Jim Oldfield

The study, published in NEJM Evidence, shows that smokers who quit smoking before age 40 can expect to live almost as long as those who never smoked. Those who quit at any age return close to never-smoker survival 10 years after quitting, and about half that benefit occurs within just three years.

Prabhat Jha (photo courtesy of the Centre for Global Health Research)

“Quitting smoking is ridiculously effective in reducing the risk of death and people can reap those rewards remarkably quickly,” said Prabhat Jha, executive director of the Centre for Global Health Research at Unity Health Toronto and a professor at U of T’s Dalla Lana School of Public Health and Temerty Faculty of Medicine.

The observational study included 1.5 million adults in four countries (the U.S., U.K., Canada and Norway), followed over 15 years. Smokers between the ages of 40 and 79 had an almost three-fold risk of dying compared to those who never smoked, meaning on average they lost 12 to 13 years of life.

Former smokers lowered their risk of death to 1.3-fold (or 30 per cent higher) compared to never smokers. Stopping smoking at any age was associated with longer survival, and even those who quit for less than three years gained up to six years in life expectancy.

“Many people think it’s too late to quit smoking, especially in middle age,” said Jha. “But these results counter that line of thought. It’s never too late, the impact is fast and you can reduce risk across major diseases, meaning a longer and better quality of life.”

In particular, the researchers found that quitting smoking reduced the risk of dying from vascular disease and cancer. Former smokers also reduced their risk of death from respiratory disease, but slightly less so – likely due to residual lung damage.

There are currently about 60 million smokers in the four countries involved in the study and over a billion worldwide. The global rate of smoking has fallen by more than 25 per cent since 1990, but tobacco is still a leading cause of preventable death.

Jha said the findings should add urgency to efforts by governments to support people who want to stop smoking.

“Helping smokers quit is one of most effective ways to substantially improve health. And we know how to do that, by raising taxes on cigarettes and improving cessation supports.”

Canada is long overdue for an increase in the federal excise tax on cigarettes, and many other countries could lower smoking rates by raising taxes, Jha said. Cessation supports can include clinical guidelines and patient resources such as helplines, but also a whole-health-system approach.

“When smokers interact with the health-care system in any way, physicians and health professionals can encourage them to quit, pointing out how well quitting works,” Jha said. “This can be done with concern and without judgement or stigma, recognizing that cigarettes are engineered to be highly addictive.”

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

Liver can generate palmitic acid to maintain brain health, study suggests

Christopher.Sorensen — Mon, 22 Jan 2024 21:58:42 +0000

Liver can generate palmitic acid to maintain brain health, study suggests

Christopher.Sorensen Mon, 01/22/2024 - 16:58

Cutline

Researchers Richard Bazinet, left, and Mackenzie Smith, right, found that the liver will generate palmitic acid when the brain isn't getting enough through food sources, suggesting the acid's importance to brain health (photo by Temerty Faculty of Medicine)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Joannah & Brian Lawson Centre for Child Nutrition

Brain

Nutritional Sciences

Research & Innovation

Subheadline

“The results were surprising because when you lower a lipid in the diet, it usually becomes lower in the brain"

Researchers at the �ؿ�ζSM have found that palmitic acid, one of the most common fats in meats and dairy products, as well as human breast milk, is made by the liver and sent to the developing brain when it’s low in the diet.

The preclinical findings underscore the importance of palmitic acid for brain health and point to a need for more research on lowering its levels in infant formula – a step some manufacturers have taken recently to reduce costs and limit the harvest of palm trees, a major source of palmitic acid.

“When we changed the levels of palmitic acid in the diets of developing mice, it didn’t do a thing to the brain,” said Richard Bazinet, principal investigator on the study and a professor and acting chair of the department of nutritional sciences in U of T’s Temerty Faculty of Medicine.

“The results were surprising because when you lower a lipid in the diet, it usually becomes lower in the brain. But here the liver was able to up-regulate production to ensure the brain gets enough of it, despite extreme differences in dietary intake.”

The findings were published in the journal Nature Communications.

Mackenzie Smith, left, and Richard Bazinet, right (photo by Temerty Faculty of Medicine)

Palmitic acid is a saturated fat that supports brain health in several ways, across the lifespan. It contributes to the structure and function of myelin sheathing, which insulates neural connections and acts as precursor to molecules that regulate inflammation and promote cell signalling.

Scientists have long known that humans and other mammals can get palmitic acid from food or generate it in a process called de novo lipogenesis, which mainly requires glucose for its synthesis. Much less is known about which source the body relies on relative to diet and at different stages of growth and maturity.

Bazinet said the study findings highlight the importance of palmitic acid for brain health at all stages, but especially during development, when need for the fat appears to be highest.

“It’s interesting that although the brain can make palmitic acid, the liver up-regulated it so much. These systemic redundancies are built in, so the body won’t take a chance on not getting enough,” said Bazinet, who is also a researcher at U of T’s Joannah & Brian Lawson Centre for Child Nutrition.

The results should give pause to manufacturers looking to reduce the amount of palmitic acid in infant formula, said Mackenzie Smith, first author on the study and a doctoral student in the Bazinet lab.

“It’s possible that we can lower levels in formula, which could have a positive ecological impact, but we don’t yet know the potential health effects,” Smith said. “Are there implications for behaviour or development when the liver produces so much? Might there be negative effects for the liver?”

