Institute of Biomedical Engineering

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

Breaking Research

Institute of Biomedical Engineering

Princess Margaret Cancer Centre

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Research & Innovation

University Health Network

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 Temerity Faculty of Medicine.

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

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

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

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

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

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

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

Research team explores next-gen vaccines to guard against sexually transmitted infections

Christopher.Sorensen — Wed, 04 Sep 2024 16:07:53 +0000

Research team explores next-gen vaccines to guard against sexually transmitted infections

Christopher.Sorensen Wed, 09/04/2024 - 12:07

Cutline

Aereas Aung, an assistant professor in the Institute of Biomedical Engineering , is developing new tools to study and manipulate immune cells and their reaction to vaccines (photo by Tim Fraser)

Qin Dai

Topic

Breaking Research

Institute of Biomedical Engineering

Connaught Fund

Faculty of Applied Science & Engineering

Research & Innovation

Vaccines

Subheadline

"This work could lay the foundation for more effective vaccines that curb the spread of STIs, particularly in marginalized communities disproportionately affected by these diseases”

A research team from the ��Ƶ is creating a new generation of vaccines that aims to overcome key hurdles faced by some existing formulations.

For example, a common shortcoming of many traditional vaccines is that they can’t produce antibodies in tissues where sexually transmitted infections (STIs) often enter the body.

“Most current vaccines fail to produce sufficient antibodies within mucosal tissues, leaving a significant gap in our defense against sexually transmitted infections,” says Aereas Aung, an assistant professor at the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering who is leading the research effort.

“Our goal is to develop a novel strategy that leverages the strengths of parenteral vaccination while also targeting the mucosal immune system.”

Normally vaccines are injected parenterally, meaning it is injected into or under the skin, into the muscle or directly into the bloodstream. The vaccine then travels to lymph nodes, which are small glands that help produce antibodies. Mucosal tissues in the cervix and rectum present a unique challenge since the mucus in these areas can break down the vaccine quickly and wash it away, making it difficult to reach the lymph nodes and be effective.

Aung’s research proposes fusing a protein carrier to the disease antigens, allowing it to reach distant mucosal lymph nodes after injection.

“We aim to incorporate potent immunostimulatory components into our antigen construct, optimizing its distribution and enhancing mucosal antibody responses,” says Aung.

“If successful, this work could lay the foundation for more effective vaccines that curb the spread of STIs, particularly in marginalized communities disproportionately affected by these diseases.”

Aung’s project is one of 51 U of T faculty members whose work is being supported by the Connaught New Researcher Awards in the most recent round – and one of eight at U of T Engineering. The award helps early-career faculty members establish their research programs.

The other U of T Engineering researchers whose projects are supported by the award are: 

Mohammed Basheer, department of civil and mineral engineering – Integrated hydrological-statistical method and tool for landslide susceptibility mapping in a changing climate
Daniel Franklin, Institute of Biomedical Engineering – Development of equitable pulse oximeters
Sarah Haines, department of civil and mineral engineering – Open Plenums & Indoor Environments (OPEN): Evaluating the impact of return air systems on indoor environmental quality
Mark Jeffrey, Edward S. Rogers Sr. department of electrical and computer engineering – Productively surmounting the memory wall with task parallelism
Caitlin Maikawa, Institute of Biomedical Engineering – Affinity-directed dynamic polymer materials for biomarker sensing
Mohamad Moosavi, department of chemical engineering and applied chemistry – Learning the Language of Metal-Organic Frameworks Topology
Cindy Rottmann, Institute for Studies in Transdisciplinary Engineering Education and Practice (ISTEP) – But I could be fired! How early career engineers hold the public paramount from organizationally subordinate locations

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

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

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

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

Cutline

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

Qin Dai

Topic

Breaking Research

Institute of Biomedical Engineering

Toronto General Hospital

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Research & Innovation

University Health Network

Subheadline

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

Researchers at the ��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.

