University Health Network

Institute of Biomedical Engineering

Leah Cowen

Sinai Health

Sunnybrook Health Sciences Centre

Centre for Addiction and Mental Health

Unity Health

Cell and Systems Biology

Anthropology

Astronomy & Astrophysics

Biochemistry

Chemistry

Computer Science

Dalla Lana School of Public Health

Ecology and Evolutionary Biology

Faculty of Arts & Science

Hospital for Sick Children

Laboratory Medicine and Pathobiology

Leslie Dan Faculty of Pharmacy

Mathematics

Physics

Psychology

UTIAS

Subheadline

From better batteries to preventing memory loss, nearly four dozen projects at U of T and its partner hospitals are being supported by the Ontario Research Fund

Researchers in the ��Ƶ’s Thermal Management Systems (TMS) Laboratory are working to improve the way battery systems handle heat and develop structural battery pack components. 

“Whether they are being used for electric vehicles or for stationary energy storage systems that reduce strain on the grid, lithium-ion batteries are transforming the way we use electricity,” said Carlos Da Silva, senior research associate at the TMS Lab in the Faculty of Applied Science & Engineering and executive director of U of T’s Electrification Hub.

“Unfortunately, today’s batteries are still sensitive to temperature: if they get too cold or too hot, it can degrade their performance and even present safety risks. We are working on new technologies that make batteries more resilient to thermal fluctuations.”

The battery-related research is among nearly four dozen projects at U of T and its partner hospitals that are receiving almost $35 million in support through the Ontario Research Fund – Research Excellence (ORF-RE) and the Ontario Research Fund – Small Infrastructure (ORF-SIF). (See the full list of projects and their principal researchers below).

"Research at the ��Ƶ and at all universities and colleges across Ontario is the foundation of the province’s competitiveness now and in the future,” said Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives.

“This investment protects and advances cutting-edge, made-in-Ontario research in important economic sectors and helps ensure universities can continue to train, attract and retain the world’s top talent."

At U of T Engineering’s TMS Lab, researchers led by Cristina Amon, a University Professor in the department of mechanical and industrial engineering, are working on two funded projects. They are developing advanced computational modelling and digital twin methodologies that predict and optimize how heat flows through battery packs. The methodologies are carefully calibrated and validated through industry-relevant experiments in the lab.

Senior Research Associate Carlos Da Silva, left, and University Professor Cristina Amon, right, chat in the Faculty of Applied Science & Engineering's Thermal Management Systems Laboratory (photo by Aaron Demeter)

These methodologies will help battery designers anticipate and prevent thermal management challenges before they arise. It can also enable them to optimize the design and deployment of fire mitigation measures, such as ultra-thin heat barriers, within their battery systems.

The team is also collaborating with Ford Canada and several other companies in the energy storage space. For example, they have worked with Jule (powered by eCAMION) on the development of direct current electric vehicle fast chargers with integrated battery energy storage systems, one of which was recently unveiled on the U of T campus.

“We are grateful for this ORF-RE funding, which will accelerate our research and help us further expand our partnerships, ensuring that battery thermal innovations have a seamless transition from the lab to the marketplace,” Amon said.

“As a result of this work, the next generation of batteries will be safer and more resilient than ever before, which is especially important in colder climates like ours here in Ontario.” 

Ontario Research Fund – Research Excellence:

