Jovana Drinjakovic

A master neuron controls movement in worms, with implications for human disease: Study

Christopher.Sorensen — Thu, 16 May 2024 15:01:59 +0000

A master neuron controls movement in worms, with implications for human disease: Study

Christopher.Sorensen Thu, 05/16/2024 - 11:01

Cutline

Researchers at the Lunenfeld-Tanenbaum Research Institute have revealed the crucial role of a neuron called AVA in controlling the worm C. elegans’s ability to shift between forward and backward motion ( photo by ZEISS Microscopy from Germany)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Cell and Systems Biology

Faculty of Arts & Science

Molecular Genetics

Research & Innovation

Subheadline

The discovery offers a major new insight into a neural circuit that scientists have studied since the inception of modern genetics.

Researchers at Sinai Health and the ��ϲ�� have uncovered a mechanism in the nervous system of the tiny roundworm C. elegans that could have significant implications for treating human diseases and advancing robotics.

The study, led by Mei Zhen and colleagues at the Lunenfeld-Tanenbaum Research Institute, was published in the journal Science Advances and reveals the crucial role of a specific neuron called AVA in controlling the worm’s ability to shift between forward and backward motion.

Crawling towards food sources and swiftly reversing from danger is a matter of life and death for the worms. This type of behaviour, where two actions are mutually exclusive, is common in many animals including humans – we cannot sit and run at the same time, for example.

Scientists long believed that control of movements in worms was due to straightforward reciprocal actions between two neurons: AVA and AVB. The former was thought to promote backward motion while AVB facilitated forward motion, with each neuron inhibiting the other to control movement direction.

However, the new data from Zhen’s team challenge this notion, uncovering a more complex interaction where the AVA neuron plays a dual role. It not only instantly stops forward motion by inhibiting AVB, but also maintains a longer-term stimulation of AVB to ensure a smooth transition back to forward movement.

The discovery highlights the AVA neuron’s ability to finely control movement through distinct mechanisms, depending on different signals and across different time scales.

“In terms of engineering, this is a very economical design,” said Zhen, who is also a professor of molecular genetics in ��ϲ��’s Temerty Faculty of Medicine. “The strong, robust inhibition of the backward circuit allows the animals to respond to bad environments and escape. At the same time, the controller neuron continues to put in constitutive gas into the forward circuit to generate movement towards safer places.”

Jun Meng, a former PhD student in the Zhen lab who led the research, said understanding how animals transition between such opposing motor states is crucial for insights into how animals move as well as neurological disorder research – and that the worms provide a unique window into basic neural wiring that's to their simple, see-through bodies.

The discovery that the AVA neuron plays such a dominant role offers a major new insight into the neural circuit that scientists have studied since the inception of modern genetics over half a century ago. The Zhen lab successfully leveraged cutting-edge technology to precisely modulate the activity of individual neurons and record data from living worms in motion.

Zhen, who is also a professor of cell and systems biology at ��ϲ��’s Faculty of Arts & Science, emphasizes the importance of interdisciplinary collaboration in this research. Meng performed key experiments, while neuronal electrical recordings were conducted by Bin Yu, a PhD student in Shangbang Gao’s lab at Huazhong University of Science and Technology in China.

Tosif Ahamed, a former post-doctoral researcher in the Zhen lab and now a Theory Fellow at the HHMI Janelia Research Campus in the United States, led mathematical modelling efforts that were crucial for testing hypotheses and gaining the new insights.

The findings provide a simplified model to study how neurons can manage multiple roles in movement control – a concept that might extend to human neurological conditions.

For example, AVA’s dual role depends on its electric potential, which is regulated by ion channels on its surface. Zhen is already exploring how similar mechanisms could be involved in a rare condition known as CLIFAHDD syndrome, caused by mutations in similar ion channels. Additionally, the new findings could inform the development of more adaptable and efficient robotic systems capable of complex movements.

“From the origin of modern science to the forefront of today’s research, model organisms like C. elegans have been instrumental in peeling back the layers of complexity in our biological systems," said Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute, vice-president of research at Sinai Health and a professor of molecular genetics in ��ϲ��’s Temerity Faculty of Medicine.

“This research is a great example of how much we can learn from simple animals, to then think about applying this new knowledge to advancing medicine and technology.”

The research was supported by the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada, the National Natural Science Foundation of China and the European Research Council.

Post-meal insulin surge not necessarily a bad thing: Study

Christopher.Sorensen — Fri, 12 Jan 2024 20:24:44 +0000

Post-meal insulin surge not necessarily a bad thing: Study

Christopher.Sorensen Fri, 01/12/2024 - 15:24

Cutline

(photo by Violeta Stoimenova/Getty Images)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Banting & Best

Diabetes

Subheadline

Researchers explored the cardiometabolic implications of insulin response over the long term in a way that accounts for baseline blood sugar levels

Researchers at Sinai Health and the ��ϲ�� have unearthed new information about the relationship between insulin levels after eating and long-term heart and metabolic health – research that upends the notion that insulin surge following food intake is a bad thing.

On the contrary, the researchers said, it could be an indicator of good health to come.

Led by Ravi Retnakaran, clinician-scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, the study – which was published in the Lancet group’s online journal eClinicalMedicine – set out to explore how insulin levels after meals impact cardiometabolic health. While past research has yielded conflicting results, suggesting both harmful and beneficial effects, this new study aimed to provide a clearer picture over an extended period of time.

“The suggestion has been made by some people that those insulin peaks have deleterious effects by promoting weight gain,” said Retnakaran, who is a professor in the department of medicine, the Institute of Medical Science and the Banting & Best Diabetes Centre in ��ϲ��’s Temerty Faculty of Medicine. “Sometimes I see patients in the clinic who have adopted this notion – maybe from the internet or what they're reading – that they can't have their insulin level go too high.

“[But] the science is just not conclusive enough to support this notion. Most studies on this topic were either conducted over a short period of time or were based on insulin measurements in isolation that are inadequate and can be misleading.”

