help scientists to harness these two contrasting macrophages to, for example, achieve “tolerance” of a new donor organ, says McGilvray. For transplant recipients, he explains, in the future, clinicians may want to downregulate the pro-inflammatory cells and upregulate the anti-inflammatory cells so that the recipient does not reject the new organ, and even may not need to take as many or any immunosuppressive medications.

MacParland adds that the new liver map gives us a new understanding of many more populations of cells found in a normal liver. Eventually, she says, as the map becomes more and more detailed, we can compare these cells to those in a diseased liver.

Then, she says, we can answer the question: “How can we get the liver back to a normal state?”

The research was funded by: �ؿ�ζSM’s Medicine by Design initiative which receives funding from the Canada First Research Excellence Fund, funds from UHN’s Transplant Program, and the Toronto General & Western Hospital Foundation.

How U of T's Michael Garton forged a career in research after being paralyzed in climbing accident

noreen.rasbach — Tue, 02 Oct 2018 20:34:35 +0000

How U of T's Michael Garton forged a career in research after being paralyzed in climbing accident

noreen.rasbach Tue, 10/02/2018 - 16:34

Cutline

(photo by Jovana Drinjakovic)

Topic

Institute for Biomaterials and Biomedical Engineering

Research & Innovation

Subheadline

On a hot July day in 2006, Michael Garton was living his dream. Then 24 years old, the British climber was scaling the tallest vertical rock face in Europe – Norway’s Troll Wall – hoping to become the first person to reach the top climbing solo.

His bid was all the more audacious in light of the country’s no-rescue policy, which said climbers stranded on the notoriously inaccessible wall had to fend for themselves. Garton estimated that if he climbed for up to 18 hours each day, he could reach the peak – about the height of two CN towers – in seven to 10 days.

Disaster struck. Garton was hit by a falling rock and plunged 40 metres down the cliff before getting caught by his climbing equipment. The fall left him paralyzed – but it also gave him new perspective on his work and what he hoped to achieve.

The same tenacity that drove Garton up the mountain 12 years ago has helped him build a successful research career, culminating this month with his appointment as assistant professor at the �ؿ�ζSM’s Institute of Biomaterials and Biomedical Engineering.

“When you are climbing and you know you are not going to be rescued if anything goes wrong, there’s a feeling of being super committed and it’s totally down to you,” he says. “The mindset I built doing that has really helped me doing science.”

With climbing, he says, “it is mostly obvious where you have to go – you just have to keep pushing forward.” But in science, “it is often difficult to know where to go. Even when you don’t feel like you’re making any progress, or you’re failing at everything, just keep trying, keep thinking about the problem in a different way.“

One of the first projects in his lab will be to engineer human cells into a kind that can mend throbbing pain in aging joints. For example, for arthritic knees in which the pain is caused by inflammation, Garton’s plan is to take out some knee cells, insert new genetic circuitry encoding components engineered to both sense the inflammation and respond to it by releasing anti-inflammatory molecules, and then put the cells back into the knee.

“The cells will respond as and when necessary and you as a patient will never experience the disease as it is being treated by your own tissue,” he says. Arthritis will be a test case, but the same principles could then be applied to a variety of diseases. “I want to develop a basic chassis of the cell that can be fine-tuned to detect and respond to different diseases.”

Garton says that being at U of T, with “world-renowned experts in various diseases working just across the street or in the next building,” will be helpful for establishing the collaborations needed to bring new therapies to patients.

A chemist by training, before the accident Garton thought little about applying his scientific knowledge to better society. But his views shifted during the year-long recovery in the hospital, where he was surrounded by caring staff while grasping the confines of his new reality.

“I could kind of see that a lot of the staff at the hospital had the same passion for their job as I had for climbing,” he says. “I realized then how selfish I’ve been my whole life by just focusing on how much I could enjoy myself going climbing. It really hit me – that the thing to do is to apply your passion and drive and hard work to something that is actually going to benefit society and other people and not just yourself.“

That Garton is alive is only thanks to a chance encounter a few days before his accident. While preparing for the climb, he asked a passerby with a telescope if he could borrow it to make out the safest route and avoid a rockfall. That summer was unusually warm and the heat had melted the ice inside the cracks of the north-facing cliff that glues together loose pieces of rock. The thawing ice released “boulders the size of trucks.”

