Faculty of Medicine

Researchers at the ��߲ݴ�ý have shown that an enzyme called RNA polymerase (Pol) II drives generation of the building blocks of ribosomes, the molecular machines that manufacture all proteins in cells based on the genetic code.

The discovery reveals a previously unknown function for the enzyme in the nucleolus, the site of ribosome manufacture inside of human cells, where the enzyme had not been seen before. Pol II is one of three RNA polymerases that together enable cells to transfer genetic information from DNA to RNA and then proteins.

“Our study redefines the division of labour among the three main RNA polymerases, by identifying Pol II as a major factor in the control of nucleolar organizations underlying protein synthesis,” said Karim Mekhail, a professor of laboratory medicine and pathobiology at U of T. “It also provides a tool for other researchers to interrogate the function of certain nucleic acid structures more precisely across the genome.”

The journal Nature published the results today.

Mekhail and his colleagues found that inside the nucleolus, Pol II enables the expression of ribosomal RNA genes – a key step in the creation of ribosomes, essential molecular complexes that make proteins in all cells. Pol II, they showed, generates R-loops – hybrid DNA-RNA structures – that directly shield ribosomal RNA genes from molecular disruptors called sense intergenic non-coding RNAs (or sincRNAs).

Those disruptors are produced by Pol I in intergenic, non-protein-coding sequences of DNA between genes, and they become more active in various conditions: disruption of Pol II, under environmental stress, and in Ewing sarcoma.

“Pol II puts the brakes on Pol I and prevents sincRNAs from ‘sinking’ the nucleolus,” said Mekhail, who holds the Canada Research Chair in Spatial Genome Organization. “That’s how we united the name and action of the disruptors in our discussions of this work.”

Mekhail and his team developed a new technology to test the function of R-loops at specific locations on chromosomes, which they dubbed the “red laser” system.

“The existing tool in the field would obliterate R-loops across the whole genome, but we wanted to test the function of R-loops associated with a given genetic locus,” said Mekhail. “We were able to turn an old technology into a modern laser-guided missile, which we are still working to further improve.”

Two U of T students were co-lead authors on the study – Karan (Josh) Abraham and Negin Khosraviani – and Mekhail said they made exceptional and complementary contributions to the research.

Abraham, an MD/PhD student, began work on the project in 2014.

“I pursued this work having observed enrichment of Pol II at ribosomal DNA genes in the nucleolus, which was compelling,” said Abraham, who will finish his medical training next year. “It’s incumbent upon every scientist to challenge existing models should the evidence support an alternate one.”

A doctoral student who joined the lab in 2018, Khosraviani said teamwork and time management were critical.

“We could not have completed this research without the help and dedication of our entire lab. Coordination with local and international collaborators was also essential.”

Mekhail’s team worked with colleagues across U of T and affiliated hospitals on the study, and with international collaborators at the University of Texas at San Antonio and the University of Miami.

Next steps based on this research could include exploration of sincRNAs and nucleolar disorganization as biomarkers for various cancers, and whether tumours with those features respond to drugs that target intergenic Pol I or II.

“COVID-19 has been devastating, but other diseases have not stopped,” said Mekhail, who temporarily closed his physical lab space during the pandemic but has continued working with his team to analyze and publish results. “For example, cancer is still rampant and affecting people’s lives. We have to do what we can and look forward to building on the progress we’ve made as soon as possible.”

This research was supported by the Canadian Institutes of Health Research, Canada Research Chairs, U.S. National Institutes of Health, Ontario Ministry of Research and Innovation, Ontario Graduate Scholarship Program, and Natural Sciences and Engineering Research Council of Canada.

Cancer cells adapt to lack of key nutrient, posing potential problems for drugmakers: U of T study

Christopher.Sorensen — Tue, 09 Jun 2020 15:21:34 +0000

Cancer cells adapt to lack of key nutrient, posing potential problems for drugmakers: U of T study

Christopher.Sorensen Tue, 06/09/2020 - 11:21

Cutline

Scanning electron micrograph of an apoptotic HeLa cell using a Zeiss Merlin HR-SEM. The images were created at the National Center for Microscopy and Imaging Research (photo by Tom Deerinck/NIH)

Jovana Drinjakovic

Topic

Donnelly Centre for Cellular & Biomolecular Research

Cancer can adapt its metabolism in a way that could overcome lipid-focused therapies being developed by drug companies, a ��߲ݴ�ý study has found.

“Several clinical trials have failed because metabolism is such an adaptive process by which cancer cells gain drug resistance,” says Michael Aregger, a co-lead author and research associate who is working with Jason Moffat, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research.

“[But] if you know how cells are able to adapt to perturbations, maybe we can target them more specifically to avoid resistance from developing.”

In addition to Moffat, the research was also led by Brenda Andrews and Charles Boone, University Professor and professor of molecular genetics at the Donnelly Centre, respectively, and Chad Myers, a professor of computer science at the University of Minnesota Twin Cities.

The study, published recently in the journal Nature Metabolism, is the first to investigate changes in cancerous cells as they adapt to a shortfall of critical nutrients such as fat molecules, or lipids, which make up the cell’s outer envelope.

When cancer cells are unable to make their own lipids, they gobble them up from their environment to ensure a steady supply of these essential building blocks, the study found. Lipids also serve as fuel and chemical signals for communication between cells, among other roles.

The switch in metabolism could be bad news for drugmakers seeking to target cancer by reducing its lipid reserves. In particular, drugs that inhibit an enzyme called FASN, for fatty acid synthase, involved in an early step of lipid synthesis, are being explored in patient trials. Fatty acids are precursors of larger lipid molecules and their production is increased in many cancers thanks to elevated FASN levels, which are also associated with poor patient prognosis.

The U of T study suggests that the effectiveness of FASN inhibitors could be short-lived owing to cancer’s ability to find another way to procure lipids.

“Because FASN is upregulated in many cancers, fatty acid synthesis is one of the most promising metabolic pathways to target,” says Keith Lawson, a co-lead author and PhD student in Moffat’s lab who is enrolled in the Surgeon-Scientist Program at the Faculty of Medicine. “Given that we know there is a lot of plasticity in metabolic processes, we wanted to identify and predict ways in which cancer cells can potentially overcome the inhibition of lipid synthesis.”