While it’s normal for insulin levels to rise after eating to help manage blood sugar, the concern is whether a rapid increase in insulin after a meal could spell bad health. Some believe an insulin surge, especially after eating carbohydrates, promotes weight gain and contributes to insulin resistance, which occurs when the body's cells don't respond well to insulin, making it harder to control blood sugar levels and increasing the risk of type 2 diabetes.

Retnakaran’s team looked at cardiometabolic implications of insulin response over the long term in a way that accounts for baseline blood sugar levels. That’s key because each person has an individual insulin response that varies depending on how much sugar is in the blood.

The study followed new mothers because the insulin resistance that occurs during pregnancy makes it possible to determine their future risk of type 2 diabetes. Over 300 participants were recruited during pregnancy, between 2003 and 2014, and underwent comprehensive cardiometabolic testing – including glucose challenge tests at one, three and five years after giving birth. The glucose challenge test measures glucose and insulin levels at varying times after a person has had a sugary drink containing 75 grams of glucose and following a period of fasting.

While the test is commonly used by health professionals, it can be misleading if one does not account for baseline blood sugar.

“It’s not just about insulin levels; it’s about understanding them in relation to glucose,” Retnakaran said, pointing out that this is where many past interpretations fell short. A better measurement, he said, is the corrected insulin response (CIR) that accounts for baseline blood glucose levels, and which is slowly gaining prominence in the field.

The study revealed some surprising trends. As the corrected insulin response increased, there was a noticeable worsening in waist circumference, HDL (good cholesterol) levels, inflammation and insulin resistance – as long as one did not consider accompanying factors. However, these seemingly negative trends were accompanied by better beta-cell function. Beta cells produce insulin and their ability to do so is closely associated with diabetes risk. In other words, the better beta cells function, the lower the risk.

“Our findings do not support the carbohydrate-insulin model of obesity,” said Retnakaran. “We observed that a robust post-challenge insulin secretory response – once adjusted for glucose levels – is only associated with the beneficial metabolic effects.”

“Not only does a robust post-challenge insulin secretory response not indicate adverse cardiometabolic health, but rather it predicts favorable metabolic function in the years to come.”

In the long run, higher corrected insulin response levels were linked with better beta-cell function and lower glucose levels, without correlating with BMI, waist size, lipids, inflammation or insulin sensitivity and resistance. Most importantly, women who had the highest CIR had a significantly reduced risk of developing pre-diabetes or diabetes in the future.

“This research challenges the notion that high post-meal insulin levels are inherently bad and is an important step forward in our understanding of the complex roles insulin plays in regulation of metabolism,” said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health, who is also a professor of molecular genetics at Temerty Medicine.

Retnakaran hopes the team’s findings will reshape how medical professionals and the public view insulin's role in metabolism and weight management.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal. But it’s not that simple,” he said.

The research was supported by grants from the Canadian Institutes of Health Research.

Study finds new roles for gut hormone GLP-1 in the brain

rahul.kalvapalle — Mon, 08 Jan 2024 17:07:09 +0000

Study finds new roles for gut hormone GLP-1 in the brain

rahul.kalvapalle Mon, 01/08/2024 - 12:07

Cutline

University Professor Daniel Drucker's team looked at how GLP-1 drugs reduce inflammation, which is common in chronic metabolic diseases (photo by Polina Teif)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Research & Innovation

Subheadline

The findings show for the first time that there is a GLP-1-brain-immune axis that controls inflammation – even in peripheral organs that lack GLP-1 receptors

A research team led by Daniel Drucker, senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute and University Professor in the department of medicine in the ��ϲ��’s Temerty Faculty of Medicine, has discovered a gut-brain-immune network that controls inflammation across the body and affects organ health.

The findings, published in Cell Metabolism, centre on the effects of glucagon-like peptide-1 (GLP-1) receptor agonists, or activators, which clinicians use to treat Type 2 diabetes and which have recently proven highly effective for weight loss.

“One of the really interesting things about the GLP-1 drugs is that beyond the control of blood sugar and body weight, they also seem to reduce the complications of chronic metabolic disease,” said Drucker, who holds the BBDC-Novo Nordisk Chair in Incretin Biology.

“We know from clinical studies that GLP-1 does all this amazing stuff in people, but we don’t fully know how it works,” said Drucker.

To help answer this question, Drucker’s team looked at how GLP-1 drugs reduce inflammation, which is common in chronic metabolic diseases. Inflammation occurs when the immune system recognizes and removes foreign agents, such as viruses and bacteria, and promotes healing. In chronic form, however, it can persist without an external cause and lead to organ damage.

Many researchers assumed that GLP-1 drugs dampen inflammation by interacting with GLP-1 receptors on immune cells. This is the case in the gut, where large numbers of immune cells are activated by GLP-1. But in other organs, the number of immune cells containing GLP-1 receptors is negligible, indicating another mechanism may be at play.

“The strange thing is that you can’t find many GLP-1 receptors in all these other organs where GLP-1 seems to work,” said Drucker, whose earlier research showed how the GLP-1 gut hormone works at the molecular level and paved the way for several diabetes and weight-loss drugs, including Ozempic and Wegovy.

Drucker and his team had a hint that the brain might be involved for two reasons: GLP-1 receptors are abundant there, and the brain and the immune system communicate with all organs in the body.

Chi Kin Wong, first author on the study and a postdoctoral scientist in the Drucker lab, induced systemic inflammation in mice by either injecting them with a bacterial cell wall component or a bacterial slur to induce sepsis — an extensive inflammation throughout the body that leads to organ damage.

Remarkably, GLP-1 agonists reduced inflammation, but only when their receptors in the brain were left unblocked. When these brain receptors were pharmacologically inhibited or genetically removed in mice, the drugs’ ability to reduce inflammation was lost.

The findings showed for the first time that there is a GLP-1-brain-immune axis that controls inflammation across the body independent of weight loss, even in peripheral organs devoid of GLP-1 receptors, said Drucker.

Drucker has received some of the world’s most prestigious awards in the life sciences for his many findings on GLP-1, including the 2023 VinFuture Emerging Innovation Prize and the 2023 Wolf Prize in Medicine. As well, GLP-1-based diabetes drugs that emerged from Drucker’s early research were named 2023 Breakthrough of the Year by the journal Science.