Norway’s Troll Wall, the tallest vertical rock face in Europe (photo by Sergei Gussev via Flickr)

Although Garton tried to avoid the worst areas of rockfall, two days into the ascent a lump of rock came off as he was climbing and knocked him off. The fall left him unconscious and when he woke up, he could not move. “I woke up and had a really excruciating pain in my neck,” he says. “That’s when I realized I had broken my neck and was paralyzed.”

“It was a very odd experience, just being conscious and not being able to fight it, just having to lie there and look at the incredibly serene landscape and just think, ‘OK, I only have a few more hours left and then it’s death.’”

But what Garton did not know was that the man with the telescope had set up camp with friends to watch him climb. When the campers noticed Garton’s body hanging off the cliff, they alerted the authorities, who despite the no-rescue policy sent a Royal Norwegian air force helicopter that was training in the area.

Ten hours passed before help arrived. It was nighttime, and despite the midnight sun, the temperature had dropped below zero. Garton was by then in a state of severe hypothermia and had slipped into a coma. His heart stopped several times, requiring 16 defibrillations to be revived during transport to the hospital, where he stayed on life support for three weeks before coming out of the coma.

In the hospital, Garton had to relearn how to do the most basic things, including how to breathe without the help of the ventilator. “When you are paralyzed, everything that you have ever learned as a tiny child, down to brushing your teeth, everything is wiped away,” he says. “You go from where what you are aiming to do this year is to be the first person to climb the highest cliff in Europe and then a few months later the main thing you are trying to achieve is breathe on your own for 10 seconds.”

Garton learned how to control a computer using his voice and in September 2007, just three months after leaving the hospital, he returned to school to earn a master's degree and then a PhD in computational biology at the University of Nottingham.

“I saw disabled people go both ways,” he says. “A lot of people give up. You have to make a choice at some point. Do I keep going or do I give up?”

In 2012, he moved to Toronto with his wife Hannah, who is Canadian. After a brief postdoctoral stint in the lab of Professor Shoshana Wodak, then at the Hospital for Sick Children, Garton joined Associate Professor Philip Kim’s group at U of T’s Donnelly Centre for Cellular and Biomolecular Research.

That experience, he says, helped him become a better scientist. “At Donnelly, I wasn’t treated any different to anybody else, not like I was anything special for being disabled. I was held to the same standards and that helped me to really up my game and become a much better scientist.”

While working with Kim, Garton invented a computational method for designing smart drug molecules that last longer in the body to reduce the frequency of taking medication. The idea came to him after a friend’s toddler was diagnosed with Type 1 diabetes and had to receive daily insulin injections. Garton came up with a way to convert natural protein molecules into their mirror-image forms, which retain the same therapeutic properties but are much longer-lasting.

“I like the feeling of being able to invent something to solve the problem. You are not restricted by what nature is doing. You can be somewhat more creative – you are only limited by what you can imagine you can do.”

Space force: Can the design of research space facilitate collaboration?

noreen.rasbach — Mon, 24 Sep 2018 18:36:57 +0000

Space force: Can the design of research space facilitate collaboration?

noreen.rasbach Mon, 09/24/2018 - 14:36

Cutline

From left, Karmen Brar, Dylan Langburt, Da Nye Kim and Shin-Haw Lee at the translational biology and engineering program (TBEP) lab, U of T’s component of the Ted Rogers Centre for Heart Research

Topic

Institute of Biomaterials and Biomedical Engineering

Research & Innovation

Ted Rogers Centre for Heart Research

When you enter the translational biology and engineering program (TBEP) labs in the west tower of MaRS, there is no telling where one researcher’s space begins or another’s ends. The large airy space, featuring floor-to-ceiling windows and great views of Queen’s Park and hospital row, buzzes with a gentle hum as graduate students and researchers go about their work.

Part of the Ted Rogers Centre for Heart Research, TBEP brings together nine principal investigators (PIs) from engineering, dentistry and medicine to study and treat heart failure. One of those researchers is Professor Michelle Bendeck of the department of laboratory medicine and pathobiology. For most of her career, Bendeck operated her own independent lab in the Medical Sciences Building.

“I was in my concrete box, which was next to other concrete boxes. We would talk at departmental events and occasionally in the halls, but I didn’t necessarily know what equipment my neighbours had, for instance,” says Bendeck. “We literally had to keep our doors closed for health and safety reasons.”