Cristina Amon in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Powering Ontario’s grid transformation and electric vehicle fast charging with thermally resilient battery energy storage & Next-gen electric vehicle battery systems: Lightweight, thermally performant and fire safe for all climates
Morgan Barense in the department of psychology in the Faculty of Arts & Science – HippoCamera: Digital memory rehabilitation to combat memory loss
Aimy Bazylak in the department of mechanical & industrial engineering in the Faculty of Applied Science and Engineering – RECYCLEAN: Critical minerals recycling & re-manufacturing for the energy transition
Ian Connell at University Health Network and the department of medical biophysics in the Temerty Faculty of Medicine – MRI-compatible innovations for neuromodulation
Simon Graham at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – Technological innovations for clinical MRI of the brain at 7 tesla
Clinton Groth in the Institute for Aerospace Studies in the Faculty of Applied Science & Engineering – Hydrogen as a sustainable aviation fuel – combustion research to remove impediments to adoption in gas turbine engines
James Kennedy at Centre for Addiction and Mental Health and the department of psychiatry in the Temerty Faculty of Medicine – Clinical utility and enhancements of a pharmacogenomic decision support tool for mental health patients
Shaf Keshavjee at University Health Network and the department of surgery in the Temerty Faculty of Medicine – Advanced solutions to human lung preservation and assessment using artificial intelligence
Aviad Levis in the department of computer science in the Faculty of Arts & Science – AI and quantum enhanced astronomy
JoAnne McLaurin at Sunnybrook Health Sciences Centre and the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – Conversion of astrocytes to neurons to treat neurodegenerative diseases of the brain and the eye
R. J. Dwayne Miller in the department of chemistry in the Faculty of Arts & Science – PicoSecond InfraRed Laser (PIRL) “cancer knife” with complete biodiagnostics via spatial imaging mass spectrometry
Javad Mostaghimi in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – A new generation of compact, transportable mass spectrometers for rapid, in-field sample analysi
Xiao Yu (Shirley) Wu in the Leslie Dan Faculty of Pharmacy – Molecular dynamics modeling and screening of excipients for designing amorphous solid dispersion formulations of poorly–soluble drugs

Ontario Research Fund – Small Infrastructure Fund:

Celina Baines in the department of ecology & evolutionary biology in the Faculty of Arts & Science – Impacts of environmental change on organismal movement
Sergio de la Barrera in the department of physics in the Faculty of Arts & Science – Facility for quantum materials and device assembly from atomically thin van der Waals layers
Michelle Bendeck in the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – 4D quantitative cardiovascular physiology centre
Laurent Bozec in the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – 21st Century challenge for Dentistry: Breaking the cycle of irreversible dental tissue loss
Mark Chiew at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – Next generation computational MRI for rapid neuroimaging and image-guided therapy
Haissi Cui in the department of chemistry in the Faculty of Arts & Science – A molecule to mouse approach to study the intracellular localization of genetic code interpretation in mammalian cells
Andy Kin On DeVeale at the University Health Network and the Dalla Lana School of Public Health – Sarcopenia and musculoskeletal interactions (sami) collaborative hub
Ali Dolatabadi in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Advanced cold spray facility
Spencer Freeman at the Hospital for Sick Children and the department of biochemistry in the Temerty Faculty of Medicine – Imaging biophysical determinants of the innate immune response
Liisa Galea at the Centre for Addiction and Mental Health and the Institute of Medical Science in the Temerty Faculty of Medicine – Sex and sex-specific factors influencing brain health across the lifespan
Maged Goubran at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – AI platform for mapping, tracking and predicting circuit alterations in Alzheimer’s disease
Eitan Grinspun in the departments of computer science and department of mathematics in the Faculty of Arts & Science – A computer graphics perspective on entanglement of slender structures
Levon Halabelian in the Department of Pharmacology and Toxicology in the Temerty Faculty of Medicine – Enabling a high-throughput drug discovery pipeline for targeting disease-related human proteins
Ziqing Hong in the department of physics in the Faculty of Arts & Science – Ultra-sensitive cryogenic detector development for dark matter and neutrino experiments
Eno Hysi at the Unity Health Toronto and the department of medical biophysics in the Temerty Faculty of Medicine – Structural and functional assessments of diabetic skin microvasculature using photoacoustic imaging
Lewis Kay in the department of biochemistry in the Temerty Faculty of Medicine – Helium recovery system for the biomolecular NMR facility
Xiang Li in the department of chemistry and the department of physic in the Faculty of Arts & Science – Real-time multi-faceted probes of quantum materials
Qian Lin in the department of cell & systems biology in the Faculty of Arts & Science – 2p-RAM for whole-brain single-neuron imaging of behaving zebrafish to study neural mechanisms of cognitive behaviours
Xilin Liu in the Edward S. Rogers Sr. department of electrical and computer engineering in the Faculty of Applied Science & Engineering – Integrated circuits for wireless brain implants with multi-modal neural interfaces
Stephen Lye at the Sinai Health System and the department of physiology in the Temerty Faculty of Medicine – Healthy Life Trajectories Initiative (HeLTI) analytics platform
Caitlin Maikawa in the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering – Biointerfacing materials for drug delivery lab
Emma Master in the department of chemical engineering & applied chemistry in the Faculty of Applied Science & Engineering – Accelerating biomanufacturing innovation through enhanced capacity for scale-up and downstream bioprocess engineering
Roman Melnyk at the Hospital for Sick Children and the department of biochemistry in the Temerty Faculty of Medicine – The H-SCREEN: A platform for high throughput and high content imaging-based small molecule screens for disease modulation
Juan Mena-Parra in the department of astronomy & astrophysics in the Faculty of Arts & Science – An advanced laboratory to enable novel radio telescopes for cosmology and time-domain astrophysics
Seyed Mohamad Moosavi in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – Machine learning for nanoporous materials design
Enid Montague in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Automation and equity in healthcare laboratory
Michael Norris in the department of biochemistry in the Temerty Faculty of Medicine – Infrastructure for structural and functional virology research hub
Amaya Perez-Brumer in the Dalla Lana School of Public Health – 3P lab: Centering power, privilege and positionality for health equity research
Monica Ramsey in the department of anthropology at the ��Ƶ Mississauga – Ramsey Laboratory for Environmental Archaeology (RLEA): How human-environment interactions shaped plant-food
Arneet Saltzman in the department of cell & systems biology in the in the Faculty of Arts & Science – Heterochromatin regulation in development and inheritance
Mina Tadrous in the Leslie Dan Faculty of Pharmacy – Developing a centre for real-world evidence to improve the use of medications for Canadians
Shurui Zhou in the department of electrical & computer engineering in the Faculty of Applied Science & Engineering – Improving collaboration efficiency for fork-based software development
Olena Zhulyn at the Hospital for Sick Children and the department of molecular genetics in the Temerty Faculty of Medicine – Targeting translation for tissue regeneration and repair
Christoph Zrenner at the Centre for Addiction and Mental Health and the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering – Next-generation real-time closed-loop personalized neurostimulation