To block fatty acid synthesis, the researchers employed a human cell line from which the FASN coding gene was removed. Using the genome editing tool CRISPR, they deleted from these cells all 18,000 or so human genes, one by one, to find those that can compensate for the halt in lipid production. Such functional relationships are also referred to as “genetic interactions.”

Data analysis, performed by Maximilian Billmann, a co-lead author and a postdoctoral fellow in Myers’ lab at Minnesota-Twin Cities, revealed hundreds of genes that become essential when cells are starved of fat. Their protein products clustered into well-known metabolic pathways through which cells vacuum up dietary cholesterol and other lipids from their surroundings.

Cells’ intake of cholesterol has become textbook knowledge since it was discovered half a century ago, winning a Nobel Prize and inspiring the blockbuster class of drugs, statins, as well as many others. But the new study found that one component of this process remained overlooked all this time. The gene encoding was known as C12orf49, named after its location on chromosome 12. But the researchers re-named the gene LUR1, for lipid uptake regulator 1, and showed that it helps switch on a set of genes directly involved in lipid import.

“This was a big surprise to us that we were able to identify a new component of the process we thought we knew everything about,” says Aregger. “It really highlights the power of our global genetic interaction approach that allowed us to identify a new player in lipid uptake in a completely unbiased way.”

By coincidence, two groups working independently in New York and Amsterdam also linked C12orf49 to lipid metabolism, lending further support to the U of T researchers’ findings. The New York team published their findings in the same journal issue as Moffat and colleagues.

Inhibiting LUR1, or other components of lipid import, along with FASN could lead to more effective cancer treatments. Such combination therapies are thought to be less susceptible to emerging drug resistance because the cells would have to simultaneously overcome two obstacles – blocked lipid production and import – which has a lower probability of occurring.

“Therapeutic context that comes out of our work is that you should be targeting lipid uptake in addition to targeting lipid synthesis, and our work highlights some specific genes that could be candidates,” says Lawson.

The research was supported by the Canadian Institutes of Health Research, Ontario Research Fund, Canada Research Chairs Program and the U.S. National Institutes of Health.

COVID-19: U of T's 'virtual' Three Minute Thesis competition draws a crowd online

Christopher.Sorensen — Wed, 15 Apr 2020 13:14:36 +0000

COVID-19: U of T's 'virtual' Three Minute Thesis competition draws a crowd online

Christopher.Sorensen Wed, 04/15/2020 - 09:14

Cutline

More than 400 viewers tuned in live to support the 12 U of T finalists in the 3MT finals, held online this year because of COVID-19, while nearly 10,000 have viewed the event on Facebook since April 2, 2020 (photo by Madeline Taylor)

Sarah MacFarlane

Topic

Our Community

Cell and Systems Biology

Chemistry

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Graduate Students

School of Graduate Studies

The annual Three Minute Thesis (3MT) competition is a unique opportunity for graduate students to present their research to a panel of non-specialist judges in a compelling and accessible way – in just three minutes.

It’s a tall order, and this year things got even more challenging when the competition was moved online due to the COVID-19 pandemic.

Open to graduate students across Canada, the 3MT competition is divided into three levels: local, provincial and national. The finals of the ��߲ݴ�ý 3MT competition usually take place at the Isabel Bader Theatre, but Liam O’Leary, graduate programming co-ordinator at the School of Graduate Studies (SGS), knew that wouldn’t be possible this year. So, instead of cancelling the event, O’Leary and Paula Karger, a PhD student at U of T’s Centre for Comparative Literature and co-host of the 3MT finals, moved the competition online. They postponed the semi-finals by a week, using that time to help grad students prepare.

“We wanted to do practice sessions,” says O’Leary. “What works best for sound? Do presenters have to sit in front of their computers, or can they stand back? We went through all these questions with everybody and, eventually, we got to some solutions.

“I'm just so impressed with the graduate students. They really wanted to continue. It was a great collaborative effort. Everything that's happening with COVID-19 is really difficult, but it also pushed people to be creative. The graduate students were willing to try something new and so were we – so we just went for it.”

The finals took place on Zoom and Facebook Live on April 2, with more than 400 viewers tuning in to support the 12 U of T finalists. The event also included a special guest appearance from CBC Radio Ideas producers Tom Howell and Nicola Luksic, whose documentary series Ideas from the Trenches showcases the work of PhD students across Canada.

Amalia Gil from the Faculty of Applied Science & Engineering earned first place in the U of T finals for her presentation “Identifying Distractions in Surgery with Eye-tracking.” She will move on to the provincial finals at the University of Windsor, which have been postponed, but O’Leary is hopeful that the success of the U of T finals will encourage other institutions to consider virtual events.

Second place went to Chris Ahuja from the department of surgery in the Faculty of Medicine while Aaron Cabral from the department of chemistry in the Faculty of Arts & Science took third place.

“At first, I was apprehensive about the change to an online format since I had never presented in this way,” says Cabral. “However, SGS did a fantastic job in setting up the event and adapting to the new challenges of video conference presentations. It still felt interactive, as if we were all in the same room, and I found that everything went smoothly.

“It ended up being a benefit that it was online since we were able to broadcast it to so many people. I even had family members watch and cheer me on from their homes during the finals.”

See the full list of U of T finalists at the School of Graduate Studies website

“We had a great turnout and there were a lot of positive responses,” says O’Leary. “People thanked us for putting it on and providing some good news. These incredible scholars and the great research they're doing offer hope for the future.”

Public interest in the event is still going strong. To date, the Facebook livestream of the U of T 3MT finals has received nearly 10,000 views.

“It makes me really happy to know that thousands of people have now watched the livestream,” says Amir Arellano Saab of the department of cell and systems biology in the Faculty of Arts & Science, who was named the people’s choice winner for his presentation. “At times during grad school, you start to wonder if what you are doing is relevant to the general public. It is quite reassuring and encouraging to know that many people outside the university would be interested in hearing what I do and what I have to say about it.”

O’Leary says future events will likely be offered in a hybrid format, with both an in-person and livestream component. For now, SGS is continuing to move events online, including mindfulness meditation sessions and virtual coffee hours, which can be accessed through the Grad Room website.

"It’s nice to be able to work on something positive that helps with community building,” he says. “I think it's so valuable because being a student in these times is challenging. They’re still trying to be productive and write and do all the things they do as graduate students, but it's hard. Being able to offer something where they can connect with others is really important right now.

