Pathway to Prevent Mono-Related Cancer

Pathway to Prevent Mono-Related Cancer

Research at the University of Toronto has led to the discovery of a possible path to prevent the development of cancers tied to the Epstein-Barr virus, which infects millions of people a year and causes mononucleosis.

Professor Lori Frappier

Published in Nature Microbiology, the research focuses on how the Epstein-Barr virus, along with the Kaposi’s sarcoma associated herpesvirus shield themselves from destruction inside the human body.

The two viruses remain in people for life, although mostly in a dormant state. However, the viruses can also lead to abnormal, cancer-causing cell growth -- about half of Hodgkin’s disease cases are tied to the Epstein-Barr virus. Lori Frappier, a professor in the Department of Molecular Genetics, along with her students, Jaime Yockteng Melgar and Natasha Malik-Soni, and co-authors at the University of Minnesota, discovered a way to suppress these viral infections.

The researchers discovered that both viruses produce defense proteins that inhibit an enzyme in humancells that would normally mutate and ultimately destroy these invaders. Using CRISPR gene editing, they were able to turn off the viral defense protein, allowing the enzyme to stop the virus from reproducing uncontrollably. They are now working on replicating these results in animals.

“Epstein-Barr virus expresses many proteins with unknown functions”, says Frappier. “We ended up finding a completely unexpected function of an Epstein-Barr virus and Kaposi’s sarcoma virus protein in disabling a cellular enzyme that can disrupt the integrity for both viral and cellular DNA. This is a great example of how an unbiased basic science experiment can lead to novel therapeutic opportunities."

The researchers hope their discovery will lead to a treatment for Epstein-Barr virus infection, which would prevent mono and the cancers associated with this infection.

Funding for this research was provided by the Canadian Institutes for Health Research, the Howard Hughes Medical Institute, the National Cancer Institute.

--Heidi Singer, with files from the University of Minnesota

Research at the University of Toronto has led to the discovery of a possible path to prevent the development of cancers tied to the Epstein-Barr virus, which infects millions of people a year and causes mononucleosis.

Professor Lori Frappier

Published in Nature Microbiology, the research focuses on how the Epstein-Barr virus, along with the Kaposi’s sarcoma associated herpesvirus shield themselves from destruction inside the human body.

The two viruses remain in people for life, although mostly in a dormant state. However, the viruses can also lead to abnormal, cancer-causing cell growth -- about half of Hodgkin’s disease cases are tied to the Epstein-Barr virus. Lori Frappier, a professor in the Department of Molecular Genetics, along with her students, Jaime Yockteng Melgar and Natasha Malik-Soni, and co-authors at the University of Minnesota, discovered a way to suppress these viral infections.

The researchers discovered that both viruses produce defense proteins that inhibit an enzyme in humancells that would normally mutate and ultimately destroy these invaders. Using CRISPR gene editing, they were able to turn off the viral defense protein, allowing the enzyme to stop the virus from reproducing uncontrollably. They are now working on replicating these results in animals.

“Epstein-Barr virus expresses many proteins with unknown functions”, says Frappier. “We ended up finding a completely unexpected function of an Epstein-Barr virus and Kaposi’s sarcoma virus protein in disabling a cellular enzyme that can disrupt the integrity for both viral and cellular DNA. This is a great example of how an unbiased basic science experiment can lead to novel therapeutic opportunities."

The researchers hope their discovery will lead to a treatment for Epstein-Barr virus infection, which would prevent mono and the cancers associated with this infection.

Funding for this research was provided by the Canadian Institutes for Health Research, the Howard Hughes Medical Institute, the National Cancer Institute.

--Heidi Singer, with files from the University of Minnesota

Pathway to Prevent Mono-Related Cancer
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Revealing the Molecular Mystery of Human Liver Cells

Revealing the Molecular Mystery of Human Liver Cells

A map of the cells in the human liver has been created by University of Toronto researchers and the University Health Network Transplant Program, revealing for the first time differences between individual cells at the molecular level which can have a profound impact on their behaviour in tissue, tumours and disease.

Assistant Professor Sonya MacParland, Associate Professor Ian McGilvray, Professor Gary Bader

The researchers, led by Assistant Professor Sonya MacParland, of Immunology and Laboratory Medicine and Pathobiology; Associate Professor Ian McGilvray, of Surgery; and Professor Gary Bader, of the Donnelly Centre for Cellular and Biomolecular Research, mapped out the cellular landscape of 8,444 individual cells obtained from the tissues of healthy deceased donor human livers.

“For the past 20 years, we have studied the liver as a soup of cells as opposed to its individual components. This makes it difficult to target individual cells that are driving liver disease,” says lead author MacParland, who is also a Scientist at the Toronto General Hospital Research Institute.

By examining the gene expression profiles of each of these cells – about 1,500 active genes per cell - the researchers found 20 distinct cell populations made up of hepatocytes, endothelial cells, cholangiocytes and various immune cells such as B cells, T cells and Natural Killer (NK) cells.

“These evaluations reveal new aspects of the immunobiology of the liver, such as the presence of two surprisingly distinct populations of liver resident macrophages (“big-eaters” of cellular debris) with inflammatory and non-inflammatory functions,” write the authors in their paper entitled, “Single Cell RNA Sequencing of human liver reveals distinct intrahepatic macrophage populations”, published today in Nature Communications.

“We present a comprehensive view of the liver at single cell resolution that outlines new characteristics of resident cells in the liver, and in particular provides a new map of the human hepatic immune microenvironment,” note the authors.

The authors will also make their research available to the Human Cell Atlas Project, an international, open-access, collaborative effort to map all human cells (www.humancellatlas.org) to help scientists understand how genetic variation impacts disease risk and influences health. Because it is an open, free resource for any researchers in the world, it will accelerate discoveries which will in turn inform new treatments and drug development.

As the Research Director of the UHN Transplant Program, McGilvray has performed hundreds of liver transplants and cancer surgeries. In order to advance treatment of liver disease, he says, scientists must understand how the liver functions at the most fundamental level of the single cell.

The variation between cells is huge, McGilvray explains, but in 2018, it is surprising how little we know about the liver’s cellular landscape. New treatments, reduction of transplant rejection rates and regenerative medicine solutions can only be found if scientists understand how liver cells develop and work together within tissues and biological systems, he argues.

The urgency to find alternative approaches is spurred on by the increasing burden of liver disease, he says. Up to 23 per cent of obese individuals are at risk of developing fatty liver with inflammation, for example, and more than 70 million people are chronically infected with hepatitis C.

In creating the liver map, the team had to overcome several challenges.

First, the project could only have been possible with a multidisciplinary team consisting of transplant surgeons, immunologists, hepatologists, computer scientists and genomics researchers from different institutions to develop the first-ever map of a solid organ.

major problem in studying the human liver is difficulty in accessing fresh tissue. Samples in the study were collected from deceased donor livers deemed acceptable for liver transplantation, with consent and ethics approvals. This makes it unique in the world, in contrast to the standard method of studying the liver from biopsy samples.

A third challenge is isolating single cells from liver tissue. Liver cells such as hepatocytes and others are delicate and often do not survive standard tissue extraction, which may involve chopping, separating and filtering of tissue into smaller parts. During this process, cells often die.

But with the experience gained in transplantation and painstaking trial and error work of many years, the researchers were able to develop the best protocols using enzyme mixtures to gently dislodge cells embedded in the spider web-like net of connective tissue of the liver, without actually harming the fragile cells themselves.

Only then could the team begin studying the molecular make-up of each cell individually. This step is absolutely essential in gaining a deeper understanding of how a small but critical change in a cell can precipitate a disease state within a complex mix of many other cells.

The latest technological advances helped the team to overcome the limitations of previous techniques such as genomics. Although it can analyze many cell types simultaneously “in bulk”, it cannot tease out the critical differences between cells or do so in combination with multiple other data.

The team reached out to colleagues in the Princess Margaret Genomics Centre with their 10X Genomics Chromium system which excels at the analysis of complex tissues and heterogeneous collections of cells, and to the Donnelly Centre’s Bader, who developed the state-of-the art data analysis pipeline and custom pathway analysis software for the project. They were then able to map out the genetic and molecular function of each cell and how each one contributes to overall liver function.

