Breaking Research

Institute of Biomedical Engineering

Connaught Fund

Faculty of Applied Science & Engineering

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

Virtual and augmented reality can temporarily change the way people perceive distances: Study

Christopher.Sorensen — Fri, 30 Aug 2024 17:23:24 +0000

Virtual and augmented reality can temporarily change the way people perceive distances: Study

Christopher.Sorensen Fri, 08/30/2024 - 13:23

Cutline

U of T researchers found that people moved differently in virtual reality and augmented reality, and that these changes led to temporary movement errors in the real world (photo by D-BASE/Getty Images)

Jelena Damjanovic

Topic

Faculty of Kinesiology & Physical Education

Virtual Reality

Subheadline

'We wanted to understand if the way our brains and bodies adapt to these digital environments changes how accurately we can move and interact with real objects"

Researchers at the ��Ƶ have found that using virtual and augmented reality (VR and AR) can temporarily change the way people perceive and interact with the real world – with potential implications for the growing number of industries that use these technologies for training purposes.

The study, published recently in the journal Scientific Reports, not only found that people moved differently in VR and AR, but that these changes led to temporary errors in movement in the real world. In particular, participants who used VR tended to undershoot their targets by not reaching far enough, while those who used AR tended to overshoot their targets by reaching too far.

This effect was noticeable immediately after using VR or AR, but gradually disappeared as participants readjusted to real-world conditions.

“Our study explored how using mixed reality (MR) technologies, like virtual reality and augmented reality, affects our ability to perform everyday physical tasks once we return to the real world,” says Xiaoye Michael Wang, a research associate in the Faculty of Kinesiology & Physical Education who co-authored the study with Professor Tim Welsh.

“Specifically, we wanted to understand if the way our brains and bodies adapt to these digital environments changes how accurately we can move and interact with real objects after using VR and AR.”

Research associate Xiaoye Michael Wang fits a VR display onto study participant Colin Dolynski (photo by Molly Brillinger)

The researchers say they were surprised by two findings: first, that movement patterns in VR and AR transfer to real-world movements; and second, by how quickly the effects of AR wore off compared to VR, with study participants readjusting to real-world conditions faster after using AR.

The difference between VR and AR, they suggest, might be because people in AR can still see and interact with their actual surroundings, which helps them maintain a more accurate sense of depth and distance.

“These findings are crucial because they highlight a potential challenge in transferring skills learned in VR or AR to the real world,” says Welsh. “As more industries and training programs adopt these technologies for skill development, it's important to understand how they might affect real-world performance.

“For example, this could be relevant for training surgeons, pilots or even everyday skills like driving. Knowing the limitations and effects of VR and AR helps ensure these technologies are used effectively and safely.”

The researchers will next be exploring how different types of VR and AR experiences, like those involving more complex or immersive scenarios, affect real-world performance. They’re also interested in seeing how training duration and individual differences such as prior experience with these technologies, influence adaptation and readjustment.

“This research will help us better understand how to design VR and AR systems that minimize negative after-effects and maximize their potential for training and skill development,” Wang says.

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

Faculty of Applied Science & Engineering

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.

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

University Health Network

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 researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen — Thu, 15 Aug 2024 12:54:41 +0000

U of T researchers develop AI model to predict 'very dynamic' peptide structures

Christopher.Sorensen Thu, 08/15/2024 - 08:54

Cutline

PhD Graduate Osama Abdin and Professor Philip M. Kim developed a deep-learning model that can predict all possible shapes of peptides, which are are of keen interest to researchers who are developing therapeutics (supplied image)

Anika Hazra

Topic

Donnelly Centre for Cellular & Biomolecular Research

Alumni

Artificial Intelligence

Computer Science

Subheadline

The new model expands on the capabilities of Google DeepMind's AlphaFold, the leading AI system for predicting protein structures

Researchers at the ��Ƶ have developed a deep-learning model that can predict all possible shapes of peptides – chains of amino acids that are shorter than proteins, but perform similar biological functions.

Called PepFlow, the model combines machine learning and physics to model the range of folding patterns that a peptide can assume based on its energy landscape.

Peptides, unlike proteins, are dynamic molecules that can take on a range of conformations. They are involved in many biological processes that are of keen interest to researchers who are developing therapeutics.

“We haven’t been able to model the full range of conformations for peptides until now,” said Osama Abdin, first author on the study and recent PhD graduate of molecular genetics at U of T’s Donnelly Centre for Cellular and Biomolecular Research. “PepFlow leverages deep-learning to capture the precise and accurate conformations of a peptide within minutes.

“There’s potential with this model to inform drug development through the design of peptides that act as binders.”