Smith also noted that even in mice that received the lowest amount of palmitic acid through diet, levels of the fat were still higher than those sought by some manufacturers of formula. That discrepancy adds to the rationale for further preclinical studies, as well as research in humans, Smith said.

To uncover the source of palmitic acid in the brains of developing mice, the researchers applied a new carbon isotope technique. Isotopes are different versions of the same chemical element that vary slightly in mass; for their study, the researchers drew on natural differences in carbon isotope ratios in the environment, based on how plants absorb carbon in photosynthesis.

“Most plants use the same path to fix carbon from the atmosphere and have the same carbon ratio, but sugars such as corn and sugar cane – which the liver uses to generate palmitic acid – have a different ratio,” said Smith.

In the brains of mice, a depleted carbon ratio signature indicated a dietary source of palmitic acid, Smith said, whereas an enriched signature suggested de novo lipogenesis.

The researchers were able to track those signatures at many stages throughout mouse development, to determine the liver was the main source of palmitic acid in the developing brain – a finding they corroborated by looking at changes in genetics.

The approach opens new research opportunities. “As opposed to traditional radioactive tracers, which are very expensive, this new technique allows for a cost-effective and long-term study design,” said Smith.

Building on the current study’s findings, researchers in the Bazinet lab are now applying the same technique in tissue from adult human brains. The method could also provide a new way to measure and track the dietary sources of other fats and nutrients, Bazinet said.

“Nutrition researchers often rely on people reporting their food intakes, which can lead to unreliable data,” he added. “Those problems could potentially be flagged with this kind of technology to track the source and amount of added sugars, for example. It could be very fruitful for nutritional science.”

The research was supported by funding from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research and the Canada Research Chairs Program.

Researchers explore changes to microbiome following weight-loss surgery

Christopher.Sorensen — Thu, 04 Jan 2024 15:30:18 +0000

Researchers explore changes to microbiome following weight-loss surgery

Christopher.Sorensen Thu, 01/04/2024 - 10:30

Cutline

(photo by Grace Cary/Getty Images)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Research & Innovation

University Health Network

Subheadline

Study suggests that microbiome-based therapies such as probiotics and fecal matter transplants have the potential to improve metabolic health

Researchers at the �ؿ�ζSM and its partner hospitals are finding that changes in gut microbiota after bariatric surgery can directly improve metabolism, independent of food intake, weight loss and other metabolic factors.

Their ongoing work – including a study published last year in the journal Cell Reports Medicine focused on patients who underwent the surgery – suggests that microbiome-based therapies such as probiotics and fecal matter transplants have the potential to improve metabolic health.

They may also one day reduce the need for weight-loss surgery itself.

“We know the microbiome contributes to metabolic improvements after bariatric surgery, but have known very little about how,” said Johane Allard, a clinician-scientist at University Health Network and a professor at U of T’s Temerty Faculty of Medicine. “We’ve recently shown that with no other changes, the altered microbiome influences that outcome, and we identify potential mechanisms.”

Bariatric surgery is a cornerstone of treatment for severe obesity. It changes the size and structure of the digestive system, limiting the amount patients can eat and absorption of nutrients. But it also comes with short- and long-term health risks, and in Canada often costs the health-care system more than $20,000 per procedure.

The surgery also releases gut hormones that improve insulin sensitivity and reduce appetite, and it alters the makeup and function of gut microbiota – changes that have surprised and perplexed clinicians, as the annual number of procedures worldwide has surged past half a million.

Researchers have sought to understand how – and how much – these additional biochemical changes contribute to metabolic improvements and weight loss, with an eye to new treatments. But studies of microbiota-related changes that could be harnessed as broadly effective therapies have been stymied by vast differences in gut microbiota among individuals.

From left to right: Researchers Susan Poutanen, Nayanan Nathan, Wendy Lou, Jitender Yadav, Dana Philpott, Johane Allard, Katherine Schwenger, Minna Woo, Tairan Qin and Tao Liang (supplied image)

The recent pre-clinical study gets around that problem through paired fecal matter transplants. The Toronto team transferred fecal matter from four people to mice – both before and after the human participants had bariatric surgery. The team fed both groups of mice the same high-fat, western diet in a germ-free facility, then observed the effects over several weeks.

Mice receiving the post-surgery transplant showed much better blood-sugar control and insulin sensitivity than the pre-surgery recipients, suggesting a strong role for the microbiome in improved metabolism, despite no change in body weight. The human study participants also became more sensitive to insulin and lost weight, as expected.

Less expected, however, was an increase in mass and energy expenditure in brown fat among mice that received the post-surgery transplant.

“We were very surprised by the data in brown adipose tissue,” said Dana Philpott, a co-principal investigator in the study and professor of immunology at Temerty Medicine. “We thought if we looked at regular [white fat] adipose tissue, we might see decreased fat or an ability to metabolize better, but the finding was very specific to brown fat.”

Heat was an early clue that something of interest was happening in brown fat, which plays a role in regulating body temperature.

“When we first put the post-surgery transplant mice in the metabolic cages, we noticed they generated more heat,” said Jitender Yadav, a postdoctoral researcher in the Philpott lab and a co-first author on the study. “We also noticed in some of the literature that bariatric surgery in mice increases brown adipose tissue and energy expenditure, and in our study, we were able to see the similar effect just by transferring the post-surgery microbiome.”

As well, the team found biochemical and transcriptional markers of reduced inflammation in the white fat of post-surgery mice – another sign of improved metabolic health. To look for microbiota-related changes that could explain all these metabolic improvements, the researchers studied and compared metabolites in stool samples from pre- and post-surgery mice.