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

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

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

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

Cutline

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

Betty Zou

Topic

Breaking Research

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Unity Health

Alumni

Faculty of Applied Science & Engineering

Leslie Dan Faculty of Pharmacy

Research & Innovation

University Health Network

Subheadline

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

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

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

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

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

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

The first-of-its-kind model builds on previous work led by Milica Radisic, Lu’s PhD adviser, a senior scientist at University Health Network and a U of T professor of biomedical engineering. The approach uses a lab-made network of blood vessels surrounded by heart tissues grown from stem cells to mimic a real human heart with its tangle of vessels going in and out.

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

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

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

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

Working with Claudia dos Santos, a scientist and critical care doctor at Unity Health Toronto, associate professor of medicine and Pitts Research Chair in Acute Care and Emergency Medicine at U of T’s Temerty Faculty of Medicine, the researchers then asked whether the presence of freely circulating mitochondrial DNA is also seen in patients experiencing COVID-19-induced heart complications.

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

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

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

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

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

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

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

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

U of T researchers develop rapid MRI technique for better cancer detection and therapy

Christopher.Sorensen — Fri, 23 Feb 2024 19:30:43 +0000

U of T researchers develop rapid MRI technique for better cancer detection and therapy

Christopher.Sorensen Fri, 02/23/2024 - 14:30

Cutline

(photo by Willie B. Thomas/Getty Images)

Matthew Tierney

Topic

Breaking Research

Institute of Biomedical Engineering

Cancer

Electrical & Computer Engineering

Faculty of Applied Science & Engineering

Research & Innovation

Subheadline

“We create images every second, and sometimes less, and those images are not going to suffer from low resolution”

Researchers at the ��Ƶ’s Faculty of Applied Science & Engineering have developed a rapid magnetic resonance imaging (MRI) technique to help doctors better detect and diagnose tumours.

The new approach – by Hai-Ling Cheng, a professor in the Institute of Biomedical Engineering and the Edward S. Rogers Sr. department of electrical and computer engineering, and PhD candidate Alex Mertens – could provide physicians with guidance during surgery and other therapeutic interventions.

Based on novel analysis of raw patient data collected from imaging sessions with standard MRI equipment, the algorithm Cheng and Mertens developed reduces the duration between each image acquisition from more than 20 seconds to one second without sacrificing image sharpness.

“People in the field have been trying to get high spatial resolution concurrently with temporal resolution for the past 25 years,” says Cheng.

Cheng and Mertens, with the help of the U of T Innovations and Partnerships Office, have applied for a patent and are partnering with companies to bring their MRI technique to market.

“In practice, doctors always follow up imaging results with a biopsy for definitive confirmation to more accurately determine the grade of cancer and its stage,” Cheng says.

“Our technique is not meant to displace the biopsy. But by better characterizing the underlying pathology at the vascular and cellular level, we can mitigate randomness in the sampling when the doctor goes in with a biopsy needle.”

Professor Hai-Ling Cheng, pictured, and ECE PhD candidate Alex Mertens have developed a novel method to analyze data acquired from magnetic resonance imaging (photo by Matthew Tierney)

MRI is used to scan soft tissues like muscle or fat because it offers the best contrast compared to other modalities such as X-rays and ultrasounds. The contrast allows doctors to discern different cell types and identify small cancerous growths.

“Let’s say you’ve got a liver and a kidney, and you want to image them both in the same area of the body,” says Cheng. “If you were to take an X-ray, you would get one contrast level – one grey scale specific to the liver and one grey scale specific to the kidney.”

With MRI technology, however, there’s different physics at play that allows for refined gradients. An MRI scanner produces a strongly magnetized field inside the patient’s body into which it pulses a radio frequency, or RF, wave. The wave affects the water protons in soft tissues, which react to the pulse and emit signature return signals.

“The data from the return signal doesn’t tell you the shape of an object but the frequency content of the object,” says Cheng. “We structure that return RF signal into a matrix, which we can then convert into a high resolution image.”

Researchers can change the magnetic strength and the frequency of the pulse to obtain different contrasts, much like a music producer can increase and decrease the volume of individual tracks in a song.