U of T researchers hunt for antivirals to treat COVID-19 patients

Christopher.Sorensen — Wed, 11 Mar 2020 14:58:03 +0000

U of T researchers hunt for antivirals to treat COVID-19 patients

Christopher.Sorensen Wed, 03/11/2020 - 10:58

Cutline

With the support of recent federal funding, Donnelly Centre researchers Sachdev Sidhu (centre), Wei Zhang (left) and Jacky Chung (right) are spearheading efforts to identify potential COVID-19 drugs (photo courtesy of Donnelly Centre)

Jovana Drinjakovic

Topic

Global Lens

Coronavirus

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Global

Hospital for Sick Children

Institute of Biomaterials and Biomedical Engineering

Molecular Genetics

Researchers from the ��߲ݴ�ý’s Donnelly Centre for Cellular and Biomolecular Research are working on developing antivirals that can combat the novel coronavirus outbreak.

Led by Sachdev Sidhu, a professor of molecular genetics, the team will apply their protein engineering technology to identify promising therapeutics.

“We have diverse expertise on our team from across U of T and the University of Manitoba, which is renowned for its virology research, and we have already demonstrated that we can engineer proteins that inhibit MERS, a related coronavirus,” says Sidhu, who, in addition to the Donnelly Centre holds cross appointments in the Faculty of Medicine and at the Institute of Biomaterials and Biomedical Engineering. “We will now expand on this work to design therapeutics for COVID-19.”

The team recently received almost $900,000 over two years from the federal government through a rapid funding competition announced on Feb. 10 to address the COVID-19 outbreak.

Sidhu is collaborating with Roman Melnyk, a senior scientist at the Hospital for Sick Children and assistant professor of biochemistry at U of T, and Brian Mark, a structural virologist and professor at the University of Manitoba. In a 2016 proof-of-principle study with Marjolein Kikkert, a virologist at Leiden University in the Netherlands, they applied a protein engineering pipeline developed by Sidhu’s team to create proteins that inhibit a related coronavirus that caused the Middle East Respiratory Syndrome (MERS) outbreak in 2012.

Wei Zhang, then a post-doctoral researcher in Sidhu’s lab and now an assistant professor at the University of Guelph, received a national innovation award for this research.

The researchers now plan to use the same strategy to battle the coronavirus behind the COVID-19 global health crisis, which the World Health Organization today declared a pandemic.

Since the outbreak began in China in late 2019, the virus has spread to every continent except Antarctica, with more than 120,000 confirmed cases and more than 4,000 deaths, according to the latest figures. And while researchers around the world are racing to develop a vaccine, that is only a part of the solution, Sidhu says.

“Even if a vaccine becomes available, not everyone is going to get vaccinated,” says Sidhu. “We see that with the flu – the vaccination rates are far from 100 per cent.” Should the virus become endemic and end up circulating in the population like the flu, medicines that stop the virus from replicating in an already infected person will be as important as vaccines, which prevent infection, according to Sidhu.

Jacky Chung, a research associate in the Sidhu lab, will spearhead the project by first engineering proteins that can inhibit the virus. The team will then search for small molecules that behave in the same way since they are easier to develop into therapeutics than proteins.

“It's important to get the therapeutic inside the cells, which is where the virus replicates,” says Chung. “And small molecules can get into cells much more readily than proteins, which are much larger.”

At the heart of the approach lies a protein called ubiquitin, named for being present in all plant and animal cells. Ubiquitin is an essential part of the cellular machinery that the virus hijacks for its own benefit. Upon infection, the virus releases proteins that interfere with human ubiquitin and allow it to bypass the host’s defence system and spread in the body.

To block the virus, the researchers will create synthetic ubiquitin variants (UbV) that thwart rather than aid its ability to replicate. By analyzing the molecular structures of different UbVs bound to the viral protein, they will gain clues into the kinds of small molecules that are most likely to be effective against the virus.

Sidhu says that, within two years, they should have candidate molecules that could be developed into therapeutics. “We know there are literally armies of medicinal chemists and various companies that could then optimize the molecule into a drug that can be given to humans,” says Sidhu who was previously at pharmaceutical giant Genentech and has founded six startups since joining the university.

'We're learning more every day': How U of T is leading efforts to understand – and respond to – COVID-19

Christopher.Sorensen — Tue, 10 Mar 2020 23:25:17 +0000

'We're learning more every day': How U of T is leading efforts to understand – and respond to – COVID-19

Christopher.Sorensen Tue, 03/10/2020 - 19:25

Cutline

From tracking its spread to developing new diagnostic tools and educating the public, U of T experts have been on the front lines of the battle to understand and ultimately respond to COVID-19 and the novel coronavirus behind it.

Topic

Factor-Inwentash Faculty of Social Work

Disease

Faculty of Arts & Science

Global

Laboratory Medicine and Pathobiology

Political Science

University Health Network

Startups

Sunnybrook Hospital

U of T Scarborough

As the world watches the spread of the COVID-19 virus, researchers from the ��߲ݴ�ý are at the forefront of monitoring, predicting, and managing the disease – from creating mathematical models that help predict its spread to working on rapid diagnostics and potential treatments.

They are also providing critical advice to world leaders – and the rest of us via numerous appearances on TV, radio and online news sources – on the best ways to respond to an outbreak that has so far sickened more than 114,000 on every continent except Antarctica and is responsible for more than 4,000 deaths.

While Canada has so far escaped the worst of the growing health crisis, with just 65 confirmed cases, Isaac Bogoch (left), a specialist in epidemiology and infectious diseases, says it’s only a matter of time before the novel coronavirus makes its presence felt here in a much larger way.

“In Canada, we're certainly not immune to this, and we will very likely see more and more imported cases into Canada as we see more cases throughout the world,” says Bogoch, who is an associate professor of medicine in the Faculty of Medicine and a clinician investigator at the Toronto General Hospital Research Institute, part of the University Health Network (UHN).

Understanding the virus and tracking its spread

In addition to making regular appearances in the media to help inform and educate a nervous public, Bogoch is one of a number of U of T researchers who is tracking the disease using official reports and computer models in an attempt to predict how bad the outbreak is likely to get. In January, he was first author on a study in the Journal of Travel Medicine that predicted the likely spread of the disease based on analyzing flights originating in or passing through Wuhan, China, which would later emerge as the epicentre of the outbreak, but at the time had only a few confirmed cases. The paper correctly predicted that the disease would soon spread to Bangkok, Hong Kong, Tokyo and Taipei.