They found increases in tryptophan metabolites, short-chain fatty acids and acylcarnitines, and decreases in amino acids, organic acid and lactic acid – all correlated with improved metabolic health. Those changes in metabolites were consistent across the post-surgery mice, despite variations in the constituents of their microbiota and in the microbiota of the four patients.

“The bacterial makeup of the microbiota wasn’t significant,” Yadav said. “We now think that microbiome-based therapies that induce the right mix of metabolites, such as pre- and probiotics, dietary changes and fecal matter transplants, could be an effective therapy for improved metabolism and weight loss.”

Co-principal investigator Herbert Gaisano, a clinician-scientist at Toronto General Hospital Research Institute and a professor in Temerty Medicine’s department of medicine, recently received funding to study how these metabolites work. Gaisano and his team, including co-first authors on the current study Tao Liang and Tairan Qin, will analyze the metabolites in human tissue samples of fat and liver, obtained during bariatric surgery.

The Philpott lab also continues to study the metabolites in the offspring of the study mice, and they hope to replicate their results with a larger number of patients at some point.

More broadly, Yadav said the study should help nudge the field of microbiome research away from a long-standing focus on bacteria. “One takeaway is that the amount and type of bacteria don’t always matter,” he said. “It’s the metabolites they produce, and which get absorbed downstream, that can influence health.”

Several other researchers participated in the study. They include Allan Okrainec and Tim Jackson, both of the University Health Network and Temerty Medicine’s department of surgery, and Daniel Winer, Susy Hota, Susan Poutanen and Hoon-Ki Sung, as well as their lab groups.

The research was supported by the Canadian Institutes of Health Research and U of T’s Banting and Best Diabetes Centre.

Researchers use generative AI to design novel proteins

Christopher.Sorensen — Fri, 05 May 2023 16:40:22 +0000

Researchers use generative AI to design novel proteins

Christopher.Sorensen Fri, 05/05/2023 - 12:40

Cutline

Professor Philip Kim and PhD student Jin Sub (Michael) Lee have developed a generative AI system that can create proteins not found in nature, promising to speed drug development (supplied images)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Artificial Intelligence

Computer Science

Faculty of Arts & Science

Molecular Genetics

Proteins

Research & Innovation

Researchers at the �ؿ�ζSM have developed an artificial intelligence system that can create proteins not found in nature using generative diffusion – the same technology behind popular AI image-creation platforms such as Midjourney and OpenAI’s DALL-E.

The system will help advance the field of generative biology, which promises to speed up drug development by making the design and testing of entirely new therapeutic proteins more efficient and flexible.

“Our model learns from image representations to generate fully new proteins at a very high rate,” says Philip M. Kim, a professor in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine. “All our proteins appear to be biophysically real, meaning they fold into configurations that enable them to carry out specific functions within cells.”

The findings were published in the journal Nature Computational Science and are the first of their kind in a peer-reviewed journal. Kim’s lab also published a pre-print on the model last summer through the open-access server bioRxiv ahead of two similar pre-prints from last December – RF Diffusion by the University of Washington and Chroma by Generate Biomedicines.

Proteins are made from chains of amino acids that fold into three-dimensional shapes, which in turn dictate protein function. Those shapes evolved over billions of years and are varied, complex and limited in number.

Now, with a better understanding of how existing proteins fold, researchers have begun to design folding patterns not produced in nature.

A major challenge, says Kim, has been to imagine folds that are both possible and functional.

“It’s been very hard to predict which folds will be real and work in a protein structure,” says Kim, who is also a professor in the departments of molecular genetics in the Temerty Faculty of Medicine and computer science in the Faculty of Arts & Science. “By combining biophysics-based representations of protein structure with diffusion methods from the image generation space, we can begin to address this problem.”

The new system, which the researchers call ProteinSGM, draws from a large set of image-like representations of existing proteins that encode their structure accurately. The researchers feed these images into a generative diffusion model that gradually adds noise until each image becomes all noise. The model tracks how the images become noisier and then runs the process in reverse, learning how to transform random pixels into clear images that correspond to fully novel proteins.

Jin Sub (Michael) Lee, a doctoral student in the Kim lab and first author on the paper, says that optimizing the early stage of this image generation process was one of the biggest challenges in creating ProteinSGM.

“A key idea was the proper image-like representation of protein structure, such that the diffusion model can learn how to generate novel proteins accurately,” says Lee, who is from Vancouver but did his undergraduate degree in South Korea and master’s degree in Switzerland before choosing U of T for his doctorate.

Also difficult was validation of the proteins produced by ProteinSGM. The system generates many structures – often unlike anything found in nature. Almost all of them look real according to standard metrics, says Lee, but the researchers needed further proof.

To test their new proteins, Lee and his colleagues first turned to OmegaFold, an improved version of DeepMind’s software AlphaFold 2. Both platforms use AI to predict the structure of proteins based on amino acid sequences.

With OmegaFold, the team confirmed that almost all their novel sequences fold into the desired protein structures. They then chose a smaller number to create physically in test tubes, to confirm the structures were proteins and not just stray strings of chemical compounds.

“With matches in OmegaFold and experimental testing in the lab, we could be confident these were properly folded proteins. It was amazing to see validation of these fully new protein folds that don’t exist anywhere in nature,” Lee says.