“As the scientific community deservingly celebrates GLP-1 agonists and their impact, there are many unknowns left,” said Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute, vice-president of research at Sinai Health and professor in the department of molecular genetics at Temerty. “Dr. Drucker and his team have remained tenacious in their efforts to unpack how these drugs work, and this study deepens our understanding of metabolism and the complex brain-immune network that regulates it.”

Drucker’s team is now trying to pinpoint the brain cells that interact with GLP-1. They are also looking at various mouse models of inflammation, including heart disease, atherosclerosis and liver and kidney inflammation, to establish whether the beneficial effects of GLP-1 are indeed mediated through the brain.

Drucker said that understanding how GLP-1 dampens inflammation may open new avenues for reducing the complications associated with Type 2 diabetes and obesity.

He added that the recognition of GLP-1 biology as Science’s 2023 Breakthrough of the Year “highlights the expanding clinical impact of GLP-1, and the tremendous potential for basic scientific discovery to continuously improve human health.”

The research was funded by the Canadian Institutes for Health Research and Novo Nordisk Inc.

Scientists create ‘cloaked’ donor cell, tissue grafts that escape immune system rejection

Christopher.Sorensen — Wed, 06 Dec 2023 16:16:29 +0000

Scientists create ‘cloaked’ donor cell, tissue grafts that escape immune system rejection

Christopher.Sorensen Wed, 12/06/2023 - 11:16

Cutline

Andras Nagy, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI) and professor in ��ϲ��’s Temerty Faculty of Medicine, led research that created transplants in pre-clinical testing without the need for immune suppression

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Medicine by Design

Research & Innovation

Subheadline

The findings could lead to advancements in cell therapies for type 1 diabetes and heart failure

Researchers at Sinai Health and the ��ϲ�� have developed a technology that may one day eliminate the need for immunosuppressive drugs in transplant patients.

Through genetic modification of donor cells, the researchers successfully created transplants that persisted long-term in pre-clinical testing without the need for immune suppression.

The findings raise hope that a similar strategy could be employed in human patients, potentially making transplantation safer and more widely available.

“Our work paves the way for an ‘off-the-shelf’ supply of cells for therapies that could be safely given to many patients,” said Andras Nagy, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI) and professor in the department of obstetrics and gynaecology and the Institute of Medical Science at ��ϲ��’s Temerty Faculty of Medicine, who led the research.

The study was published in the journal Nature Biomedical Engineering.

Immune rejection poses a major challenge in donor cell therapy, said Nagy, who is Canada Research Chair in Stem Cells and Regeneration and has done seminal work in the field. In such cases, the recipient’s immune system recognizes the transplanted cells as foreign invaders and launches an attack, leading to rejection.

“Transplant and cell therapy patients are required to take immunosuppressive drugs – sometimes for the rest of their lives – to prevent their bodies from rejecting the transplant,” explained Nagy. The extended use of these drugs can lead to serious health issues, including recurring infections and an elevated cancer risk.

Scientists worldwide have been exploring various solutions, including creating therapeutic cells from the patient’s own cells or encapsulating donor cells in inorganic material for protection.

But these methods face challenges such as high costs, long preparation times and foreign body immune response, complicating their widespread and cost-effective application.

Stem cells have the unique ability to divide indefinitely and give rise to specialized cells that form our organs. They make an ideal source for cell therapies as large numbers of cells can be obtained and converted into desired cell types to replace those lost to disease or injury.

But there are major safety concerns: in addition to addressing immune-matching, scientists must ensure that no unwanted dividing cells remain in the transplant that could cause cancer in the future.

Nagy, who established Canada’s first human embryonic stem cell line in 2005, has dedicated his career to engineering safeguards for future cell therapies. In 2018, his team published a landmark paper in Nature about a drug-inducible “kill-switch” called FailSafe that protects from cancer by eliminating unwanted proliferating cells in transplants.

For the current study, postdoctoral researcher Jeff Harding and PhD student Kristina Vintersten-Nagy combined the kill-switch technology with a strategy they called “immune cloaking.”

Nagy’s team selected eight key genes that regulate how the immune system responds to threats, including foreign cells. Forced overexpression of these genes in mouse embryonic stem cells prevented the immune system from recognizing them as foreign.

The modification effectively created an immune cloak around the cells following their injection under the skin of genetically unmatched hosts.

“Patient safety is paramount, and Dr. Andras Nagy is globally renowned for his sustained efforts to develop safeguards for future cell therapies,” said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health, and a professor of molecular genetics at Temerty Medicine.

“This study demonstrates the combined potential of FailSafe and immune cloaking for the creation of a universal source of cells that could be applied to a multitude of diseases.”

Uncloaked cells are typically rejected within 10 days of transplantation. In contrast, the cloaked cells persisted for more than nine months at the endpoint of the experiment. “This is the first time that we’ve been able to achieve this length of time without rejection in a fully functional immune system,” said Nagy, who is also a professor at Monash University in Australia.

In another key finding, the researchers showed that unmodified cells can escape rejection when embedded into the tissue created by the cloaked donor cells below the skin surface. The protection extended to cells from another species, as shown by the ability of unmodified human cells to survive within a cloaked mouse graft.

This suggests that modified cells also act as an immune-privileged implantation site for unmodified cells, with implications for interspecies transplants. Researchers at other institutions are exploring the potential of pigs as donors because their organs are very similar in size and function to humans.

Building on this success, PhD student Huijuan Yang selected human counterparts of the eight immunomodulatory genes and used them to create the first FailSafe and cloaked human cells. Co-culturing these cells alongside human immune cells from an unmatched host revealed their ability to escape destruction, unlike their unmodified counterparts.

This shows that cloaking has the potential to work for human patients as well, said Nagy.