BlueDot Health, founded by the Dalla Lana School of Public Health’s Kamran Khan, alerted its clients to the outbreak of an infectious illness in China about one week earlier than the World Health Organization (photo by TK)

Bogoch's co-authors on the paper included Kamran Khan, an associate professor at the Dalla Lana School of Public Health. Khan is the founder of a company called BlueDot that uses data analytics to track and predict infectious disease risk – essentially an automated global surveillance system that can peer into the future. The power of the technology was underscored when the company alerted its clients to the unusual outbreak of illness in China about a week before the World Health Organization alerted the world to the emergence of the novel coronavirus.

On Feb. 5, epidemiologists Ashleigh Tuite and David Fisman (both at left), both of the Dalla Lana School of Public Health, published a paper in the Annals of Internal Medicine that looked at data on the spread of the disease and concluded that it must have originated in November, a month earlier than previously thought. They also published an online model that allows researchers to test different assumptions about the novel coronavirus such as how infectious it is and how well control efforts are working.

“Modelling allows us to move from data to understanding,” says Fisman, who has also been a fixture on TV, radio and online publications in recent weeks. “You can easily do interventions or experiments on the population on your computer. And that can give you ideas, for example, about how you might slow this epidemic – what might be the impact of flattening the epidemic curve, for instance, so the epidemic is less fierce at any given point of time, but lasts longer?”

More recently, Bogoch, Khan, Fisman and Tuite wrote a paper to predict the size of the COVID-19 outbreak in Iran. At the time they wrote the paper, Iran had confirmed only 43 cases of the disease. But three international cases had also been traced back to Iran. Based on that number and an analysis of travel patterns, they calculated that Iran likely had 18,300 active cases. Since then, Iran has identified thousands of confirmed cases.

Despite successes like these, Bogoch points out that a lot is still unknown about the disease. For instance, although the mortality rate is reported at two to three per cent, the rate could go down as we discover that more people than we thought had mild cases of the disease and recovered without anyone knowing.

It's also difficult to say how widespread the disease will eventually become, or how it will compare in severity to other diseases such as SARS or the seasonal flu.

“I think we have to be careful and humble in our approach to this infection. We're learning more and more every day, and we don't have all the answers,” he says.

New tools to combat COVID-19

Robert Kozak and Samira Mubareka, both in U of T’s department of laboratory medicine and pathobiology and at Sunnybrook Health Sciences Centre, are working on new tools to help hospitals diagnose the virus more quickly (photo by Nick Iwanyshyn)

Beyond understanding the spread of COVID-19, there are several U of T researchers who are racing to develop new tools for physicians to combat the virus both here in Canada and around the world.

Samira Mubareka and her colleague Robert Kozak, both in U of T’s department of laboratory medicine and pathobiology in the Faculty of Medicine and at Sunnybrook Health Sciences Centre, are using the latest in whole-genome sequencing technology to help hospitals characterize the virus more quickly. The research also promises to help track the virus’s evolution and spread.

“If the virus’s genome was a book, we’re going to figure out its entire story,” Kozak told U of T News in late February.

At the same time, a U of T startup company that was co-founded by former PhD student Ali Punjani played a key role in helping researchers create the first 3D, atomic scale map of the part of the virus that attaches to and infects human cells – a key step toward developing a vaccine that some described as a “critical breakthrough.”

There will likely be more discoveries to come. Late last week, the federal government announced it was investing $27 million in coronavirus-related research, nearly $6 million of which is going to U of T and affiliated institutions.

Getting our act together

Ross Upshur, a researcher and bioethicist, says some of the responses to COVID-19 from governments have been questionable (photo courtesy of Dalla Lana School of Public Health)

Ross Upshur is a researcher and bioethicist with the Dalla Lana School of Public Health. He is especially interested in the ethics of responses to infectious disease outbreaks, and is chairing a World Health Organization working group on the topic.

Upshur says that the ethics of responses to emergencies like COVID-19 have been laid out in a number of recommendations and enjoy a general consensus. But he says that, with each new outbreak, there’s a tendency for governments tend to forget lessons of the past.

“Most outbreaks start out interesting, then they become weird, then they become weirder, but structurally the same sorts of issues arise again and again and again. That's the thing I find fascinating. When are we going to get our act together on this?”

Even though there are well-established ethical guidelines about the best ways to respond to disease outbreaks, Upshur says that governments never seem to remember those lessons from one outbreak to another.

For instance, measures to control the outbreak have been more restrictive than usual, and look more like security responses than public health measures. And Upshur thinks at least some of the measures are questionable. For instance, Japan quarantined 3,711 passengers and crew on the Diamond Princess cruise ship, and 705 eventually became sick. Upshur says an alternative would have been to send everyone home with thermometers and to check in with them daily. Such a measure was effective in dealing with a similar incident during an Ebola outbreak, he says.

Zoonotic disease

An assistant professor in the Faculty of Medicine, Kerry Bowman points to the widespread trade of wild animals as a contributor to a number of diseases, including SARS, Ebola, and now COVID-19 (photo by Jacklyn Atlas)

Kerry Bowman is an assistant professor of medicine and a bioethicist with an interest in the effects of environmental degradation and wild animal consumption on the spread of disease. Several years ago, he visited the market in Wuhan that is the epicentre of the disease and saw first-hand the wild animals for sale there.

He counted 56 species of animals for sale, wild and domestic, crowded together in stacked cages. Not only were the animals suffering, but the conditions were perfect for the spread of disease, he says.

Bowman acknowledged that there are cultural sensitivities around consumption of wild animals, and that it occurs in many countries, including eating of deer and other game animals in Canada. But he says the widespread trade of wild animals has contributed to a number of diseases, including SARS, Ebola, and now COVID-19. In each case, the disease seems to have originated in a wild animal being used for food.

“Unless we collectively begin to deal with the commodification of wildlife and the consumption of wildlife we are not going to get on top of this,” he says.