To enhance the RF signal further, a contrast agent is intravenously injected into the patient beforehand: usually gadolinium, which is non-radioactive. The dynamics of the gadolinium distribution – that is, the speed of its uptake and washout in cells – give doctors additional information about the malignancy of the tumour.

“Tumours not only have a larger blood volume, but because their blood vessels are very messed up and tortuous, they also tend to be very, very leaky,” says Cheng.

However, the MRI procedure is notoriously slow. The scanner must repeatedly acquire frequency domain data at different coarse and fine-grain resolutions. Typical temporal resolution is 20 seconds and gadolinium washout in a tumour can take as little as 10 seconds.

“Typically, it takes 256 acquisition lines to create one image,” says Cheng. “Rather than reconstructing a full image every 20 seconds or every minute – that’s kind of pointless, because you’re missing the dynamics – our algorithm extrapolates information based on successive sampling of just one acquisition line.

“We create images every second, and sometimes less, and those images are not going to suffer from low resolution.”

“The work that Hai-Ling and her team are doing is a testament to how electrical and computer engineering technologies can impact the health-care sector,” says Professor Deepa Kundur, chair of the electrical and computer engineering department in the Faculty of Applied Science & Engineering. “Hai-Ling and Alex have spent years building on their knowledge of MRI physics and human biology, demonstrating how interdisciplinary perspectives in engineering save lives. Well done.”

U of T researchers' AI model designs proteins to deliver gene therapy

Christopher.Sorensen — Mon, 29 Jan 2024 18:44:19 +0000

U of T researchers' AI model designs proteins to deliver gene therapy

Christopher.Sorensen Mon, 01/29/2024 - 13:44

Cutline

Michael Garton, left, an associate professor of biomedical engineering, and PhD candidate Suyue Lyu, right, used AI to custom-design variants of hexons that are distinct from natural sequences to help evade the immune system (photo by Qin Dai)

Qin Dai

Topic

Breaking Research

Institute of Biomedical Engineering

Artificial Intelligence

Faculty of Applied Science & Engineering

Gene Therapy

Graduate Students

Research & Innovation

Subheadline

Dubbed ProteinVAE, the model can be trained to learn the characteristics of a long protein using limited data

Researchers at the ��Ƶ used an artificial intelligence framework to redesign a crucial protein involved in the delivery of gene therapy.

The study, published in Nature Machine Intelligence, describes new work optimizing proteins to mitigate immune responses, thereby improving the efficacy of gene therapy and reducing side effects.

“Gene therapy holds immense promise, but the body’s pre-existing immune response to viral vectors greatly hampers its success. Our research zeroes in on hexons, a fundamental protein in adenovirus vectors, which – but for the immune problem – hold huge potential for gene therapy,” says Michael Garton, an assistant professor at the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering.

“Immune responses triggered by serotype-specific antibodies pose a significant obstacle in getting these vehicles to the right target; this can result in reduced efficacy and severe adverse effects.”

To address the issue, Garton’s lab used AI to custom-design variants of hexons that are distinct from natural sequences.

“We want to design something that is distant from all human variants and is, by extension, unrecognizable by the immune system,” says PhD candidate Suyue Lyu, who is lead author of the study.

Traditional methods of designing new protein often involve extensive trial and error as well as mounting costs. By using an AI-based approach for protein design, researchers can achieve a higher degree of variation, reduce costs and quickly generate simulation scenarios before homing in on a specific subset of targets for experimental testing.

While numerous protein-designing frameworks exist, it can be challenging for researchers to properly design new variants because of the lack of natural sequences available and hexons’ relatively large size – consisting, on average, of 983 amino acids.

With this in mind, Lyu and Garton developed a different AI framework. Dubbed ProteinVAE, the model can be trained to learn the characteristics of a long protein using limited data. Despite its compact design, ProteinVAE exhibits a generative capability comparable to larger available models.