At TBEP, the equipment – though brought into the space by different PIs – is largely communal. And increasingly, the grant applications and graduate student supervision are a shared responsibility.

“My colleagues and I are asking new questions and my interest and enthusiasm for exploring them together is growing as a result,” she says.

It begs the question: How important is the configuration of research space in facilitating research collaborations?

Building the foundation

The sleek glass tower that houses the Donnelly Centre for Cellular and Biomolecular Research, which opened its doors in 2005, was the first to pioneer collaborative laboratory space at U of T. University Professor Brenda Andrews, who is director of the centre, says the concept wasn’t only new to U of T, but relatively unseen elsewhere in the world.

“When we opened, there was really no other centre like ours. With space like ours. We were – we are – doing something different,” she says.

The open concept labs have allowed for a high degree of flexibility and variability. It’s enabled researchers in similar areas – such as computational biology – to cluster together to share equipment and expertise. It’s also allowed some labs to integrate more seamlessly, including her own with Professor Charlie Boone.

“Charlie and I would describe our lab as a joint lab. We share equipment, we explore projects together, we co-supervise many of our students. We’ve become fully integrated,” says Andrews.

Gene genies: How Toronto became became a global hub for genetic research

Collaboration extends throughout the building, with many other PIs co-supervising students or pursuing joint projects. Andrews anticipates that the Donnelly Centre has more co-supervised students than anywhere else in the Faculty of Medicine. That’s fuelled in part by space – including the shared social space outside of the labs – but also the culture that’s been formulated at the centre.

And that was no accident.

“We thought very carefully when we were inviting people to join the Donnelly Centre about who would work well together – and will work well with others,” says Andrews. “And it’s something we think about in our ongoing recruitment.”

But space and people alone are not enough, says Andrews. It also takes funding structures that support collaborative research.

“The Donnelly Centre was the brainchild of Professors Cecil Yip and James Friesen who foresaw the development of genomic technologies,” says Andrews. “And, thanks to new government funding opportunities they saw on the horizon – and the generous support of Terrence Donnelly – we were able to secure the funds to build this centre.

"But, if it were not for changes in grant applications that made it possible to secure collaborative grants, I’m not sure we would be able to operate as we do today."

Renovate. Elevate. Collaborate?

In July 2016, the federal and provincial governments announced $190-million in funding to support the Lab Innovation for Toronto (LIFT) project. By the time it was completed this past spring, 47 per cent of U of T’s research space would be renovated – including 25 per cent of the Medical Sciences Building, which captured $40-million of the total project costs. The renovations broke down the concrete boxes Bendeck described in favour of shared laboratories. Among the occupants of new shared lab space is Professor Paul Hamel of the department of laboratory medicine and pathobiology, who shared space with colleagues Stephen Girardin, Jeffrey Lee and Jeremy Mogridge.

Form follows function

Bendeck agrees with Hamel: Space alone doesn’t enable collaboration. And she agrees with Andrews that even if you put the right people in the right spaces, it won’t be enough unless there is funding to support collaboration.

Yet, she has found that by gathering researchers together with similar interests in shared spaces, new collaborations and new funding have resulted. This includes her work with Professor Paul Santerre, of the Faculty of Dentistry and the Institute of Biomaterials and Biomedical Engineering.

“We’ve both been at U of T for many years but had very little interaction before we both moved to TBEP. I had a lab in [the Medical Sciences Building]. He had a lab in Dentistry. But now we are co-supervising two graduate students. We’ve secured two grants together. I’m not sure that would have happened before,” says Bendeck.

This story first appeared in the Faculty of Medicine's 2018 Dean's Report. Read the report.

New genetic test predicts risk of leukemia relapse

noreen.rasbach — Thu, 13 Sep 2018 18:36:24 +0000

New genetic test predicts risk of leukemia relapse

noreen.rasbach Thu, 09/13/2018 - 14:36

Cutline

Histological view of leukemia cells in smear of a patient’s bone marrow (image via Wikimedia Commons)

Topic

A new test developed by Canadian and Korean scientists and physicians can tell which patients with acute myeloid leukemia (AML) are at risk of relapse – as early as three weeks after they receive treatment.

“In AML, it is very important to predict who is going to relapse,” says Dennis Kim, of the Princess Margaret Cancer Centre at the University Health Network (UHN). The associate professor in U of T’s department of medicine was a co-leader of the study.