Researchers uncover new role for cell’s waste disposal system in spread of pancreatic cancer

Christopher.Sorensen — Tue, 22 Oct 2024 14:02:57 +0000

Researchers uncover new role for cell’s waste disposal system in spread of pancreatic cancer

Christopher.Sorensen Tue, 10/22/2024 - 10:02

Cutline

Associate Professor Leonardo Salmena, post-doctoral researcher Golam Saffi and former master’s student Lydio To investigated the role of a gene called INPP4B in pancreatic cancer’s ability to spread (supplied images)

Betty Zou

Topic

Princess Margaret Cancer Centre

Cancer

A preclinical study is revealing new insights into the molecular machinery that drives the aggressiveness of pancreatic cancer.

The ability of pancreatic cancer to invade and spread to other parts of the body is a major factor in its poor prognosis, with an overall five-year survival rate of less than 10 per cent.

“Pancreatic cancer cells are known to be very metastatic and that’s a big problem,” says Leonardo Salmena, an associate professor of pharmacology and toxicology in the ��Ƶ’s Temerty Faculty of Medicine.

Salmena is the senior author of a study, published in the Journal of Cell Biology, that investigates the role of a gene called INPP4B in pancreatic cancer’s ability to spread. Led by post-doctoral researcher Golam Saffi and former master’s student Lydia To, the team found that INPP4B exerts its tumour-promoting effects via a cellular organ called the lysosome.

“Classically, the lysosome is a garbage disposal organelle where old and tired proteins and other organelles get degraded to be used for energy and other building blocks for the cell,” says Salmena.

In most cells, lysosomes typically cluster around the nucleus. But in pancreatic cancer cells, the researchers found that INPP4B drove the lysosomes from the cell interior to the periphery, where these organelles fuse with the cell’s outer membrane. In doing so, the enzymes and other lysosomal factors responsible for breaking down cellular waste are dumped into the space surrounding the tumour cells.