“Our model takes advantage of pre-trained protein language models for efficient learning on small datasets. We also incorporated many tailored engineering approaches to make the model suitable for generating long proteins,” says Lyu, adding that ProteinVAE was intentionally designed to be lightweight. “Unlike other, considerably larger models that demand high computational resources to design a long protein, ProteinVAE supports fast training and inference on any standard GPUs. This feature could make the model more friendly for other academic labs.

“Our AI model, validated through molecular simulation, demonstrates the ability to change a significant percentage of the protein’s surface, potentially evading immune responses.”

The next step is experimental testing in a wet lab, Lyu adds.

Garton believes the AI-model can be utilized beyond gene therapy protein design and could likely be expanded to support protein design in other disease cases as well.

“This work indicates that we are potentially able to design new subspecies and even species of biological entities using generative AI,” he says, “and these entities have therapeutic value that can be used in novel medical treatments.”

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

With heart-on-a-chip, researchers study genetic mutation underlying cardiac muscle disease

Christopher.Sorensen — Tue, 09 Jan 2024 16:44:17 +0000

With heart-on-a-chip, researchers study genetic mutation underlying cardiac muscle disease

Christopher.Sorensen Tue, 01/09/2024 - 11:44

Cutline

Professor Milica Radisic and U of T alumna Marianne Wauchop developed a heart-on-a-chip device to study the effects of a genetic mutation that causes dilated cardiomyopathy (supplied images)

Anika Hazra

Topic

Breaking Research

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Research & Innovation

University Health Network

Subheadline

Device was used to observe the effects of a sodium channel mutation that disrupts regular electrical activity in the heart

Researchers at the ��Ƶ and its partner hospitals have led the development of a heart-on-a-chip device to study the effects of a genetic mutation that causes dilated cardiomyopathy, a heart muscle disease that impairs blood flow throughout the body.

While it’s been difficult to study cardiac muscle cells due to incomplete tissue maturation in the lab, the U of T-led team was able to use the device to mature stem cells into adult cardiac tissue to observe the effects of a sodium channel mutation that disrupts regular electrical activity in the heart.

“Thanks to our heart-on-a-chip, we were able to overcome the challenges associated with the developmental regulation of the sodium channel mutation,” said Marianne Wauchop, first author of the study and former PhD student in the department of physiology in the Temerty Faculty of Medicine and the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering.

“Using the same device, we were also able to determine the effects of the mutation on cardiac function.”

The journal Biomaterials recently published the findings.

The results could help advance personalized treatment for heart diseases such as dilated cardiomyopathy, a heart condition in which the chambers of the heart lose their ability to contract, through a mutation-targeted approach – even in cases where the mutation is not often linked to the disease or associated symptoms. If left untreated, the condition can result in arrhythmia – and eventually heart failure.

“Currently, patients with dilated cardiomyopathy caused by sodium channel mutations are treated for heart failure, such as with beta blockers and diuretics,” said Milica Radisic, a co-principal investigator on the study and professor at U of T’s Donnelly Centre for Cellular and Biomolecular Research and Institute of Biomedical Engineering. “Responses to these treatment methods are varied because they don’t target the specific mutations responsible for dilated cardiomyopathy.”

The researchers found the mutation disrupts interactions between sodium channels and structural proteins that are critical for cardiac muscle cells, leading to tissue dilation and impaired contractile performance.

The cells that carry the mutation were provided for the study by a patient of Kumaraswamy Nanthakumar, senior scientist in the Toronto General Hospital Research Institute at University Health Network and professor at U of T’s Institute of Medical Science in the Temerty Faculty of Medicine.

The patient went into cardiac arrest while giving birth and has a family history of arrythmia, an irregular heartbeat. Nanthakumar sequenced the patient’s genome to identify the particular sodium channel mutation.

“We were faced with the challenge of culturing stem cells that express the mutation in question, as this only occurs following maturation of the cells,” says Wauchop. “To address this issue, we developed a heart-on-a-chip device, also called a biowire, to mature the heart tissues cultured from stem cells.”