“If we are able to identify someone who is at high risk of relapse then we can do therapeutic intervention earlier, which can improve their outcome in the long run.”

The first DNA-based test of its kind, it is administered to patients after they've received a standard course of treatment for AML: chemotherapy, followed by a bone marrow transplant.

“We can detect mutations in patients’ bone marrow cells three weeks after the transplant and based on that predict the likelihood of their relapse,” says Zhaolei Zhang, principal investigator in the �ؿ�ζSM’s Donnelly Centre for Cellular and Biomolecular Research and a professor in the departments of molecular genetics and computer science, who co-led the study.

The findings, published recently in the journal Blood, could help doctors improve patient outcomes by changing the treatment before cancer has returned in full force.

AML is the most common type of leukemia in adults, comprising about one-quarter of all cases. It affects the bone marrow, the spongy tissue inside the bone where all blood cells are made. The disease stems from an overproduction of immature blood cells that over time outgrow normal blood cells. It’s a type of cancer that starts suddenly and progresses quickly, requiring urgent treatment.Treatment involves chemotherapy to wipe out the diseased bone marrow, followed by a bone marrow transplant to reconstitute the patient’s blood with cells from a healthy donor.

While most patients go into remission after chemotherapy, about one-third will relapse three to six months after receiving the transplant.

Jae-Sook Ahn (Chonnam National University Hwasun Hospital, Republic of Korea and a visiting researcher in the Donnelly Centre), Dennis Kim (Princess Margaret Cancer Centre), Zhaolei Zhang (Donnelly Centre) and TaeHyung (Simon) Kim (Donnelly Centre)

Until now, there was no good way to detect the trace amounts of leukemia cells that resisted the treatment and drive relapse. By the time these cells are picked up by available methods, the cancer is usually already at an advanced stage.

Using new DNA sequencing technology called next generation sequencing, or NGS, the team was able to identify the treatment-resistant leukemia cells, or clones, even when they make up a tiny proportion of all cells in the bone marrow. The nature of mutations reveals further clues about how best to target the disease with drugs.

“With our method, not only can we say that this patient will relapse, but we can also say their relapsing clone contains certain mutations which can be a target for therapeutic compounds that can be used to treat the patient,” says Kim.

For the study, the researchers collected 529 bone marrow samples from 104 AML patients who underwent chemotherapy and bone marrow transplants. The samples were collected at different time points: at the time of diagnosis, during the chemotherapy-induced remission, and three weeks after the bone marrow transplant. A subset of patients also gave samples three, six and 12 months after the transplant. Some samples were also taken from bone marrow donors to rule out the possibility that the leukemia cells were introduced by the transplant.

The researchers then identified DNA mutations that were present at the time of diagnosis and looked for those same mutations at each sampling point. They found that while chemotherapy and bone marrow transplant eliminated most leukemia cells, leading to a reduction in mutation frequency, some initial mutations could still be detected three weeks after the transplant, indicating the presence of treatment-resistant cancer cells. As these same mutations expand in frequency upon relapse, the data suggest that the same cancerous cells that started the leukemia are also responsible for the disease comeback.

Data analysis required Zhang’s team to develop new computational tools to parse the leukemia-driving mutations from the sea of sequence data. This allowed them to identify low residual mutation frequency of 0.2 per cent to use as a surrogate marker for giving a personal chance of relapse.

“Patients who had a mutation burden greater than 0.2 per cent were four times more likely to relapse than patients who had a lower burden or no mutation burden,” says TaeHyung (Simon) Kim, a computer science graduate student in Zhang’s lab who analyzed the data along with Joon Ho Moon, from Kyungpook National University Hospital in Korea, and Jae-Sook Ahn, from Chonnam National University Hwasun Hospital in Korea, who is part of Zhang’s lab as visiting professor.

The researchers hope their DNA-based test will become routine for monitoring disease prognosis although they say this could take five to ten years. In some hospitals, DNA tests are becoming routine for diagnosis of AML, but not for predicting prognosis nor guiding treatment plan.

The research was done as a three-sided collaboration between U of T, UHN and the team led by Hyeoung-Joon Kim, president of the Korean Society of Hematology and a professor in the department of hematology-oncology at the Chonnam National University Hwasun Hospital in the Republic of Korea, who oversaw collection and sequencing of patient samples.