This space contains a network of proteins and molecules that provides crucial structural support to cells and tissues while also restricting a cell’s ability to move. The release of the lysosome’s protein-degrading contents into this extracellular space causes the stabilizing network to fall apart, thus making it easier for pancreatic cancer cells to migrate and invade other tissues.

Crucially, Salmena and his team also identified the signalling pathway by which INPP4B drives the movement of lysosomes to the cell edge. INPP4B works with two other proteins – PIKfyve and TRPML-1 – to modify the lysosome’s surface structure and alter local calcium levels so that the organelle is propelled to the cell periphery.

Based on these findings, the researchers are testing two experimental drugs that target TRPML-1 and PIKfyve in a preclinical model of pancreatic cancer. They are also studying how the release of lysosomal contents can change the immunological environment of the cancer cells, and what effects that might have on the immune system’s ability to respond to the tumour.

Salmena first became interested in INPP4B when, during his post-doctoral research, he found that it was involved in breast cancer. Since then, he and his team have shown that the effects of INPP4B vary depending on the context.

For example, in some breast cancer types, INPP4B behaves as a tumour suppressor whereas it has an activating role in other aggressive cancers like pancreatic cancer – which the Canadian Cancer Society expects to be the third leading cause of cancer death in Canada in 2024, with an estimated 6,100 people dying from the disease.

Salmena and his colleagues later showed that among all cancers, INPP4B levels are highest in pancreatic tumours, and that high levels of the protein are associated with decreased overall survival in people with pancreatic cancer.

The study was a collaboration between Salmena’s group, Roberto Botelho, a professor of chemistry and biology at Toronto Metropolitan University, and Steven Gallinger, a hepatobiliary and pancreatic surgical oncologist and clinician-scientist at Princess Margaret Cancer Centre, University Health Network and a professor of surgery and laboratory medicine and pathobiology in Temerty Medicine. He is also director of the PanCuRx Translational Research Initiative at the Ontario Institute for Cancer Research.

The study was supported by the Cancer Research Society and the Canadian Institutes of Health Research.

Congratulations pour in for ��Ƶ after Nobel win

mattimar — Tue, 08 Oct 2024 19:43:16 +0000

Congratulations pour in for ��Ƶ after Nobel win

mattimar Tue, 10/08/2024 - 15:43

Cutline

(Photo by Johnny Guatto/��Ƶ)

Mariam Matti

Topic

Faculty of Arts & Science

Alumni

Artificial Intelligence

Computer Science

Vector Institute

Subheadline

“You always knew when Geoff had a new idea. The excitement, the joy radiated out of his office down the hall. The air was buzzing with possibility"

Reactions to ��Ƶ’s Nobel Prize win began almost immediately after it was announced Tuesday morning.

Known as the “godfather of AI,” the University Professor Emeritus of computer science at the ��Ƶ shared the Nobel Prize in Physics with John J. Hopfield of Princeton University for groundbreaking work that laid the foundation for machine learning using artificial neural networks.

U of T’s ��Ƶ and Princeton’s John J. Hopfield are pictured during the announcement for the 2024 Nobel Prize in Physics (photo by Jonathan Nackstrand/AFP via Getty Images)

At U of T, students, faculty and staff gathered at an event hosted by the department of computer science in the Faculty of Arts & Science, which Hinton joined as a professor in 1987.

Those in attendance described a revered and beloved figure, citing Hinton’s determination, playful approach to research and excitement for new ideas.

"I really don’t think there’s anyone more deserving of this recognition," said Chris Maddison, assistant professor in U of T’s departments of computer science and statistical sciences, and one of Hinton’s former students.

"Geoff was a fantastic adviser. He worked really, really hard to remove the barriers for his students and he was laser focused on ideas and building his own understanding."

Hinton also received congratulations from universities and other research organizations around the world, including the Royal Society, the Alan Turing Institute and Cambridge University, Hinton’s alma mater.

Meanwhile, friends, colleagues and leaders in politics and business took to social media to express their congratulations for Hinton’s remarkable achievement.