While the research is still at an early stage, it holds great promise for regenerative medicine and cell-based therapies. Nagy envisions injecting uncloaked insulin-producing cells, or islets, into subcutaneous cloaked tissue to treat diabetes. Subcutaneous cell delivery may be less risky for patients than the current approach, where islets are delivered into the liver and may interfere with its normal function, Nagy said.

“This study gives invaluable insights into elegant alternatives to the toxic consequences of conventional immunosuppression,” said Michael Sefton, scientific director of Medicine by Design, a ��ϲ�� institutional strategic initiative focused on regenerative medicine that primarily funded the research, who is a University Professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering in ��ϲ��’s Faculty of Applied Science & Engineering.

“These findings significantly advance cell therapies that can help people who live with chronic diseases such as type 1 diabetes or heart failure.”

Beyond diabetes, Nagy is also developing applications for patients who have age-related macular degeneration, arthritis, chronic pain and lung diseases. To bring these advances to patients faster, he co-founded a startup company, panCELLa, which recently merged with the U.S. company Pluristyx to continue to develop safe and cost-effective clinical-grade, off-the-shelf cells for therapy.

The research was funded by Medicine by Design, ��ϲ��, the Canadian Institutes for Health Research, Canada Research Chairs program and Ontario Research Fund.

This story was originally published at Sinai Health.

Researchers uncover molecular vulnerability in childhood brain cancer, identify treatment

Christopher.Sorensen — Thu, 12 Jan 2023 15:04:24 +0000

Researchers uncover molecular vulnerability in childhood brain cancer, identify treatment

Christopher.Sorensen Thu, 01/12/2023 - 10:04

Cutline

A brain scan of child with medulloblastoma tumour (Wikimedia Commons)

Jovana Drinjakovic

Topic

Breaking Research

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Research & Innovation

A team of researchers from the ��ϲ��’s Donnelly Centre for Cellular & Biomolecular Research and McMaster University have made a potential breakthrough in medulloblastoma, a form of brain cancer that predominantly affects children and infants – a finding that could lead to new, targeted treatments that are less harmful to developing brains.

Rafael Montenegro-Burke, a senior co-author of the research and an assistant professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at ��ϲ��’s Temerty Faculty of Medicine, says the current available treatment has been around for decades and consists of non-selective chemotherapy and radiation that destroy not only the cancer cells but also the healthy stem cells that are essential for brain development.

“The damage that you do to the stem cells will have a huge impact on the brain development of these kids and cognitive function later in life,” he says. “The goal is to find a way to exclusively kill medulloblastoma and not harm the stem cells.”

Working with Sheila Singh, a pediatric neurosurgeon and director of the Centre for Discovery in Cancer Research at McMaster University, the team was able to identify a molecule that is essential for the survival of medulloblastoma cells and target it with drugs to destroy cancer without touching the stem cells.

The journal Cancer Cell recently published the findings.

From left to right: ��ϲ�� Assistant Professor Rafael Montenegro Burke, post-doctoral researcher William Gwynne and McMaster University’s Sheila Singh (photos supplied)

The researchers took a relatively new approach of unbiased metabolomics to look for unique molecular signatures in the medulloblastoma cells that could be exploited for therapy. The field of metabolomics concerns the study of small molecules, or metabolites, that are produced by metabolic reactions in cells, or are taken up as nutrients from their surroundings. These include amino acids, sugars, lipids and other small molecules.

Montenegro-Burke joined the Donnelly Centre in 2020 to establish one of the first metabolomics labs at the university. His group seeks to map metabolite diversity in healthy and diseased cells, and find out how metabolites contribute to disease, including cancer. He was recently named Canada Research Chair in functional metabolomics and lipidomics, a prestigious federal appointment reserved for top scholars in the country.

Compared to genes and proteins, metabolite diversity and function remain largely unexplored, says Montenegro-Burke. Yet metabolic rewiring is a key mechanism that allows cancer cells to rapidly adapt to a changing environment. It was first reported a century ago by German scientist Otto Heinrich Warburg, who won the Nobel Prize for his work in 1931.

“We’ve known for a long time that cancer affects metabolism,” says Montenegro-Burke. “The cancer needs all those nutrients not only to be able to grow, but also to adapt to survive treatment and the immune system.

“Every time we look at these cancer cells and profile them, we see substantial metabolic differences.”

The researchers focused on group 3 medulloblastoma, caused by an overabundance of the MYC protein that spurs cell proliferation. These tumours are “a particularly sinister subtype” as they often spread prior to diagnosis and recur, says William Gwynne, a former post-doctoral researcher in the Singh lab and first author on the paper.

“Once the disease recurs, it is almost ostensibly incurable,” said Gwynne, who recently joined Montenegro-Burke’s lab to conduct more post-doctoral work.

The team compared metabolite diversity between the cell lines derived from patient tumours and healthy stem cells. Using untargeted mass spectrometry, a method for detecting molecules based on their mass, they were able to detect tens of thousands of metabolites – the vast majority of which were unknown. They then applied computational biology approaches that allowed them to identify about 1,000 metabolites, reaching the limit of available technology.

What immediately struck them was that high MYC levels correlated with availability of pyrimidine, a small molecule that is used to create a coating around the MYC protein that shields it from degradation.

They reasoned that removing pyrimidine from medulloblastoma cells would lead to MYC destruction and halt cell proliferation –which is exactly what they observed. Depleting pyrimidine either by removing the enzyme responsible for its biosynthesis, or by inhibiting its function with drugs, triggered MYC degradation in cancer cells, leading them to undergo apoptosis, also known as “cellular suicide”.

“This metabolite is absolutely necessary for MYC to be functional and to drive tumours,” says Montenegro-Burke. “We don’t yet fully understand its role, but we can start thinking about how to treat medulloblastoma.”

Gwynne adds that the inhibitors of pyrimidine biosynthesis have a real potential as drug candidates due to their ability to kill cancer at low doses while sparing healthy stem cells.

Similar compounds are already making their way through clinical trials for the treatment of several other cancers. Here the drugs are used to kill cancer cells by blocking DNA synthesis that also requires pyrimidine. The researchers hope the ongoing clinical studies pave the way for a medulloblastoma trial soon.