“We found some very cool things about the human liver that we did not expect,” says Dr. McGilvray. “Until this study, very little was known about what the liver macrophage – the ‘tank’ of the immune system that destroys foreign substances and co-ordinates the immune response - actually is. We found that there are two distinct populations of macrophages in the human liver, one which is pro-inflammatory and the other anti-inflammatory.”

This new understanding can help scientists to harness these two contrasting macrophages to, for example, achieve “tolerance” of a new donor organ, says McGilvray. For transplant recipients, he explains, in the future, clinicians may want to downregulate the pro-inflammatory cells and upregulate the anti-inflammatory cells so that the recipient does not reject the new organ, and even may not need to take as many or any immunosuppressive medications.

MacParland adds that the new liver map gives us a new understanding of many more populations of cells found in a normal liver. Eventually, she says, as the map becomes more and more detailed, we can compare these cells to those in a diseased liver.

Then, she says, we can answer the question: “How can we get the liver back to a normal state?”

The research was funded by: University of Toronto’s Medicine by Design initiative which receives funding from the Canada First Research Excellence Fund, funds from UHN’s Transplant Program, and the Toronto General & Western Hospital Foundation.

A map of the cells in the human liver has been created by University of Toronto researchers and the University Health Network Transplant Program, revealing for the first time differences between individual cells at the molecular level which can have a profound impact on their behaviour in tissue, tumours and disease.

Assistant Professor Sonya MacParland, Associate Professor Ian McGilvray, Professor Gary Bader

The researchers, led by Assistant Professor Sonya MacParland, of Immunology and Laboratory Medicine and Pathobiology; Associate Professor Ian McGilvray, of Surgery; and Professor Gary Bader, of the Donnelly Centre for Cellular and Biomolecular Research, mapped out the cellular landscape of 8,444 individual cells obtained from the tissues of healthy deceased donor human livers.

“For the past 20 years, we have studied the liver as a soup of cells as opposed to its individual components. This makes it difficult to target individual cells that are driving liver disease,” says lead author MacParland, who is also a Scientist at the Toronto General Hospital Research Institute.

By examining the gene expression profiles of each of these cells – about 1,500 active genes per cell - the researchers found 20 distinct cell populations made up of hepatocytes, endothelial cells, cholangiocytes and various immune cells such as B cells, T cells and Natural Killer (NK) cells.

“These evaluations reveal new aspects of the immunobiology of the liver, such as the presence of two surprisingly distinct populations of liver resident macrophages (“big-eaters” of cellular debris) with inflammatory and non-inflammatory functions,” write the authors in their paper entitled, “Single Cell RNA Sequencing of human liver reveals distinct intrahepatic macrophage populations”, published today in Nature Communications.

“We present a comprehensive view of the liver at single cell resolution that outlines new characteristics of resident cells in the liver, and in particular provides a new map of the human hepatic immune microenvironment,” note the authors.

The authors will also make their research available to the Human Cell Atlas Project, an international, open-access, collaborative effort to map all human cells (www.humancellatlas.org) to help scientists understand how genetic variation impacts disease risk and influences health. Because it is an open, free resource for any researchers in the world, it will accelerate discoveries which will in turn inform new treatments and drug development.

As the Research Director of the UHN Transplant Program, McGilvray has performed hundreds of liver transplants and cancer surgeries. In order to advance treatment of liver disease, he says, scientists must understand how the liver functions at the most fundamental level of the single cell.

The variation between cells is huge, McGilvray explains, but in 2018, it is surprising how little we know about the liver’s cellular landscape. New treatments, reduction of transplant rejection rates and regenerative medicine solutions can only be found if scientists understand how liver cells develop and work together within tissues and biological systems, he argues.

The urgency to find alternative approaches is spurred on by the increasing burden of liver disease, he says. Up to 23 per cent of obese individuals are at risk of developing fatty liver with inflammation, for example, and more than 70 million people are chronically infected with hepatitis C.

In creating the liver map, the team had to overcome several challenges.

First, the project could only have been possible with a multidisciplinary team consisting of transplant surgeons, immunologists, hepatologists, computer scientists and genomics researchers from different institutions to develop the first-ever map of a solid organ.

major problem in studying the human liver is difficulty in accessing fresh tissue. Samples in the study were collected from deceased donor livers deemed acceptable for liver transplantation, with consent and ethics approvals. This makes it unique in the world, in contrast to the standard method of studying the liver from biopsy samples.

A third challenge is isolating single cells from liver tissue. Liver cells such as hepatocytes and others are delicate and often do not survive standard tissue extraction, which may involve chopping, separating and filtering of tissue into smaller parts. During this process, cells often die.

But with the experience gained in transplantation and painstaking trial and error work of many years, the researchers were able to develop the best protocols using enzyme mixtures to gently dislodge cells embedded in the spider web-like net of connective tissue of the liver, without actually harming the fragile cells themselves.

Only then could the team begin studying the molecular make-up of each cell individually. This step is absolutely essential in gaining a deeper understanding of how a small but critical change in a cell can precipitate a disease state within a complex mix of many other cells.

The latest technological advances helped the team to overcome the limitations of previous techniques such as genomics. Although it can analyze many cell types simultaneously “in bulk”, it cannot tease out the critical differences between cells or do so in combination with multiple other data.

The team reached out to colleagues in the Princess Margaret Genomics Centre with their 10X Genomics Chromium system which excels at the analysis of complex tissues and heterogeneous collections of cells, and to the Donnelly Centre’s Bader, who developed the state-of-the art data analysis pipeline and custom pathway analysis software for the project. They were then able to map out the genetic and molecular function of each cell and how each one contributes to overall liver function.

“We found some very cool things about the human liver that we did not expect,” says Dr. McGilvray. “Until this study, very little was known about what the liver macrophage – the ‘tank’ of the immune system that destroys foreign substances and co-ordinates the immune response - actually is. We found that there are two distinct populations of macrophages in the human liver, one which is pro-inflammatory and the other anti-inflammatory.”

This new understanding can help scientists to harness these two contrasting macrophages to, for example, achieve “tolerance” of a new donor organ, says McGilvray. For transplant recipients, he explains, in the future, clinicians may want to downregulate the pro-inflammatory cells and upregulate the anti-inflammatory cells so that the recipient does not reject the new organ, and even may not need to take as many or any immunosuppressive medications.

MacParland adds that the new liver map gives us a new understanding of many more populations of cells found in a normal liver. Eventually, she says, as the map becomes more and more detailed, we can compare these cells to those in a diseased liver.

Then, she says, we can answer the question: “How can we get the liver back to a normal state?”

The research was funded by: University of Toronto’s Medicine by Design initiative which receives funding from the Canada First Research Excellence Fund, funds from UHN’s Transplant Program, and the Toronto General & Western Hospital Foundation.

Revealing the Molecular Mystery of Human Liver Cells
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Researcher James Till Receives International Honour

Researcher James Till Receives International Honour

James Till, Professor Emeritus in the Department of Medical Biophysics, is the inaugural recipient of the Edogawa-Niche Prize.

The international award recognizes a physician or scientist based on their contributions to interdisciplinary research leading to health care solutions in disease prevention, diagnosis or treatment.

Till will be officially honoured in Tokyo, Japan this weekend at the 2018 Nichi-In Centre for Regenerative Medicine (NCRM) NICHE International Stem Cells and Regenerative Medicine meeting.

Till and his collaborator, Professor Emeritus Ernest McCulloch, were first to find evidence of clone cells, which at the time they referred to as ‘lumps’, in the spleens of mice. They published their findings in Radiation Research in 1961. In 1963, the pair followed up with publications in Nature and the Journal of Cellular and Comparative Physiology, which established that the ‘lumps’ were in fact multilineage stem cells capable of self-renewal and becoming specialized cells.

Born in Lloydminster, Saskatchewan, Till received a Bachelor of Science at the University of Saskatchewan, where he also completed a Master of Science in physics in 1954. After finishing his PhD in biophysics at Yale University in 1957, Till was recruited to the Ontario Cancer Institute at Princess Margaret Hospital as a U of T postdoctoral fellow, where he began working with McCulloch.