Here’s a snapshot of what some of them said:

From left: Melanie Woodin, Chris Maddison, Nick Frosst, Kevin Swersky and Eyal de Lara (photo by Johnny Guatto)

“Congratulations to ��Ƶ on this fantastic recognition which is a testament to the importance of supporting basic research and the long journey that can lead to profound discoveries like deep learning that forever change our world. Hinton's phenomenal work has seeded new and innovative research by his former students and many around the world who are using AI to solve global challenges in areas like medicine and climate change.“

– Leah Cowen, vice-president, research and innovation, and strategic initiatives at U of T

“I would say his approach to science has stuck with me. Everything I know about how to do science, I mostly learned from him. It's his curiosity and playfulness ... that has been most impactful. I would also say his thoughtfulness, thinking about the consequence of the technology and how it affects society is something that we have taken seriously at Cohere as well.”

– Nick Frosst, U of T alumnus and co-founder of Cohere

“You always knew when Geoff had a new idea. The excitement, the joy radiated out of his office down the hall. The air was buzzing with possibility. He was famous for bursting into a room and pronouncing that, he now finally, after all these years, understood how the brain worked. Above all, he understood that research was a human endeavor. Research is really hard. It becomes personal. It's intertwined with tragedies and compromises. I saw him go through some of his own when I was a student in the group, and I went through my own. I remember when I was going through some health challenges, I went to him and I said, 'Geoff, sometimes it's really hard to go on.’ And he looked at me and he said, ’But we're not going to let that slow us down, will we?’"

– Chris Maddison, assistant professor in U of T’s departments of computer science and statistical sciences, Faculty of Arts & Science

U of T is the only computer science department with a Nobel Prize winner, says Professor Michael Brudno (photo by Johnny Guatto)

“It's a once-in-a-lifetime opportunity to celebrate an award for somebody who has made huge contributions – obviously in AI broadly, [and] to this department. No other computer science department can say that they have a Nobel Laureate. But I think beyond that, it really goes back to show how the birthplace of modern AI is Toronto, how this is the place where it all started and how it's upon us as the AI faculty in this department to continue this legacy.”

– Michael Brudno, professor in U of T’s department of computer science, acting vice-dean, graduate education in Faculty of Arts & Science, a chief data scientist at University Health Network and a faculty member at the Vector Institute

��Ƶ shares a laugh with fellow AI researcher Raquel Urtasun, left, at the Vector Institute’s opening in 2017 (photo by Lisa Lightbourn)

"Geoff is the most influential person in AI, and our field would certainly not be the same without his immense contributions. He is also a tremendous educator, and has mentored many students and postdocs who have gone on to become very influential in the field of AI. Geoff cares deeply about the Toronto and Canadian ecosystem and was the driving force in the formation of the Vector Institute, which we co-founded together. Through our time as colleagues at the ��Ƶ, I've deeply admired his commitment to the advancement of AI for good. This recognition is well-deserved and acknowledges his decades of work leading AI innovation and building the foundation for the AI revolution that is happening today.”

– Raquel Urtasun, professor in U of T’s department of computer science, faculty member and co-founder at the Vector Institute, founder and CEO of Waabi

“I was the first to call Geoff Hinton “Godfather of Deep Learning,” which later became “Godfather of AI.” Thrilled to see him win the Nobel prize together with John Hopfield for AI. Congrats @geoffreyhinton.”

– Andrew Ng, co-founder of Coursera, founder GoogleBrain, former chief scientist at Baidu

Prime Minister Justin Trudeau speaks with ��Ƶ at a 2019 event (photo by Nick Iwanyshyn)

“Dr. Hinton is a stalwart in his field. Celebrated as one of the ‘Godfathers of AI’, he brings decades of leading expertise in AI research as a Professor Emeritus at the ��Ƶ’s Department of Computer Science, and the current Chief Scientific Advisor at the Vector Institute in Toronto – one of our three national AI institutes. Dr. Hinton is also an outspoken advocate for the responsible development and adoption of AI, educating the world about the benefits and challenges this technology poses.

