Genetics

A team of researchers from the �ؿ�ζSM has identified a gene in fruit flies that regulates the types of connections between flies within their “social network.”

The researchers studied groups of two distinct strains of Drosophila melanogaster fruit flies and found that one strain showed different types or patterns of connections within their networks than the other strain.

The connectivity-associated gene in the first strain was then isolated. When it was swapped with the other strain, the flies exhibited the connectivity of the first strain.

Researchers named the gene after Hollywood star Kevin Bacon (photo by Theo Wargo/Getty Images)

The researchers named the gene “degrees of Kevin Bacon” (dokb), for the prolific Hollywood star of such films as Footloose and Apollo 13. Bacon’s wide-ranging connections to other actors is the subject of the parlour game called “The Six Degrees of Kevin Bacon,” which plays on the popular idea that any two people on Earth can be linked through six or fewer mutual acquaintances.

“There's been a lot of research around whether social network structure is inherited, but that question has been poorly understood,” says Rebecca Rooke, a post-doctoral fellow in the department of ecology and evolutionary biology in the Faculty of Arts & Science and lead author of the paper, published in Nature Communications. “But what we’ve now done is find the gene and proven there is a genetic component.”

The work was carried out as part of Rooke’s PhD thesis in Professor Joel Levine’s laboratory at U of T Mississauga before he moved to the department of ecology and evolutionary biology, where he is currently chair.

“This gives us a genetic perspective on the structure of a social group,” says Levine. “This is amazing because it says something important about the structure of social interactions in general and about the species-specific structure of social networks.

Post-doctoral researcher Rebecca Rooke (supplied image)

“It's exciting to be thinking about the relationship between genetics and the group in this way. It may be the first time we’ve been able to do this.”

The researchers measured the type of connection by observing and recording on video groups of a dozen male flies placed in a container. Using software previously developed by Levine and post-doctoral researcher Jon Schneider, the team tracked the distance between flies, their relative orientation and the time they spent in close proximity. Using these criteria as measures of interaction, the researchers calculated the type of connection or “betweenness centrality” of each group.

Rooke, Levine and their colleagues point out that individual organisms with high betweenness centrality within a social network can act as “gatekeepers” who play an important role in facilitating interactions within their group.

Gatekeepers can influence factors like the distribution of food or the spread of disease. They also play a role in maintaining cohesion, enhancing communication and ensuring better overall health of their group.

In humans, betweenness centrality can even affect the spread of behaviours such as smoking, drug use and divorce.

Professor Joel Levine (supplied image)

At the same time, the researchers point out that social networks are unbiased and favour neither “good” nor “bad” outcomes. For example, high betweenness centrality in a network of scientists can increase potential collaborators; on the other hand, high betweenness centrality in another group can lead to the spread of a disease like COVID-19.

“You don't get a good or a bad outcome from the structure of a network,” explains Levine. “The structure of a network could carry happiness or a disease.”

Rooke says an important next step will be to identify the overall molecular pathway that the gene and its protein are involved in “to try to understand what the protein is doing and what pathways it’s involved in – the answers to those questions will really give us a lot of insight into how these networks work.”

And while the dokb gene has only been found in flies so far, Rooke, Levine and their colleagues anticipate that similar molecular pathways between genes and social networks will be found in other species.

“For example, there's a subset of cells in the human brain whose function relates to social experience – what in the popular press might be called the ‘social brain,’” says Levine.

“Getting from the fly to the human brain – that's another line of research. But it almost has to be true that the things that we're observing in insects will be found in a more nuanced, more dispersed way in the mammalian brain.”

Consider long-term effects before employing 'genetic welding' in natural populations: U of T expert

Christopher.Sorensen — Tue, 25 Apr 2023 16:33:57 +0000

Consider long-term effects before employing 'genetic welding' in natural populations: U of T expert

Christopher.Sorensen Tue, 04/25/2023 - 12:33

Cutline

(photo by CRAFTSCI/Science Photo Library/Getty Images)

Faculty of Arts & Science Staff

Topic

Our Community

Ecology & Environmental Biology

Faculty of Arts & Science

Genetics

With CRISPR-Cas9 technology – a specific and versatile gene editing technology that can be used to modify, delete or correct precise regions of DNA – humans can now rapidly change the evolutionary course of animals or plants by inserting genes that can easily spread through entire populations.