Next steps based on this work include further development of ProteinSGM for antibodies and other proteins with the most therapeutic potential, Kim says. “This will be a very exciting area for research and entrepreneurship.”

Lee says he would like to see generative biology move toward joint design of protein sequences and structures, including protein side-chain conformations. Most research to date has focused on generation of backbones, the primary chemical structures that hold proteins together.

“Side-chain configurations ultimately determine protein function, and although designing them means an exponential increase in complexity, it may be possible with proper engineering,” Lee says. “We hope to find out.”

This research was funded by the Canadian Institutes of Health Research.

GTA parents concerned about limited access to school food programs: Researchers

Christopher.Sorensen — Tue, 18 Apr 2023 13:19:09 +0000

GTA parents concerned about limited access to school food programs: Researchers

Christopher.Sorensen Tue, 04/18/2023 - 09:19

Jim Oldfield

Topic

Our Community

Temerty Faculty of Medicine

Joannah & Brian Lawson Centre for Child Nutrition

Graduate Students

Nutritional Sciences

Early results from a �ؿ�ζSM stakeholder study on school food programs find that parents and caregivers in the Greater Toronto Area are concerned about limited access to current programs and the ability of schools to provide culturally appropriate food, among other issues.

Based on online surveys and focus groups, the analysis is part of a larger effort launched by U of T researchers at the Joannah & Brian Lawson Centre for Child Nutrition called Feeding Kids, Nourishing Minds, which looks at how school food programs function across Canada.

“The need for universality in school food programs has really been a key theme of our research to date,” said Selina Mae Quibrantar, a master’s student in the Temerty Faculty of Medicine who is leading the caregiver analysis with direction from Vasanti Malik, an assistant professor in the department of nutritional sciences. “Universality means broad access to programs, which was a problem before the pandemic and has since worsened – but also local flexibility so that schools can adapt programs for their physical environments and diverse student populations.

“A key goal with Feeding Kids, Nourishing Minds is a broadly inclusive approach, and I hope our study will help enable that – in particular through parental and community knowledge, which is often missing from policymaking on child nutrition.”

Selina Mae Quibrantar says a key theme that has emerged from the stakeholder study focuses on the need for universality in school food programs (photo by Don Campbell)

Preliminary results showed child participation in school food programs in the Greater Toronto Area was about 65 per cent. Many parents and caregivers commented on program reductions, noting less food and fewer days of access per week after the COVID-19 pandemic.

While public health restrictions forced some of those changes as the pandemic began, food inflation costs have since become a significant challenge to school food programs in Toronto and elsewhere, Quibrantar said.

In addition, some schools lack kitchen facilities and volunteers to help prepare food while meeting health and safety guidelines, the study showed.

Caregiver perspectives, especially those from ethnic minority households, have received little attention in child nutrition research, Quibrantar said. Here too, the stakeholder analysis is helping fill a knowledge gap.

The researchers recently ran four focus groups with caregivers from households that identify as South Asian and Southeast Asian, finding that participants stressed the importance of culturally adapted food in school programs. “It’s important to caregivers that children see their own cultures’ food served in schools to foster a sense of belonging and inclusion,” Quibrantar said.

As well, caregivers emphasized the need for an intentional approach when bringing foods from various cultures into school food programs.

“Caregivers want a program that is meaningful and does not run the risk of cultural appropriation,” Quibrantar said. “They instead see programs as a way to teach [children] about cultural heritage and sustainability, such as where a food comes from and how it’s made, or by taking time to learn about a culture while sampling the food.”

Quibrantar has presented early results from a pilot study to colleagues in U of T’s department of nutritional sciences and plans to share more findings at the Canadian Nutrition Society annual conference in May.

She and researchers from the Feeding Kids, Nourishing Minds project will assemble some of their findings into a dashboard to be shared with other researchers, schools, non-profit groups and policymakers later this year.

Feeding Kids, Nourishing Minds is funded by a $2-million investment from President’s Choice Children’s Charity, and by the Joannah & Brian Lawson Centre for Child Nutrition at the �ؿ�ζSM.

More evidence that sugary drinks cause weight gain: Study

Christopher.Sorensen — Mon, 06 Mar 2023 14:23:54 +0000

More evidence that sugary drinks cause weight gain: Study

Christopher.Sorensen Mon, 03/06/2023 - 09:23

Cutline

(photo by Seksan Mongkhonkhamsao/Getty Images)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Joannah & Brian Lawson Centre for Child Nutrition

A review of dozens of studies from the last decade recently found that sugar-sweetened beverages promote weight gain in children and adults.

The review, led by researchers at the �ؿ�ζSM and Harvard University, is the largest and most thorough analysis to date of research on sweetened drinks, and overweight and obesity – both of which heighten risks for diabetes, heart disease, some cancers and other diseases.

Vasanti Malik led the study – published in the American Journal of Clinical Nutrition – with colleagues in Toronto and Boston. Malik is an assistant professor of nutritional sciences at U of T’s Temerty Faculty of Medicine and the Joannah & Brian Lawson Centre for Child Nutrition.

She recently spoke with writer Jim Oldfield about the findings and what they mean for public policy and personal health.

Why do this study now?