The research team created biowires with either tissues taken directly from Nanthakumar’s patient or tissues in which the mutation was corrected with CRISPR, a gene-editing tool.

While it typically takes a few years for patients to start experiencing symptoms of dilated cardiomyopathy after heart cells carrying the sodium channel mutation mature to their adult form, the biowires allowed the team to study the impacts of the mutation on cardiac tissue after only eight weeks.

Throughout this period, the researchers stimulated maturation of the stem cells through electrical current.

Dilated cardiomyopathy and other heart diseases can be caused by more than one type of mutation, Wauchop notes. But, she adds, “We can give patients a fighting chance by first making the connection between the mutation and the disease, and then developing targeted treatments for that specific mutation.”

This research was supported by the Canadian Institutes of Health Research (CIHR), the Peter Munk Cardiac Centre Innovation Committee and the National Institutes of Health (NIH).

U of T course on brain-machine interfaces introduces undergrads to next-gen health care

Christopher.Sorensen — Fri, 05 Jan 2024 15:18:55 +0000

U of T course on brain-machine interfaces introduces undergrads to next-gen health care

Christopher.Sorensen Fri, 01/05/2024 - 10:18

Cutline

Assistant Professor Xilin Liu, standing, guides students Mona Murphy, left, and Nishant Kumar, right, as they analyze Kumar’s EEG (photo by Matthew Tierney)

Matthew Tierney

Topic

Our Community

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Electrical & Computer Engineering

Faculty of Applied Science & Engineering

Undergraduate Students

University Health Network

Subheadline

“You start to look at the brain differently, the mechanisms of its disorders, what clinicians and neuroengineers are doing to treat them”

Undergraduate students taking a new ��Ƶ course have to use their brains in more ways than one.

Called Interfacing and Modulating the Nervous System (ECE441), the course in the Edward S. Rogers Sr. department of electrical engineering and computer engineering in the Faculty of Applied Science & Engineering introduces fourth-year students to neuromodulation, a multidisciplinary area that draws on knowledge about signal processing, control theory, electronics and machine learning.

Devices employing neuromodulation deliver therapeutic stimulation to targeted areas of the brain and are used to treat a range of conditions, including chronic pain, neurological disorders such as Parkinson’s disease and epilepsy, depression, spinal cord injuries and hearing or vision loss.

During one recent lab session, students Jannis Gabler and Aurora Nowicki said they were amazed by what they could learn after they hooked up a team member.

“We were measuring electrical activity in his visual cortex,” Gabler says. “Just by extracting data from his signature, we could tell whether his eyes were closed or not.”

The course was developed through the combined efforts of faculty members Xilin Liu and Ervin Sejdić, as well as the CRANIA Neuromodulation Institute. Support from the department included the purchase of specialized equipment – biosensing headsets that allow students to acquire an electroencephalograph (EEG) – and technical support from Afshin Poraria, director of teaching labs, and lab manager Iman Makhmal Koohi.

Liu, an assistant professor in the electrical and computer engineering department, says hands-on work is a crucial component of the course, which exposes students to neural interfacing techniques and applications at a time when many are considering graduate research or starting their career.

While he notes that universities such as MIT and Stanford University offer similar courses, he says they tend to be geared toward graduate students.

“Introducing such a course at the ECE undergraduate level is quite a unique approach,” he says. “By leveraging the strengths of ECE labs, we implemented hands-on experiments enabling students to collect, analyze and modulate their own EEG signals in real-time.”

A student holds a biosensing headset during a lab session (photo by Matthew Tierney)

The course material combines Liu’s teachings on electronics and neural interfacing technology with Sejdić’s work on signal processing, control theory and machine learning. It also includes guest lecturers with various clinical expertise. They include Milos Popovic, a professor in the Institute of Biomedical Engineering (BME), and Taufik Valiante, a scientist at the University Health Network and an associate professor of surgery in the department of surgery in the Temerty Faculty of Medicine with a cross appointment at BME – both early supporters of the course.