In an opinion paper published recently in the journal Trends in Genetics, �ؿ�ζSM evolutionary geneticist Asher Cutter says we must scientifically and ethically scrutinize the potential consequences of this “genetic welding” before we put it into practice.

Asher Cutter

“The capability to do genetic welding has only taken off in the last few years, and much of the thinking about it has focused on what can happen in the near term,” says Cutter, a professor in the department of ecology and evolutionary biology in the Faculty of Arts & Science.

“Ethically, before humans apply this to natural populations, we need to start thinking about what the longer-term consequences might be on a time scale of hundreds or thousands of generations.”

In classical Mendelian genetics, genes have a 50-50 chance of getting passed from parent to offspring – but this isn’t always the case. In a natural phenomenon known as “genetic drive,” some genes are able to bias their own transmission so that they are much more likely to be inherited.

Genetic welding is the human-mediated version of this: introducing genes that have an unfair advantage when it comes to heritability in natural populations. Because these genes spread easily and rapidly through populations, they result in much faster evolutionary change than the usual slow plod that we see from natural and artificial selection.

In contrast to natural selection, genetic drives and genetic welding can perpetuate genes that don’t necessarily benefit the organisms that carry them – making them an attractive potential method to control problematic and invasive disease-bearing species.

For example, genetic welding has been proposed as a tool to control disease-bearing mosquito populations and invasive species. It could also be used to genetically engineer endangered species to be resistant to infectious pathogens that threaten them with extinction.

“It raises the question of how much should humans intervene into processes that are normally beyond our control,” Cutter says.

“If ethicists, medical practitioners and politicians decide that it is acceptable in some cases to edit the ‘germline’ of humans – the population of cells that pass on their genetic material to offspring – then that would open the possibility that genetic welding could be used as a tool in that regard. This would open a much bigger can of worms by virtue of the fact that genetic welding could change the entirety of a population or species – not just a few individuals that elected to have a procedure.”

Though it might be difficult to experimentally assess the long-term implications of genetic welding, Cutter says that thought experiments, mathematical theory, computer simulations and conversations with bioethicists could all play important roles, as could experiments in organisms with short lifespans and rapid reproduction.

Cutter’s research is supported by the Natural Sciences and Engineering Research Council of Canada.

With files from Cell Press

'An urgency to contribute': U of T's Choong Chin (C.C.) Liew considered a visionary for work on cardiovascular genetics

noreen.rasbach — Mon, 16 Sep 2019 20:34:32 +0000

'An urgency to contribute': U of T's Choong Chin (C.C.) Liew considered a visionary for work on cardiovascular genetics

noreen.rasbach Mon, 09/16/2019 - 16:34

Cutline

Choong Chin Liew, known as C.C., "really had a vision of translating basic research in genomics into a practical application for the benefit of humankind,” says Peter Lewis, Professor Emeritus of biochemistry at U of T (photo courtesy of the Liew family)

Topic

Research & Innovation

Choong Chin Liew was a visionary research scientist whose work on cardiovascular genetics is still paving the way for early detection of a wide variety of diseases from simple blood tests.

Liew, who died in August at the age of 81, was also an enthusiastic mentor to many medical researchers, an entrepreneur and a devoted family man who loved Ontario’s cottage country.

Liew, known to everyone as “C.C.,” arrived in Canada from Malaysia in 1962 to do graduate work at the �ؿ�ζSM with Charles Best (pictured left with his wife), the co-discoverer of insulin. He became an assistant professor in 1970, achieved full tenure in 1979, and was a Professor Emeritus in clinical biochemistry and medicine at the time of his death.

