Lunenfeld-Tanenbaum Research Institute

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle — Thu, 26 Sep 2024 14:44:39 +0000

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle Thu, 09/26/2024 - 10:44

Cutline

Living with a dog between ages five and 15 is associated with reduced risk of developing Crohn’s disease, according to new research from Sinai Health and U of T (photo by Kseniya Starkova/Getty Images)

Jovana Drinjakovic

Topic

Breaking Research

Department of Immunology

Department of Medicine

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Mount Sinai Hospital

Subheadline

Research from Sinai Health and U of T found early exposure to dogs is linked to a healthier gut and reduced risk of developing Crohn's disease

Dog lovers can attest to the range of benefits that come with having a canine companion, but improved gut health likely isn’t one of them.

That may be about to change following research from Sinai Health and the ��Ƶ that shows exposure to dogs during childhood is linked to beneficial changes in gut bacteria, gut permeability and blood biomarkers.

The study, published in Clinical Gastroenterology and Hepatology, found living with a dog between ages five and 15 is associated with a healthier gut microbiome and reduced risk of developing Crohn’s disease.

The research shines new light on how environmental factors influence the onset of Crohn’s – an inflammatory bowel condition – and could inform future prevention strategies.

For the study, researchers led by Kenneth Croitoru and Williams Turpin of Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease (IBD) investigated how dozens of environmental factors impact the likelihood of developing Crohn’s as part of their overarching effort to be able to predict those at risk and potentially intervene early.

“The idea behind predicting someone's risk of disease is that you can then also begin to understand who you might want to do something to try and prevent disease,” says Croitoru, a clinician-scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, and a professor of medicine and immunology at U of T’s Temerty Faculty of Medicine.

Croitoru notes the study doesn’t reveal why living with a dog makes someone less prone to Crohn’s disease. “We have established associations between environmental factors and Crohn’s and are now trying to understand how these environmental factors affect the triggering of the disease,” says Croitoru, who is also a gastroenterologist at Mount Sinai Hospital.

The study also found living with a large-sized family in the first year of life to reduce the likelihood of getting Crohn’s. It also found people who lived with a bird at the time of study were more likely to develop the disease.

Caused by inflammation in the gastrointestinal tract, Crohn’s disease can have far-reaching consequences on overall health and well-being. Its incidence among children under 10 has doubled since 1995, while the annual cost of inflammatory bowel disease to Canada is estimated at $5.4 billion per year, according to Crohn’s and Colitis Canada, a national non-profit.

The likelihood of getting Crohn’s is strongly influenced by genetics, but the environment also plays a role, says Croitoru, who holds the Canada Research Chair in Inflammatory Bowel Diseases. While we can’t change our genes, we can modify our surroundings and diet, for example, to potentially prevent the disease from occurring.

These findings come from the Genetic, Environmental and Microbial (GEM) Project, the largest study of its kind that seeks to identify potential triggers of Crohn’s disease.

Coordinated at Mount Sinai Hospital since 2008, the GEM Project has been collecting comprehensive medical and lifestyle data from over 5,000 healthy first-degree relatives of people who have Crohn’s and come from all over the world, including Australia, Canada, Israel, New Zealand, the U.K. and the U.S.

The project is funded by Crohn’s and Colitis Canada, the Canadian Institutes of Health Research and the Helmsley Charitable Foundation.

In the 15 years since the study began, over 120 people have developed the disease. “By understanding what is different about those who develop the disease, we should be able to predict who is at risk,” says Croitoru.

Previously, the group identified differences in the microbiome and other biomarkers in people who go on to develop Crohn’s and those who don’t.

In another recent report published in Gastroenterology, Sun-Ho Lee, a clinician-scientist at Mount Sinai Hospital’s IBD Centre and an assistant professor at the Institute of Medical Science at Temerty Medicine, used available data and machine learning to develop an “integrative risk score” that predicts the risk of Crohn’s with a high degree of accuracy.