The study was supported by research grants from the Natural Science and Engineering Council of Canada, Leukemia and Lymphoma Society of Canada, Princess Margaret Foundation and National Research Foundation of Korea.

U of T grad’s AI startup raises US$1.5 million to accelerate cancer drug discovery

noreen.rasbach — Tue, 19 Jun 2018 04:00:00 +0000

U of T grad’s AI startup raises US$1.5 million to accelerate cancer drug discovery

noreen.rasbach Tue, 06/19/2018 - 00:00

Cutline

Oren Kraus, who receives his PhD on Tuesday, has launched a startup that develops computer vision tools for a faster and more accurate analysis of microscopy data

Topic

Artificial Intelligence

Convocation

Creative Destruction Lab

Donnelly Centre

Faculty of Applied Science & Engineering

Faculty of Medicine

Graduate Students

Innovation & Entrepreneurship

Rotman School of Management

Startups

Oren Kraus took up coding because, by his own admission, he was not cut out for doing experiments in the lab. Now his artificial intelligence-powered startup has raised US$1.5 million to transform biomedical research and drug discovery.

Called Phenomic AI, the startup develops computer vision tools for a faster and more accurate analysis of microscopy data. Its name comes from the word “phenotype,” which biologists use to describe how a cell – and its inner parts – look. The tools developed will help researchers spot subtle differences between cells that could be early signs of disease and identify promising drugs.

“We’re able to apply deep learning to microscopy datasets,” says Kraus, who will receive his PhD on Tuesday. His graduate research was co-supervised by University Professor Brenda Andrews, the director of the Donnelly Centre for Cellular and Biomolecular Research and a pioneer in large-scale cell microscopy research, and Professor Brendan Frey, of the department of electrical and computer engineering. Frey is also a founder of Deep Genomics, a startup using AI for interpretation of genome data.

How dividing cells accurately split their DNA to avoid terrible consequences: U of T study

noreen.rasbach — Fri, 08 Jun 2018 18:27:55 +0000

How dividing cells accurately split their DNA to avoid terrible consequences: U of T study

noreen.rasbach Fri, 06/08/2018 - 14:27

Cutline

A laboratory Petri dish with yeast cells growing (photo by Rainis Venta)

Topic

Research & Innovation

Subheadline

As cells divide, they must accurately split their DNA between the two daughter cells or risk having an uneven number of chromosomes that can lead to developmental disorders and cancer. A new �ؿ�ζSM study uncovers how a key molecular machinery drives this process and offers clues to why some children develop aggressive kidney tumours.

Tina Sing, a PhD student in Professor Grant Brown’s lab in the Donnelly Centre for Cellular and Biomolecular Research and the department of biochemistry, led the study that is published in the Journal of Cell Biology.

Brown likens the genome to an instruction book organized into a set number of chapters, or chromosomes. “It’s important that the number of chapters stay constant,” he says. “It would be bad if you lack instructions for certain processes, but surprisingly, it’s also bad if you have too many instructions.”

Having an extra copy of chromosome 21 leads to Down syndrome, while an absence of one X chromosome will turn women sterile as seen in Turner syndrome. In cancer cells, whole genome duplication followed by haphazard chromosome loss allows tumour cells to accumulate genes that help them outgrow healthy cells.

“When a cell makes a decision to divide it needs to make sure its DNA is equally segregated between both daughter cells,” says Sing, who is now a postdoctoral researcher at the University of California, Berkeley. “The cells must first replicate their DNA and then they have to pull apart these two copies of the DNA so that each daughter cell receives one complete copy of the entire genome.”

Sing uncovered a new role for a known protein machinery called RSC – for “remodels the structure of chromatin” and pronounced as “risk” – in helping separate the duplicated chromosomes equally between daughter cells. RSC does this by helping the formation of the centrosome, a structure that sprouts tiny filaments that grab each set of chromosomes and pulls them apart.

“We found that if cells lack RSC function then this causes abnormal DNA segregation and a spontaneous doubling of chromosome number in cells,” says Sing.

In their experiments, Sing and Brown used budding yeast – the same single-celled microbe that helps bread rise and beer ferment – that showed uncanny resemblance to cancer cells when RSC is no longer working. Besides having a higher number of chromosomes, yeast cells lacking RSC function also have more centrosomes. Whereas heathy cells typically have two centrosomes during cell division, RSC mutants often had many more, making it difficult for them to segregate their chromosomes properly.