Liew’s early work was on diabetes and heart failure, but he is best known for developing what he called the “Sentinel Principle,” the concept that many diseases can be detected and monitored through their gene expression in the blood. Because of the transfer of information between blood cells and tissue cells, he postulated, blood tests can unlock information about diseases elsewhere in the body.

Liew was active in transferring his discoveries to the private sector, earning many patents and founding companies that are still in the process of developing diagnostic tools. A blood test for early assessment of colorectal cancer risk, based on the Sentinel Principle, is currently on the market. Other tests, for several other cancers and even Alzheimer’s disease, are in development.

“C.C. really had a vision of translating basic research in genomics into a practical application for the benefit of humankind,” says Peter Lewis, Professor Emeritus of biochemistry at U of T, and a colleague and friend of Liew’s for several decades. “His goal was to turn the discovery, from back in the 1990s, into a practical application for the prognostication of disease from a drop of blood.”

A younger C.C. Liew at his microscope (photo courtesy of Liew family)

Liew was “driven,” Lewis says, and “there was not enough time in the day for all the activities he was pursuing.” But he was a delight to work with and very modest about his accomplishments, Lewis adds. “He didn’t seek out recognition publicly, and really flew below the radar.”

Liew’s enthusiasm for research was infectious, and that energy influenced many students who worked with him. ”I got a positive vibe from him,” says Mansoor Husain, who spent time in Liew’s lab as a medical trainee and is now director of the Toronto General Hospital Research Institute. “He obviously loved science. He always had a sparkle in his eye and excitement in his voice when he talked about research.”

As well as being passionate about the work, Liew was also welcoming, and trusted his students, Husain says.

Liew maintained that vigour right until the end of his life, as he continued to work to apply his discoveries. In recent years he collaborated with Alberta-based entrepreneur and scientist Jacqueline Shan, on research into potential applications of his techniques in treating Alzheimer's disease. Shan, co-creator of Cold-FX, recognized that Liew’s work on early detection of illnesses from the analysis of genomic markers in blood was revolutionary, and might lead to the creation of targeted medicines for Alzheimer’s patients.

“He was one of the best scientists I’ve ever seen,” Shan says. “He was very persistent,” even in his later years when he was ill and having chemotherapy treatment. “He worked harder than anybody in the lab. He had an urgency to contribute.”

At the same time, Liew was very caring, she says, and concerned about his colleagues’ families and health. On one long-distance airplane trip, he offered her tips on getting to sleep, so she would be fresh upon arrival, she says.

C.C. Liew and his wife Eng in 2017 on a family trip to Sungai Siput, where he was born (photo courtesy of Liew family)

Choong Chin Liew was born in 1937 in the small village of Sungai Siput in what was then called Malaya. (It became part of Malaysia in 1963). His father was a teacher from China who had moved to Malaya, while his mother was a Chinese-Malayan from Penang. Liew did not have a peaceful childhood, he noted in an autobiography he wrote in 2010, because of the Japanese invasion of Malaya during the Second World War and Japan’s persecution of its Chinese population.

“To escape these upheavals our family moved deep into the jungle,” Liew wrote. “There, we were able to wait out the war in safety.” But after the war there was more turmoil, as the British colonial government tried to crack down on communist insurgents, in what developed into a bloody guerrilla war.

Liew’s family moved to the city of George Town on Penang island, where he went to high school before studying biology at Nanyang University in Singapore. After graduation he taught and worked as a teaching assistant, then decided to pursue graduate work overseas. He wrote to Charles Best, who was then head of the physiology department at U of T. Best offered him a fellowship.

Liew arrived in Canada by boat in 1962. He noted in his biography that “I was only one of thousands in a history of Chinese immigrants to Canada, over a time span that stretches back to the eighteenth century.” He was lucky, he added, because “by the time I arrived in the 1960s, Toronto was considered quite welcoming.”