The study was recently published in the journal Nature Machine Intelligence.

A peptide’s role in the human body is directly linked to how it folds since its 3D structure determines the way it binds and interacts with other molecules.

“Peptides were the focus of the PepFlow model because they are very important biological molecules and they are naturally very dynamic, so we need to model their different conformations to understand their function,” said Philip M. Kim, the study’s principal investigator and a professor at the Donnelly Centre. “They’re also important as therapeutics, as can be seen by the GLP1 analogues, like Ozempic, used to treat diabetes and obesity.”

Peptides are also cheaper to produce than their larger protein counterparts, said Kim, who is also a professor of computer science in U of T’s Faculty of Arts & Science and a professor of molecular genetics in the Temerty Faculty of Medicine.

The new model expands on the capabilities of AlphaFold, the leading Google DeepMind AI system for predicting protein structure. It does this by generating a range of conformations for a given peptide. Taking inspiration from highly advanced physics-based machine learning models, PepFlow can also model peptide structures that take on unusual formations, including the ring-like structure that results from a process called macrocyclization. Peptide macrocycles are currently a highly promising venue for drug development.

“It took two-and-a-half years to develop PepFlow and one month to train it, but it was worthwhile to move to the next frontier beyond models that only predict one structure of a peptide,” Abdin said.

There are, however, limitations given that PepFlow represents the first version of a new model. The study authors noted a number of ways in which PepFlow could be improved, including training the model with explicit data for solvent atoms, which would dissolve the peptides to form a solution, and for constraints on the distance between atoms in ring-like structures.

Yet, even as a first version, the researchers say PepFlow is a comprehensive and efficient model with potential for furthering the development of treatments that depend on peptide binding to activate or inhibit biological processes.

“Modelling with PepFlow offers insight into the real energy landscape of peptides,” said Abdin.

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

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen — Wed, 14 Aug 2024 12:51:57 +0000

Common antibiotics carry small but serious risks of life-threatening drug reactions: Study

Christopher.Sorensen Wed, 08/14/2024 - 08:51

Cutline

(photo by vorDa/Getty Images)

Misty Pratt

Topic

Sunnybrook Health Sciences

Subheadline

Researchers say physicians should consider prescribing lower-risk antibiotics for patients when clinically appropriate

Two classes of commonly prescribed oral antibiotics are associated with the greatest risk for severe drug rashes that can lead to emergency department visits, hospitalizations and even death, according to a study by researchers at ICES, Sunnybrook Research Institute and the ��Ƶ.

The study, published in the journal JAMA, found that sulfonamides (“sulfa drugs”) and cephalosporins were associated with the highest risk of reactions. The findings were based on a case-control study that used health-care data from ICES of adults 66 years or older who received a prescription for at least one oral antibiotic between 2002 and 2022 in Ontario.

Serious cutaneous adverse drug reactions (cADRs), or severe drug rash, are a group of rare but potentially life-threatening delayed reactions involving the skin and, often, internal organs. Some of these reactions carry mortality rates from 20 to 40 per cent. While many different classes of drugs can cause serious reactions, antibiotics are among the most commonly reported triggers.

The researchers say physicians should consider prescribing lower-risk antibiotics for patients when clinically appropriate.

“Clinicians have speculated that certain antibiotics carry greater risk for these severe reactions, but no study has ever confirmed these claims,” says Erika Lee, an allergist and a trainee with ICES and the Temerty Faculty of Medicine’s Eliot Phillipson Clinician-Scientist Training Program.

“Our objective was to explore the risk for cADRs in a population of older adults, who tend to receive disproportionately more antibiotic prescriptions than younger adults.”

Over the study period, 21,758 adults had an emergency department visit or hospitalization for a serious reaction following oral antibiotics and were matched with 87,025 controls who did not have a reaction.

“The good news is that most patients who visited the hospital with these reactions were discharged without being admitted, so that should be reassuring to providers and patients,” says Lee. “However, of those who were admitted to hospital with the most severe reactions, 20 per cent were treated in the ICU and five per cent of hospitalized patients died, which underscores the need for careful prescribing practices.”

The most commonly prescribed antibiotics were penicillins (29 per cent), followed by cephalosporins (18 per cent), fluoroquinolones (17 per cent), macrolides (15 per cent) nitrofurantoin (nine per cent) and sulfonamides (six per cent). Less commonly prescribed antibiotics were grouped together and accounted for seven per cent of prescriptions.