But risk prediction is only the first step, says Croitoru, whose ultimate goal is to be able to intervene and prevent the disease from starting.

He and his team are now conducting research that seeks to devise and test strategies for prevention by, for example, adding supplements to the diet to promote a healthy microbiome.

“Sinai Health is committed to groundbreaking research and bringing those discoveries to patients," said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health.

“By integrating genetic, environmental, and microbial data, Dr. Croitoru and colleagues are paving the way towards personalized intervention strategies that could significantly reduce the incidence of Crohn’s disease.”

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle — Thu, 25 Jul 2024 14:46:33 +0000

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle Thu, 07/25/2024 - 10:46

Cutline

A team led by Daniel Schramek, a researcher at the Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health and U of T's Temerty Faculty of Medicine, identified two genes that are associated with fast-growing tumours in the pancreas (photo courtesy of Mount Sinai)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Cancer

Molecular Genetics

Research & Innovation

Subheadline

The findings mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options

��Ƶ researchers have identified two genes that play a critical role in tumour growth in the pancreas – findings that have significant implications for understanding and treating pancreatic cancer.

The tumour suppressor genes USP15 and SCAF1 were discovered by a research team led by Daniel Schramek, a senior investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI) and deputy director of discovery research and Tony Pawson Chair in Cancer Research at Sinai Health.

The team found that people who have mutations in these genes are more likely to develop fast-growing tumours – but these tumours are also more susceptible to chemotherapy. The findings, described in a study published in Nature Communications, mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options.

“While mutations in USP15 and SCAF1 make tumours more aggressive, they also sensitize tumours towards standard chemotherapy,” says Schramek, who is also an associate professor in the department of molecular genetics and Canada Research Chair in functional cancer genomics at the Temerty Faculty of Medicine.

“And that means that you could stratify patients and they should have a better response to treatment.”

The project was spearheaded by Sebastien Martinez, a former postdoctoral fellow at LTRI who is now a senior scientist at Centre de Recherche en Cancérologie de Lyon (CRCL) in France.

Pancreatic cancer continues to have few treatment options with devastatingly low survival rates, under five years post-diagnosis. According to one estimate, pancreatic cancer could be the second leading cause of cancer deaths in the United States by 2040.

Schramek's team achieved their breakthrough by leveraging advances in genomic medicine, specifically tumour DNA sequencing, to identify mutations and genome editing technologies.

“Sequencing tumours allows you to find the genes that are affected and use that knowledge to develop treatments. But the problem is that every cancer has a plethora of mutations, and not all of them are disease-causing,” says Schramek.

Cancers often feature common mutated genes in many patients, along with hundreds of less frequent mutations that appear in a smaller subset. While mutations in USP15 and SCAF1 were found in less than five per cent of patients, their effects on cancer remained unclear.

Traditionally, tumour suppressor genes have been pinpointed by sequentially deleting genes in cancer cell lines and noting which deletions increase cell growth. However, these cell-based studies don't replicate the tumour's natural environment and interactions with the immune system, which are crucial for cancer progression. This likely explains why previous screens overlooked USP15 and SCAF1.

A few years ago, Schramek's team developed a genome editing approach enabling them to remove hundreds of genes simultaneously from individual cells. This method helps identify genes that, when absent, trigger cancer in the natural body environment.

Utilizing this technology, the Schramek lab targeted 125 genes recurrently mutated in patient pancreatic tumours and pinpointed USP15 and SCAF1 as crucial tumor suppressors and potentially prognostic factors for chemotherapy response.

It just so happens that these genes are also absent in about 30 per cent of patients due to common genomic rearrangements in cancer.

This finding indicates that as many as a third of pancreatic patients who lack these genes might benefit from chemotherapy and have better outcomes.

“Historically, mutations in USP15 and SCAF1 would have been considered less important because they are not found in many patients,” Schramek says. “Our work shows that it is critical that we understand the functional consequences of these rare mutations as they can reveal new biology and therapeutic opportunities”

Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute and vice-president of research at Sinai Health, says the study “represents an important step forward in our understanding of the genes involved in pancreatic cancer.