Politics and xenophobia

An associate professor of political science, Lynette Ong says China's government didn't respond well during the outbreak’s early days (photo by Riley Stewart)

Lynette Ong has been watching the effect of the outbreak on the Chinese government and its relationship with its citizens and other countries. The associate professor of political science says that China's centralized, authoritarian government did not initially respond well in the course of the outbreak.

“Because of the authoritarian nature of the political system, people are afraid to report bad news, even if it's the truth. People try to avoid responsibility,” she says. On the other hand, once the government is convinced there is a problem, it does have the ability to take strong measures.

She also thinks the outbreak has made Chinese citizens more interested in holding their government accountable. “This is an awakening moment in China for people as they become aware that information is controlled tightly. People are realizing that the information being controlled can affect them,” she says.

Almost as soon as people became aware of the outbreak in China, xenophobic and racist comments began circulating in Canada and elsewhere. Carmen Logie (left), an associate professor in the U of T's Factor-Inwentash Faculty of Social Work, told U of T News that fear of infection during disease outbreaks can amplify existing prejudices and intensify discriminatory behaviours

That was particulary the case during the initial days of the COVID-19 outbreak, when it was largely confined to Asia, and Chinese-Canadians were being unfairly targeted.

“We need a multi-pronged approach,” Logie says in the interview. “Yes, we need the information, but we also need to share how this is connected to our biases towards, say, Chinese people in Canada, as well as the negative impacts it's currently having on communities."

Bowman, who worked as a doctor during the SARS outbreak, says that racism was a factor then, too, and it is important to address it quickly.

"An outbreak is not just a biological event,” he says. “It's a political and sociological event as well, and an economic one. And sometimes the economic and social and political can be as powerful or even more destructive than the physical threat, and ‘us against them’ is something that sets in very quickly under this kind of pressure.”

Although he says he has seen racism emerge in similar ways to the SARS outbreak, he thinks that there was more and quicker pushback against it in the media and elsewhere. He also thinks that as the virus spreads to more countries, it will no longer be associated in people's minds solely with China.

Lessons from SARS?

Passengers on the deck of the Diamond Princess cruise ship, which recorded 705 infections and raised serious questions about Japan’s decision to quarantine thousands of people aboard the vessel (photo by Kyodo News via Getty Images)

Canada, not surprisingly, has tended to look at the COVID-19 outbreak through the lens of the 2003 SARS epidemic. But Bogoch points out that they are actually very different diseases. SARS tended to cause severe illness, and had a death rate of around 10 per cent. Coronavirus, on the other hand, usually comes with milder symptoms and a lower rate of death.

Nevertheless, the experience of SARS seems to have taught Canada important lessons that will help it control COVID-19.

“Our systems are so much more robust than they were in the time of SARS, just in terms of the coordination and communication between the various levels of public health and clinical medicine,” he says. “And the infection prevention and control initiatives in hospitals are much more robust now than they were.”

Upshur isn't so sure. He acknowledges that Canada has invested a great deal in public health since SARS, including creating the Public Health Agency of Canada and the position of chief public health officer. On the other hand, the Government of Ontario has proposed cutting funding for public health service.

“Public health is always the first to go because you don't notice it when it's working,” he says. “But woe on you when you start to mess with it. Because you pay the price every time.”

In the meantime, U of T experts will continue to be on the front lines of the current outbreak. That includes experts like Seema Yasmin, a former epidemic intelligence officer at the U.S. Centers for Disease Control and Prevention and global journalism fellow at U of T’s Munk School of Global Affairs & Public Policy, who has been a frequent commentator on U.S. media like CNN and Wired magazine.

It also includes Abdu Sharkawy, an assistant professor in the Faculty of Medicine and infectious disease specialist at Toronto Western Hospital, part of UHN, who recently penned a viral Facebook post that, if nothing else, is helping to keep the wall-to-wall coverage of the COVID-19 crisis in perspective.

Sharkawy argued that while the illness does indeed pose a danger, the panic surrounding it could ultimately do more damage. His prescription? “Facts not fear. Clean hands. Open hearts. Our children will thank us for it.”

How will the coronavirus spread? U of T epidemiologist deciphers 'messy data'

geoff.vendeville — Fri, 06 Mar 2020 16:20:58 +0000

How will the coronavirus spread? U of T epidemiologist deciphers 'messy data'

geoff.vendeville Fri, 03/06/2020 - 11:20

Cutline

(photo by Robert Atanasovski/AFP via Getty Images)

Geoffrey Vendeville

Topic

Coronavirus

Subheadline

David Fisman uses data and computer modelling to predict spread of COVID-19

When it comes to the tipping point for the spread of COVID-19, ��߲ݴ�ý epidemiologist David Fisman said: “We may have passed it.”

Since he made the comment in an interview with CBC’s Quirks & Quarks at the end of last month, more than 100,000 people have been infected around the world, most in China’s Hubei province. About 3,400 people have died of the disease as of Friday.

Fisman is a professor in the division of epidemiology in the Dalla Lana School of Public Health with cross-appointments at the Institute of Health Policy, Management and Evaluation and the department of medicine in the Faculty of Medicine.

He and a team of other epidemiologists, doctors, statisticians and public health experts use data analysis and computer modelling to understand parts of an epidemic that are hidden from view. For example, his group accurately predicted that the size of the outbreak in Iran was larger than originally reported.

Fisman and his colleagues were among the teams that received federal funding this week for research related to the novel coronavirus.

He spoke to U of T News about how the models work and why they're useful for health authorities and the public.

Can you briefly tell me about you and your colleagues’ experience dealing with previous outbreaks caused by other viruses: SARS, H1N1 and Ebola?

We've been involved in these outbreaks in a few different ways, but mostly on the modelling front. In SARS and H1N1 I also had some experience in government public health agencies, which provides valuable perspectives. But during SARS I was quarantined (briefly) in Toronto and started working on a simple model based on what I knew about chains of transmission; unfortunately the province wasn't willing to share data for modelling, and my former prof and current friend Marc Lipsitch from Harvard managed to get needed data from Singapore, which was also in the midst of a SARS outbreak. That resulted in an important paper in Science, which showed that SARS could be controlled.

During H1N1, Dr. Ashleigh Tuite and I worked on characterizing early epidemic dynamics and were able to develop models around optimal use and timing of vaccination. We also did a lot of work modelling emergence and control of Ebola in 2015 in West Africa.

Can you break down how your disease-transmission model works in layman's terms?