During off-campus excursions to nearby hospitals and clinical settings, such as Toronto Western Hospital, the students hear from neurosurgeons and neuroscientists about real-world advancements in this field.

“The first lecture was one of the most interesting I’ve ever had at U of T,” Nowicki says.

“We learned early on how little we understand the brain. It’s incredibly complex,” adds Gabler.

Liu says we may never have an accurate general model of the brain, which means therapeutic determinations must be considered on patient-by-patient basis – a challenge for clinicians.

“You cannot keep people in the hospital for a long time just to monitor the progression of the disease,” Liu says. “And optimization done at the hospital might only be calibrated for the specific time of day, or might not work when they go back home, or while asleep.”

But wearable or implantable neural devices that use machine learning are ideally suited to address this challenge because they collect large amounts of data from patients over long periods of time. With this data, machine learning can learn the optimal timing and parameter configuration.

The field is growing so fast that the electrical and computer engineering department looks forward to expanding its course offerings in neurotechnology, says Deepa Kundur, a professor and department chair, who adds that this course helps build a strong foundation in the field.

“It’s an excellent example of how bringing awareness of cutting-edge applications into the classroom setting, through access to research labs and a diverse instructor team, allows students to see the incredible potential opportunities for their electrical and computer engineering skill set,” she says.

The department also plans to make equipment available to students outside the class. The instructors are working with the student club NeuroTECH to organize workshops and hands-on sessions.

Nowicki, for one, recommends the course to fellow students even if they’re not considering a future in health care.

“You start to look at the brain differently, the mechanisms of its disorders, what clinicians and neuroengineers are doing to treat them,” she says. “And so many people have friends or a family member who has experienced a disorder.”

Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

Christopher.Sorensen — Fri, 15 Dec 2023 20:01:28 +0000

Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

Christopher.Sorensen Fri, 12/15/2023 - 15:01

Cutline

“The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development,” says Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering (photo by Steve Southon)

Kate Richards

Topic

Breaking Research

Institute of Biomedical Engineering

Institutional Strategic Initiatives

PRiME

Cancer

Graduate Students

Leslie Dan Faculty of Pharmacy

Research & Innovation

Vaccines

Subheadline

Study also showed the mRNA triggered potent cellular-level immune responses, suggesting it could be used to develop a melanoma cancer vaccine

A team of researchers based at the ��Ƶ’s Leslie Dan Faculty of Pharmacy have discovered an ionizable lipid nanoparticle that delivers mRNA to muscles while avoiding other tissues.

The study, led by Assistant Professor Bowen Li and published in Proceedings of the National Academy of Sciences, also showed that mRNA delivered using the lipid nanoparticles triggered potent cellular-level immune responses – a proof-of-concept that could lead to a potential melanoma cancer vaccine.

Called iso-A11B5C1, the new lipid nanoparticle demonstrates exceptional mRNA delivery efficiency in muscle tissues while also minimizing unintended mRNA translation in organs such as the liver and spleen. Additionally, study results show that intramuscular administration of mRNA formulated with this nanoparticle caused potent cellular immune responses, even with limited expression observed in lymph nodes.

“Our study showcases for the first time that mRNA lipid nanoparticles can still effectively stimulate a cellular immune response and produce robust anti-tumor effects, even without direct targeting or transfecting lymph nodes,” said Li.

“This finding challenges conventional understandings and suggests that high transfection efficiency in immune cells may not be the only path to developing effective mRNA vaccines for cancer.”

Lipid nanoparticles, also called LNPs, are crucial for delivering mRNA-based therapies including COVID-19 mRNA vaccines that were used worldwide during the recent pandemic. However, many LNP designs can inadvertently result in substantial mRNA expression in off-target tissues and organs like the liver or heart, resulting in often treatable but unwanted side effects. The drive to improve the safety of mRNA therapies that have the potential to treat a broad range of diseases means there is an urgent need for LNPs designed to minimize these off-target effects, explains Li, a recent recipient of the Gairdner Early Career Investigator Award.