“It also shows how a cutting-edge technology developed at Sinai Health is enabling new discoveries with the potential to create benefits to patients.”

This research was supported by funding from the Ontario Institute of Cancer Research, Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Foundation, Terry Fox Research Institute, Canadian Cancer Society Research Institute, Pancreatic Cancer Canada and the Canadian Institute of Health.

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 ��Ƶ’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 U of T’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 ��Ƶ 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 U of T’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 U of T 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 U of T’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, U of T, the Canadian Institutes for Health Research, Canada Research Chairs program and Ontario Research Fund.

This story was originally published at Sinai Health.

U of T and Toronto hospitals mount research response to monkeypox

Christopher.Sorensen — Thu, 07 Jul 2022 13:23:29 +0000

U of T and Toronto hospitals mount research response to monkeypox

Christopher.Sorensen Thu, 07/07/2022 - 09:23

Cutline

(Photo by Lisa Lightbourn)

Betty Zou

Topic

Our Community

Institutional Strategic Initiatives

Sinai Health

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Unity Health

Lunenfeld-Tanenbaum Research Institute

Global

Hospital for Sick Children

Research and Innovation

St. Michael's Hospital

University Health Network

The ��Ƶ and its partner hospitals, including Sunnybrook Research Institute, Unity Health Toronto and the University Health Network, are leading a rapid research response to the global monkeypox outbreak to better understand disease symptoms, genetic evolution of the virus and transmission risks, among other factors.

The research effort is centred in the Emerging and Pandemic Infections Consortium (EPIC), which includes the university, its high-containment lab and five Toronto hospital research institutes.

Monkeypox has infected 300 people in Canada since May and more than 5,000 worldwide.

“We’ve worked hard to link together Toronto’s broad expertise and research capacity so that our community can effectively respond to infectious challenges,” says Natasha Christie-Holmes, director, partnerships and strategy at EPIC. “It’s been thrilling to see how quickly the partners came together to respond to this unexpected emergence of monkeypox in Canada.”

The research response leverages the university’s Combined Containment Level 3 Unit – a lab equipped to safely and securely study infectious pathogens – and partnerships among Toronto hospitals and community-based groups.

Projects include:

An observational cohort study to understand the range of symptoms associated with monkeypox infection, viral shedding and transmission risks as well as the social, economic and psychosocial impacts of infection
An immunological study to understand how the immune system responds to infection
A genetics study to examine how the virus is evolving and how changes in the virus’s genetic code correspond with changes in its ability to cause disease
Transmission studies to understand the potential and risks of surface and aerosol transmission, and transmission from people who are pre-symptomatic or asymptomatic

Monkeypox is caused by a poxvirus closely related to the smallpox virus. Until recently, monkeypox infections had been limited to people living in central and western Africa and travelers who visited those regions. As of June 30, Public Health Ontario reported a total of 77 cases in Ontario, including 63 in Toronto. Although the virus can infect anyone, all cases in Ontario have so far involved males.

“One of the key learnings from the history of infectious disease outbreaks is that community engagement from the very beginning is critical,” says Darrell Tan, a co-principal investigator and operational co-lead with Sharmistha Mishra of EPIC’s monkeypox rapid response efforts. “That’s why we are taking part in community meetings where we’re working with different local groups to respond. Already there’s some amazing advocacy, actions, knowledge sharing and collaboration that has come out of these meetings that have shaped the research questions we hope to answer.”

Tan and Mishra are both associate professors in the Temerty Faculty of Medicine and infectious disease physicians at St. Michael’s Hospital, a site of Unity Health Toronto, where some of Toronto’s first patients with monkeypox were identified and cared for.