Liew was intensely committed to his studies, and often slept in the lab. He also stayed away from the demonstrations and protests that were erupting on campus in the 1960s. “I had already experienced more than a fair share of war and politics in Malaysia,” he wrote. “I had left all of that behind in the forests of rubber.”

But it was a tough time, as he found the Canadian winters difficult, and he struggled to work and live in an English-speaking environment.

Eng and C.C. when they were dating: She moved to Canada two years after he arrived and they marrried soon after (photo courtesy of Liew family)

Two years after his arrival in Canada things improved when his girlfriend Eng came from Malaysia to join him, and they were married at Toronto City Hall a few months later.

After getting his master's degree in physiology and a PhD in pathological chemistry under renowned U of T professor Allan Gornall, Liew conducted post-doctoral research in Britain and in New York. He had planned to return to Malaysia, but an explosion of anti-Chinese violence there in 1969 changed his mind, and he took a job at U of T as assistant professor in clinical biochemistry.

Liew’s daughter Gailina says her father was absolutely devoted to the pursuit of science, but he also carved out time for his family. “We would have supper with him every night, but it would be late because he would be working in the lab.” She and her brothers would occasionally spend evenings and weekends in their father’s lab at the Banting Institute on College Street.

“I remember sometimes helping to wash test tubes.”

The family also accompanied Liew on his sabbatical travels, including time in Europe and a three-month tour of Chinese universities. There was always music in the house, Gailina says, because her father loved classical music and opera, and learned to play the piano.

C.C. (second from left in front row) with his family this past June in Lisbon, Portugal (photo courtesy of Gailina Liew)

In the mid 1970s Liew bought a cottage north of Toronto, cementing his connection to Canada. Several of his colleagues at U of T had cottages, he wrote in his memoir, and “it seemed to me like the thing to do in Canada.” The cottage was a place to relax, read and write, he wrote, and became a treasured weekend getaway.

In the 1990s Liew’s work evolved into the study of cardiac gene sequencing, and in 2000 he established a lab at Harvard Medical School in Boston to continue the research. He made significant discoveries linking gene expression with disease, and found that changes in blood genes reflected broader changes in health.

Recognizing the commercial possibilities of this research – and the need for capital to pursue the work – Liew formed a private company called GeneNews, which is now traded on the Toronto Stock Exchange under the name StageZero Life Sciences. Later he created other business ventures to apply the Sentinel Principle, including companies in Malaysia and China. His long-term aim, he wrote in his memoir, was to “build a personalized health management system that would allow anyone to manage their own health from the information that can be read in a single drop of blood.”

For several years, he worked closely with his daughter Gailina, who held senior executive positions at GeneNews thanks to her background in molecular genetics and her experience as a lawyer. It was a privilege working alongside her father, she says. “He was the scientific visionary and the rest of us just had to help capture all that thinking and turn it into a product.”

Liew’s most important goal throughout his life of research “was to make a positive difference to the patient” by helping prevent diseases or detect them early, Gailina says. But he also touched people all around the world, because he was so outgoing, gregarious, generous and kind-hearted.

Liew died after several years fighting multiple myeloma, but ”he was working up until his last day,” Gailina says.

He leaves his wife Eng, brother Jack Chor, daughter Gailina, sons Allan and Victor, and seven grandchildren. The family has set up an endowment fund in C.C. Liew’s memory to award scholarships and grants to support research aimed at improving human health.

'Discover everything there is': U of T's Tak Mak awarded prestigious Gold Leaf Prize for pioneering research

Christopher.Sorensen — Thu, 23 May 2019 15:42:29 +0000

'Discover everything there is': U of T's Tak Mak awarded prestigious Gold Leaf Prize for pioneering research

Christopher.Sorensen Thu, 05/23/2019 - 11:42

Cutline

The Canadian Institutes of Health Research has named U of T's Tak Mak the recipient of its prestigious Gold Leaf Prize for Discovery, which recognizes groundbreaking health research (photo courtesy of University Health Network)

Topic

Princess Margaret Hospital

Stem Cells

Tak Mak still recalls his surprise upon learning that Canada’s Medical Research Council had granted him more money than he requested. It was the early 1980s, and Mak was an assistant professor competing for funds with the other scientists pushing Canada into a global revolution in cell biology.