Our last meta-analysis on this topic was 2013. You want to update a meta-analysis every five to 10 years anyway, but especially in this area because there has been so much new research in the last decade. Evidence has continued to accumulate showing associations among sugar-sweetened beverages – or SSBs, as we call them – and weight and chronic disease. And it’s very important to have an updated synthesis of that evidence, especially for public policy. The Canada Food Guide is clear on the need to limit SSBs and recommends water as the drink of choice – and added sugar intake, including SSBs, has declined in Canada, in part due to public policies. But levels here are still too high. As well, the USDA Dietary Guidelines for Americans are arguably not as strong – and with U.S. policymakers coming together soon to discuss the 2025 guidelines, our study will be an important piece of evidence to inform their work.

What did your study show?

We expected to find a positive association between SSBs and weight gain among adults and children, and in cohort studies and randomized clinical trials. And that was exactly what we found. We analyzed 85 studies, which totaled over half a million participants. In cohort studies, which follow people over long periods of time, each serving-per-day increase in SSBs was associated with a 0.42-kilogram (almost one pound) higher body weight in adults. In children, we saw a 0.07-unit higher body-mass index (just under one-twelfth of a BMI unit). Perhaps most striking, findings from our dose-response analysis showed that weight gain increases with increasing levels of SSB intake in both children and adults. A dose-response relationship provides strong evidence for a cause-and-effect relationship.

How much weight gain might one drink per day lead to over time?

We estimated the associated change in body weight over a one-year period. For adults, one additional 12-ounce serving per day was linked to a 0.20-kg higher body weight (about half a pound) in one year. Over 10 years, that could be about five pounds. In children, we observed a 0.03-unit higher BMI for each additional daily serving of SSBs over a one-year period. Although these results may seem modest, weight gain is a gradual process, with adults averaging about one pound (0.45 kg) of weight gain per year. So, limiting SSB consumption could be an effective way to prevent age-related weight gain. Limiting SSB intake among children is also an important strategy to help them develop healthy lifestyle habits and weight trajectories.

How common is excess consumption of these drinks?

It’s very common. Sugar-sweetened beverages include sodas, fruit drinks, sports and energy drinks, and they are the largest source of added sugar in the North American diet. Moreover, the rise in consumption of these drinks has mirrored the epidemic of overweight and obesity. In 2016, almost two billion adults were estimated as overweight and 650 million had obesity. Even more worrying, the rate of increase in obesity in children and adolescents is now greater than in adults. The prevalence of childhood obesity has increased more than four-fold globally since the 1970s, which is truly alarming.

What are some of the health effects of SSBs?

A typical 12-ounce serving of an SSB contains over 140 calories and more than eight teaspoons of sugar. That nearly reaches the recommended daily limit for added sugar, which is no more than 10 per cent of total calories, or about 200 calories for a 2000-calorie per day diet. These drinks are sugar in liquid form. They’re usually made with table sugar, high-fructose corn syrup or other sweeteners that provide calories and are digested rapidly – more so than sugar consumed as a solid. This bolus of glucose increases blood sugar levels, which triggers a glycemic response that over time can lead to insulin resistance and diabetes. The fructose component also floods the liver, which can cause lipogenesis (creation of fat), that puts a person on the path to fatty liver and metabolic disease. Fructose also increases uric acid, which contributes to insulin resistance and risk for cardiovascular and other diseases. Insulin spikes from the glycemic response can result in an appetite cascade and over-eating, as can excess insulin in the blood over longer periods. Some evidence shows that SSBs activate the dopaminergic reward system in the brain and encourage addictive behaviour and that they alter the gut microbiome – but we need more research on those effects.

Are you optimistic, given these effects and the research evidence?

Intake levels of SSBs have come down in the developed world. We’re still seeing increases in the developing world, but taxes in some of those countries are working. Thailand introduced a tax that has reduced consumption, as has Mexico and South Africa. At least 85 countries now have a tax on SSBs, which in part reflects the World Health Organization’s stand on this issue. In Canada, Newfoundland introduced a tax recently and several U.S. regions and cities have had a tax for years in response to public health efforts, more awareness and advocacy. The general effect of these taxes is reduced intake and the revenues can be put toward further public health measures and health care. Other changes will help in Canada and elsewhere as well, such as limiting marketing to children and better front-of-pack and nutrition labels. All these efforts will push intake down, but it’s important to remember that people need access to clean, safe drinking water as an alternative. That’s an ongoing challenge globally and in many parts of Canada that we really need to address.

Malik holds a Canada Research Chair in Nutrition and Chronic Disease Prevention at U of T and an adjunct faculty position in nutrition at the Harvard T.H. Chan School of Public Health. Michelle Nguyen, a doctoral student at U of T, conducted the study analysis and wrote the paper.

Researchers explore gene therapy model using zinc finger proteins

Christopher.Sorensen — Thu, 02 Feb 2023 16:59:36 +0000

Researchers explore gene therapy model using zinc finger proteins

Christopher.Sorensen Thu, 02/02/2023 - 11:59

Cutline

Philip Kim, a researcher in the Donnelly Centre for Cellular and Biomolecular Research, says designing zinc finger proteins that can bind to DNA targets should enable a new generation of therapeutics (supplied photo)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Research & Innovation

Researchers at the �ؿ�ζSM and New York University have developed a novel technology that can engineer proteins to target any stretch of DNA in the human genome, opening a door to gene therapies for a broader range of health conditions.

The researchers fed data from billions of interactions between zinc finger proteins – a common class of human proteins that regulate gene expression, a process that transcribes genetic information into RNA molecules and proteins – and DNA into a machine-learning model, which can then generate engineered zinc fingers that bind to any given sequence of DNA.