Arthur Ham, who washead of the biological division at the Ontario Cancer Institute where Ernest and I were research recruits, encouraged us to get to know each other. Ernest made a great presentation to the group, which prompted me to volunteer to help him when he wanted to use our irradiation facility. That’s how the inspiration for our work began,” recalled Till, who would collaborate with McCulloch for more than 20 years.

Till and McCulloch’s work has had applications in the field of bone marrow transplantation, cancer treatment and the treatment of autoimmune disease and tolerance induction. He also helped blaze a trail for other ground-breaking scientists.

“Perhaps the greatest testimony to Dr. Till has been the training of other exceptional scientists. Including Professors Norman Iscove, Robert Phillips and Ron Worton to name a few,” said Gary Levy, a professor in the departments of Medicine, Immunology, Laboratory Medicine & Pathobiology. “As well, Toronto continues to be a great world stem cell centre.”

Levy, who is also the founding director of University of Toronto Transplant Institute and the CIHR Training Program in Regenerative Medicine, presented Till with a medal and plaque in Toronto last month. The award presentation will be videocast at the NCRM NICHE event on Sunday.

Upon receiving the award, Till dedicated the honour to his collaborator, McCulloch, who passed away in 2011.

“Ernest’s contributions to our team made our work possible. Without him, it wouldn’t have happened,” said Till.

The prize is awarded by the NCRM, which is devoted to research, training and clinical applications-protocol development in regenerative medicine with a special emphasis on stem, progenitor and autologous adult cells with regenerative capability. The institute provides a platform for collaboration between scientists across various specialties.

NCRM is an Indo-Japanese joint venture institute affiliated with Tamilnadu Dr. MGR Medical University and Acharya Nagarjuna University. In 2009, the institute entered a formal agreement for training students with the CIHR Training Program in Regenerative Medicine at U of T.

Till’s plaque and medal will be displayed at the Edogawa-Niche Hall of Fame, which is set to open in Tokyo next year.

Till was also awarded one million Japanese yen (approximately $11,800), which he donated back to NCRM NICHE to establish the Joyce and James Till Travel Grant, which will support travel and other associated necessities for young scholars from developing countries to take part in future NCRM NICHE events.

Till’s Edogawa-Niche prize is the most recent in a string of honours and appointments including:

  • Gairdner Foundation International Award, 1969
  • Officer, Order of Canada in 1994
  • Order of Ontario in 2006
  • Royal Society of London in 2000
  • Canadian Medical Hall of Fame in 2004
  • Albert Lasker Award for Basic Medical Research in 2005

James Till, Professor Emeritus in the Department of Medical Biophysics, is the inaugural recipient of the Edogawa-Niche Prize.

The international award recognizes a physician or scientist based on their contributions to interdisciplinary research leading to health care solutions in disease prevention, diagnosis or treatment.

Till will be officially honoured in Tokyo, Japan this weekend at the 2018 Nichi-In Centre for Regenerative Medicine (NCRM) NICHE International Stem Cells and Regenerative Medicine meeting.

Till and his collaborator, Professor Emeritus Ernest McCulloch, were first to find evidence of clone cells, which at the time they referred to as ‘lumps’, in the spleens of mice. They published their findings in Radiation Research in 1961. In 1963, the pair followed up with publications in Nature and the Journal of Cellular and Comparative Physiology, which established that the ‘lumps’ were in fact multilineage stem cells capable of self-renewal and becoming specialized cells.

Born in Lloydminster, Saskatchewan, Till received a Bachelor of Science at the University of Saskatchewan, where he also completed a Master of Science in physics in 1954. After finishing his PhD in biophysics at Yale University in 1957, Till was recruited to the Ontario Cancer Institute at Princess Margaret Hospital as a U of T postdoctoral fellow, where he began working with McCulloch.

Arthur Ham, who washead of the biological division at the Ontario Cancer Institute where Ernest and I were research recruits, encouraged us to get to know each other. Ernest made a great presentation to the group, which prompted me to volunteer to help him when he wanted to use our irradiation facility. That’s how the inspiration for our work began,” recalled Till, who would collaborate with McCulloch for more than 20 years.

Till and McCulloch’s work has had applications in the field of bone marrow transplantation, cancer treatment and the treatment of autoimmune disease and tolerance induction. He also helped blaze a trail for other ground-breaking scientists.

“Perhaps the greatest testimony to Dr. Till has been the training of other exceptional scientists. Including Professors Norman Iscove, Robert Phillips and Ron Worton to name a few,” said Gary Levy, a professor in the departments of Medicine, Immunology, Laboratory Medicine & Pathobiology. “As well, Toronto continues to be a great world stem cell centre.”

Levy, who is also the founding director of University of Toronto Transplant Institute and the CIHR Training Program in Regenerative Medicine, presented Till with a medal and plaque in Toronto last month. The award presentation will be videocast at the NCRM NICHE event on Sunday.

Upon receiving the award, Till dedicated the honour to his collaborator, McCulloch, who passed away in 2011.

“Ernest’s contributions to our team made our work possible. Without him, it wouldn’t have happened,” said Till.

The prize is awarded by the NCRM, which is devoted to research, training and clinical applications-protocol development in regenerative medicine with a special emphasis on stem, progenitor and autologous adult cells with regenerative capability. The institute provides a platform for collaboration between scientists across various specialties.

NCRM is an Indo-Japanese joint venture institute affiliated with Tamilnadu Dr. MGR Medical University and Acharya Nagarjuna University. In 2009, the institute entered a formal agreement for training students with the CIHR Training Program in Regenerative Medicine at U of T.

Till’s plaque and medal will be displayed at the Edogawa-Niche Hall of Fame, which is set to open in Tokyo next year.

Till was also awarded one million Japanese yen (approximately $11,800), which he donated back to NCRM NICHE to establish the Joyce and James Till Travel Grant, which will support travel and other associated necessities for young scholars from developing countries to take part in future NCRM NICHE events.

Till’s Edogawa-Niche prize is the most recent in a string of honours and appointments including:

  • Gairdner Foundation International Award, 1969
  • Officer, Order of Canada in 1994
  • Order of Ontario in 2006
  • Royal Society of London in 2000
  • Canadian Medical Hall of Fame in 2004
  • Albert Lasker Award for Basic Medical Research in 2005
Researcher James Till Receives International Honour
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Cancer Survival and a Key Gene Mutation

Cancer Survival and a Key Gene Mutation

University of Toronto researchers have shone light on a well-known but mysterious gene that plays a key role in the growth of cancer.

Genes contain blueprints for making proteins, the molecules that actually carry out tasks in a cell. The p53 gene helps make a protein known as p53, which tells cells to grow or not. This protein helps stop tumours from growing.

Scientists and doctors have known about p53 for a long time, and that it plays a role in halting tumour growth.

But, the p53 has remained rather mysterious. Even though doctors have been aware that the p53 gene is the most frequently mutated gene when a person is diagnosed with cancer, and collect information about what mutations are present, they haven’t really known how best to use that information in their clinics.

The new study looked at decades of DNA analyses of the p53 gene in cancer patients and compared the survival data with how specific p53 gene mutations affect the way p53 protein works.

Researchers found a big variation in survival rates in men with stomach or brain cancer — depending how much of the activity of the p53 protein was lost due to a specific mutation. The key was the way it mutated.

Now physicians can look more closely at the gene and use the information to help discuss treatment options with patients and keep a closer eye on others who are at higher-risk for tumour growth.

“If p53 is mutated but still working at about 5 per cent, that is good news for patients,” says Professor Jean Gariépy, of the departments of Medical Biophysics and Pharmaceutical Sciences, and a senior scientist at Sunnybrook Research Institute. “If it’s known that p53 will do some of the work to suppress the tumour growth, perhaps other harsh forms of treatment can be avoided and the tumour can still be controlled.”

Think of it like a cellphone battery, Dr. Gariépy says.

“If you have 5 per cent battery left, you can still call 9-1-1. You can still send a text message. It’s only when you actually reach 0 per cent battery that you can no longer use the cell phone.”