The joint effort is the first co-ordinated response from Canadian researchers to address the current monkeypox outbreak and paves the way for future collaborations with other Canadian and international groups. The data generated from the projects in the coming months will help inform the province and country’s public health response to the outbreak and could also inform and support efforts in other countries where the virus is endemic.

“The speed with which this research initiative came together is a testament to the strength of EPIC and its partnerships and their ability to pivot and respond rapidly to new infectious threats like monkeypox,” says Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives.

The monkeypox rapid research response is led by EPIC in partnership with the Toronto Academic Health Science Network.

EPIC is a U of T Institutional Strategic Initiative that brings together infectious disease experts at the university and five hospital research partners – the Hospital for Sick Children (SickKids) Research Institute, the Lunenfeld-Tanenbaum Research Institute at Sinai Health, Sunnybrook Research Institute, Unity Health Toronto and University Health Network – to facilitate an integrated and innovative response to infectious diseases in an effort to help prevent future pandemics.

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 ��Ƶ 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.

Researchers reveal largest catalogue of gene activators

Christopher.Sorensen — Wed, 09 Feb 2022 17:23:09 +0000

Researchers reveal largest catalogue of gene activators

Christopher.Sorensen Wed, 02/09/2022 - 12:23

Cutline

Mikko Taipale, of the Donnelly Centre for Cellular and Biomolecular Research, was part of a team that a catalogue of proteins that activate gene expression, also known as transcriptional activators (photo by Julia Soudat)

Daniela Isaacs-Bernal

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Lunenfeld-Tanenbaum Research Institute

Molecular Genetics

��Ƶ researchers have created a first-in-class functional catalogue of proteins that activate gene expression, with implications for tailored therapy for cancer and other diseases that occur when wrong genes are switched on.

Also known as transcriptional activators for their ability to induce transcription of genes into RNA messages, these proteins are essential for the cells to function properly. Yet little is known about these proteins, and it wasn’t clear how many activators there might be in human cells – until now.

The research was led by Mikko Taipale, an associate professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the Temerty Faculty of Medicine, in collaboration with Anne-Claude Gingras, a senior investigator at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System and professor of molecular genetics at U of T.

The work was spearheaded by Taipale’s graduate student Nader Alerasool, who defended his PhD thesis last month – a day after the study was published online in the journal Molecular Cell, and ahead of print publication this week.

In the article, the researchers describe the first unbiased proteome scale study that has expanded the number of known transcriptional activators from a handful to around 250. They have also established how these proteins combine with other cellular machineries to turn genes on, and how protein misregulation can lead to cancer.

“This study was a classic fishing expedition where we did not know what we were going to find,” said Taipale, who holds Canada Research Chair in Functional Proteomics and Protein Homeostasis. “Grant reviewers typically frown upon research that is not hypothesis driven, but that’s the beauty of proteomics. It allows you to cast a net in an unbiased way, and we have found some interesting stuff.

“We now have a better understanding of which proteins are very strong activators. And we can begin to understand the mechanisms by which they activate transcription.”

To find the activators, the researchers tested the majority of 20,000 human proteins for their ability to activate gene expression in human cells. Many activators were transcription factors (TFs), which directly bind DNA and turn on their target genes, whereas others were helper proteins, or co-factors, that bind TFs and activate their targets together.

They also found that TFs that are highly similar can talk to different co-factors, explaining why two TFs with essentially identical DNA binding specificities can trigger distinct gene expression programs.

“These activators are not activators in all contexts. It could be that in a gene X they activate, but in gene Y they might actually repress,” Taipale said.

Transcriptional activation occurs through the interaction of the so-called transactivation domains, which are present in the TFs, with the activators. Since the sequences of activation domains are not conserved, they can't be pinpointed by computational methods.

For that reason, the team resorted to chopping up 75 activators into pieces and tested the ability of each piece to activate transcription. They identified around 40 activation domains this way.