“I applied for $50,000 and they gave me $67,000,” says Mak, a University Professor of medical biophysics and immunology at the �ؿ�ζSM and a senior scientist at the Princess Margaret Cancer Centre who is renowned for a career that has spanned biochemistry, virology, genetics, cancer metabolism and clinical therapy.

“Over the years Canada’s granting agencies have really supported my work in a very paramount way.”

That relationship has now come full circle after the Canadian Institutes of Health Research named Mak the recipient of its prestigious Gold Leaf Prize for Discovery, which recognizes groundbreaking health research and comes with $100,000.

The award will support new research, but for Mak it’s also a recognition that CIHR’s investments in his work was money well spent. “We did all we could to achieve the scientific excellence and innovation CIHR wanted, and to some extent we have fulfilled that intention,” says Mak. “That is gratifying, because when a person or agency is really generous, you don’t want to disappoint them.”

Mak has indeed given Canadians many reasons to be proud.

Mak’s lab co-discovered the T-cell receptor in 1984 – a finding that fundamentally changed how scientists understood the immune system and led to major advances in T-cell biology, autoimmune disease and immunotherapy. His lab was also one of the first to generate knockout mice – genetically modified mice – that enabled scientists worldwide to study the effects of individual genes. And Mak co-founded Agios Pharmaceuticals, whose leukemia drug IDHIFA became the first clinically approved therapy to target cancer metabolism in 2017.

Earlier this year, Mak’s group used genetics to show that the nervous system and immune system communicate through a molecule called acetylcholine. The discovery confirmed a long-suspected, but poorly understood, link between the two systems, and again opened several new avenues of research.

Mak attributes these and other achievements in part to the co-operation of the Canadian scientific community.

“One thing that makes Canada great is congenial and collaborative scientists across the land,” he says. “And looking back at the metamorphosis of our lab from field to field to field, it was in many cases through work with Canadian scientists.”

To take two examples: the development of genetically altered mice, Mak says, would not have happened without close collaboration from stem cell biologist and U of T University Professor Janet Rossant. And when his lab shifted focus from immunology to cancer, Mak says the approach and vision of the late Anthony Pawson, a professor of molecular genetics, was invaluable.

Mak has also benefitted from many talented trainees who have passed through his lab. That group now numbers over 130, and includes a university president, medical school deans and dozens of institute directors and departmental chairs. Mak often visits these former colleagues – most recently on a trip to the Technical University of Munich this week, where he received an honorary professorship – and he says that seeing this extended “family” succeed brings great gratification.

“There’s no substitute for that. I am reminded of the Indian proverb, ‘All the flowers of all the tomorrows are in the seeds of today.’”

Mak offers special praise for the mentorship he received as a young researcher, including his time in the lab of Nobel laureate Howard Temin, and his early years in Toronto working with Ernest McCulloch and James Till, who discovered stem cells.

“McCulloch taught me to think differently, to have original ideas and integrate my thoughts,” Mak says. “Till was a staunch, vigorous physicist, who insisted that all results be statistically significant and re-confirmed. The two together made an almost perfect mentorship for me.”

Today, that oblique but rigorous approach to science still informs Mak’s thinking, which increasingly centres on inflammation, another frontier in medical science. Inflammation is essential to the immune system’s ability to fight germs, but it can create problems that result in autoimmune diseases. Researchers are recognizing the role of inflammation in neuro-degeneration, cardiac disease and many other conditions, and in our ability to fight cancer.

“We need to understand that important yin and yang,” says Mak. “When the thermostat of inflammation needs to be up, and when certain aspects need to come down – this is where we need to focus.”

Mak is still very engaged with these and other scientific questions. The “party,” he notes, is still going strong.

“I have tremendous gratitude for the support I’ve received from the Canadian scientific community and from CIHR,” he says.