The same seems to be the case with p53. Some mutations result in a p53 form that is still working well, while other mutations cause p53 to not work at all.

The researchers have now put together a chart of all the known p53 mutations observed in the clinic and categorized them based on their “battery power”.

“People with mutations that lead to a totally idle p53 have a poorer survival outcome and therefore might be considered for more aggressive treatment,” says Nicholas Fischer, a PhD student in Gariepy’s lab and lead author of the study.

The study is a great step towards more personalized treatment, he says: “We hope this data will help oncologists and their patients make better informed decisions about their care plan.”

University of Toronto researchers have shone light on a well-known but mysterious gene that plays a key role in the growth of cancer.

Genes contain blueprints for making proteins, the molecules that actually carry out tasks in a cell. The p53 gene helps make a protein known as p53, which tells cells to grow or not. This protein helps stop tumours from growing.

Scientists and doctors have known about p53 for a long time, and that it plays a role in halting tumour growth.

But, the p53 has remained rather mysterious. Even though doctors have been aware that the p53 gene is the most frequently mutated gene when a person is diagnosed with cancer, and collect information about what mutations are present, they haven’t really known how best to use that information in their clinics.

The new study looked at decades of DNA analyses of the p53 gene in cancer patients and compared the survival data with how specific p53 gene mutations affect the way p53 protein works.

Researchers found a big variation in survival rates in men with stomach or brain cancer — depending how much of the activity of the p53 protein was lost due to a specific mutation. The key was the way it mutated.

Now physicians can look more closely at the gene and use the information to help discuss treatment options with patients and keep a closer eye on others who are at higher-risk for tumour growth.

“If p53 is mutated but still working at about 5 per cent, that is good news for patients,” says Professor Jean Gariépy, of the departments of Medical Biophysics and Pharmaceutical Sciences, and a senior scientist at Sunnybrook Research Institute. “If it’s known that p53 will do some of the work to suppress the tumour growth, perhaps other harsh forms of treatment can be avoided and the tumour can still be controlled.”

Think of it like a cellphone battery, Dr. Gariépy says.

“If you have 5 per cent battery left, you can still call 9-1-1. You can still send a text message. It’s only when you actually reach 0 per cent battery that you can no longer use the cell phone.”

The same seems to be the case with p53. Some mutations result in a p53 form that is still working well, while other mutations cause p53 to not work at all.

The researchers have now put together a chart of all the known p53 mutations observed in the clinic and categorized them based on their “battery power”.

“People with mutations that lead to a totally idle p53 have a poorer survival outcome and therefore might be considered for more aggressive treatment,” says Nicholas Fischer, a PhD student in Gariepy’s lab and lead author of the study.

The study is a great step towards more personalized treatment, he says: “We hope this data will help oncologists and their patients make better informed decisions about their care plan.”

Cancer Survival and a Key Gene Mutation
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Toronto-led study to change transfusion practices around the world

Toronto-led study to change transfusion practices around the world

A global study led by Toronto researchers is expected to change transfusion practices for cardiac surgery around the world to make more blood available, reduce costs and lead to similar or better outcomes. The study is published in the New England Journal of Medicine.

Lower thresholds for blood transfusions for cardiac surgery patients compared to traditional thresholds provide positive patient outcomes and safety at six months after surgery, according to the world’s largest research study on this topic.

The research found that in addition to providing good patient outcomes six months after hospital discharge, the lower threshold - known as ‘restrictive transfusion therapy’ - reduces the amount of blood transfused and money spent on blood per procedure. The higher, traditional threshold is called ‘liberal transfusion therapy.’

Physicians who practice the liberal transfusion approach give blood transfusions early in the surgery to prevent patients’ hemoglobin level from falling. Hemoglobin is the protein that allows red blood cells to deliver oxygen to body tissues. Physicians who practice a restrictive approach wait longer to see if the hemoglobin level remains stable or if the patient has further bleeding.

Professor David MazerThese findings were presented at the European Society of Cardiology Annual Congress in Munich, Germany by principal investigator David Mazer, a professor in the Departments of Anesthesia and Physiology. Mazer is also an anesthesiologist at St. Michael’s Hospitaland an associate scientist in its Keenan Research Centre for Biomedical Science.

“Our research question was, at what point does the risk of anemia, or the risk of a lower hemoglobin, outweigh the risk of transfusion?” Mazer said. “We wanted to know whether it is safe to let your hemoglobin go to a lower level before you transfuse. The answer is yes. It'll save blood, make blood more available, reduce costs of transfusion and result in similar or better outcomes."

This work builds on Mazer’s research published less than a year ago in the New England Journal of Medicine, which analyzed immediate postoperative patient outcomes. The randomized trial involved more than 5,200 patients at 74 sites in 19 countries and every continent in the world except Antarctica. At the six-month mark, data was available for 96 per cent of the patients.

Mazer co-led the study with Nadine Shehata, a professor in the Department of Laboratory Medicine and Pathobiology and hematologist at the Sinai Health System. The research team found no clinical or statistical difference in four patient outcomes (death, heart attack, stroke and new kidney failure), whether the patients had contemporary restrictive therapy or traditional liberal practices. In fact, use of the restrictive transfusion protocol during and after heart surgery may actually reduce the incidence of complications in older patients, including heart attack, stroke, kidney failure and death.

“This research has already started to change transfusion practice around the world,” said Mazer. “With this data at six months, we’ve proven the longer term safety of restrictive therapy. This approach has already been adopted into guidelines and will likely become the standard of care worldwide.”

The large size of this study provides Mazer and his team additional opportunity to answer several other important questions related to transfusion and cardiac surgery.

This study received funding from the Canadian Institutes of Heart Research, Canadian Blood Services, the National Health and Medical Research Council in Australia and the Health Research Council of New Zealand.

A global study led by Toronto researchers is expected to change transfusion practices for cardiac surgery around the world to make more blood available, reduce costs and lead to similar or better outcomes. The study is published in the New England Journal of Medicine.

Lower thresholds for blood transfusions for cardiac surgery patients compared to traditional thresholds provide positive patient outcomes and safety at six months after surgery, according to the world’s largest research study on this topic.

The research found that in addition to providing good patient outcomes six months after hospital discharge, the lower threshold - known as ‘restrictive transfusion therapy’ - reduces the amount of blood transfused and money spent on blood per procedure. The higher, traditional threshold is called ‘liberal transfusion therapy.’

Physicians who practice the liberal transfusion approach give blood transfusions early in the surgery to prevent patients’ hemoglobin level from falling. Hemoglobin is the protein that allows red blood cells to deliver oxygen to body tissues. Physicians who practice a restrictive approach wait longer to see if the hemoglobin level remains stable or if the patient has further bleeding.

Professor David MazerThese findings were presented at the European Society of Cardiology Annual Congress in Munich, Germany by principal investigator David Mazer, a professor in the Departments of Anesthesia and Physiology. Mazer is also an anesthesiologist at St. Michael’s Hospitaland an associate scientist in its Keenan Research Centre for Biomedical Science.

“Our research question was, at what point does the risk of anemia, or the risk of a lower hemoglobin, outweigh the risk of transfusion?” Mazer said. “We wanted to know whether it is safe to let your hemoglobin go to a lower level before you transfuse. The answer is yes. It'll save blood, make blood more available, reduce costs of transfusion and result in similar or better outcomes."

This work builds on Mazer’s research published less than a year ago in the New England Journal of Medicine, which analyzed immediate postoperative patient outcomes. The randomized trial involved more than 5,200 patients at 74 sites in 19 countries and every continent in the world except Antarctica. At the six-month mark, data was available for 96 per cent of the patients.

Mazer co-led the study with Nadine Shehata, a professor in the Department of Laboratory Medicine and Pathobiology and hematologist at the Sinai Health System. The research team found no clinical or statistical difference in four patient outcomes (death, heart attack, stroke and new kidney failure), whether the patients had contemporary restrictive therapy or traditional liberal practices. In fact, use of the restrictive transfusion protocol during and after heart surgery may actually reduce the incidence of complications in older patients, including heart attack, stroke, kidney failure and death.