Other key findings include:

There were two antibiotic reaction-related hospital visits for every 1,000 antibiotic prescriptions dispensed
About one in eight patients who arrived at the emergency department with antibiotic-related reactions were hospitalized, likely because their reactions were more severe or because of concerns about potential complications
Twenty per cent of hospitalized patients with the most severe forms of reactions were treated in a critical care unit, and five per cent of those patients died

“While rare, these severe drug reactions can be life-threatening. Patients should be aware of rash, fever and other symptoms, which can start weeks after a prescription has been started and even after the course of antibiotics has stopped,” says David Juurlink, a staff internist and head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre, senior core scientist with ICES and professor in the department of medicine in the Temerty Faculty of Medicine.

“It’s also one more reason why antibiotics should be prescribed only when they’re truly needed.”

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Utah's Great Salt Lake a significant source of greenhouse gas emissions, study finds

Christopher.Sorensen — Tue, 13 Aug 2024 17:35:47 +0000

Utah's Great Salt Lake a significant source of greenhouse gas emissions, study finds

Christopher.Sorensen Tue, 08/13/2024 - 13:35

Cutline

(Photo courtesy of Soren Brothers)

ROM/A&S News Staff

Topic

Subheadline

Researchers say drying lake beds are a potentially significant, but overlooked, source of greenhouse gases that may increase due to climate change

Researchers at the Royal Ontario Museum and ��Ƶ estimate that 4.1 million tonnes of carbon dioxide and other greenhouse gases were released in 2020 by the drying lake bed of Great Salt Lake in Utah.

The finding, published in the journal One Earth, suggest that drying lake beds are an overlooked, but potentially significant, source of greenhouse gases, which may further increase due to climate change.

Soren Brothers’ research examines the effects of climate change on lakes, and how changes in aquatic systems influence their greenhouse gas emissions into the atmosphere (photo courtesy of Soren Brothers)

“Human-caused desiccation of Great Salt Lake is exposing huge areas of lake bed and releasing massive quantities of greenhouse gases into the atmosphere,” says lead author Soren Brothers, who is an assistant professor in the department of ecology and evolutionary biology in the Faculty of Arts & Science and Allan and Helaine Shiff Curator of Climate Change at the Royal Ontario Museum.

“The significance of lake desiccation as a driver of climate change needs to be addressed in greater detail and considered in climate change mitigation and watershed planning.”

The Great Salt Lake’s water level varies depending on the volume of meltwater that flows into the lake from the surrounding mountains – from record highs in the 1980s to a record low in 2022. However, growing freshwater consumption by agriculture, industry and municipalities has depleted the lake over time.

Similar trends are observed worldwide as competing uses for water have a significant impact on lake levels. As iconic saline lakes such as the Aral Sea, Lake Urmia, the Caspian Sea and Great Salt Lake dry up, they not only destroy critical habitat for biodiversity and create air quality conditions that deteriorate human health, but they accelerate climate change as newly exposed sediments emit carbon dioxide and methane.

Melissa Cobo, of Utah State University, conducts gas sampling in the field (photo courtesy of Soren Brothers)

The research team measured carbon dioxide and methane emissions from the exposed sediments of Great Salt Lake from April to November 2020 and compared them with aquatic emissions estimates to determine the anthropogenic greenhouse gas emissions associated with desiccation. Calculations based on this sampling indicate the lake bed emitted 4.1 million tonnes of greenhouse gases to the atmosphere – primarily carbon dioxide (94 per cent), constituting an approximately seven per cent increase to Utah’s human-caused greenhouse gas emissions.

Fieldwork was conducted while Brothers was assistant professor of limnology at Utah State University (USU). Lead author Melissa Cobo, meanwhile, was a master’s student at USU and co-author Tobias Goldhammer is a collaborating researcher at the Leibniz Institute for Freshwater Research (IGB Institute) in Berlin, Germany.

Measurements of carbon dioxide and methane gases were made every two weeks from the dried-up lake bed using a portable greenhouse gas analyzer attached to a closed chamber. Seven sites at one location at the south end of the lake were visited repeatedly over the course of the year, and another three locations were sampled during an intensive three-day campaign to determine spatial variability across the 4,400-square-kilometre lake, which is the largest saline lake in the western hemisphere. As methane is 28 times more powerful a greenhouse gas than carbon dioxide, the global warming impact of these emissions was calculated as “carbon dioxide equivalents.”

Ultimately, the research indicated that greenhouse gas emissions from the dried lake bed were strongly and positively related to warm temperatures – even at sites exposed for more than two decades. To determine whether the lake would have historically been a significant source of greenhouse gases, the team carried out measurements of near-shore greenhouse gas emissions, as well as analyzing water chemistry collected by the team and government data sets. Together, these analyses showed that the original lake was not likely a significant source of greenhouse gases to the atmosphere, making the dried-up lake bed a novel driver of atmospheric warming.