If effective, other patient populations could also benefit, as MYC is a known driver of different types of leukemia and breast and lung cancer, says Gwynne.

The study was funded by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research and donations from the Box Run Foundation and Team Kelsey Foundation.

Researchers crack 30-year-old mystery of odour switching in worms

Christopher.Sorensen — Tue, 02 Aug 2022 19:06:40 +0000

Researchers crack 30-year-old mystery of odour switching in worms

Christopher.Sorensen Tue, 08/02/2022 - 15:06

Cutline

The head of an adult C. elegans worm, with the olfactory neuron expressing a particular type of odorant receptor shown in green (image by Daniel Merritt)

Jovana Drinjakovic

Topic

Breaking Research

Donnelly Centre for Cellular & Biomolecular Research

Molecular Genetics

Research & Innovation

Soil-dwelling nematodes depend on their sophisticated sense of smell for survival, able to distinguish between more than a thousand different scents – but the molecular mechanism behind their olfaction has baffled scientists for decades.

Now, researchers at the ��ϲ��'s Terrence Donnelly Centre for Cellular & Biomolecular Research appear to have solved the long-standing mystery – and the implications of their findings stretch beyond nematode olfaction, perhaps offering insights into how the human brain functions.

Derek van der Kooy, a professor of molecular genetics at the Donnelly Centre in the Temerty Faculty of Medicine, led a research team that uncovered the molecular mechanism behind the worms' sense of smell, suggesting that it involves a conserved protein that helps equilibrate vision in humans.

The van der Kooy lab is renowned for its neuroscience research that uses a variety of model organisms, including the nematode Caenorhabditis elegans.

The researchers' study was published in the Proceedings of the National Academy of Sciences (PNAS) last week.

“The worms have an incredible sense of smell – it’s absolutely amazing,” says Daniel Merritt, a first co-author on the paper and recent PhD graduate who worked in the van der Kooy lab.

“They can detect a very wide variety of compounds, such as molecules released from soil, fruit, flowers and bacteria. They can even smell explosives and cancer biomarkers in the urine of patients,” he adds.

C. elegans are champion sniffers thanks to their 1,300 odorant receptors. As in humans, who possess a mere 400 receptors, each receptor is dedicated to sensing one type of smell – but that's where the similarities end.

Human noses are lined with hundreds of sensory neurons, each expressing only one receptor type. When an odorant activates a given neuron, the signal travels deeper into the brain along its long process, or axon, where it is perceived as smell. Smell discrimination is enabled by a physical separation of axonal cables carrying different smell signals.

The worms, however, have only 32 olfactory neurons, which hold all of their 1,300 receptors.

“Clearly, the one-neuron-one-smell strategy is not going to work here,” Merritt says.

Yet, the worms can discriminate between different smells sensed by the same neuron. Pioneering research from the early 1990s showed that when exposed to two attractive odours, where one is uniformly present and the other is localized, the worms crawl towards the latter. But how this behaviour is regulated at the molecular level remained unclear.

“It seems that all the information that is sensed by this neuron gets compressed into one signal, and yet the worm can somehow tell the difference between the upstream components. That’s where we came to it,” Merritt says.

Merritt and former master’s of science graduate Isabel MacKay-Clackett, a co-first author on the paper, reasoned that perhaps the worms are sensing how strong the smells are.

According to their hypothesis, the smells that are everywhere are not the most informative cues and would become desensitized in some way, meaning the worms would ignore them. This would leave the weakly present smells, which might be more useful in guiding behaviour, able to activate their receptors and cause signal transduction.

They also had a hunch for how this could work at the molecular level. A protein named arrestin is a well-established desensitizer of the so-called G protein coupled receptors (GPCRs), a large family of proteins that perceive external stimuli, which odorant receptors belong to. Arrestins for example allow us to adjust vision in bright light by damping down signalling through the photon-sensing receptors in the retina.

The team wondered if arrestin might also act in worms to desensitize receptors for a stronger smell in favour of those for a weaker one, when both are sensed by the same neuron. To test their hypothesis, they exposed the worms lacking the arrestin gene to two different attractive smells in a Petri dish. They mixed one smell into the agar medium to make it uniform, and put the worms on top. The other smell was placed at one spot some distance from the worms.

Without arrestin, the worms were no longer able find the source of the weaker smell. Like in the human eye squinting in bright sunshine, arrestin helps remove an overpowering sensation – ambient smell in this case – so that the worms can sense a localized smell and move towards it, MacKay-Clackett says.

Arrestin is not required, however, when the smells are sensed with different neurons, suggesting that the worms employ the same discrimination strategy as the vertebrates when the smell signals travel down different axons.

The team looked at different sets of smells and neurons and found they all obeyed the same logic, Merritt says. They also used drugs to block arrestin and found that this too abolished smell discrimination.

The finding is significant because it is the first evidence showing that arrestin can fine tune multiple sensations.

“There is no case known in biology before this where arrestin is being used to allow for discrimination of signals external to the cell,” Merritt says.

He adds that the same mechanism could be playing out in other animals when multiple GPCRs are expressed on the same cell, especially in the brain. Our brains are bathed in neurochemicals that signal through hundreds of different GPCRs, raising a possibility that arrestin, of which there are four types in humans, could be key for information processing.

“Our work provides one piece of puzzle how the worms’ amazing sense of smell works, but it also informs our understanding of how GPCR signalling works more broadly within animals,” Merritt says.

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

Researchers use rapid antibody test to gauge immune response to SARS-CoV-2 variants

Christopher.Sorensen — Wed, 06 Jul 2022 13:17:59 +0000

Researchers use rapid antibody test to gauge immune response to SARS-CoV-2 variants

Christopher.Sorensen Wed, 07/06/2022 - 09:17

Cutline

A ��ϲ�� study found the antibodies generated by people who were vaccinated and/or recovered from COVID-19 prior to 2022 failed to neutralize today's variants (photo by Shawn Goldberg/SOPA Images/LightRocket via Getty Images)

Jovana Drinjakovic

Topic

Breaking Research

COVID-19

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Biochemistry

Research & Innovation

COVID-19 infections are once again on the rise as our immune systems struggle to combat new variants.