“This research has already started to change transfusion practice around the world,” said Mazer. “With this data at six months, we’ve proven the longer term safety of restrictive therapy. This approach has already been adopted into guidelines and will likely become the standard of care worldwide.”

The large size of this study provides Mazer and his team additional opportunity to answer several other important questions related to transfusion and cardiac surgery.

This study received funding from the Canadian Institutes of Heart Research, Canadian Blood Services, the National Health and Medical Research Council in Australia and the Health Research Council of New Zealand.

Toronto-led study to change transfusion practices around the world
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U of T Summer Mentorship Program Creates Connections for Black and Indigenous Youth

U of T Summer Mentorship Program Creates Connections for Black and Indigenous Youth


Weaving needles into silicon skin pads isn’t what you’d expect many high school students to do on their summer break.

But this workshop in suturing — which creates strong, supportive connections to seal a wound — is just one example of the experiences offered by the U of T Summer Mentorship Program (SMP). It’s also a metaphor for the program’s goals.

Support and connection are key themes throughout the month-long program, which provides more than 70 high school students of Indigenous, African and other under-represented backgrounds with mentorship opportunities and hands-on experience in health sciences.

Idil Abdi, who will start grade 12 in Thornhill this fall, was among the group of aspiring health care professionals to take part in SMP this year. The group explored health-related professions – including medicine, nursing, public health and social work – through lab work, lectures and practical experience.

“I was eager to join SMP for a taste of university life,” says Abdi. “It surprised me to see all the academic options available in health sciences and I learned that with hard work and dedication, the possibilities are endless.”

Among the medical professionals the students met were paediatricians, radiation technologists and family doctors.

“It was incredible to see how they all support patients and have a positive impact on their lives,” says Jacob Fraser, an SMP participant who hopes to become a family doctor.

SMP also provides students with career services like resume and networking workshops. “Learning how to write a cover letter, present yourself and network was one of the highlights for me. These skills will help me navigate my way through the workforce today and later on in my profession,” says Tyler Cobbinah.

Since the program launched in 1994, more than 900 students have participated and 85 per cent of surveyed graduates have since begun working toward or completed a university degree.

SMP alumna Tonya-Leah Watts is starting her last year of undergraduate studies in biomedical sciences. Inspired by her time in the program, Watts is also preparing to write the Medical College Admissions Test.

“Where I grew up, I didn’t see people like me pursuing medicine. In SMP, I made connections with other people of colour who supported me outside of the program and helped me apply to university,” she says.

As it approaches its 25th year, SMP continues to be a catalyst for building strong connections between adolescents and health sciences and increasing the representation of Black and Indigenous people in medicine by investing in their success.

Husam Abdel-Qadir graduated from SMP in 1998 after immigrating from the Middle East. Today, he is a cardiologist and clinician-scientist who volunteers with U of T’s Diversity Mentorship Program and is the Director of Continuing Professional Development for the Black Physicians’ Association of Ontario.

“The SMP broke down barriers for me — I was exposed to Black leaders in health care who proved someone like me can be successful in medicine,” Abdel-Qadir says. “I want to keep the momentum going and continue to create a strong and supportive community for Black and Indigenous youth — showing them, they too can be a face in medicine.”   


Weaving needles into silicon skin pads isn’t what you’d expect many high school students to do on their summer break.

But this workshop in suturing — which creates strong, supportive connections to seal a wound — is just one example of the experiences offered by the U of T Summer Mentorship Program (SMP). It’s also a metaphor for the program’s goals.

Support and connection are key themes throughout the month-long program, which provides more than 70 high school students of Indigenous, African and other under-represented backgrounds with mentorship opportunities and hands-on experience in health sciences.

Idil Abdi, who will start grade 12 in Thornhill this fall, was among the group of aspiring health care professionals to take part in SMP this year. The group explored health-related professions – including medicine, nursing, public health and social work – through lab work, lectures and practical experience.

“I was eager to join SMP for a taste of university life,” says Abdi. “It surprised me to see all the academic options available in health sciences and I learned that with hard work and dedication, the possibilities are endless.”

Among the medical professionals the students met were paediatricians, radiation technologists and family doctors.

“It was incredible to see how they all support patients and have a positive impact on their lives,” says Jacob Fraser, an SMP participant who hopes to become a family doctor.

SMP also provides students with career services like resume and networking workshops. “Learning how to write a cover letter, present yourself and network was one of the highlights for me. These skills will help me navigate my way through the workforce today and later on in my profession,” says Tyler Cobbinah.

Since the program launched in 1994, more than 900 students have participated and 85 per cent of surveyed graduates have since begun working toward or completed a university degree.

SMP alumna Tonya-Leah Watts is starting her last year of undergraduate studies in biomedical sciences. Inspired by her time in the program, Watts is also preparing to write the Medical College Admissions Test.

“Where I grew up, I didn’t see people like me pursuing medicine. In SMP, I made connections with other people of colour who supported me outside of the program and helped me apply to university,” she says.

As it approaches its 25th year, SMP continues to be a catalyst for building strong connections between adolescents and health sciences and increasing the representation of Black and Indigenous people in medicine by investing in their success.

Husam Abdel-Qadir graduated from SMP in 1998 after immigrating from the Middle East. Today, he is a cardiologist and clinician-scientist who volunteers with U of T’s Diversity Mentorship Program and is the Director of Continuing Professional Development for the Black Physicians’ Association of Ontario.

“The SMP broke down barriers for me — I was exposed to Black leaders in health care who proved someone like me can be successful in medicine,” Abdel-Qadir says. “I want to keep the momentum going and continue to create a strong and supportive community for Black and Indigenous youth — showing them, they too can be a face in medicine.”   

U of T Summer Mentorship Program Creates Connections for Black and Indigenous Youth
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Remembering Paul Walfish

Remembering Paul Walfish

Professor Emeritus Paul Walfish
The University of Toronto is remembering a leader in thyroid research, Professor Emeritus Paul G. Walfish, who died on Saturday of blood cancer. He was 83.

“Paul has left a lasting legacy to U of T Medicine as a student, teacher and researcher,” said Trevor Young, dean of the Faculty of Medicine and vice-provost, relations with health care institutions. 

“He was recognized globally for his landmark work in endocrinology, and he has helped to improve health care in Canada, especially for newborn infants. Paul’s commitment to his work and service to our community and profession will be missed.”  

Walfish received his medical degree from the University of Toronto before completing his residency in internal medicine. He was then awarded a McLaughlin Foundation Fellowship and furthered his clinical studies in endocrinology at Harvard Medical School.

He joined U of T’s department of medicine as a clinical teacher and founded the department of nuclear medicine at Mount Sinai Hospital in 1965, where he would work for more than 50 years. He was appointed full professor in 1982, and became professor emeritus in the departments of medicine, pediatrics, laboratory medicine and pathobiology and otolaryngology – head and neck surgery in 2002.

Walfish’s early-career research focused on carbohydrate and lipid metabolism. His work laid the foundation for the discovery of a new way to detect congenital hypothyroidism (CH) – a condition that affects approximately one in 3,600 infants and can be easily treated with daily medication. Walfish and his collaborator Dr. Jean Dussault pioneered a new application for the heel prick blood test to detect CH a few days after birth.

Between 1978 and 1983, Walfish helped Ontario become one of the world’s first jurisdictions to establish a province-wide newborn screening program for CH. The test is now used around the world, and has saved millions of babiesfrom CH-related developmental disabilities. In Ontario, newborn screening is now used to diagnose at least 29 rare diseases, helping infants receive early treatment and achieve healthier outcomes.

In 1976, Walfish was part of a team who helped introduce fine needle aspiration biopsy to North America to detect thyroid cancer early.

Walfish also pioneered the use of a blood biomarker called thyroglobulin to distinguish which patients need radioactive iodine treatment. Prior to this finding, a patient’s age or a tumour’s size determined the need for radiation. The finding has saved many patients with low-risk thyroid cancer from being hospitalized for treatments that have a potential for serious side effects and has become the new standard of care.