“Designing zinc fingers to bind specific DNA targets has been an unsolved problem for decades,” said Philip Kim, a researcher in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine. “Our work should enable a new generation of in vivo therapeutics, which have proven difficult to develop with CRISPR and other DNA targeting technologies.”

The findings were recently published in the journal Nature Biotechnology.

Scientists have long seen the potential of zinc finger proteins because they naturally bind with DNA, are less likely than CRISPR and related technologies to trigger an immune reaction, and are small enough to work with clinical delivery methods. But zinc fingers were hard to engineer – for every new DNA target, scientists had to engineer a new protein through a laborious and often unsuccessful workflow. The new system solves this problem with a universal model that offers ease of use comparable to CRISPR and potentially higher DNA specificity.

“I think this system levels the playing field for zinc fingers and CRISPR,” said Kim, who is a professor of molecular genetics and computer science. “CRISPR is very established for fundamental science, but our system has many advantages for applications in living systems – in particular that zinc fingers are human proteins and would be safer as injected drugs.”

The system can also generate many different proteins that do the same thing, offering more options for moving treatments toward the clinic.

Kim and his lab developed the zinc finger model with a research group at NYU Langone Health led by Marcus Noyes, an assistant professor of biochemistry and molecular pharmacology in the Institute for Systems Genetics at the Grossman School of Medicine.

The Noyes lab has studied zinc fingers for years and compiled data on 49 billion interactions among zinc finger proteins. Their approach combined two levels of data: interactions between single zinc fingers and DNA, and between each zinc finger and its neighbouring finger.

These zinc finger pair interactions influence DNA binding and hence gene expression.

The machine-learning model developed by Kim and his group mirrors the data synthesis approach in the Noyes lab.

Osama Abdin

“Our model is hierarchical, so it takes advantage of existing data from their first stage of screening – and a subset of their stage-two data – to develop predictions about which zinc fingers will be compatible with others in certain contexts,” said Osama Abdin, a doctoral student in Kim’s lab and co-first author on the paper.

The model is based in part on technology that also forms the basis of ChatGPT, a software application developed by OpenAI that simulates human conversation. The model generates amino acid sequences for zinc finger proteins using large, highly detailed data sets and techniques similar to natural language processing.

The researchers showed the utility of the zinc finger system, which they dubbed ZFDesign, by reprogramming human transcription factors – zinc finger proteins that regulate the transcription of DNA to RNA. They tweaked the DNA binding targets of several transcription factors and programmed them to either activate or repress multiple genes, working with faculty members Tim Hughes and Mikko Taipale in the Donnelly Centre.

Clinical application of reprogrammed transcription factors could target diseases caused by haploinsufficiency – deletion or inactivation of a copied gene, which occurs in some cancers and the connective tissue disorders known as Ehlers-Danlos syndrome – or those linked to toxic genetic repeats such as in neurodegenerative conditions such as ALS, Parkinson’s and Huntington’s disease.

Kim said the system already generates designs for zinc finger proteins with clinical potential and that both his team in Toronto and the group in New York were surprised by how well it worked. The researchers have started a company, TBG Therapeutics, that aims to develop new therapies using this technology.

The new system also holds promise for gene editing and other applications where CRISPR is useful, although its impact will likely be strongest in the area of reprogramming transcription factors, Kim said.

The next step is to improve specificity in the system. “The current model is designed to optimize the engagement of a given zinc finger protein with its target, but has no built-in awareness of interactions to other targets,” said Kim. “Optimizing for specificity will entail modeling these other interactions.”

The researchers are well on their way to building a model that offers more specificity, Kim added. “There is a lot of excitement around this work in the fields of epigenetics and gene therapy, and I look forward to seeing what we can achieve with this technology.”

The research was supported by grants from the U.S. National Institutes of Health, Canadian Institutes of Health Research, Compute Canada Resource Allocation, Frederick Banting and Charles Best Canada Graduate Scholarship and the Ontario Graduate Scholarship.

Link between coffee and kidney disease may depend on genetic variant, study finds

Christopher.Sorensen — Tue, 31 Jan 2023 15:58:11 +0000

Link between coffee and kidney disease may depend on genetic variant, study finds

Christopher.Sorensen Tue, 01/31/2023 - 10:58

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(photo by Nitat Termmee/Getty Images)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Food

Health

Nutritional Sciences

Research & Innovation

Researchers at the �ؿ�ζSM and University of Padova have found that the association between heavy coffee consumption and kidney dysfunction hinges on a common genetic variation.

In a study, the researchers showed that markers of kidney dysfunction were nearly three times higher in heavy coffee drinkers with a variant of the CYP1A2 gene that makes them slow metabolizers of caffeine than for other heavy coffee drinkers who had a different version of the gene that enables faster caffeine metabolism.

Ahmed El-Sohemy

“We think fast metabolizers can eliminate caffeine from their systems more efficiently and avoid harmful build-ups of caffeine,” said Ahmed El-Sohemy, a professor of nutritional sciences in U of T’s Temerty Faculty of Medicine. “These individual differences in caffeine metabolism help explain why previous studies on coffee and kidney disease have been inconsistent.”

The study, published in the journal JAMA Network Open, was observational in design and included data from more than a thousand participants in Italy, collected over a decade by Professor Paolo Palatini and colleagues at the University of Padova.

Some previous studies have found that caffeine is associated with impaired kidney function and kidney failure, while others have found that coffee may protect against kidney disease. Few have looked at whether individual genetic differences account for these positive or negative associations.