From left to right: researchers Jingan Chen, Bowen Li and Yue Xu (photo by Steve Southon)

The new research shows that, compared to the current benchmark LNP developed by the Massachusetts-based biotechnology company Moderna, iso-A11B5C1 demonstrated a high level of muscle-specific mRNA delivery efficiency. It also triggered a different kind of immune response than what is seen in vaccines used to treat infectious diseases.

“Interestingly, iso-A11B5C1 triggered a lower humoral immune response, typically central to current antibody-focused vaccines, but still elicited a comparable cellular immune response. This finding led our team to further explore this as a potential cancer vaccine candidate in a melanoma model, where cellular immunity plays a pivotal role,” Li said.

The interdisciplinary research team that conducted the study includes Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering, and Yue Xu, a postdoctoral researcher in the Li lab and a research fellow associated with PRiME, a U of T institutional strategic initiative.

“Although iso-A11B5C1 showed limited capacity to trigger humoral immunity, it effectively initiated cellular immune responses through intramuscular injection,” said Chen. “The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development.”

New platform allows for faster, more precise lipid design

The research team identified iso-A11B5C1 by using an advanced platform developed to quickly create a range of chemically diverse lipids for further testing. This platform, newly introduced as part of the study, overcomes several challenges by streamlining the process of creating ionizable lipids that have a high potential to be translated into therapies.

By rapidly combining three different functional groups, hundreds to thousands of chemically diverse ionizable lipids can be synthesized within 12 hours.

“Here we report a powerful strategy to synthesize ionizable liquids in a one-step chemical reaction,” said Xu. “This new platform provides new insights that could help guide lipid design and evaluation processes going forward and allows the field to tackle challenges in RNA delivery with a new level of speed, precision and insight.”

��Ƶ fields questions from scholars, students during academic talk on responsible AI

Christopher.Sorensen — Thu, 02 Nov 2023 14:48:22 +0000

��Ƶ fields questions from scholars, students during academic talk on responsible AI

Christopher.Sorensen Thu, 11/02/2023 - 10:48

Cutline

��Ƶ, a University Professor Emeritus of computer science who has been dubbed the “Godfather of AI,” delivers an academic talk about artificial intelligence in U of T’s Convocation Hall (photo by Johnny Guatto)

Chris Sorensen

Topic

Our Community

Institute of Biomedical Engineering

Schwartz Reisman Institute for Technology and Society

Artificial Intelligence

Computer Science

Deep Learning

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Subheadline

'Godfather of AI' asks: Will Digital Intelligence Replace Biological Intelligence?

Does artificial intelligence actually understand? Would knowing more about its inner workings help to keep it in check? Could AI come up with the law of gravity if it hadn’t yet been devised?

These were among the questions that professors and students put to ��Ƶ during a recent event at the ��Ƶ’s 1,730-seat Convocation Hall.

The U of T University Professor emeritus of computer science and “godfather of AI” was there to deliver an academic talk about – and take queries on – the key differences between biological and digital intelligences, whether large language models such as ChatGPT understand what they are doing and the existential risks posed by unfettered development of the technology he helped create.

“My guess is that they will take over – they'll be much, much more intelligent than people ever were,” said Hinton, who added that humanity was likely “just a passing stage” in intelligence’s evolution.

“That's my best guess and I hope I'm wrong.”

The Oct. 27. event was co-hosted by U of T’s Schwartz Reisman Institute for Technology and Society and the department of computer science in the Faculty of Arts & Science in collaboration with the Vector Institute for Artificial Intelligence and the Cosmic Future Initiative.

Hinton’s talk came amid a flurry of AI-related developments. Three days earlier, Hinton, fellow Turing Award-winner Yoshua Bengio and 22 other AI experts, including U of T professors Gillian Hadfield, Tegan Maharaj and Sheila McIlraith, released a paper calling for governments and Big Tech firms to take action on the issue, including by devoting one-third of their AI research and development budgets to AI safety. And on Oct. 30, U.S. President Joe Biden signed an Executive Order on Safe, Secure and Trustworthy Artificial Intelligence.