Walfish also broadened his focus to other kinds of biomarkers, including those for oral cancer. In collaboration with Professor Ranju Ralhan of the department of otolaryngology, he identified a protein that can help determine the aggressiveness of an oral dysplastic lesion, predict which lesions might lead to cancer and identify patients who would benefit from early intervention.

Over the course of his career, Walfish also established a database of all of the thyroid cancer cases he has treated. He has followed the patients through the years to find new information about the disease and how it responds to treatment.                     

Walfish was elected Fellow of The Royal Society of Medicine in Endocrinology Section in 1986. Among his many other honours and awards are the Order of Canada, the Order of Ontario, the March of Dimes’ Jonas Salk Prize, the Paul Starr Award from the American Thyroid Association and the Canadian Medical Association Medal of Service.

Professor Emeritus Paul Walfish
The University of Toronto is remembering a leader in thyroid research, Professor Emeritus Paul G. Walfish, who died on Saturday of blood cancer. He was 83.

“Paul has left a lasting legacy to U of T Medicine as a student, teacher and researcher,” said Trevor Young, dean of the Faculty of Medicine and vice-provost, relations with health care institutions. 

“He was recognized globally for his landmark work in endocrinology, and he has helped to improve health care in Canada, especially for newborn infants. Paul’s commitment to his work and service to our community and profession will be missed.”  

Walfish received his medical degree from the University of Toronto before completing his residency in internal medicine. He was then awarded a McLaughlin Foundation Fellowship and furthered his clinical studies in endocrinology at Harvard Medical School.

He joined U of T’s department of medicine as a clinical teacher and founded the department of nuclear medicine at Mount Sinai Hospital in 1965, where he would work for more than 50 years. He was appointed full professor in 1982, and became professor emeritus in the departments of medicine, pediatrics, laboratory medicine and pathobiology and otolaryngology – head and neck surgery in 2002.

Walfish’s early-career research focused on carbohydrate and lipid metabolism. His work laid the foundation for the discovery of a new way to detect congenital hypothyroidism (CH) – a condition that affects approximately one in 3,600 infants and can be easily treated with daily medication. Walfish and his collaborator Dr. Jean Dussault pioneered a new application for the heel prick blood test to detect CH a few days after birth.

Between 1978 and 1983, Walfish helped Ontario become one of the world’s first jurisdictions to establish a province-wide newborn screening program for CH. The test is now used around the world, and has saved millions of babiesfrom CH-related developmental disabilities. In Ontario, newborn screening is now used to diagnose at least 29 rare diseases, helping infants receive early treatment and achieve healthier outcomes.

In 1976, Walfish was part of a team who helped introduce fine needle aspiration biopsy to North America to detect thyroid cancer early.

Walfish also pioneered the use of a blood biomarker called thyroglobulin to distinguish which patients need radioactive iodine treatment. Prior to this finding, a patient’s age or a tumour’s size determined the need for radiation. The finding has saved many patients with low-risk thyroid cancer from being hospitalized for treatments that have a potential for serious side effects and has become the new standard of care.

Walfish also broadened his focus to other kinds of biomarkers, including those for oral cancer. In collaboration with Professor Ranju Ralhan of the department of otolaryngology, he identified a protein that can help determine the aggressiveness of an oral dysplastic lesion, predict which lesions might lead to cancer and identify patients who would benefit from early intervention.

Over the course of his career, Walfish also established a database of all of the thyroid cancer cases he has treated. He has followed the patients through the years to find new information about the disease and how it responds to treatment.                     

Walfish was elected Fellow of The Royal Society of Medicine in Endocrinology Section in 1986. Among his many other honours and awards are the Order of Canada, the Order of Ontario, the March of Dimes’ Jonas Salk Prize, the Paul Starr Award from the American Thyroid Association and the Canadian Medical Association Medal of Service.

Remembering Paul Walfish
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Smarter Radiation Therapy With Artificial Intelligence

Smarter Radiation Therapy With Artificial Intelligence

Beating cancer is a race against time. Developing radiation therapy plans — individualized maps that help doctors determine where to blast tumours — can take days. Now, Aaron Babier, a PhD candidate in Engineering, has developed automation software that aims to cut the time down to mere hours.

Aaron Babier (MIE PhD candidate) demonstrates his AI-based software’s visualization capabilities. (Credit: Brian Tran)

He, along with co-authors Justin Boutilier, Professor Timothy Chan, of the Faculty of Applied Science and Engineering,  and Assistant Professor Andrea McNiven, of Radiation Oncology, are looking at radiation therapy design as an intricate — but solvable — optimization problem.

Their software uses artificial intelligence (AI) to mine historical radiation therapy data. This information is then applied to an optimization engine to develop treatment plans. The researchers applied this software tool in their study of 217 patients with throat cancer, who also received treatments developed using conventional methods.

The therapies generated by Babier’s AI achieved comparable results to patients’ conventionally planned treatments. — and it did so within 20 minutes. The researchers recently published their findings in Medical Physics.

“There have been other AI optimization engines that have been developed. The idea behind ours is that it more closely mimics the current clinical best practice,” says Babier.

If AI can relieve clinicians of the optimization challenge of developing treatments, more resources are available to improve patient care and outcomes in other ways. Health-care professionals can divert their energy to increasing patient comfort and easing distress.

“Right now treatment planners have this big time sink. If we can intelligently burn this time sink, they’ll be able to focus on other aspects of treatment. The idea of having automation and streamlining jobs will help make health-care costs more efficient. I think it’ll really help to ensure high-quality care,” says Babier.

Babier and his team believe that with further development and validation, health-care professionals can someday use the tool in the clinic. They maintain, however, that while the AI may give treatment planners a brilliant head start in helping patients, it doesn’t make the trained human mind obsolete. Once the software has created a treatment plan, it would still be reviewed and further customized by a radiation physicist, which could take up to a few hours.

“It is very much like automating the design process of a custom-made suit,” explains Chan. “The tailor must first construct the suit based on the customer’s measurements, then alter the suit here and there to achieve the best fit. Our tool goes through a similar process to construct the most effective radiation plan for each patient.”

Trained doctors, and often specialists, are still necessary to fine-tune treatments at a more granular level and to perform quality checks. These roles still lie firmly outside the domain of machines.

For Babier, his research on cancer treatment isn’t just an optimization challenge.

“When I was 12 years old, my stepmom passed away from a brain tumour,” Babier says.

“I think it’s something that’s always been at the back of my head. I know what I want to do, and that’s to improve cancer treatment. I have a family connection to it. It adds a human element to the research,” says Babier.

Beating cancer is a race against time. Developing radiation therapy plans — individualized maps that help doctors determine where to blast tumours — can take days. Now, Aaron Babier, a PhD candidate in Engineering, has developed automation software that aims to cut the time down to mere hours.

Aaron Babier (MIE PhD candidate) demonstrates his AI-based software’s visualization capabilities. (Credit: Brian Tran)

He, along with co-authors Justin Boutilier, Professor Timothy Chan, of the Faculty of Applied Science and Engineering,  and Assistant Professor Andrea McNiven, of Radiation Oncology, are looking at radiation therapy design as an intricate — but solvable — optimization problem.

Their software uses artificial intelligence (AI) to mine historical radiation therapy data. This information is then applied to an optimization engine to develop treatment plans. The researchers applied this software tool in their study of 217 patients with throat cancer, who also received treatments developed using conventional methods.

The therapies generated by Babier’s AI achieved comparable results to patients’ conventionally planned treatments. — and it did so within 20 minutes. The researchers recently published their findings in Medical Physics.

“There have been other AI optimization engines that have been developed. The idea behind ours is that it more closely mimics the current clinical best practice,” says Babier.

If AI can relieve clinicians of the optimization challenge of developing treatments, more resources are available to improve patient care and outcomes in other ways. Health-care professionals can divert their energy to increasing patient comfort and easing distress.

“Right now treatment planners have this big time sink. If we can intelligently burn this time sink, they’ll be able to focus on other aspects of treatment. The idea of having automation and streamlining jobs will help make health-care costs more efficient. I think it’ll really help to ensure high-quality care,” says Babier.