We use a lot of different kinds of models. Some just describe epidemic growth without worrying too much about what's happening under the hood; Ashleigh has developed a more realistic “compartmental” model where we think about the “flow” of people from susceptible to infected using approaches that physicists would use to model systems with feedback loops (so called disease dynamic models).

We are already using the compartmental model to project health resource use (hospital beds and ventilators) for Ontario and Canada and can also use the model as a platform for experiments related to things like social distancing –such as closing schools – and quarantines.

We also have some “forensic” statistical tools that we can use to infer underlying outbreak sizes in countries that aren't reporting a lot of cases, based on exports. At this stage of the epidemic we have been doing a lot of that.

How have you tested the accuracy of your forecasting so far, and how have your predictions compared to reality?

We were able to project the decline and end of the Chinese COVID outbreak in early March using a very simple model, fit to data up to Jan. 31. So our models do seem to work quite well in some contexts. We have also been modelling likely unreported epidemic sizes in countries like Iran which have been sources of large numbers of case exports and, unfortunately, our assessments have proved correct.

Your project uses public data that is often “messy or noisy”. Can you explain what you mean by that and why it’s sometimes hard for experts and policymakers to make sense of data behind disease outbreaks?

There's a lot that goes into public health surveillance; we get disease case counts but those are often the tip of the iceberg. We, and some of our colleagues in the U.K., are developing models that allow us to infer unseen components of surveillance systems (like the underlying chains of transmission that result in the cases that we can actually observe). The forensic statistics are an example of this, but we can also make inferences about likely underlying rates of disease progression (from onset to hospitalization to death, for example) based on crude death and case counts that may be put out by WHO and other organizations.

Based on your disease-transmission model, can you provide best and worst case scenarios for Canada?

We can. That's a great application for models.

How can your disease-transmission model be used by Canadian health agencies? What kinds of decisions would they make using your tool?

It can help them make decisions about control activities that involve short- and long-term trade-offs.

One line of your research proposal that really stuck out to me was the one about how your model can help reduce fear, xenophobia and anxiety surrounding the outbreak. Can you tell me how your model can help avoid a panic?

A big driver of fear during epidemics is uncertainty, and a feeling of lack of control. We can use models to dampen fear in a few ways: we can identify actions communities can take to protect themselves and we can demonstrate that epidemic curves are being bent downwards by interventions. We can also build apps that allow non-epidemiologists to explore how epidemics work, in order to understand them better.

U of T's Trey Coffey on how to support health-care workers when they need help themselves

Christopher.Sorensen — Wed, 05 Feb 2020 17:31:57 +0000

U of T's Trey Coffey on how to support health-care workers when they need help themselves

Christopher.Sorensen Wed, 02/05/2020 - 12:31

Cutline

Dr. Trey Coffey of U of T's Faculty of Medicine is involved in a peer support initiative at SickKids to help health-care workers who are experiencing mental health challenges (photo courtesy of Trey Coffey)

Ciara Parsons

Topic

Our Community

Hospital for Sick Children

Mental Health

Thanks to advocacy efforts and public outreach campaigns, mental health issues have shed much of the stigma they once carried.

Health-care providers have played an integral role in helping to transform the mental health-care system and educate the public about the importance of accessing services when they require care.

But who do doctors and other health-care providers turn to when they are experiencing mental health difficulties? In a field based around competency and that requires a high degree of resiliency, asking for help may not feel easy for some physicians.

In an effort to break down social barriers around mental health, health-care and academic institutions have looked to workplace-based peer support programs to help employees access care.

Dr. Trey Coffey, an associate professor at the ��߲ݴ�ý's Faculty of Medicine, pediatrician and medical officer for patient safety at the Hospital for Sick Children, spoke to writer Ciara Parsons about the importance of initiatives like SickKids' peer support program; the notion of the “second victim,” or how health-care providers suffer after being involved in a mistake or other adverse event on the job; and how to be an ally to those facing difficulties in the workplace.

What is the Peer Support and Trauma Program at SickKids?

The program officially launched in January 2018. The goal is to help improve staff members’ psychological health and safety and to provide them with a support system through a network of trained peers.

The program is open to anyone who wears a SickKids badge and can assist with a range of issues one might be encountering in a health-care setting, such as burnout, second victim distress and traumatic stress while also providing support for personal or family issues.

SickKids’ Peer Team is comprised of cross-disciplinary staff who volunteer their time to the program and act as supporters to their colleagues. Before taking up their roles as peer supporters, volunteers receive specialized training and certification in assessment, communication skills, trauma principles and trauma response.

Those who have experienced a traumatic or distressing event may engage in a critical incident debriefing enabling them to confidentially share and decompress about the incident. The role of the peer in these situations is to allow participants to process thoughts and reactions about the event, to validate and to provide information on common responses and self-care. If preferred, one-to-one support is available to colleagues. For staff requiring more assistance, a variety of professional counselling options are available.

The second phase of this program, which began in the spring of 2018, focuses on physician peer support.

What is a second victim?

The idea of the second victim refers to a physician or health-care worker who has been involved in an adverse event on the job. Second victim responses can sometimes spur feelings of guilt, distress, anxiety, fear and insufficiency.

Research focused on second victim responses explains that there are six stages of progression within the second victim phenomenon. They include:

Chaos and accident response: Error realized, distracted, possible need for others to take over treating patient
Intrusive reflections: Loss of confidence in self, feelings of inadequacy
Restoring personal integrity: Help is sought, but there is fear of how others will react
Enduring the inquisition: Internal investigation, fears about employment outcomes and litigation
Obtaining emotional first aid: Seeking and receiving professional support
Moving on: Dropping out, surviving or thriving

This research also suggests that second victims require formal support at the department or unit level, which is why peer support programs are often recommended to help assist with second victim responses.

How did you become involved with this program?

Before the launch of our Caring Safely initiative, where we brought patient and employee safety together under one umbrella, I knew there were issues with trauma to health-care workers, but I had a volume of patient safety problems to work on and felt like maybe employee safety was someone else’s issue to deal with.

However, learning more about incredibly high rates of health-care worker harm and injury, along with my own direct experience being involved in a serious safety event, helped to change my perspective. These two things made me want to have more of a hand in directly supporting the peer support program at SickKids – and I think that sometimes the best way to support a program is to get involved and participate in helping to bring about change.