The amount of caffeine a person consumes also appears to be important. For the current study, risk of kidney dysfunction was only significant in people who drank three or more cups of coffee a day, which is about 300 mg of Italian espresso. Current guidelines in Canada and the US recommend no more than 400 mg per day for healthy adults.

The researchers also found that prevalence of the CYP1A2 gene variant that makes people slow metabolizers of caffeine was similar in both the study group and the general population: roughly 50 per cent.

Many companies and clinics now include CYP1A2 in personalized genetic tests, as different versions of the gene can affect risk for several conditions associated with caffeine consumption.

Sara Mahdavi

“Heart disease, prediabetes and hypertension are all affected by variations in CYP1A2, which can also alter athletic performance,” said Sara Mahdavi, lead author on the study and a former post-doctoral fellow in El-Sohemy’s lab. “We can now be confident that whether or not coffee is deleterious to kidney health depends, in part, on CYP1A2.”

The researchers studied three markers of kidney dysfunction: albuminuria (too much of the protein albumin in urine); hyperfiltration (high glomerular filtration rate in the kidney); and hypertension.

Estimates put the prevalence of kidney disease in Canada at about 13 per cent, with most cases going undiagnosed. Kidney disease is a leading cause of death globally.

“Hopefully, this study will raise awareness about the importance of personalized nutrition recommendations based on individual genetic make-up,” said Mahdavi. “This is an exciting area of research and clinical practice with a very bright future.”

El-Sohemy is the founder and Chief Science Officer of Nutrigenomix Inc., which provides genetic testing for personalized nutrition, including the CYP1A2 gene and caffeine metabolism.

Study suggests honey reduces cardiometabolic risks

Christopher.Sorensen — Thu, 17 Nov 2022 19:11:27 +0000

Study suggests honey reduces cardiometabolic risks

Christopher.Sorensen Thu, 11/17/2022 - 14:11

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(Photo by Paul J. Richards/AFP via Getty Images)

Jim Oldfield

Topic

Breaking Research

Temerty Faculty of Medicine

Unity Health

Nutritional Sciences

Research & Innovation

Researchers at the �ؿ�ζSM have found that honey improves key measures of cardiometabolic health, including blood sugar and cholesterol levels – especially if the honey is raw and from a single floral source.

The researchers conducted a systematic review and meta-analysis of clinical trials on honey and found that it lowered fasting blood glucose, total and LDL, or “bad,” cholesterol, triglycerides and a marker of fatty liver disease. It also increased HDL or “good,” cholesterol and some markers of inflammation.

Tauseef Khan (photo by Nema McGlynn)

“These results are surprising, because honey is about 80 per cent sugar,” said Tauseef Khan, a senior researcher on the study and a research associate in nutritional sciences at U of T’s Temerty Faculty of Medicine. “But honey is also a complex composition of common and rare sugars, proteins, organic acids and other bioactive compounds that very likely have health benefits.”

Previous research has shown that honey can improve cardiometabolic health, especially in in vitro and animal studies. The current study is the most comprehensive review to date of clinical trials, and it includes the most detailed data on processing and floral source.

The journal Nutrition Reviews published the findings this week.

“The word among public health and nutrition experts has long been that “a sugar is a sugar,” said principal investigator John Sievenpiper, a clinician-scientist at Unity Health Toronto and a U of T associate professor of nutritional sciences and medicine. “These results show that’s not the case, and they should give pause to the designation of honey as a free or added sugar in dietary guidelines.”

Sievenpiper and Khan emphasized that the context of the findings was critical: clinical trials in which participants followed healthy dietary patterns, with added sugars accounting for 10 per cent or less of daily caloric intake.

“We’re not saying you should start having honey if you currently avoid sugar,” said Khan. “The takeaway is more about replacement – if you’re using table sugar, syrup or another sweetener, switching those sugars for honey might lower cardiometabolic risks.”

The researchers included 18 controlled trials and over 1,100 participants in their analysis. They assessed the quality of those trials and found there was a low certainty of evidence for most of the studies, but that honey consistently produced either neutral or beneficial effects, depending on processing, floral source and quantity.

The median daily dose of honey in the trials was 40 grams, or about two tablespoons. The median length of trial was eight weeks. Raw honey drove many of the beneficial effects in the studies, as did honey from monofloral sources such as Robinia (also marketed as acacia honey) – a honey from False Acacia or Black Locust Trees – and clover, which is common in North America.

Khan said that while processed honey clearly loses many of its health effects after pasteurization – typically 65 degrees Celsius for at least 10 minutes – the effect of a hot drink on raw honey depends on several factors, and likely would not destroy all its beneficial properties.

John Sievenpiper

He also noted other ways to consume unheated honey such as with yogurt, as a spread and in salad dressings.

Future studies should focus on unprocessed honey, Khan said, and from a single floral source. The goal would be higher quality evidence, and a better understanding of the many compounds in honey that can work wonders for health. “We need a consistent product that can deliver consistent health benefits,” said Khan. “Then the market will follow.”

The research was supported by the Canadian Institutes of Health Research, Canada Foundation for Innovation, the Ministry of Research and Innovation's Ontario Research Fund, and Diabetes Canada.

Khan has received prior funding support from the Canadian Institutes of Health Research, the International Life Sciences Institute and the U.S. National Honey Board. For a full list of all researchers’ past funding, see the Declaration of Interest section at the end of the journal article.