Babier and his team believe that with further development and validation, health-care professionals can someday use the tool in the clinic. They maintain, however, that while the AI may give treatment planners a brilliant head start in helping patients, it doesn’t make the trained human mind obsolete. Once the software has created a treatment plan, it would still be reviewed and further customized by a radiation physicist, which could take up to a few hours.

“It is very much like automating the design process of a custom-made suit,” explains Chan. “The tailor must first construct the suit based on the customer’s measurements, then alter the suit here and there to achieve the best fit. Our tool goes through a similar process to construct the most effective radiation plan for each patient.”

Trained doctors, and often specialists, are still necessary to fine-tune treatments at a more granular level and to perform quality checks. These roles still lie firmly outside the domain of machines.

For Babier, his research on cancer treatment isn’t just an optimization challenge.

“When I was 12 years old, my stepmom passed away from a brain tumour,” Babier says.

“I think it’s something that’s always been at the back of my head. I know what I want to do, and that’s to improve cancer treatment. I have a family connection to it. It adds a human element to the research,” says Babier.

Smarter Radiation Therapy With Artificial Intelligence
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Addressing Unprofessional Behaviour Among Physicians

Addressing Unprofessional Behaviour Among Physicians

It’s not a topic anyone likes to discuss publicly – which is one of the reasons incivility, bullying and other forms of unprofessional behavior by physicians to physicians has persisted. To help turn the tide, University of Toronto researcher Sharon Straus and colleagues recently reviewed the scope of the problem and combed the scientific literature for possible solutions.

Professor Sharon Straus

Prof. Straus, a geriatrician at St. Michael’s Hospital and Vice-Chair, Mentorship, Equity and Diversity in the Department of Medicine, spoke with writer Heidi Singer about what she found.

How common is incivility among physicians?

The evidence shows when students and residents are in training, 60 percent of people experience at least one incident of harassment. When physicians are surveyed, up to 98 percent have experienced unprofessional behaviour. Most commonly, it comes from patients or their families. But it’s also perpetrated by co-workers and supervisors. It is unfortunately not an uncommon issue and has an impact on individuals.

What is the impact on medical students and residents?

When you experience unprofessional behaviour, it can lead to anxiety and depression and impacts workplace retention. Ultimately it can impact patient care, as people are under stress. In an academic centre we have to worry about the role modeling that happens for trainees. When they witness or experience this, how does that impact their behavior by seeing this behavior go unchecked? This is what we call the ‘hidden curriculum.’

What are some ways to address this behavior?

We did a literature review, and found 23 articles that were eligible for inclusion in our paper. Strategies mostly focused on targeting clinicians – generally by increasing awareness of unprofessional behaviour. But we know education is not sufficient to change behavior. There wasn’t a lot of specific work on how we address the behavior, particularly in ways that would lead to change. For example, only four studies targeted the organization. We have to address this behavior on an institutional level – like making sure we have explicit transparent processes for victims of these behaviors to come forward. And institutions need clear timelines for addressing these issues, and support for remediation and rehabilitation for both the perpetrator and victim.

Another institutional change is tying professionalism to awards and promotions. In the Department of Medicine over last 18 months, we have made it a requirement that people have to have demonstrated professionalism to go forward for promotion or to pass their continuing faculty appointment review. This is critical. We also know from literature that if people are behaving unprofessionally and this is a new pattern, we have to ask why the change. It’s a physician wellness issue.

Have you experienced unprofessional behaviour in your career?

When I was thinking of applying for geriatrics, I remember being told what a waste, why would I ever want to do that? Even as a trainee, I was being denigrated for choosing geriatric medicine. That’s probably one of the more gentle examples. Many of us have experienced comments because we’re women, like interviewing for a new job and right away being asked our age, marriage and family plans because of worries about how these might impact our job productivity.

Do you think unprofessional behaviour is getting better or worse?

That 60 per cent figure for trainees has been constant over many years. But I do agree people now are feeling more comfortable coming forward and talking about it. The MeToo movement really highlighted how important it is to look at this, and how important this is to physician wellness and ultimately patient care.

It sounds like there’s reason for optimism.

Yes, over the last two years we’ve really been working to establish explicit and transparent processes in the hospitals and at the university, although we can always do a better job making clear what those processes are. And that there’s good communication between the hospitals and university.

It’s not a topic anyone likes to discuss publicly – which is one of the reasons incivility, bullying and other forms of unprofessional behavior by physicians to physicians has persisted. To help turn the tide, University of Toronto researcher Sharon Straus and colleagues recently reviewed the scope of the problem and combed the scientific literature for possible solutions.

Professor Sharon Straus

Prof. Straus, a geriatrician at St. Michael’s Hospital and Vice-Chair, Mentorship, Equity and Diversity in the Department of Medicine, spoke with writer Heidi Singer about what she found.

How common is incivility among physicians?

The evidence shows when students and residents are in training, 60 percent of people experience at least one incident of harassment. When physicians are surveyed, up to 98 percent have experienced unprofessional behaviour. Most commonly, it comes from patients or their families. But it’s also perpetrated by co-workers and supervisors. It is unfortunately not an uncommon issue and has an impact on individuals.

What is the impact on medical students and residents?

When you experience unprofessional behaviour, it can lead to anxiety and depression and impacts workplace retention. Ultimately it can impact patient care, as people are under stress. In an academic centre we have to worry about the role modeling that happens for trainees. When they witness or experience this, how does that impact their behavior by seeing this behavior go unchecked? This is what we call the ‘hidden curriculum.’

What are some ways to address this behavior?

We did a literature review, and found 23 articles that were eligible for inclusion in our paper. Strategies mostly focused on targeting clinicians – generally by increasing awareness of unprofessional behaviour. But we know education is not sufficient to change behavior. There wasn’t a lot of specific work on how we address the behavior, particularly in ways that would lead to change. For example, only four studies targeted the organization. We have to address this behavior on an institutional level – like making sure we have explicit transparent processes for victims of these behaviors to come forward. And institutions need clear timelines for addressing these issues, and support for remediation and rehabilitation for both the perpetrator and victim.

Another institutional change is tying professionalism to awards and promotions. In the Department of Medicine over last 18 months, we have made it a requirement that people have to have demonstrated professionalism to go forward for promotion or to pass their continuing faculty appointment review. This is critical. We also know from literature that if people are behaving unprofessionally and this is a new pattern, we have to ask why the change. It’s a physician wellness issue.

Have you experienced unprofessional behaviour in your career?

When I was thinking of applying for geriatrics, I remember being told what a waste, why would I ever want to do that? Even as a trainee, I was being denigrated for choosing geriatric medicine. That’s probably one of the more gentle examples. Many of us have experienced comments because we’re women, like interviewing for a new job and right away being asked our age, marriage and family plans because of worries about how these might impact our job productivity.

Do you think unprofessional behaviour is getting better or worse?

That 60 per cent figure for trainees has been constant over many years. But I do agree people now are feeling more comfortable coming forward and talking about it. The MeToo movement really highlighted how important it is to look at this, and how important this is to physician wellness and ultimately patient care.

It sounds like there’s reason for optimism.

Yes, over the last two years we’ve really been working to establish explicit and transparent processes in the hospitals and at the university, although we can always do a better job making clear what those processes are. And that there’s good communication between the hospitals and university.

Addressing Unprofessional Behaviour Among Physicians
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Faces of U of T Medicine: Kevin Wang

Faces of U of T Medicine: Kevin Wang

Kevin Wang and Dr. Michael YoungFor Kevin Wang, the idea of meeting some of his scientific heroes (and Nobel Laureates) had been a dream — until last month. The recent U of T MD/PhD graduate was among the first five Canadian scientists to be nominated to attend the Lindau Nobel Laureate Meeting. The annual event brings together about 40 Nobel Laureates and 600 undergraduate students, PhD candidates and post-doctoral researchers from 84 countries around the world. The idea is to foster dialogue and share knowledge and ideas across generations, cultures and disciplines. Wang, who began his residency in Internal Medicine here in Toronto earlier this month, shared his experience with U of T Medicine writer Erin Howe.

Is there anyone you were particularly excited to meet at Lindau?