“When you’re a kid you get to play with toys and figure things out, and you’re not supposed to do that as an adult. But science is like toys for adults, and we get to discover everything there is.”

Twins in space: U of T expert on how space travel affects gene expression

noreen.rasbach — Thu, 10 Jan 2019 15:37:04 +0000

Twins in space: U of T expert on how space travel affects gene expression

noreen.rasbach Thu, 01/10/2019 - 10:37

Cutline

Astronaut Scott Kelly during a spacewalk on Dec. 21, 2015: Astronauts on space missions experience various physiological effects (photo by NASA via Getty Images)

Topic

Research & Innovation

Space

Researchers have had a rare opportunity to see how conditions on the International Space Station translate to changes in gene expression by comparing identical twin astronauts. One of the twins spent close to a year in space, while the other remained on Earth.

The environment of the space station induced changes in gene expression through a process called epigenetics.

NASA scientists already know that astronauts will be affected differently by the physical stresses they experience. Studies of astronauts’ genetic backgrounds might explain why some are more susceptible to health problems when they come back to Earth. These findings could translate to personalized preventive measures for the vulnerable astronauts.

Surprisingly, it seems that these discoveries could also lead to therapy development for common syndromes affecting us on Earth.

NASA has been studying the consequences of space travel on the human body since the dawn of the space age. At a news conference held approximately a week after arriving at the International Space Station (ISS), Canadian astronaut David Saint-Jacques said he felt a “little congested” and “had a big red puffy face … like the feeling you get hanging from the monkey bars.” The basis for this uncomfortable feeling relates to fluid redistribution from the lower to the upper body.

NASA Glenn’s Advanced Exercise Countermeasures Project studies how microgravity affects astronaut health (photo by NASA)

Health after long space missions

The health effects that result from long missions in space are not well understood. Overall, astronauts remain in excellent mental and physical health relative to the general population, even after their return from long-term missions. And yet, the health consequences of such missions have been recognized, including cardiovascular deconditioning and vision problems, the causes for which are being investigated.

NASA scientists are exploring how gene expression – the way DNA is converted to tissues – changes in response to the environment inside the ISS. The field of epigenetics describes mechanisms through which environmental factors, like microgravity, relatively high carbon dioxide levels and possible surges in radiation alter the way DNA is read.

Researchers also want to know how each astronaut’s unique DNA will determine their response to the space station environment. Right now, of the 37 studies under way in the space station, three focus specifically on genetic research.

Two of a kind

Preliminary results of the exceptional study of identical twin astronauts support the idea that space travel can affect gene expression in different organs. From 2015 to 2016, astronaut Scott Kelly was aboard the ISS for a consecutive 340 days. His twin brother Mark stayed on Earth. Scott’s basic genetic code was not altered, but the environment of the space station affected the way in which this code was converted into tissue.

According to one of the lead scientists in the twin study, Christopher Mason, these changes occurred in important biological pathways relevant to bone formation and the immune system. The gene expression changes were categorized with respect to possible risk, “as low, medium or high.”

Low-risk changes to gene expression (approximately 93 per cent of all the changes) reset to normal when Scott returned to Earth. Possible medium- to high-risk changes didn’t reverse after six months and “are changes that we’ll want to keep an eye on,” according to Mason. For example, there are expression changes that lead to the immune system being on “high alert,” says Mason.

Although the study of identical twins provides the best evaluation of space effects on gene expression, there are not too many twin astronauts around.

Validation of the findings in the Kelly twins will, by necessity, involve studies in other astronauts. Right now, these validation studies are happening on the International Space Station as liquid biopsies (cell-free DNA and RNA samples from blood) are collected for analysis. But the experiments on the twins really provided a “springboard for all of these subsequent studies,” says Mason.

Vision changes after missions

Previous studies of eye health in a group of astronauts suggest that not all astronauts will respond the same way to life on the space station. Astronaut ophthalmic syndrome is a condition that affects some astronauts. These ocular changes are classified by NASA “as a significant risk for human space travellers,” and include changes to the lens and shape of the eye.