“Canada is at the forefront of AI technology thanks to trailblazers like Dr. Hinton. His curiosity for discovery and contributions to innovation will inspire generations to come. On behalf of all Canadians, I congratulate him on his remarkable achievement.”

– Justin Trudeau, Prime Minister of Canada

A.M. Turing Award winners Yann LeCun, left, Yoshua Bengio, middle, and ��Ƶ at an AI summit in Montreal (photo courtesy of RE•WORK)

"@HopfieldJohn and @geoffreyhinton, along with collaborators, have created a beautiful and insightful bridge between physics and AI. They invented neural networks that were not only inspired by the brain, but also by central notions in physics such as energy, temperature, system dynamics, energy barriers, the role of randomness and noise, connecting the local properties, e.g., of atoms or neurons, to global ones like entropy and attractors. And they went beyond the physics to show how these ideas could give rise to memory, learning and generative models; concepts which are still at the forefront of modern AI research. Their ideas inspired me so profoundly that I decided to choose learning in neural networks for my own research as a graduate student. They motivated me to look for abstract principles that could be as simple as the laws of physics, but could explain biological as well as artificial intelligence. I'm truly delighted for them and for our field."

– Yoshua Bengio, professor at Université de Montréal and co-winner of the A.M Turing Award with ��Ƶ and Yann LeCun

“It was the first thing I saw in the morning. I opened my phone, and it was the headline of The New York Times and I was like, ‘Yes!’ I was very excited. I saw his perseverance – he always goes with what he believes, not what the flow is – and it's quite inspirational for me. That’s what I look for, especially in the health care area. I want to do something meaningful, something big.”

–Tina Behrouzi, second year PhD student in U of T’s department of computer science

��Ƶ poses with graduate students Ilya Sutskever, left, and Alex Krizhevsky, right, in 2013 (photo by Johnny Guatto)

“Congratulations to @geoffreyhinton for winning the Nobel Prize in physics!!”

– Ilya Sutskever, U of T alumnus, co-founder of OpenAI and co-founder and chief scientist at Safe Superintelligence

“Going to Geoff’s office was always fun. Normally when you go to a supervisor's office, you give them a progress update. You go through what your latest results are, you talk about a couple of your ideas and you get some feedback. Going to Geoff’s office was a completely different story. He would be telling you what his latest idea was. He would show you his latest results. And his whole thing was just that he was really excited about it, and his hope was to inspire you enough to start running with it.”

– Kevin Swersky, U of T alumnus and research scientist at Google DeepMind

“[Hinton's] pioneering research at the ��Ƶ not only revolutionized the field of AI but has also been instrumental in establishing Canada as a global powerhouse in AI research and innovation."

– Tony Gaffney, president and CEO of the Vector Institute

Fei-Fei Li and ��Ƶ speak at a 2023 event in Toronto (photo by Polina Teif)

“This is beyond exciting! #AI’s far reaching impact is just beginning.”

– Fei-Fei Li, professor of computer science at Stanford University and co-director of Stanford’s Human-Centered AI Institute

“Congratulations to @geoffreyhinton, University Professor Emeritus at@UofT, on winning the 2024 Nobel Prize in Physics! Widely regarded as the “godfather of AI,” Hinton’s pioneering work in artificial neural networks has transformed the global AI landscape. Dr. Hinton’s achievement highlights the best of #Ontario’s world-class talent and thriving AI ecosystem, driving innovation and shaping the future of critical #technology!

– Victor Fedeli, Ontario’s minister of economic development, job creation and trade

"On behalf of the Department and the University, we are very proud to acknowledge Geoff's global achievements and this international recognition. His contributions to machine learning and artificial intelligence have benefited virtually every discipline in science, engineering, social sciences and medicine. As we celebrate the department’s 60th anniversary, this award embodies six decades of impact and innovation in computer science and technology.”

– Eyal de Lara, professor and chair of U of T’s department of computer science, Faculty of Arts & Science

“Heartfelt congratulations to Geoff Hinton @geoffreyhinton on winning the Nobel Prize! What an incredible honor! I feel deeply privileged to have had the opportunity to be your PhD student, work with you, and learn from you.”