They also used AlphaFold, a revolutionary bioinformatic tool developed for the prediction of protein structures, to find the interaction interfaces between the TFs and their activators. Although AlphaFold was not designed to predict protein-protein interactions, this unexpected feature was a highlight for Taipale, who said the software will become the standard tool for these kinds of studies to find functional connections between proteins.

“This has been previously nearly impossible to do computationally,” Taipale said.

While many of the identified proteins are novel, some of them were previously detected in tumours in which a TF and its helper protein are permanently joined in an oncogenic fusion protein which ends up activating the wrong genes.

Piecing together the puzzle of how TFs interact with different activators could be a major step towards tailored therapy. One challenge in therapeutics development has been that TFs are not amenable to targeting by small-molecule drugs.

“Transcription factors are really hard to target because they often don’t have druggable pockets, but many of the co-activators are enzymes which means they have pockets that can be targeted,” said Taipale. “For example, when you have a cancer fusion of the transcription factor to the co-activator and you understand the co-activator that the transcription factor interacts with, you may be able to target the co-activator to halt cell proliferation.”

The research was supported by the Donnelly Centre startup funds, a Canada Foundation for Innovation John R. Evans Leaders Fund grant and the Canadian Institutes of Health Research.

Common diabetes drug not effective against early-stage breast cancer, researchers say

Christopher.Sorensen — Wed, 08 Dec 2021 03:53:19 +0000

Common diabetes drug not effective against early-stage breast cancer, researchers say

Christopher.Sorensen Tue, 12/07/2021 - 22:53

Cutline

(Photo by andresr via Getty Images)

Amanda Ferguson

Topic

Breaking Research

Princess Margaret Cancer Centre

Temerty Faculty of Medicine

Institute of Health Policy Management and Evaluation

Lunenfeld-Tanenbaum Research Institute

Breast Cancer

Cancer

Dalla Lana School of Public Health

Mount Sinai Hospital

Research and Innovation

University Health Network

A widely used and inexpensive type 2 diabetes drug, once hoped to hold enormous promise in treating breast cancer, does not prevent or stop the spread of the most common forms of the disease, according to new research.

The study, which has yet to be peer-reviewed, was led by Toronto researchers and run by the Canadian Cancer Trials Group under the umbrella of the Breast International Group network. It is the largest study of its kind to date, tracking more than 3,600 breast cancer patients from across Canada, the U.S., Switzerland and the U.K.

Pamela Goodwin (photo courtesy of Sinai Health)

The randomized, double-blind trial enrolled patients who were treated with two pills a day of either placebo or the diabetes drug metformin. Overall, researchers found the addition of metformin to standard breast cancer treatments did not improve outcomes in the two most common types of breast cancer, hormone receptor-positive or negative.

“The results tell us that metformin is not effective against the most common types of breast cancer and any off-label use of this drug for the treatment of these common types of breast cancer should be stopped,” said Pamela Goodwin, a professor in the department of medicine at the ��Ƶ’s Temerty Faculty of Medicine, who also is a medical oncologist at Sinai Health and a clinician scientist at the Lunenfeld-Tanenbaum Research Institute.

Goodwin presented the findings this week at the 2021 San Antonio Breast Cancer Symposium.

While metformin was found not to be effective in treating the most common forms of breast cancer, Goodwin said the trial found a potentially important result for individuals with a less common but aggressive form of the disease called HER2-positive breast cancer.

For this subtype of breast cancer, researchers found there was evidence that use of metformin for five years might lead to a reduction in deaths. HER2-positive cancer makes up about 20 per cent of all breast cancers.

“Metformin is not beneficial for use in most common breast cancers, but in the cases of HER2 positive breast cancer, our findings suggest it may be beneficial,” said Goodwin, who is also a professor in the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health.

“These results need to be replicated in future research before metformin is used as a breast cancer treatment, however, it could provide an additional treatment option for HER2-positive breast cancer,” said Goodwin.

Metformin belongs to a class of drugs called biguanides, which are used to treat high blood sugar or diabetes. Previous observational and pre-clinical studies suggested metformin may also reduce the risk of development and increase survival of some cancers, including breast cancer.

