Institute of Biomedical Engineering

Subheadline

“It’s our goal to develop technologies, such as a pill, that make disease management easier and more effective so that it easily fits into patient’s lifestyles"

A team of researchers at the University of Toronto is researching how to develop a pill to deliver treatment of chronic diseases that are currently managed by medications administered by injection.

Led by Caitlin Maikawa, the team aims to increase the accessibility of treatment by removing the burden on patients who are required to visit their doctor’s office to receive medication.

“Taking a pill is the patient-preferred method of administration since it gives them autonomy over their treatment and the ability to easily do it themselves at home,” says Maikawa, an assistant professor at the Institute for Biomedical Engineering in the Faculty of Applied Science & Engineering.

“We hope our research will lead to new technologies that will improve the efficacy of current therapeutics and reduce the patient burden associated with managing chronic diseases.” 

Maikawa is one of two ��οEngineering professors to receive funding from the latest round of the Canadian Foundation for Innovation John R. Evans Leaders Fund (CFI-JELF). The other recipient is Mohamad Moosavi, an assistant professor of chemical engineering and applied chemistry, whose research incorporates artificial intelligence to accelerate the discovery of new materials to combat climate change.

The support will help Maikawa’s lab engineer dynamic polymer biomaterial systems to develop new drug delivery and bio-sensing technologies to treat chronic diseases, including inflammatory bowel disease and diabetes.

Polymers are large molecules composed of repeating structural units that can be designed to interact with disease markers in the body to target therapeutics to disease sites, time the release of therapeutics or even release signalling molecules for disease monitoring.

(photo by Tim Fraser)

Maikawa’s research group focuses on the design and synthesis of dynamic polymer systems by using stimuli-responsive chemistries, also known as affinity-based interactions – a concept where certain molecules respond to external stimuli and interact selectively with a particular substance – and applying these polymer materials to address challenges in treating chronic disease.

“One way of thinking about dynamic polymer systems is that we have a kind of molecular Velcro where these molecular units stick together when we make the material,” says Maikawa. “But in the presence of disease markers in the body, the Velcro pulls apart allowing the material to degrade or in some cases to release the drug.”

Maikawa’s lab aims to collaborate with clinicians to understand how to address impactful challenges with biomaterials. Since chronic diseases are often difficult to manage, her team is looking at the whole picture of chronic disease treatment and its efficacy.

“It’s our goal to develop technologies, such as a pill, that make disease management easier and more effective so that it easily fits into patient’s lifestyles,” she says.

Researchers' lab technique could speed forensic analysis in sexual assault cases

Christopher.Sorensen — Tue, 17 Sep 2024 14:43:28 +0000

Researchers' lab technique could speed forensic analysis in sexual assault cases

Christopher.Sorensen Tue, 09/17/2024 - 10:43

Cutline

(photo by Science Photo Library/Getty Images)

Chris Sasaki

Topic

Centre for Research and Applications in Fluidic Technologies

Donnelly Centre for Cellular & Biomolecular Research

Chemistry

Faculty of Arts & Science

��οMississauga

A team of researchers has developed a new approach to analyzing DNA evidence in sexual assault cases – one that could reduce lengthy delays in the processing of evidence.

While there are almost half a million sexual assaults in Canada every year, many more go unreported because victims are reluctant to come forward.

One of the reasons cited by victims is that analysis of forensic evidence is too slow.

Mohamed Elsayed (supplied image)

“For this research, we read reports and surveys that asked victims why they weren’t reporting assaults,” says the study’s lead author Mohamed Elsayed, who worked on the project as part of his PhD in biomedical engineering at the University of Toronto. “And the most common answer was that they didn't have confidence in the justice system – and that lack of confidence was partly because of how long the process takes.”

Elsayed, now a post-doctoral researcher in the department of chemistry in the Faculty of Arts & Science, co-authored the study with, among others, Leticia Bodo, a master’s student in the department of chemistry, and Aaron Wheeler, a professor in the department of chemistry, the Institute of Biomedical Engineering and the Centre for Research and Applications in Fluidic Technologies, a ��οinstitutional strategic initiative.