That’s according to a ��ϲ�� study that found the antibodies generated by people who were vaccinated and/or recovered from COVID-19 prior to 2022 failed to neutralize the variants circulating today.

Furthermore, the researchers expect that the antibody test they developed to measure immunity in the study’s participants will become a valuable tool for deciding who needs a booster and when, helping to save lives and avoid future lockdowns.

“The truth is we don’t yet know how frequent our shots should be to prevent infection,” said Igor Stagljar, a professor of biochemistry and molecular genetics at the Donnelly Centre for Cellular and Biomolecular Research and at the Temerty Faculty of Medicine. “To answer these questions, we need rapid, inexpensive and quantitative tests that specifically measure Sars-CoV-2 neutralizing antibodies, which are the ones that prevent infection.”

The study was led by Stagljar and Shawn Owen, an associate professor of pharmaceutics and pharmaceutical chemistry, at the University of Utah.

The journal Nature Communications recently published their findings.

Many antibody tests have been developed over the past two years. But only a few of the authorized ones are designed to monitor neutralizing antibodies, which coat the viral spike protein so that it can no longer bind its receptor and enter cells.

It's an important distinction, as only a fraction of all Sars-CoV-2 antibodies generated during infection are neutralizing. And while most vaccines were specifically designed to produce neutralizing antibodies, it’s not clear how much protection they give against variants.

“Our method, which we named Neu-SATiN, is as accurate as – but faster and cheaper than – the gold standard, and it can be quickly adapted for new variants as they emerge,” Stagljar said.

Neu-SATiN stands for Neutralization Serological Assay based on split Tri-part Nanoluciferase, and it is a newer version of SATiN, which monitors the complete IgG pool they developed last year.

The development of Neu-SATiN was spearheaded by Zhong Yao, a senior research associate in Stagljar’s lab, and Sun Jin Kim, a post-doctoral researcher in Owen’s lab, who are the co-first authors on the paper.

The pinprick test is powered by the fluorescent luciferase protein from a deepwater shrimp. It measures the binding between the viral spike protein and its human ACE2 receptor, each of which is attached to a luciferase fragment. The engagement of the spike protein with ACE2 pulls the fragments close, catalyzing reconstitution of the full length luciferase with a concomitant glow of light captured by the luminometer instrument. When a patient’s blood sample is added into the mixture, the neutralizing antibodies bind to – and mop up – all spike protein, while ACE2 remains in unengaged state. Consequentially, the luciferase remains in pieces and the light signal drops. The researchers say the plug-and-play design of the test means it can be adapted to emerging variants by engineering mutations in the spike protein.

The researchers applied Neu-SATiN to blood samples collected from 63 patients with different histories of COVID-19 and vaccination up to November 2021. Patient neutralizing capacity was assessed against the original Wuhan strain and the following variants: Alpha, Beta, Gamma, Delta and Omicron.

“We thought it would be important to monitor people that have been vaccinated to see if they still have protection and how long it lasts,” said Owen, who did his post-doctoral training in the Donnelly Centre with distinguished bioengineer and University Professor Molly Shoichet of the Faculty of Applied Science & Engineering. “But we also wanted to see if you were vaccinated against one variant, does it protect you against another variant?”

The neutralizing antibodies were found to last about three to four months before their levels would drop by about 70 per cent irrespective of infection or vaccination status. Hybrid immunity, acquired through both infection and vaccination, produced higher antibody levels at first, but these too dropped significantly four months later.

Most worryingly, infection and/or vaccination provided good protection against the previous variants, but not Omicron or its sub-variants BA.4 and BA.5.

The data match those from a recent U.K. study that showed that both neutralizing antibodies and cellular immunity – a type of immunity provided by memory T cells – from either infection, vaccination, or both, offered no protection from catching Omicron. In a surprising twist, the U.K. group also found that infections with Omicron boosted immunity against earlier strains, but not against Omicron itself for reasons that remain unclear.

“It's important to stress that vaccines still confer significant protection from severe disease and death,” said Stagljar. Still, he added that the findings from his team and others call for vigilance in the coming period given that the more transmissible BA.4 and BA.5 sub-variants can escape immunity acquired from earlier infections with Omicron, as attested by rising reinfections.

“There will be new variants in the near future for sure,” Stagljar said. “Monitoring and boosting immunity with respect to circulating variants will become increasingly important and our method could play a key role in this since it is fast, accurate, quantitative and cheap.”

He is already collaborating with the Canadian vaccine maker Medicago to help determine the efficacy of their candidates against Omicron and its sub-variants. Meanwhile, ��ϲ�� is negotiating to license Neu-SATiN to a company which will scale it up for real world uses such as population immunosurveillance and vaccine development.

The research was supported with funding from the Toronto COVID-19 Action Fund, Division of the Vice-President, Research & Innovation and the 3i Initiative at the University of Utah.

RNA map of cell nucleus reveals new insights into gene regulation and cell division

Christopher.Sorensen — Fri, 18 Mar 2022 15:17:55 +0000

RNA map of cell nucleus reveals new insights into gene regulation and cell division

Christopher.Sorensen Fri, 03/18/2022 - 11:17

Cutline

Microscopy images of cell nuclei with labeled RNA transcripts that contain retained introns (Image courtesy of Barutcu, Wu et al. in Molecular Cell).

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Lunenfeld-Tanenbaum Research Institute

Hospital for Sick Children

Molecular Genetics

Research & Innovation

Most people are familiar with the cell nucleus from grade school biology as a storage compartment for DNA. But the nucleus also contains several distinct structures called nuclear bodies or domains – and some of them are brimming with genes’ messages, also known as RNA transcripts.

Scientists are just now beginning to understand these structures, with ��ϲ�� researchers recently reporting the first large-scale survey of RNA transcripts that are associated with different nuclear bodies in human cells.

The work, published in the journal Molecular Cell, suggests that the structures act as hubs to co-ordinate gene regulation and cell division.