This year, the 68th Lindau Nobel meeting, took place on the beautiful islands of Lindau and Mainau in Germany, featured laureates from the disciplines of medicine and physiology. As a cancer researcher and aspiring oncologist, I was particularly excited to meet Dr. Harold Varmus and Dr. Michael Bishop, who shared the Nobel prize in 1989 for their discovery of the first human oncogene, c-Src, a type of gene that has the potential to transform a cell in to a tumour cell. Their pioneering work ushered in a new era of cancer research, a field that I worked in and contributed to over the course of my MD/PhD training. I had the opportunity to meet and discuss with both laureates on the future of cancer research.

How exciting was the opportunity to meet and speak to Nobel Laureates?

It was truly a once in a lifetime experience. A definite highlight for me was interacting with Nobel Laureates, often in intimate settings. Through various formats including lectures, panel discussions, master classes and science walks, the meeting encouraged idea sharing between the Nobel Laureates and attendees. What I found most rewarding were the small group discussions where generations of scientists gathered in a small circle to share lessons learned over illustrious careers in scientific discovery. More than just the eureka moments, I had a glimpse into the triumphs and failures that led to their Nobel prize winning work.

As one of hundreds of guests at Lindau, what was it like to meet others who make up the ‘next generation of leading scientists’?

It was definitely a humbling experience. I thank my PhD supervisor, Professor Michael Taylor, and my sponsoring organizations, the Canadian Student Health Research Forum, Canadian Institute of Health Research and the Department of Laboratory Medicine and Pathobiology for this opportunity. What was most amazing about a meeting of this scale is that no matter what people’s language, gender, ethnicity or political affiliations were, everyone had a common goal — to advance scientific knowledge. Science allows us to search for the truth and understand who we are and our place in this world.

What do you see as the larger impact of these meetings? Will you keep in touch with any of the other young scientists you met?

I think meetings like this go beyond the exchange of scientific ideas and inspire young scientists to engage in our greater community. Many of the talks not only touch upon the scientific method, but also upon how science can be disseminated around the world. As scientists and medical doctors, we have a social responsibility to engage and educate the public. If more of us talk about issues like the benefits of vaccines or the harms of greenhouse gas emissions, perhaps more of the public will be able to get on board. A personal bonus from attending this meeting is that I had the privilege of meeting many brilliant young scientists with whom I’ve become great friends.

The guiding idea for this year’s meeting was that scientific evidence is an answer to ‘fake news’ — having been at the meeting, how has your thinking about science communications changed?

It was interesting to see how this odd concept of ‘fake news’ has spread from the US and espoused a toxic environment globally. On the last day of the conference, there was a panel discussion on ‘Strategies for Science Communication in a Post-Factual Era’. One of the panelists, Nobel Laureate Steven Chu, the former US Secretary of Energy, highlighted the importance of finding common ground when speaking with non-scientists. We live in an age where opinions are easily confused as facts, especially through social media. The traditional view that knowledge comes from a few individuals in positions of authority is no longer relevant today. I believe this creates an exciting opportunity for scientists to educate and learn from the public by avoiding jargon and using a common language to communicate.

What was the best part of your experience at the Lindau Nobel Laureate Meeting?

I thoroughly enjoyed learning about other disciplines relevant to medicine. It was fascinating to learn about the work that led to cryo-electron microscopy and characterization of G-protein coupled receptors, a discovery that led to most of the drugs we prescribe today. Perhaps the coolest moment was learning about how the structure and function of ribosomes was uncovered by Ada Yonath and colleagues, who won the Nobel prize in Chemistry in 2009. Her work today focuses on leveraging structural information to design new antibiotics to target the bacterial ribosome. I remember first learning about ribosomes as the engine of life in middle school — to hear the person who discovered it talk about the decades of research that led to that discovery was truly inspiring!

Kevin Wang and Dr. Michael YoungFor Kevin Wang, the idea of meeting some of his scientific heroes (and Nobel Laureates) had been a dream — until last month. The recent U of T MD/PhD graduate was among the first five Canadian scientists to be nominated to attend the Lindau Nobel Laureate Meeting. The annual event brings together about 40 Nobel Laureates and 600 undergraduate students, PhD candidates and post-doctoral researchers from 84 countries around the world. The idea is to foster dialogue and share knowledge and ideas across generations, cultures and disciplines. Wang, who began his residency in Internal Medicine here in Toronto earlier this month, shared his experience with U of T Medicine writer Erin Howe.

Is there anyone you were particularly excited to meet at Lindau?

This year, the 68th Lindau Nobel meeting, took place on the beautiful islands of Lindau and Mainau in Germany, featured laureates from the disciplines of medicine and physiology. As a cancer researcher and aspiring oncologist, I was particularly excited to meet Dr. Harold Varmus and Dr. Michael Bishop, who shared the Nobel prize in 1989 for their discovery of the first human oncogene, c-Src, a type of gene that has the potential to transform a cell in to a tumour cell. Their pioneering work ushered in a new era of cancer research, a field that I worked in and contributed to over the course of my MD/PhD training. I had the opportunity to meet and discuss with both laureates on the future of cancer research.

How exciting was the opportunity to meet and speak to Nobel Laureates?

It was truly a once in a lifetime experience. A definite highlight for me was interacting with Nobel Laureates, often in intimate settings. Through various formats including lectures, panel discussions, master classes and science walks, the meeting encouraged idea sharing between the Nobel Laureates and attendees. What I found most rewarding were the small group discussions where generations of scientists gathered in a small circle to share lessons learned over illustrious careers in scientific discovery. More than just the eureka moments, I had a glimpse into the triumphs and failures that led to their Nobel prize winning work.

As one of hundreds of guests at Lindau, what was it like to meet others who make up the ‘next generation of leading scientists’?

It was definitely a humbling experience. I thank my PhD supervisor, Professor Michael Taylor, and my sponsoring organizations, the Canadian Student Health Research Forum, Canadian Institute of Health Research and the Department of Laboratory Medicine and Pathobiology for this opportunity. What was most amazing about a meeting of this scale is that no matter what people’s language, gender, ethnicity or political affiliations were, everyone had a common goal — to advance scientific knowledge. Science allows us to search for the truth and understand who we are and our place in this world.

What do you see as the larger impact of these meetings? Will you keep in touch with any of the other young scientists you met?

I think meetings like this go beyond the exchange of scientific ideas and inspire young scientists to engage in our greater community. Many of the talks not only touch upon the scientific method, but also upon how science can be disseminated around the world. As scientists and medical doctors, we have a social responsibility to engage and educate the public. If more of us talk about issues like the benefits of vaccines or the harms of greenhouse gas emissions, perhaps more of the public will be able to get on board. A personal bonus from attending this meeting is that I had the privilege of meeting many brilliant young scientists with whom I’ve become great friends.

The guiding idea for this year’s meeting was that scientific evidence is an answer to ‘fake news’ — having been at the meeting, how has your thinking about science communications changed?

It was interesting to see how this odd concept of ‘fake news’ has spread from the US and espoused a toxic environment globally. On the last day of the conference, there was a panel discussion on ‘Strategies for Science Communication in a Post-Factual Era’. One of the panelists, Nobel Laureate Steven Chu, the former US Secretary of Energy, highlighted the importance of finding common ground when speaking with non-scientists. We live in an age where opinions are easily confused as facts, especially through social media. The traditional view that knowledge comes from a few individuals in positions of authority is no longer relevant today. I believe this creates an exciting opportunity for scientists to educate and learn from the public by avoiding jargon and using a common language to communicate.

What was the best part of your experience at the Lindau Nobel Laureate Meeting?

I thoroughly enjoyed learning about other disciplines relevant to medicine. It was fascinating to learn about the work that led to cryo-electron microscopy and characterization of G-protein coupled receptors, a discovery that led to most of the drugs we prescribe today. Perhaps the coolest moment was learning about how the structure and function of ribosomes was uncovered by Ada Yonath and colleagues, who won the Nobel prize in Chemistry in 2009. Her work today focuses on leveraging structural information to design new antibiotics to target the bacterial ribosome. I remember first learning about ribosomes as the engine of life in middle school — to hear the person who discovered it talk about the decades of research that led to that discovery was truly inspiring!

Faces of U of T Medicine: Kevin Wang
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