Pre-flight images of normal optic disc. Post-flight right and left optic disc showing visual changes from long-duration space flight: grade 1 (superior and nasal) edema at the right optic disc (photos by NASA)

In some cases, astronauts with excellent vision before space flight “come back needing to wear glasses,” says Scott Smith, the lead nutritional biochemist at NASA.

“We saw chemical differences in blood samples (from astronauts) before flight, so we started to look at genetics.”

Seventy-two astronauts provided blood samples for this study. On analysis, the research findings suggest that each astronaut’s genetic background plays a role in determining their eyes’ vulnerability, or epigenetic response, to detrimental triggers in the space station.

Space eyes and Earth wombs

This research means that certain astronauts could be warned of their personal risk of developing vision problems during long space missions. Better yet, personalized preventive measures or personalized medicine could be discovered and implemented for those with the greatest risk of disease.

“Virtually all the work that NASA does has implications for the general population,” says Smith.

Ophthalmic Syndrome in astronauts is related to another, much more common health problem here on Earth. It turns out that the same genetic variants and changes in serum factors that are associated with ocular problems in astronauts are also connected to polycystic ovary syndrome (PCOS), a form of infertility in women.

PCOS affects up to 10 per cent of women. A genetic component for this syndrome was previously suspected.

Genetic and epigenetic studies in astronauts promise to provide astronauts with personalized medical interventions while in space. And they could also provide those of us on Earth with potential therapies.

Christine Bear is a professor in the �ؿ�ζSM's Faculty of Medicine.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

U of T scientists uncover DNA ‘shield’ with crucial roles in normal cell division, the immune system and cancer

noreen.rasbach — Wed, 18 Jul 2018 20:19:58 +0000

U of T scientists uncover DNA ‘shield’ with crucial roles in normal cell division, the immune system and cancer

noreen.rasbach Wed, 07/18/2018 - 16:19

Cutline

Daniel Durocher is a professor in the department of molecular genetics and a senior investigator in the Lunenfeld-Tanenbaum Research Institute at the Sinai Health System

Topic

Research & Innovation

Scientists have made a major discovery about how cells repair broken strands of DNA that could have exciting implications for the treatment of cancer.

Their study, published in Nature on Wednesday, uncovered a brand new protein complex in cells that shields broken DNA ends and controls the way in which it is repaired.

The new complex pushes cancer cells to use a particular type of DNA repair system that is vulnerable to targeting by new drugs called PARP inhibitors or platinum-based chemotherapies.

The landmark study was a result of collaboration between the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, the �ؿ�ζSM, The Institute of Cancer Research, London, The Netherlands Cancer Institute and the University of Bern.

The discovery could lead to tests to direct and monitor treatment for patients with mutations in BRCA1, BRCA2 or other DNA repair genes.

“PARP inhibitors hold great promise for breast and ovarian cancer treatment, but we must understand why they sometimes don't work, or stop working altogether,” says Daniel Durocher, a professor in the department of molecular genetics and senior investigator in the Lunenfeld-Tanenbaum Research Institute at the Sinai Health System.

“Knowing more about how cancer evades PARP inhibition by studying basic DNA repair mechanisms brings us a big step closer to this objective, which will improve how we treat some of the most intractable cancers."

The newly named "Shieldin" complex was also found to be important for generating the right type of antibodies during an immune response, and mutations could lead to immune-related disorders.

PARP inhibitors are hugely promising treatments because they take advantage of a major vulnerability of some cancers – a weakness in the ability of cancer cells to repair their DNA. Traditional platinum-based chemotherapies are also being used in a more targeted way to take advantage of DNA repair weaknesses.

When intact, the newly discovered Shieldin complex was found to contribute to this vulnerability by attaching to the broken DNA, forcing cancer cells to attempt to repair their DNA in a way that makes them susceptible to PARP inhibitors and platinum chemotherapies.