Hinton took questions from audience members, many of them professors and students (photo by Johnny Guatto)

“AI is poised to transform how we live and work,” said Professor Melanie Woodin, dean of the Faculty of Arts & Science, after she summarized the seminal work Hinton did on deep learning neural networks with the help of his graduate students.

“At this pivotal moment when we consider the opportunities and risks of AI, who better to guide us in this conversation than Dr. Hinton himself?”

Hinton, who is also a cognitive scientist, explained why he began sounding the alarm about AI earlier this year after spending decades developing the technology to better understand how the human mind works. In short: It is the rapid advances in large language models such as OpenAI’s ChatGPT and Google’s PaLM coupled with the scaling advantages that digital intelligences enjoy due to their ability to be copied and share information.

And he warned that neural networks’ learning capacity is likely to grow even further as more sources of information, including video, are incorporated into their training. “They could also learn much faster if they manipulated the physical world,” he said.

He finished his presentation by suggesting AI chatbots may even be capable of subjective experience – a concept that is tied up with ideas about consciousness and sentience. “The reason I believe that is because I think people are wrong in their analysis of what subjective experience is,” he said.

Left to right: Sheila McIlraith, ��Ƶ, Gillian Hadfield and Melanie Woodin (photo by Johnny Guatto)

The talk was followed by a lengthy Q-and-A session co-ordinated by McIlraith, a professor in the department of computer science and a faculty member at the Vector Institute, where Hinton is chief scientific adviser. McIlraith said she hoped the event would inspire attendees to “help chart a course toward a future where digital and biological intelligence both enrich the human experience.”

Scholars – both professors and students – in fields ranging from philosophy to cognition probed Hinton’s thinking and, in some cases, his conclusions.

Shalev Lifshitz, a fourth-year undergraduate student in computer science who is doing AI research in McIlraith’s group at U of T and the Vector Institute, got into a back-and-forth discussion with Hinton about whether tools like ChatGPT ever truly understand what they are doing (Hinton says yes).

“I’m on the fence – I was on the fence before – but I thought he made very interesting points,” Lifshitz said immediately following the event. “I think it depends on what the definition of ‘understanding’ is. I’m not clear on that yet.”

Others, like Jennifer Nagel, a professor in the department of philosophy at U of T Mississauga, wondered if future AI might find us interesting or special “in a way that would make the best and brightest artificial intelligences take our side.”

Scholars in fields ranging from philosophy to cognition probed Hinton’s thinking during the Q-and-A (photo by Johnny Guatto)

“I mean, for me to be an interesting conversational partner with you right now, I don't even have to be smarter than you … I just have to have some knowledge that you don't have – or even just some way of looking at a problem that you find interesting,” she said.

Hinton was also asked to give advice to students studying in the field.

“Work on AI safety,” he said, noting that top researchers such as OpenAI co-founder Ilya Sutskever, a U of T alumnus, and Roger Grosse and David Duvenaud – both associate professors of computer science at the university and Vector Institute faculty members – are all working on the subject.

For many, the event was simply a rare chance to hear directly from a world-renowned researcher whose work has already forever changed our lives.

Guijin Li, a PhD student in biomedical engineering, said she is really interested in Hinton’s thoughts on AI development and jumped at the chance to hear him in person.

“It’s a once-in-a-lifetime opportunity.”

—with files from Mariam Matti

Institute of Biomedical Engineering

Researchers develop new method for delivering RNA and drugs into cells

Research team explores next-gen vaccines to guard against sexually transmitted infections

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

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

U of T researchers develop rapid MRI technique for better cancer detection and therapy

U of T researchers' AI model designs proteins to deliver gene therapy

With heart-on-a-chip, researchers study genetic mutation underlying cardiac muscle disease

U of T course on brain-machine interfaces introduces undergrads to next-gen health care

Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

New platform allows for faster, more precise lipid design

������Ƶ fields questions from scholars, students during academic talk on responsible AI

��Ƶ fields questions from scholars, students during academic talk on responsible AI