Previously, RSC was known for its role in switching genes on and off. Sing’s finding that RSC is also important for DNA segregation was unexpected and ties together with previous findings from other labs to potentially help explain how a form of childhood cancer develops.

Mutations in the human version of RSC also lead to spontaneous increase in chromosome numbers and have been found in rhabdoid tumours, a highly aggressive form of kidney cancer. Also, if mouse cells lose RSC function, they can turn cancerous. However, there was nothing known about RSC that would suggest its involvement in chromosome segregation. Now, thanks to the insights from yeast cells, it is now known that it is possible that RSC has a similar role in humans.

“It’s always surprising to think about how fundamental processes in yeast also take place in humans,” Sing says. “We think that our study gives some insight into this observation in cancer cells and we think it’s possible that this complex is also helping with chromosome segregation in human cells.”

Sing’s finding was serendipitous. When she started working on RSC, her goal was to dig deeper into some of its more conventional roles. It was only after she repeatedly noticed that cells lacking RSC function had twice the normal number of chromosomes that she realized she was onto something unexpected.

“The increase in chromosomes was more interesting than what we were looking for,” she says. “I think the study is a good example of how sometimes when you set out to study a specific biological problem you can be surprised by the data that you find and sometimes just following your curiosity down a different path can lead to understanding another aspect of biology.”

The research was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research.

Cells are like Jenga: U of T study sheds light on how genes work together to keep cells healthy

noreen.rasbach — Thu, 19 Apr 2018 17:58:10 +0000

Cells are like Jenga: U of T study sheds light on how genes work together to keep cells healthy

noreen.rasbach Thu, 04/19/2018 - 13:58

Cutline

(photo by Pixabay)

Topic

Research & Innovation

Subheadline

To understand how cells work, biologists like to take them apart. By removing genes from cells in diverse combinations, researchers have now uncovered how different genes work together to keep cells alive. The research will help scientists understand how faults in multiple genes combine to drive common diseases such as cancer or heart disease.

Led by Charles Boone, a professor at the �ؿ�ζSM’s Donnelly Centre and in the department of molecular genetics, Brenda Andrews, University Professor in the department of molecular genetics and director of the Donnelly Centre, and Chad Myers, a professor at the University of Minnesota Twin Cities, the research builds on the team's previous work that showed how genes combine in pairs to underpin a cell’s health.

The new study, published in the journal Science, examines for the first time how higher-order gene combinations – comprising three genes – help maintain normal cell physiology.

“There’s a growing understanding that interactions between genes can drive inherited disease susceptibility, which is why we have to understand the general principles of these genetic interactions,” said Boone.

It’s very much like a giant game of Jenga, with thousands of gene blocks that can be removed. While most single blocks can be taken out without compromising the structure, when critical combinations of blocks are removed, the system collapses. Similarly, genes with different roles can combine to keep the cell alive. By unpicking such gene alliances, scientists hope to reveal clues about the foundations of personal health.

Removing multiple genes in diverse combinations revealed new gene alliances that keep cells alive (Jovana Drinjakovic)

It’s now clear from genome sequencing studies that each person carries thousands of genetic variants – differences in genes’ DNA sequence – that could combine to impact our health. However, these studies do not have the statistical power to predict a person’s risk of disease from their unique combination of genetic variants. This poses a major obstacle for personalized medicine, which seeks to use genome information to predict risk of disease and tailor treatment.

To uncover the rules of combinatorial gene function, the team previously investigated how genes work in pairs in yeast cells. Yeast is one of biologists’ favourite cell models due to its relatively small genome comprising 6,000 genes and an already existing wealth of data. Having previously removed from yeast all possible gene pairs –18 million of them – the team went a step further to examine what happens when you remove a subset of 36 billion possible trigenic combinations.

Researchers Charles Boone and Brenda Andrews in their lab in the Donnelly Centre, with a custom-built robotic platform for large-scale experiments in cell genetics.

They found that, similar to interactions between two genes, trigenic interactions also mainly occur between genes that are functionally related – they code for parts belonging to the same molecular machine or that exist in the same part of the cell, for example. But with trigenic interactions, the researchers also began to see more surprising partnerships between genes that have unrelated function and are involved in different bioprocesses in the cell.