“It was known that some nuclear domains contain RNA, but the composition of that RNA was not systematically probed in previous studies,” said Benjamin Blencowe, senior author on the study and a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the Temerty Faculty of Medicine.

“Our data has shed light not only on the RNA composition of different nuclear domains, but also provides clues as to the functions of some of these domains.”

Until now, the information on nuclear body composition has trickled in piecemeal because there were no methods enabling a systematic survey of RNA localized to these structures. But post-doctoral researcher Rasim Barutcu and graduate student Mingkun Wu realized they could apply a method called APEX-Seq, which had been developed by scientists at Stanford University and the University of California, Berkeley.

APEX is an enzyme that can be fused to any protein of interest and allows labeling of RNAs and other biomolecules in its proximity. The labeled RNAs can then be isolated and identified by sequencing. By fusing APEX to various marker proteins residing in the different nuclear bodies, Barutcu and Wu were able to create RNA maps for each.

The pair collaborated with Ulrich Braunschweig, a senior research associate in Blencowe’s lab, and with the groups of: Anne-Claude Gingras, a senior scientist at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, and professor of molecular genetics; Philipp Maass, a scientist at The Hospital for Sick Children and assistant professor of molecular genetics; and Robert Weatheritt, a principal investigator at the Garvan Institute of Medical Research in Australia.

The team discovered swaths of novel RNAs – from several hundred to thousands – across the nuclear bodies. Previously, only a handful of transcripts were known to be associated with some of these structures, said Barutcu, whose research was supported by the Banting Postdoctoral Fellowship and a fellowship from the Canadian Institutes of Health Research (CIHR).

One piece of data immediately struck the researchers: The nuclear bodies known as speckles were associated with surprisingly high numbers of RNA transcripts with retained introns – segments that do not code for proteins. When a gene is transcribed into RNA, introns must be spliced out in the nucleus before the transcript can be released into the cell’s interior to serve as a template for making proteins.

The finding led them to realize that speckles are associated with a class of introns with delayed splicing. The nature of the transcripts provided a clue to their function. They were transcribed from genes that control various aspects of gene regulation and the cell division cycle. Genes controlling cell cycle progression must be activated in a timely manner so that their protein products are made only when they are needed. Errors in this process are well known drivers of cancer.

The researchers came up with a model in which the role of the speckles might be to co-ordinate intron removal from transcripts in order to regulate their release from the nucleus, and their subsequent translation into protein factors required for gene regulation and the cell cycle. This mechanism would help ensure a rapid response to cellular signals to make the right kinds of proteins at the right time.

Furthermore, when speckles were disrupted, this altered the splicing of the retained introns, including those located in genes that are directly involved in control of the cell cycle, supporting the idea that the speckles are linked to cell cycle progression.

The model opens up new ways of thinking about cell cycle regulation with implications for cancer research, said Blencowe, who holds a Canada Research Chair in RNA Biology and Genomics and Banbury Chair in Medical Research.

“We’ve uncovered a mechanism involving differential intron retention linked to speckle integrity that could play an important role in not just normal cell division but also how it goes wrong in cancers,” he said, noting that the project was made possible by the now defunct CIHR Foundation grant scheme, which provided long-term research funding.

In addition to the speckles, the team also found large numbers of intron-retained transcripts associated with the nuclear lamina, which forms at the periphery of the nucleus. However, the functional significance of this observation remains unclear.

The researchers said they hope others in the field will take advantage of their datasets and open new avenues of research into nuclear body function where many questions remain.

Startup spun out of Igor Stagljar's ��ϲ�� lab to develop precision cancer therapies

Christopher.Sorensen — Tue, 15 Feb 2022 20:55:17 +0000

Startup spun out of Igor Stagljar's ��ϲ�� lab to develop precision cancer therapies

Christopher.Sorensen Tue, 02/15/2022 - 15:55

Cutline

Professor Igor Stagljar, left, has partnered with drug discovery firm Cyclica, co-founded by CEO Naheed Kurji, right, to launch the biotech startup Perturba, which is focused on difficult-to-treat cancers (photos courtesy of Tonko Buterin and Cyclica)

Jovana Drinjakovic

Topic

Our Community

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Biochemistry

Entrepreneurship

Innovation & Entrepreneurship

Molecular Genetics

Startups

The ��ϲ�� and the AI drug discovery company Cyclica have launched a biotech startup that will develop targeted therapies for difficult-to-treat cancers.

In partnership with Cyclica, Igor Stagljar, a professor in the Donnelly Centre for Cellular and Biomolecular Research in ��ϲ��’s Temerty Faculty of Medicine, founded Perturba to bring together Cyclica’s AI drug design technology with two live cell-based assays from the Stagljar lab, called MaMTH and SIMPL, for validation of selected compounds.

“I am very excited about our collaboration with Cyclica, thanks to their powerful AI platform that has transformed research in my laboratory over the past few years,” said Stagljar, who is also a professor of biochemistry and molecular genetics at Temerty Medicine. “Our combined approach allows us to go after some of the most intractable cancers by selecting in silico drug molecules that specifically target oncogenic proteins.

“It will also accelerate drug development by cutting the time to preclinical testing from several years to months.”

The company builds on an earlier collaboration between Stagljar’s lab and Cyclica, which produced two inhibitors of the osimertinib-resistant triple mutant EGF receptor for the treatment of non-small cell lung cancer, the most common type of lung cancer, which Perturba will initially focus on advancing. Osimertinib is currently the drug of last resort for this type of cancer.

Perturba will also launch four programs targeting small GTPases – enzymes that are mutated in many cancers, but which have been difficult to target with conventional methods.

“What others view as ‘undruggable,’ we see as potential,” said Naheed Kurji, co-founder, CEO and president of Cyclica.

The Stagljar lab is renowned for its study of protein-protein interactions (PPIs). MaMTH and SIMPL were initially developed for mapping human protein networks on a global scale. Understanding how proteins talk to each is important, because when those interactions go awry, it can lead to disease.

Stagljar’s team previously mapped interactions between disease-causing proteins and their partners, revealing potential “weak spots” that can be targeted by small molecule drugs for potential treatments of diseases ranging from cancer to cystic fibrosis.