Why do you think physicians are hesitant to ask for help?

I think the major reason physicians are hesitant to ask for help, whether we're conscious of it or not, is that we’re preoccupied by reputation and we're kind of socialized to be somewhat “invincible.” We pass a lot of tests and go through medical training to demonstrate that we can withstand the rigours of medicine and go through things that society might deem “extreme” – and that’s a source of pride.

So to fit this idea in which we have of ourselves, sometimes asking for help to handle difficult situations you are going through might be thought of as risky, because of how we think others might perceive us as maybe not being up to the challenges that we face in the workplace.

How can someone spot a colleague in need of help or distress?

People should be aware that it can be hard to spot someone in need of help or distress – especially within medicine, where we are trained to appear confident and competent in the workplace. Every time you have a moment of self-doubt, you can't show that as a doctor – and we're pretty good at pushing through these moments and ignoring them. That's a very adaptive thing to do in many situations.

The other thing that's really tricky is that some people will just kind of withdraw from a lot of things they normally would engage in when they’re in a situation of psychological distress and or emotional distress – this is a more visible sign that someone is not OK. But others undergoing the same types of distress may appear to be unaffected because they are acting in line with how they regularly do, so this is why it is hard to pinpoint specific behaviours that might flag that someone is distressed.

What are some tips you can give about how to be an ally in the workplace?

I’ll give an example of what meant the most to me when I was struggling with an unexpected event and what helped me get back on track.

I found that being recognized as a valuable member of the team helped me to get back on track. Sometimes when you’re in these situations, where you’ve experienced a safety event or something of that nature, you can have a very distorted view of yourself and think that everybody perceives you as a failure. There have been times over my career when somebody has made a remark like, “You know, everybody knows what a hard worker you are” or, “Well, we all know how much you care about this stuff and how seriously you take it.” These are seemingly minor remarks, but they can make a big difference – especially when you are a physician or a health-care provider going through a crisis of self-doubt from something like a safety event or burnout.

It can be helpful to acknowledge that everyone has a turn with these types of issues or feelings – they aren’t just things that affect some minority outlier population. I think, in this regard, it is necessary to treat these events as part of life so that seeking treatment can be normalized and individuals can recover. These are important messages that educators and leaders should be sharing.

How do you think the field of medicine can embrace a new culture around self-care and wellness?

I think the medical community has steadily come to embrace the rhetoric around self-care and wellness. It remains to be seen how deeply and sincerely we will commit as a profession, though. I have noticed that the younger generations have been talking about self-care and wellness more openly and share a different mindset about it in terms of how they prioritize things like occupational wellness and work-life balance, and I hope that will be a driver for implementing better self-care and wellness in our community. However, there are some major barriers and so I would be naive to think that they are easy to solve.

What would some of these barriers to wellness look like?

Well, some of the barriers are structural and would include things like duty-hours and the strenuous working conditions that medical professionals and trainees face.

You can acknowledge that some of the working conditions are beyond what would be considered healthy, but that doesn't mean that overnight you can have the resources and the restructuring to re-engineer the health–care systems that we currently work within.

U of T infectious disease expert Allison McGeer on coronavirus risks – and uncertainties

geoff.vendeville — Thu, 23 Jan 2020 16:47:28 +0000

U of T infectious disease expert Allison McGeer on coronavirus risks – and uncertainties

geoff.vendeville Thu, 01/23/2020 - 11:47

Cutline

Red Cross employees demonstrate equipment to measure of the body temperature of travellers at Vienna International Airport (photo by Martin Juen/SEPA.Media via Getty Images)

Geoffrey Vendeville

Topic

Global Lens

Laboratory Medicine and Pathobiology

Global

Mount Sinai Hospital

A new strain of coronavirus that originated in China has killed 17 people and infected hundreds. Chinese authorities have closed off Wuhan, the port city of 11 million at the centre of the outbreak, and suspended travel from other cities.

The respiratory virus has spread beyond mainland China, with cases detected in Japan, South Korea, Hong Kong and the United States.

In Canada, Health Minister Patty Hajdu says the risk remains low though some people are being monitored for the virus. Meanwhile, the World Health Organization held a second emergency meeting today to decide if the outbreak meets the definition of a “public health emergency of international concern,” but decided against making such a declaration since the number of cases in countries outside China remains relatively small.

“At this time, there is no evidence of human-to-human transmission outside China,” Dr. Tedros Adhanom Ghebreyesus, the WHO’s director general, said at a news conference today in Geneva, according to a report in the New York Times. “That doesn’t mean it won’t happen.”

U of T News spoke with Dr. Allison McGeer (left) on Wednesday about what we know and still don’t know about the mysterious illness, and the risk of a global pandemic.

McGeer is a professor at the ��߲ݴ�ý’s Dalla Lana School of Public Health, a professor in the departments of medicine and laboratory medicine and pathobiology in the Faculty of Medicine, as well as director of the Infectious Diseases Epidemiology Research Unit at Mount Sinai Hospital. She contracted SARS when she was on the front lines of that outbreak in Toronto in 2003.

(photo by Chris So/Toronto Star via Getty Images)

Is this a global emergency yet?

As a reflection of the disagreement (at the WHO), it is very close to being yes. Remember, you may be thinking of global health emergency in small letters, but they're thinking of Global Health Emergency with capital letters. It's a defined circumstance and the naming of it has a defined purpose. And so they're not just looking at the risk to the population, they're looking at whether calling it a global health emergency is going to help the situation or make it worse.

How could calling it a global health emergency make things better or worse?

I think making people more worried about it than they need to be is one downside. Potentially restricting travel is another downside of it.

What people might do with borders is clearly of concern.

The benefits of it are that people do pay more attention, to some degree. I'm not sure that's a benefit in this case, but it helped with people in the DRC (Democratic Republic of Congo) recently (in context of Ebola).

It also helps at the WHO level to mobilize funding for additional investigations and for support for the people on the ground dealing with the outbreak and trying to interpret data and trying to get protocols in place for treatment trials and all the other things that need to be done.

It does cut both ways. Every time the subject comes up we learn more about what the advantages and disadvantages of the naming is.

Setting aside the WHO definition, is this something the world should be worried about?

Too early to tell.

What do we know about the Wuhan coronavirus so far?