– Russ Salakhutdinov, professor of computer science at Carnegie Mellon University

Hinton approached his research with an “almost childlike playfulness,” says Graduate student Ujan Sen (photo by Johnny Guatto)

“Waking up today, seeing that news, just motivates me even more and reaffirms the decision that coming to U of T was the absolutely the best decision I could have taken. I think one of the people who had previously worked with him mentioned something along the lines of: Geoff didn't really care too much about pedigree. He cared about ideas, regardless if you have a master's or PhD. And the way he approached his research and the almost childlike playfulness and innocence he had with sort of getting to the answer is something that I really resonate with.”

– Ujan Sen, master’s student in U of T’s department of computer science, Faculty of Arts & Science

"I want to extend my heartfelt congratulations to Dr. ��Ƶ on winning the 2024 Nobel Prize in Physics. His groundbreaking work in machine learning has made Canada world-renowned in the field of AI. He is a true inspiration for the next generation of Canadian researchers!"

– François-Philippe Champagne, Canada’s minister of innovation, science and industry

“I’m originally a chemist. It was a surprising thing for me that a Nobel Prize is being awarded to a computer scientist. This is a big moment for computer science. I think it will bring recognition to physics-based approaches and core thinking.

“I think it’s great that some universities like U of T are willing to believe in crazy ideas. People need to encourage outside-the-box thinking.”

– Ella Rajaonson, PhD student in the Matter Lab with U of T professor Alán Aspuru-Guzik

“Congratulations!”

– Olivia Chow, mayor of Toronto

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen — Mon, 16 Sep 2024 15:02:15 +0000

Researchers develop new method for delivering RNA and drugs into cells

Christopher.Sorensen Mon, 09/16/2024 - 11:02

Cutline

PhD candidate Kai Slaughter, left, and University Professor Molly Shoichet are exploring how ionizable drugs can be used to co-formulate small interfering RNA (siRNA) for more effective intracellular delivery (supplied images)

Qin Dai

Topic

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Donnelly Centre for Cellular & Biomolecular Research

Subheadline

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

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

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

The team – including Molly Shoichet, the study’s corresponding author and a University Professor in U of T’s department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – specifically targeted drug-resistant cells with the delivery of a relevant siRNA. The siRNA was discovered study co-author and collaborator David Cescon, a clinician scientist at the Princess Margaret Cancer Centre, University Health Network, and an associate professor in U of T’s Temerty Faculty of Medicine.

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

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

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

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

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

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

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

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

Institute of Biomedical Engineering

Toronto General Hospital

Donnelly Centre for Cellular & Biomolecular Research

Subheadline

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

Researchers at the ��Ƶ 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.

Researchers propose biologically based classification system for Parkinson’s disease

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

Researchers propose biologically based classification system for Parkinson’s disease

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

Cutline

The "SynNeurGe" classification system for Parkinson's disease, proposed by researchers led by Professor Anthony Lang of the University Health Network and U of T, is based on three key biomarkers (photo by FG Trade/Getty Images)

Eileen Hoftyzer

Topic

Department of Medicine

Tanz Centre for Research in Neurodegenerative Diseases

Parkinson's

Subheadline

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

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

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

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

Professor Anthony Lang (supplied image)

“This is a complex group of disorders that may cause similar symptoms, but biologically they're very different,” says Lang, a senior scientist and Lily Safra Chair in Movement Disorders at UHN and a professor in the department of medicine and the Tanz Centre for Research in Neurodegenerative Disease at U of T’s Temerty Faculty of Medicine, where he holds the Jack Clark Chair for Parkinson’s Disease Research

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

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

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

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

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

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

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

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

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

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

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

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

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

U of T community members recognized with Order of Canada

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

U of T community members recognized with Order of Canada

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

Cutline

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

Adina Bresge

Topic

Institute of Health Policy Management and Evaluation

Unity Health

Alumni

Chemistry

Dalla Lana School of Public Health

Faculty of Arts & Science

Faculty of Music

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Order of Canada

Political Science

St. Michael's College

University College

Victoria College

Subheadline

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

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

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

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

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

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

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

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

Current and former faculty

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

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

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

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

Daphne Maurer, a professor emeritus of psychology, neuroscience and behaviour at McMaster University who holds a status appointment at U of T’s Institute of Health Policy Management and Evaluation in the Dalla Lana School of Public Health, was appointed an Officer of the Order for her research on visual and cognitive development in early childhood.