Perturba’s compounds work by specifically perturbing oncogenic PPIs in cancer cells, thereby sparing the surrounding healthy tissue from harmful effects. But the hunt for such drugs has been slow using traditional approaches, which often resulting in compounds with off-target effects. In other words, they act on unintended proteins as well as their targets, which can have wide side-effects in the body.

Advances in AI have transformed drug discovery thanks to machine learning algorithms that can pick the best candidates from vast chemical libraries containing billions of molecules, which selectively inhibit disease-causing PPIs. That has opened the door to targeting previously “undruggable” proteins, which make up the majority of the human proteome.

“Lots of proteins have smooth surfaces with no pockets for drugs to bind to. But using Cyclica’s approach we can screen protein surfaces for wild type and oncogenic versions, and we can then test our molecules very quickly in our live cell-based assays,” said Stagljar.

“Cyclica’s AI-augmented polypharmacology based drug design platform technology, complemented with Professor Stagljar’s empirical live cell assays, allows us to approach targets we could not before,” said Kurji. “We’re so excited to partner with the world-class Stagljar lab in driving forward our shared vision.”

��ϲ�� art installation pulls back curtain on molecular science

Christopher.Sorensen — Mon, 20 Dec 2021 15:09:42 +0000

��ϲ�� art installation pulls back curtain on molecular science

Christopher.Sorensen Mon, 12/20/2021 - 10:09

Cutline

Ten images depicting diverse research projects pursued by investigators at ��ϲ��'s Donnelly Centre for Cellular and Biomolecular Research comprise a unique art installation on campus (image courtesy of Ronit Wilk)

Jovana Drinjakovic

Topic

City & Culture

Temerty Faculty of Medicine

Resarch & Innovation

Donnelly Centre for Cellular & Biomolecular Research

Hospital for Sick Children

A remarkable collection of images normally reserved for the eyes of scientists is now available to the ��ϲ�� community via an exhibition celebrating cutting-edge research in biomedicine.

The recently unveiled installation, which won’t be available for general viewing until pandemic restrictions ease, features stunning data visualizations and microscopy images created by ��ϲ�� researchers working in the fields of genomics, computational biology and bioengineering in the Donnelly Centre for Cellular and Biomolecular Research at the Temerty Faculty of Medicine.

Envisioned as a single art piece, the installation comprises 10 images depicting diverse research projects pursued by the centre’s investigators. These include the world’s first complete genetic network of a cell resembling a dandelion, grown-from-scratch human nerve fibers lacing the surface of a Petri dish that hold potential for regenerative medicine and the world’s first map of the human liver at the molecular level that could unlock future treatments.

With the individual pieces laser-printed on aluminum panels, which heightens image quality and preserves colour from fading, the exhibit offers visitors a chance to revel in a world less seen while they learn about ongoing research at the Donnelly Centre.

“As scientists it’s our job to make sense of data patterns and of what we capture under the microscope, and it’s easy to overlook the sheer beauty of biology,” says University Professor Brenda Andrews, who was founding director of the centre and commissioned the exhibit.

“We wanted to share this beauty with the public and to use the artwork to tell stories about some of the discoveries that have made the centre globally known as a leading hub for research in biomedicine.”

The exhibition was intended to mark the 15th anniversary of the Donnelly Centre in 2019, but its realization got delayed due to the coronavirus pandemic.

Founded in 2004, the centre brought under one roof researchers from across scientific disciplines to harness genomic technology for the advancement of science, medicine and health. During this time, the centre’s investigators carried out landmark studies that have transformed our understanding of cellular function and how it is linked to disease.

Andrews helmed the centre from its founding through three consecutive terms before stepping down in 2020 after completing her final term. Public outreach also blossomed under her leadership, with multiple initiatives aimed at instilling curiosity and the love of science among Canadians of all ages, especially schoolchildren.

For Ronit Wilk, the scientist and artist who created the piece, the exhibit is a dream come true. Wilk, who was previously a research associate in the centre and performed a lot of microscopy, always wanted to bring the “magical world” of cells to a wider audience.

“It’s a real privilege that we have as scientists to look into this world that’s invisible to most people,” said Wilk, who obtained her PhD at ��ϲ�� in the lab of Professor Howard Lipshitz at the department of molecular genetics, followed by a post-doctoral stint at the Hospital for Sick Children before joining the centre in 2009.

“You transform into this tiny being looking around a cell that is colour-coded for you,” she said, referring to fluorescent markers scientists use to label different structures inside cells.

To prepare the exhibit, Wilk solicited scientific images from all 30 Donnelly Centre labs. She then selected the final 10 based on their theme, colour and composition to create a collage that captures the diverse research landscape in the centre. Wilk also artistically rendered each image using image-processing software before printing.

One panel in particular holds special value for Wilk. It shows exquisite patterns of RNA localization in fruit fly embryos, which Wilk herself took when she worked in Professor Henry Krause’s lab in the centre. The lab was the first to show that the majority of genes’ messages, transcribed into intermediate RNA molecules, show specific and dynamic localization within the embryo – and even inside individual cells – which helps ensure that the encoded proteins are made at the right place and time.

Although Wilk has moved on from the lab, she remains a staunch supporter of science by donating 10 per cent of her artist fee to foundational research.

“Basic research gets overlooked and usually there’s excitement about discoveries that can be applied right away,” said Wilk.

“But people don’t realize that by studying, for example, how RNA works, what is controlling it – those types of questions can lead to amazing discoveries later on, like we’ve seen with the first RNA-based vaccines in this pandemic.”

Jovana Drinjakovic

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Read more about the research in the Toronto Star

RNA map of cell nucleus reveals new insights into gene regulation and cell division

Startup spun out of Igor Stagljar's ������ϲ����� lab to develop precision cancer therapies

������ϲ����� art installation pulls back curtain on molecular science

Startup spun out of Igor Stagljar's ��ϲ�� lab to develop precision cancer therapies

��ϲ�� art installation pulls back curtain on molecular science