All three researchers are also affiliated with the Donnelly Centre for Cellular and Biomolecular Research.

Processing forensic evidence in sexual assault cases is a technical, multi-step process that involves collecting DNA evidence and sending it to a well-equipped forensic laboratory for analysis by a skilled technician. Once there, the sample is first processed to isolate the assailant’s DNA from the victim’s so the assailant’s DNA can then be analyzed and used to identify a suspect.

The entire process can take days, weeks or longer. Most of that time is taken up with transporting the evidence to the lab, where its analysis can be further delayed depending on how many other cases are being investigated.

To speed things up, researchers focused on the first step: separating two individuals’ DNA from a single sample. At present, this is usually done manually by trained and experienced experts.

Elsayed and his collaborators, by contrast, developed a process called ’differential digestion” using digital microfluidics that helped simplify the overall process and reduce the number of manual steps needed to isolate the assailant’s DNA from 13 to five. “Also, because micro-fluidic processes tend to be faster, we expect that one of the eventual benefits will be shortening the overall time needed,” says Elsayed.

What’s more, the new approach could lead to a mobile solution that no longer requires a lab. For example, testing could be done at a hospital, circumventing the lab’s queue.

The new technique, described in a paper published in the journal Advanced Science, is compatible with the technology known as Rapid DNA analysis that is already in use for the second step of identifying an individual from their DNA. The study’s authors, which included researchers from ��οMississauga’s forensic science program, say the long-term goal is to integrate the two technologies to make the process even more streamlined.

While there remain several challenges to deploying the new technique, Elsayed says he is confident they can be overcome and has turned his efforts toward making it widely accessible and commercially viable.

“Our plan is to develop an instrument that will do in five minutes what currently takes 45,” says Elsayed. “And to run many more samples than previously. Once we do that, the next step would be to introduce the technology to forensic labs and hospitals.

“It will take years, but the potential is very exciting.”

The research was supported by the ANDE Corporation and NSERC Alliance Society.

"I’m grateful to NSERC for having the foresight to establish the ‘Alliance Society’ program which has a mission to ‘address a societal challenge that will result in new natural sciences and engineering knowledge and societal impact,” Wheeler says.

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Forensic Science

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)

Topic

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 University of Toronto 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.”

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)

Topic

Connaught Fund

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 University of Toronto 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 ��οfaculty members whose work is being supported by the Connaught New Researcher Awards in the most recent round – and one of eight at ��οEngineering. The award helps early-career faculty members establish their research programs.

The other ��οEngineering 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

��οresearchers integrate crucial immune cells onto heart-on-a-chip platform

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

��οresearchers integrate crucial immune cells onto heart-on-a-chip platform

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

Cutline

L-R: ��οpost-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)

Topic

Donnelly Centre for Cellular & Biomolecular Research

Toronto General Hospital

Subheadline

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

Researchers at the University of Toronto 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

Unity Health

Alumni

Leslie Dan Faculty of Pharmacy

Subheadline

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

Researchers at the University of Toronto 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 ��οprofessor 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 ��οCOVID-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.

��οresearchers develop rapid MRI technique for better cancer detection and therapy

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

��οresearchers 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

Electrical & Computer Engineering

Cancer

Subheadline

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

Researchers at the University of Toronto’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 ��οInnovations 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.”

��οresearchers' AI model designs proteins to deliver gene therapy

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

��οresearchers' 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)

Topic

Artificial Intelligence

Gene Therapy

Graduate Students

Subheadline

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

Researchers at the University of Toronto 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 ��οalumna 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

Donnelly Centre for Cellular & Biomolecular Research

Subheadline

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

Researchers at the University of Toronto 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).

��οcourse on brain-machine interfaces introduces undergrads to next-gen health care

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

��οcourse on brain-machine interfaces introduces undergrads to next-gen health care

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

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

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