“Studying genetic networks allows you to see how genes are connected, how biological processes talk to one another and how a cell deals with perturbations in multiple genes,” said Elena Kuzmin, a lead author on the paper and a previous graduate student in the Boone lab who is now a postdoctoral researcher at McGill University in Montreal.

“You get a global view of the cell,” she said.

Read the research in the journal Science

Using mathematical modelling, the researchers estimate that all genes in the cell have a role to play when trigenic interactions are taken into account. This could finally explain why only a tenth of yeast’s 6,000 genes are essential for cell survival, a rule that holds for other cell types, including human cells.

Thanks to recent advances in gene editing, it is now possible to remove combinations of genes from human cells, which the Boone and Andrews labs are currently doing in collaboration with Associate Professor Jason Moffat’s group in the Donnelly Centre to map relationships between disease genes.

“Our yeast work demonstrates how mutations in multiple genes combine to have unexpected effects and is providing a road map for understanding genetic interactions in much more complex cells and organisms, including humans,” said Andrews. “Identifying combinations of genes that work together to underpin robust biological systems is important for deciphering what goes wrong with its collapse into a disease state.”

The study was supported by research grants from the Canadian Institute for Health and Research and the U.S. National Institute of Health.

U of T scholar giving ‘voice’ to marginalized communities among 30 researchers sharing $7.3 million in federal funding

noreen.rasbach — Wed, 11 Apr 2018 04:00:00 +0000

U of T scholar giving ‘voice’ to marginalized communities among 30 researchers sharing $7.3 million in federal funding

noreen.rasbach Wed, 04/11/2018 - 00:00

Cutline

To reach marginalized communities, Syed Ishtiaque Ahmed and his team go out into the field and talk to people to understand their cultures, practices, history and politics – “only then you can design an application that can help them,” he said

Jennifer Robinson

Topic

Our Community

Donnelly Centre

Factor-Inwentash Faculty of Social Work

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Faculty of Dentistry

Faculty of Medicine

Research & Innovation

U of T Mississauga

U of T Scarborough

The cacophony of voices on social media may be deafening but to U of T researcher Syed Ishtiaque Ahmed, the voices of the silent, the marginalized and the fearful are worthy of new platforms designed to meet their needs.

The assistant professor in computer science is one of 30 scholars who are sharing $7.3 million in federal funding announced Wednesday through the Canada Foundation for Innovation’s John R. Evans Leaders Fund.

The money will fund new state-of-the-art equipment, new collaborations and research space.

For Christina Starmans, assistant professor of psychology (pictured left), this means getting a new lab up and running where children and families can meet with her research team as she probes how we come to understand the “self.”

“The �ؿ�ζSM congratulates our researchers – many of them recent recruits to our campuses,” said Vivek Goel, U of T’s vice-president of research and innovation.

“The continuing support from the Government of Canada and the Canada Foundation for Innovation enables us to attract and retain top global scholars like today’s recipients and push towards breakthroughs across an incredible breadth and depth of research areas.”

Originally from Bangladesh, Ahmed arrived at U of T last September, bringing with him his Computing for Voice research project, which fuses computer science and ethnography together to create new technology that enables marginalized people to share their experiences and opinions.

For example, “there are millions of refugees around the world now who keep silent online out of fear,” he said. “Millions of factory workers do not talk about the oppression they experience because they fear they might lose their job.

“In many countries, people cannot freely criticize government decisions. That’s why the data we get over digital platforms are mostly shaped by the powerful entities in our society.”

To reach these communities, he and his team go out into the field and talk to people to understanding their cultures, practices, history and politics – “only then you can design an application that can help them,” said Ahmed.

This has led to the creation of a mobile phone app called Protibadi that enabled women in Bangladesh to combat sexual harassment anonymously. He’s also working with graduate student Dina Sabie on new software tailored for Syrian refugees in Ontario.

Working with Tovi Grossman, who will join U of T's computer science department as an assistant professor this summer, Ahmed will use the federal funding to buy new equipment for a Collaborative Mobile Interaction Workshop that will reduce the need for on-the-ground interactions for people involved in complex projects like building a house.

Instead, drones, robots and humans will work together, requiring a new collaborative way of communicating that is based on the same principles of voice – the technical means of expressing thoughts and listening.