It was theorized the drug may slow breast cancer growth by improving patient metabolism, notably insulin levels, leading to reduced growth of cancer cells, or that it might impact cancer cells directly.

The results have been submitted for publication. A potential next step will be to prospectively test the impact of metformin in patients with HER2-positive breast cancer in a randomized clinical trial.

The multinational trial involved a large team of scientists including Goodwin and Vuk Stambolic, a professor of medical biophysics at U of T and at senior scientist at the Princess Margaret Cancer Centre, University Health Network.

Professors Wendy Parulekar and Bingshu Chen of Queen's University and the Canadian Cancer Trials Group were also involved with the study.

The research was funded by the Canadian Cancer Society Research Institute, National Cancer Institute (U.S.), Canadian Breast Cancer Foundation, Breast Cancer Research Foundation, Cancer Research UK, Hold’Em for Life Charity Challenge and Apotex (Canada).

Terry Fox to be celebrated on U of T’s Rehabilitation Sciences Building with one of five mural designs

Christopher.Sorensen — Wed, 20 Oct 2021 15:54:07 +0000

Terry Fox to be celebrated on U of T’s Rehabilitation Sciences Building with one of five mural designs

Christopher.Sorensen Wed, 10/20/2021 - 11:54

Cutline

Five proposals for a mural on the Rehabilitation Sciences Building feature art, as seen in this composite, by: Alexander Bacon and Que Rock; Emmanuel Jarus; Keitha Keeshig-Tobias Biizindam; Christiano De Araujo; and Jason Pinney.

Scott Anderson

Topic

City & Culture

Toronto Rehabilitation Institute

Lunenfeld-Tanenbaum Research Institute

John H. Daniels Faculty of Architecture

Mount Sinai Hospital

Occupational Therapy

Research & Innovation

University Health Network

The ��Ƶ has teamed up with the City of Toronto and the Legacy Art Project to commemorate Terry Fox, the Canadian hero who – with one leg amputated due to cancer – embarked on a quest to run across Canada in 1980 to raise money for cancer research.

The city recently unveiled five shortlisted designs – submitted by local artists – for a giant mural of Fox on the north side of the university’s Rehabilitation Sciences Building at 500 University Avenue.

When it’s finished, the mural will overlook part of the route where people gathered to cheer on Fox as he made his way to Nathan Phillips Square in downtown Toronto on July 11, 1980.

Darrell Fox, senior adviser to the Terry Fox Research Institute and Terry’s younger brother, says the Fox family was especially pleased to find a location for the mural on University Avenue with a connection to the university.

“It was Terry’s vision to support cancer research,” Fox told U of T News. “So, a ��Ƶ building is a fitting place for it.”

Fox added that his older brother probably would have felt sheepish about the towering mural of himself.

Artists participating in the mural project, including (from left) Alexander Bacon, Que Rock, Christiano De Araujo and Jason Pinney, as well as representatives for Keitha Keeshig-Tobias Biizindam and Emmanuel Jarus, pose for a picture with Darrell Fox (photo by Johnny Guatto)

“Terry would be quite embarrassed and uncomfortable with the recognition. He was always about raising one more dollar [for research]. But the mural will be in a location – on University Avenue and on a ��Ƶ building where research is happening – that will inspire others. He would have been happy about that.”

Barbara Fischer, executive director and chief curator of the U of T Art Centre and a member of the mural advisory committee, echoed Fox’s comments, noting that the mural’s location among several U of T partner hospitals “underscores and perhaps makes newly visible the role that hospitals, research centres and universities play in research that is very much at the heart of Terry Fox’s heroic achievement.”

Fischer, who is also a professor in the John H. Daniels Faculty of Architecture, Landscape, and Design, added that the mural will be “a wonderful marker … of the university’s dedication to contribute to and improve the health and well-being of the city and region.”