Community of Support: How U of T's Temerty Faculty of Medicine is moving the dial on representation

Christopher.Sorensen — Fri, 14 Oct 2022 19:27:50 +0000

Community of Support: How U of T's Temerty Faculty of Medicine is moving the dial on representation

Christopher.Sorensen Fri, 10/14/2022 - 15:27

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Ali Butt, right, is a second-year MD student in U of T's Temerty Faculty of Medicine who credits the faculty’s Community of Support program for helping him believe he could become a physician (photo by Mark Bennett)

Jim Oldfield

Topic

Our Community

Temerty Faculty of Medicine

Ali Butt was an unlikely future doctor in 2014. A child of immigrants whose family had hit sudden health troubles, he worked three jobs to pay for undergraduate studies in kinesiology at McMaster University.

Today, Butt is a second-year student in the MD program at the �ؿ�ζSM’s Temerty Faculty of Medicine with plans to specialize in family and emergency medicine. He hopes to be a clinician-educator and global health practitioner.

What changed Butt’s career path? Hard work and persistence, no doubt – he keeps the poem ‘Do it Anyway,’ often attributed to Mother Teresa, on his desk – but he also credits the faculty’s Community of Support program for helping him believe he could become a physician.

“I used to feel I had no place in medicine, partly because I had volunteered in hospitals and did not see myself reflected in the workforce,” Butt says. “My mentors in the Community of Support were compassionate and understanding, and the diversity in their backgrounds helped me see a way forward in the field.”

The Community of Support program supports under-represented students who aspire to study medicine, health professions, rehabilitation and basic sciences – particularly those who are Indigenous, Black, Filipino or economically disadvantaged, and who identify as having a disability.

Program offerings include admissions information, experiential opportunities in research and leadership, and application-related support such as MCAT test and interview preparation.

Butt joined the Community of Support program RASI (Research Application Support Initiative), through which he gained medical research work experience, and SASI (Supporting Applications, Supporting Interviews), which pairs prospective students with current MD students who guide candidates on medical school applications.

He says he was inspired by those experiences and grateful for the opportunity to study medicine. Acceptance to medical school felt like winning the lottery, he says.

Now, Butt now volunteers with Community of Support as a mentor.

“It’s been very meaningful as the person on the other side of those beneficial relationships. I want to give back and help foster change, starting with youth. To me, mentorship is part of what medicine is, or at least what it should be,” Butt says.

Ike Okafor (photo by Nick Iwanyshyn)

Involving physicians and students to level the playing field was a founding idea behind the Community of Support, says Ike Okafor, a senior officer for service learning and diversity outreach who founded the program and has led it since 2015.

“Each one of our initiatives represents an idea that has been developed with current students and the communities we serve,” Okafor says. “None of what we do would be possible without outstanding student leaders who take on roles as tutors and co-ordinators, as well as physicians and support from the communities we serve.”

The program has seen remarkable success and growth. Since 2015, over 440 matriculants from the Community of Support have entered medical school, including 23 per cent of the second-year medical school class. This past summer, more than 1,000 students engaged with program opportunities at the Temerty Faculty of Medicine and other North American schools, and Okafor says new program growth will target learners interested in basic and rehabilitation sciences.

Enrolment of Black medical students in particular has spiked at U of T recently. The university accepted at least 14 students who identified as Black to the MD Program in 2018, and at least 18 in 2022.

The success is attributable to a two-pronged strategy at Temerty Medicine that includes the Community of Support but also the Black Student Application Program, an optional entry stream that involves Black applicants writing a personal essay, and which enables file review and admission interviews by members of the Black community.

Most Black Student Application Program students at Temerty Medicine have come through the Community of Support, and other Canadian medical schools are now emulating that model, supporting Black students both before and during the application process.

Okafor and colleagues at Temerty Medicine have partnered with Western University, the University of Ottawa, McMaster University, McGill University and Dalhousie University on program delivery, and have supported program development at universities in British Columbia and Alberta.

This fall, McGill admitted 24 Black medical students through its Black Candidate Pathway; they all accessed McGill’s own Community of Support Program, says Iyman Ahmed, a former project manager for both programs who now works in the management consulting industry.

Ahmed says the structure of programs at Temerty Medicine were formative in the creation of customized programs at McGill, and she cites U of T’s numbers – an increase in Black medical students from one to eight per cent over four years – as key to the internal funding that helped launch the McGill programs.

Similarly, a new Black Applicant Admissions Process at the University of Calgary’s Cumming School of Medicine helped enable the entry of eight students who identify as Black to the MD program this year.

Mairi Babey, a program co-ordinator with the office of professionalism, equity and diversity at the Cumming School, says the U of T programs were the main influence in how the school set up its Black applicant stream and Support to Entry Program, which, like the Community of Support, offers MCAT materials and test prep, as well as mentorship, to students from underrepresented groups.

“The Community of Support program in Toronto is really the envy, given its success and the number of partnerships they’ve established with Black, Indigenous and other health organizations,” Babey said.

And while it’s too early to tell whether the Support to Entry Program has had a direct and sustained impact on the demographics of MD students at the Cumming School, Babey said, the involvement of more than three dozen student volunteers as mentors in the new program has been heartening.

“Our mentors have been very active, they really want to give back,” Babey says. “That bodes well for our MD Program and ultimately for patients, who will benefit from having physicians who understand their needs because they’ve walked similar paths in life.”