In addition to Ahmed, other U of T researchers receiving funding through the John R. Evans Leaders Fund are:

Syed Ishtiaque Ahmed of the department of computer science for “Collaborative mobile interaction workshop.”
Faezeh Azhari of the department of mechanical and industrial engineering for “Materials characterization system for developing and testing self-sensing cementitious composites.”
Robert Chen of the department of medicine and the University Health Network for “Enabling biomarker identification and treatment optimization for prevalent neurological disorders.”
Kim Connelly of the department of medicine and St. Michael’s Hospital for “Cell therapy for organ repair, restore, regenerate and support (COR3S).”
Laura Corbit of the department of psychology for “Neural control of reward seeking and behavioural control.”
Shelley Craig of the Factor-Inwentash Faculty of Social Work for “Facilitating the resilience of sexual and gender minority youth: An infrastructure to leverage research and technology.”
Christine Démoré of the department of medical biophysics and the Sunnybrook Research Institute for “Microultrasound for diagnosis and image-guided intervention.”
Barbara Fallon of the Factor-Inwentash Faculty of Social Work for “Tracking trajectories for vulnerable children: Using data to understand outcomes.”
Jason Fish of the department of laboratory medicine & pathobiology and the University Health Network for “Novel mechanisms of heart failure: Discovery to translation.”
Cynthia Guidos of the department of immunology and SickKids for “High dimensional single cell immuno-analytic platforms for deciphering immune complexity in health and disease.”
Christina Guzzo of the department of biological sciences, U of T Scarborough for “A viral pathogenesis laboratory for the study of HIV disease and host immunity.”
Baohua Liu of the department of biology, U of T Mississauga for “Synaptic, cellular and circuit mechanisms underlying the cortical control of the optokinetic reflex.”
Sonya MacParland of the departments of laboratory medicine & pathobiology and Immunology, as well as the University Health Network for “Improving outcomes for organ transplantation: A live imaging platform to target immunologic and fibrotic events.”
Massieh Moayedi of the Faculty of Dentistry for “The Centre for Multimodal Sensorimotor and Pain Research.”
Monika Molnar of the department of speech-language pathology for “Neural and physiological correlates of bilingual development across the life span.”
Faiyaz Notta of the department of medical biophysics and the University Health Network for “Cellular and molecular mechanisms underpinning the initiation, progression and metastasis of pancreatic cancer.”
Meaghan O’Reilly of the department of medical biophysics and the Sunnybrook Research Institute for “Ultrasound technology for image-guided interventions in the spine.”
Hui Peng of the department of chemistry for “Infrastructure for the unbiased identification of environmental chemicals and their protein targets.”
Vincent Piguet of the department of medicine and Women's College Research Institute for “Skin immune cells and pathogens facility (SPF).”
Steven Prescott of the department of physiology and SickKids for “Imaging and electrophysiology equipment for multi-neuron stimulation and recording.”
R. Scott Prosser of the department chemical and physical sciences, U of T Mississauga for “Infrastructure for advanced structure and spectroscopic studies of G-protein-coupled receptors.”
Aaron Reinke of the department of molecular genetics for “Infrastructure for the study of microsporidia and the co-evolution of host-pathogen interactions.”
Ho-Sung Rhee of the department of biology, U of T Mississauga for “High-resolution mapping of functional genomic elements in spinal motor neurons.”
Njal Rollinson of the department of ecology and evolutionary biology for “Integration of long-term data and experimental manipulation to study life-history evolution under rapid climate warming.”
Shoshanna Saxe of the department of civil and mineral engineering for “Improving sustainability of urban infrastructure systems.”
John Sievenpiper of the department of nutritional sciences for “Knowledge syntheses and clinical trials of important food sources of sugars and cardiometabolic health.”
Christina Starmans of the department of psychology for “Development of reasoning about the self.”
Hannes Luc Röst Steiner of the Donnelly Centre for Cellular and Biomolecular Research for “High resolution mass spectrometry for longitudinal personalized metabolomics profiling.”
Michael Taylor of the department of laboratory medicine & pathobiology and SickKids for “Oxygen is poison – how incorrect modelling of the human microenvironment has impeded paediatric research.”
Subodh Verma of the department of surgery and St. Michael’s Hospital for “The CardioLink Research Platform: Innovations in cardiovascular surgery & cardiometabolic care.”

Donnelly Centre

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Read the research in the journal Science

U of T scholar giving ‘voice’ to marginalized communities among 30 researchers sharing $7.3 million in federal funding