Jim Woodgett, the president and scientific director of the Terry Fox Research Institute, says raising funds for cancer research continues to be a priority since one in four Canadians will be diagnosed with cancer in their lifetimes – half of whom will die from it.

Over the past decade, the institute has provided tens of millions of dollars to support cancer research at the University Health Network and U of T – primarily to collaborations among small groups of scientists that other funding agencies don’t typically support.

Woodgett, himself a cancer researcher and a professor of medical biophysics at the Temerty Faculty of Medicine and a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute, says progress is incremental but new cancer therapies are becoming available thanks to ongoing research.

Toronto Mayor John Tory, who spoke at the event, commended the city’s partnership with the Legacy Art Project and U of T – part of the ArtworxTO initiative – as an example of how to bring together people and inspire them through public art.

“What Terry Fox did was so extraordinary, so courageous, so inspirational and so important,” said Tory, adding that the story of a heroic Canadian is an apt subject for a mural.

Mayor John Tory speaks at an event showcasing the mural project at U of T’s Rehabilitation Sciences Building on University Aveneue (Photo by Johnny Guatto)

In addition to the mural, U of T has worked with the city and other partners on a number of projects for ArtworxTO. They include an Indigenous public art installation on tree-protection hoardings in the Hart House Commons; exhibitions and programming at the U of T Art Museum on the St. George campus and at U of T Scarborough; and student-led research through U of T’s School of Cities to evaluate the Year of Public Art initiative that’s currently underway.

Terry Fox began his Marathon of Hope in 1980, with the goal of crossing the country from east to west by running at least 42 km a day and raising one dollar from every Canadian to support cancer research. He had completed 143 days and reached as far as Thunder Bay, Ont., when the spread of his cancer forced him to end his quest.

He died in 1981, from cancer, at the age of 22. Since then, Fox’s legacy has inspired millions of Canadians and others around the world to give to the Terry Fox Foundation, which has raised more than $850 million for cancer research.

Katrina Jang, who is pursuing a master’s degree in occupational therapy at U of T, spoke about how Fox’s hope and determination had inspired her.

“I want to be able to help, support and advocate for my future patients of all ages and abilities to engage in activities that are meaningful to them – even in the face of challenge and adversity,” she said at the event. “Terry’s values are something I’ll try to channel.”

The Toronto-based artists who were invited to submit mural designs are: Alexander Bacon and Que Rock, Christiano De Araujo, Keitha Keeshig-Tobias Biizindam, Emmanuel Jarus and Jason Pinney.

Pinney shared his own experience of being treated for childhood cancer at Sick Kids Hospital. “My family and I are grateful to Terry Fox for helping to normalize the conversation about cancer and the importance of early diagnosis,” he said at the event. “We’re grateful for the money he raised for research that helped save my life and so many others through research that continues to save lives today.”

Members of the public can view the mural concepts and share feedback until Oct. 31. A selection committee that includes Darrell Fox, Fischer and Jang will review the designs and consider feedback from the public before selecting a winner.

The mural is scheduled to be painted in the summer of 2022.

In memoriam: Louis Siminovitch, the father of genetic research in Canada

Christopher.Sorensen — Thu, 08 Apr 2021 15:28:46 +0000

In memoriam: Louis Siminovitch, the father of genetic research in Canada

Christopher.Sorensen Thu, 04/08/2021 - 11:28

Cutline

Louis Siminovitch was the first chair of what is now U of T's department of molecular genetics and the founding director of Sinai Health's Lunenfeld-Tanenbaum Research Institute (photo by Dave Chan/Sinai Health Foundation)

Amanda Ferguson

Jim Oldfield

Topic

Our Community

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Molecular Genetics

Mount Sinai Hospital

The ��Ƶ community is remembering University Professor Louis Siminovitch, a scientific visionary who was the first chair of what is today the department of molecular genetics in the Temerty Faculty of Medicine.