As climate change exacerbates drought in arid regions, researchers say desiccation of rivers and lakes may be contributing to climate change feedback loops and should be considered in assessments of global greenhouse gas output as well as reduction policies and efforts.

With files from the Royal Ontario Museum

U of T researchers develop RNA-targeting technology to precisely manipulate parts of human genes

Christopher.Sorensen — Thu, 08 Aug 2024 18:26:00 +0000

U of T researchers develop RNA-targeting technology to precisely manipulate parts of human genes

Christopher.Sorensen Thu, 08/08/2024 - 14:26

Cutline

From left to right: PhD student Jack Daiyang Li, Professor Benjamin Blencowe and Associate Professor Mikko Taipale (supplied images)

Anika Hazra

Topic

Donnelly Centre for Cellular & Biomolecular Research

Genes

Subheadline

“Our new tool makes possible a broad range of applications, from studying gene function and regulation to potentially correcting splicing defects in human disorders and diseases”

Researchers at the ��Ƶ have harnessed a bacterial immune defence system, known as CRISPR, to efficiently and precisely control the process of RNA splicing.

The technology opens the door to new applications, including systematically interrogating the functions of parts of genes and correcting splicing deficiencies that underlie numerous diseases and disorders.

“Almost all human genes produce RNA transcripts that undergo the process of splicing, whereby coding segments, called exons, are joined together and non-coding segments, called introns, are removed and typically degraded,” said Jack Daiyang Li, first author on the study and PhD student of molecular genetics, working in the labs of U of T researchers Benjamin Blencowe and Mikko Taipale at the Donnelly Centre for Cellular and Biomolecular Research in the Temerty Faculty of Medicine.

Exons from the same gene can be mixed and matched in various combinations to produce different versions of RNA, and consequently, different proteins. This process, called alternative splicing, contributes to the diverse expression of the 20,000 human genes that encode proteins, allowing the development and functional specialization of different types of cells.

However, it is unclear what most exons or introns do and the misregulation of normal alternative splicing patterns is a frequent cause or contributing factor to various diseases, including cancers and brain disorders. In addition, there is a lack of existing methods that allow for the precise and efficient manipulation of splicing.

The new study, published in the journal Molecular Cell, describes how a catalytically deactivated version of an RNA-targeting CRISPR protein, referred to as dCasRx, was joined to more than 300 splicing factors to discover a fusion protein called dCasRx-RBM25. This protein is capable of activating or repressing alternative exons in an efficient and targeted manner.

“Our new effector protein activated alternative splicing of around 90 per cent of tested target exons,” said Li. “Importantly, it is capable of simultaneously activating and repressing different exons to examine their combined functions.”

This multi-level manipulation will facilitate the experimental testing of functional interactions between alternatively spliced variants from genes to determine their combined roles in critical developmental and disease processes.

“Our new tool makes possible a broad range of applications, from studying gene function and regulation, to potentially correcting splicing defects in human disorders and diseases,” said Blencowe, principal investigator on the study, Canada Research Chair in RNA Biology and Genomics, Banbury Chair in Medical Research and a professor of molecular genetics at the Donnelly Centre and Temerty Medicine.

“We have developed a versatile engineered splicing factor that outperforms other available tools in the targeted control of alternative exons,” said Taipale, also principal investigator on the study, Canada Research Chair in Functional Proteomics and Proteostasis, Anne and Max Tanenbaum Chair in Molecular Medicine and associate professor of molecular genetics at the Donnelly Centre and Temerty Medicine. “It is also important to note that target exons are perturbed with remarkably high specificity by this splicing factor, which alleviates concerns about possible off-target effects.”

The researchers now have a tool in hand to systematically screen alternative exons to determine their roles in cell survival, cell-type specification and gene expression.

When it comes to the clinic, the splicing tool has potential to be used to treat numerous human disorders and diseases, such as cancers, in which splicing is often disrupted.

The research was supported by the Canadian Institutes of Health Research and the Simons Foundation.

What makes a chess move brilliant? Researchers use AI to find out

Christopher.Sorensen — Wed, 07 Aug 2024 17:25:51 +0000

What makes a chess move brilliant? Researchers use AI to find out

Christopher.Sorensen Wed, 08/07/2024 - 13:25

Cutline

U of T Engineering researchers Kamron Zaidi, left, and Michael Guerzhoy, right, use game trees and deep neural networks to enable chess engines to recognize brilliant moves (photo by Safa Jinje)

Safa Jinje

Topic

Faculty of Applied Science & Engineering

Alumni

Artificial Intelligence

Mechanical & Industrial Engineering