Linda Rabeneck, a gastroenterologist, health executive and professor in the Temerty Faculty of Medicine and the Dalla Lana School of Public Health, was named a Member of the Order for her leadership in colorectal cancer screening and prevention. Formerly the director of the Division of Gastroenterology at U of T, she led the rollout of ColonCancerCheck, Canada’s first province-wide screening program.

Stephen Randall, who earned his master's degree and doctorate at U of T and taught at the university from 1971 to 1974, was named a Member of the Order for his academic contributions and advisory role in international relations. A professor emeritus at the University of Calgary, Randall’s expertise in myriad issues affecting the United States and Latin America, notably Colombia, has informed Canada’s foreign policy.

Bibudhendra Sarkar, senior scientist emeritus at the Research Institute of the Hospital for Sick Children and professor emeritus at U of T’s department of biochemistry in the Temerty Faculty of Medicine, was named a Member of the Order for his achievements in advancing medical research in Canada and abroad. He discovered a novel treatment for patients with Menkes disease, a rare genetic condition, and led international efforts in South and Southeast Asia to address public health crises from contaminated groundwater.

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

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

Alumni and friends

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

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

Martha Friendly, who founded the Childcare Resource and Research Unit at U of T’s Centre for Urban and Community Studies in the early 1980s, was appointed an Officer of the Order for her work with the now-independent non-profit and her advocacy for accessible, publicly funded early childhood education and care, and women’s equality.

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

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

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

James David Meekison, with a 45-year career spanning investment banking, cable television and private equity, was named a Member of the Order for his extensive philanthropy. The Jim Meekison and Carolyn Keystone Foundation supported U of T’s Leslie Dan Faculty of Pharmacy’s efforts to launch the Discovery Pharmacy on the St. George campus.

Michael Perley, a U of T alumnus who completed a master’s degree in French language and literature, was named a Member of the Order for his lifelong dedication to tackling environmental and health challenges. He has been an advocate for tighter tobacco control laws, reducing second-hand smoke exposure and has led coalitions on acid rain and air pollution.

Dan Poenaru, a pediatric surgeon and professor at McGill University who earned two degrees at U of T, was named a Member of the Order for his contributions to pediatric surgery in Africa, including establishing a surgical unit and training program in Kenya, co-founding three medical schools and leading initiatives for children's surgery globally.

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

– with files from Mariam Matti and Rahul Kalvapalle

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

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

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

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

Cutline

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

Misty Pratt

Topic

Sunnybrook Health Sciences Centre

Subheadline

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

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

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

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

“We wanted to challenge the binary approach of comparing female and male clinicians and rather highlight the importance of diversity as a team asset or bonus in enhancing quality care,” says lead author Julie Hallet, a scientist with ICES and Sunnybrook Research Institute, and associate professor of surgery at U of T’s Temerty Faculty of Medicine.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cutline

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

Erin Howe

Topic

Princess Margaret Cancer Centre

Laboratory Medicine and Pathobiology

Resarch & Innovation

Cancer

Subheadline

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

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

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

“We think this research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells,” said Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology in U of T’s Temerty Faculty of Medicine.

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

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

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

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

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

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

The answer is both surprising and elegant.

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

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

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

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

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

The findings have significant implications for some cancer treatments.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

U of T, hospitals launch pilot program to boost commercialization of medical innovations

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

U of T, hospitals launch pilot program to boost commercialization of medical innovations

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

Cutline

(photo by Daria Perevezentsev)

Rahul Kalvapalle

Topic

Institutional Strategic Initiatives

Acceleration Consortium

Sunnybrook Health Sciences Centre

Artificial Intelligence

Department of Chemistry

Department of Computer Science

Entrepreneurship

Faculty of Art & Science

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Startups