Siminovitch, who was also the founding director of the Lunenfeld-Tanenbaum Research Institute (LTRI) at Sinai Health, died this week nearly one year after celebrating his 100th birthday, which took place as COVID-19 forced the world to physically distance and scientists stepped up to confront the challenge of a lethal new virus.

Many former colleagues of “Lou,” as he was affectionately known, used the occasion to highlight his many contributions, and U of T established a catalyst trainee award in his name.

“Lou had a transformative impact on biomedical research in Canada and around the globe,” said Leah Cowen, associate vice-president, research and former chair of molecular genetics at U of T.

“He was relentless in his pursuit of research excellence, with an inspiring commitment to mentoring generations of scientists and leading scientific communities.”

As a molecular biologist and pioneer in human genetics, Siminovitch made important contributions in the fields of bacterial and animal virus genetics, human genetics and cancer research, publishing more than 200 papers.

His work helped uncover the genetic bases of muscular dystrophy and cystic fibrosis, and it laid the groundwork for genetic connections to cancer. “The better the science, the better the patient care,” Siminovitch used to say.

Siminovitch contributed to the Nobel Prize-winning work in molecular genetics of Jacques Monod and Andre Lwoff during his years at the Pasteur Institute in Paris. He was an inductee in the Canadian Medical Hall of Fame, and a Companion of the Order of Canada.

Daniel Drucker recalled that when he returned from a postdoctoral position at Harvard University in the 1980s to set up a lab in Toronto as a principal investigator, a colleague suggested he speak to Siminovitch.

“Lou didn’t know me but he was very generous of his time and he gave me valuable advice on grants and direction in research that continued for many years,” said Drucker, a professor in the department of medicine at the Temerty Faculty of Medicine and a senior investigator at LTRI.

“He was a strong, opinionated personality, and not everyone was thankful when, unsolicited, he told them what to do and when. But he was a huge force in building the modern molecular biology research ecosystem in Toronto, Canada and the world.”

Siminovitch was renowned as a mentor and researcher, but also as a scientific builder. He played key roles in establishing and developing several top research environments in Canada, including the Ontario Cancer Institute at Princess Margaret Hospital and The Hospital for Sick Children Research Institute.

At age 65, when others might have contemplated retirement, Siminovitch was at the top of his game. Mount Sinai recruited him to build an academic research institute and, as inaugural director, he attracted 25 of the globe’s most eminent scientists to the team. Thanks to his foundational efforts, LTRI is today the top-ranked biomedical research institute in Canada.

“Canadian biomedical research owes a huge debt to Lou,” said Jim Woodgett, a professor of medical biophysics at the Temerty Faculty of Medicine and former Koffler director of research at LTRI. “He instilled the importance of mentorship, of quality, and of balance – and inspired us all to fulfill our potential. His impact will live on in the many scientists and leaders he inspired.”

A giant of science, Siminovitch was also a well-rounded individual with wide-ranging interests in the arts and a deep commitment to family. The Elinore and Lou Siminovitch Prize in Theatre bears his name and that of his late wife, a highly respected playwright.

Even in his final years, Siminovitch could still be found regularly at LTRI – often in the office of his daughter, Katherine Siminovitch, professor of medicine and immunology at the Temerty Faculty of Medicine and senior investigator at LTRI.

“Lou’s leadership to the scientific and academic community changed so many careers,” said Gary Newton, president and CEO of Sinai Health. “His work shaped Canadian medicine in a very profound way and his impact can be seen every day in the halls and labs of Mount Sinai Hospital.”

Mount Sinai Hospital will mark its 100th anniversary in 2023, and the hospital’s foundation is honouring Siminovitch’s achievements through a Sinai 100 Chair in his name.

At U of T, the department of molecular genetics will offer the Dr. Lou Siminovitch Catalyst Award on a competitive basis to the best acclaimed senior PhD student (3rd year or beyond), working in the broad area of genetics who demonstrates a commitment to mentorship and the importance of mentorship in enabling their scientific career.