It's a coronavirus. It causes respiratory infections. Some of those respiratory infections are fatal. It is transmitted from person to person in some circumstances in close-contact in households, and also in health-care settings at least occasionally. That's about the size of it.

World Health Organization Director-General Tedros Adhanom Ghebreyesus speaks during a press conference in Geneva on Jan. 22 (photo by Pierre Albouy/AFP via Getty Images)

Evidence grows for iron deficiency screening in childhood: U of T researchers

Christopher.Sorensen — Mon, 06 Jan 2020 13:59:43 +0000

Evidence grows for iron deficiency screening in childhood: U of T researchers

Christopher.Sorensen Mon, 01/06/2020 - 08:59

Cutline

Two studies from U of T and the Hospital for Sick Children look at iron deficiency and suggest that Canadians would benefit from more screening programs in early childhood (photo by Godong/Universal Images Group via Getty Images)

Jim Oldfield

Topic

Joannah & Brian Lawson Centre for Child Nutrition

Pediatrics

Hospital for Sick Children

Nutrition

Centre for the Commercialization of Regenerative Medicine

Research and Innovation

Two recent studies from the ��߲ݴ�ý and the Hospital for Sick Children are adding to mounting evidence that Canadians would benefit from more screening for iron deficiency in early childhood.

One study details the known association between iron levels and cognitive function, and identifies a new threshold in blood tests that could guide more effective clinical intervention. The other is the first health-economic analysis of potential screening programs for iron deficiency in Canada, which shows that both targeted and universal screening would be cost-effective.

Iron is critical for growth and development, yet experts estimate that over 10 per cent of young children in developed countries are iron deficient. Canada has no recommendation on screening, which is left to the discretion of physicians and parents.

The current studies, published in The Journal of Pediatrics and CMAJ Open, respectively, build on the researchers’ previous work that showed screening with a ferritin blood test can detect iron deficiency earlier than the more standard hemoglobin test, which only reveals a deficiency that has progressed to anemia.

“We found a fairly strong association between serum ferritin and cognitive function, but also that the association peaks and does not improve beyond a certain level,” says Patricia Parkin, a professor of paediatrics at U of T and a clinician-investigator at SickKids. “That threshold is important for clinicians, because it enables them to make a quick and accurate decision on further tests or therapies.”

Parkin and her colleagues identified a cut-off of 17 micrograms of serum ferritin per litre, which is five micrograms higher than the current level that clinicians use in practice. Five micrograms may sound small, but the researchers found the increase in cognition associated with a five-unit rise in ferritin is similar to the increase in IQ associated with a 1000-gram increase in birth weight, in a comparison with data from another study.

The results were based on screening tests in more than 700 participants in TARGet Kids!, the largest research cohort of young Canadian children recruited in primary care.

Parkin says that while the new cut-off is not definitive, she hopes it will open up discussion about the suitability of the current number in clinical practice. She also hopes that more practitioners in the U.S. will consider measuring ferritin in addition to a hemogloblin test, which they typically administer to children at the age of one.

“A serum ferritin test with a well defined threshold would identify far more children in the U.S. and prevent many more from developing a chronic deficiency or anemia,” says Parkin, who is also the research director of the Paediatric Outcomes Research Team at SickKids and a scientist in the Joannah & Brian Lawson Centre for Child Nutrition at U of T.

In Canada, a key question for researchers and policy-makers has been the potential cost of new screening programs. The health-economic study in CMAJ Open offers an answer on the possible cost of screening for iron deficiency in childhood through a comparison of costs for universal screening, targeted screening for high-risk groups, and no screening (the current standard of care).

“We found that, across the board, screening would be cost-effective,” says Sarah Carsley, an assistant professor at U of T’s Dalla Lana School of Public Health who completed her PhD in the Parkin lab. “Moreover, universal screening was almost a third more cost-effective than targeted screening, although both were clearly cost-effective, using standard willingness-to-pay thresholds.”

Carsley and her colleagues estimated health care costs and quality-adjusted life years to arrive at an “incremental cost-effectiveness ratio,” which for both types of screening and with conservative estimates was well below the level at which an intervention would be deemed too expensive.

Children in Ontario typically see a primary care physician for an in-depth, enhanced well-baby visit at 18 months of age. Parkin, Carsley and others have previously suggested that this might be an ideal time to discuss screening with a serum ferritin test, which is inexpensive and available in most labs.

One drawback with the ferritin and hemoglobin tests is that they require a small blood draw, which many children find upsetting. Parkin says more research is needed on whether parents would feel the value of screening outweighs the upset of a blood draw, and whether family physicians and pediatricians would embrace screening based on the existing evidence.

Meanwhile, parents can reduce the risk of iron deficiency by providing children with a diet rich in iron and in vitamin C (which helps iron absorption), and by limiting cow’s milk to two cups a day, as it can inhibit iron absorption and may reduce consumption of other healthy foods. Those worried about iron deficiency can discuss risk factors and options with health-care providers, before birth and in the first year of life.

Treatment for iron deficiency is very effective, and can include dietary advice and daily supplements in pill or liquid form. “The fix is pretty easy,” says Parkin. “It’s short in duration and inexpensive, which should drive interest in a broader discussion about how we can better address this issue. Iron deficiency has been an under-recognized public health problem for too long.”

The research was supported by the Canadian Institutes of Health Research, The Hospital for Sick Children Foundation and St. Michael’s Hospital Foundation. The Applied Research Group for Kids (TARGet Kids!) is a partnership among primary care physicians in the community and researchers at SickKids, St. Michael’s Hospital and McMaster University.

Medicine by Design draws hundreds to annual research event, praise from federal innovation minister

Christopher.Sorensen — Mon, 09 Dec 2019 14:51:21 +0000

Medicine by Design draws hundreds to annual research event, praise from federal innovation minister

Christopher.Sorensen Mon, 12/09/2019 - 09:51

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Michael Sefton (centre), the executive director of Medicine by Design, says the regenerative medicine initiative wouldn't have been possible without the support of the federal government, which provided a $114-million grant (photo by Neil Ta)

Ann Perry

Topic

Our Community

Chemistry

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Institute of Biomaterials and Biomedical Engineering

Leslie Dan Faculty of Pharmacy

MaRS

Medicine by Design

Mount Sinai Hospital

Regenerative Medicine