But when mutations are introduced in the components of the complex, the researchers found that cancer cells grown in the lab and in mice used an alternative way to repair DNA and quickly became resistant to PARP inhibitors.

The PARP inhibitor drug olaparib is approved in the U.S. and Europe for treating ovarian and breast cancers with BRCA mutations, and looks promising against some prostate cancers – so the results could have a wide impact on cancer treatment if mutations in the Shieldin complex are shown to lead to treatment failure in the clinic.

To uncover the complex, the international team of researchers analyzed breast cancer cells and mice that had mutations in the gene BRCA1.

Read the research in Nature

They used cutting-edge Crispr/Cas9 genetic manipulation technology to search for gene mutations that caused cells to become resistant to the PARP inhibitor drugs olaparib and talaoparib, as well as the platinum chemotherapy cisplatin.

Through painstaking experiments, the researchers were able to pick out key gene mutations that led to drug resistance, which proteins these had an effect on, and work out what these proteins did in cells.

They found the new complex is composed of newly identified proteins, now named SHLD1, SHLD2, and SHLD3.

In healthy cells, the complex was found to attach to the ends of broken DNA so that the "blunt ends" of the DNA have to be stuck back together directly – a quicker, messier way of repairing DNA that can sometimes be necessary for making antibodies during immune responses.

When the researchers introduced mutations into the Shieldin complex – which stop it from forming and protecting broken DNA ends – cells are free to repair DNA via a different method, and this means PARP inhibitors are no longer effective.

The study was funded by a variety of organizations worldwide, including the Canadian Cancer Society and the Canadian Institutes of Health Research, and Cancer Research UK and Breast Cancer Now in the U.K.

Psychiatric disorders share an underlying genetic basis, says landmark paper with U of T research

noreen.rasbach — Thu, 21 Jun 2018 19:19:01 +0000

Psychiatric disorders share an underlying genetic basis, says landmark paper with U of T research noreen.rasbach Thu, 06/21/2018 - 15:19

Cutline

Autism researcher Professor Stephen Scherer is one of nine U of T researchers from the Faculty of Medicine who contributed to the major international study

Topic

Research & Innovation

Nine researchers from the �ؿ�ζSM's Faculty of Medicine contributed to a major international study, published in the journal Science, showing the underlying genetic similarities between mental illnesses like schizophrenia and bipolar disorder.

The team, led by Harvard University’s Broad Institute, determined that psychiatric disorders share many genetic variants, while neurological disorders such as Parkinson’s or Alzheimer’s appear more distinct.

The study takes the broadest look yet at how genetic variation relates to brain disorders – and highlights the power of large international collaborations to amplify Canada’s investment in research.

The results indicate that psychiatric disorders likely have important similarities at a molecular level, even though they have always been considered separate diseases.

“Because these diseases look and act differently, we’ve always assumed they were different genetically too – that there would be a gene, or group of genes, for schizophrenia, and a gene or a group of genes for autism, and so on,” says Russell Schachar, a professor in U of T’s department of psychiatry and a co-author of the paper.

“A cake and a flan have similar ingredients, but the result is different because of the way they’re put together. We didn’t expect psychiatric disorders that are so different to have such similar ‘ingredients.’"

Only about five years ago, scientists started to see significant genetic overlap between psychiatric diseases, says Schachar (pictured left). Understanding what a broad spectrum of mental health conditions share might hasten better treatments in particular for the most intractable and serious diseases, like schizophrenia.

U of T contributors to the paper include Alzheimer’s researchers Professors Peter St. George-Hyslop and Ekaterina Rogaeva; Tourette syndrome researchers Professors Cathy Barr and Paul Sandor; ADHD researcher Assistant Professor Jennifer Crosbie, OCD researcher Associate Professor Margaret Richter, autism researcher Professor Stephen Scherer, along with Professors Jacob Vorstman and Schachar, who study the confluence of ADHD and autism.

The unprecedented scope of international co-operation could be a model for Canadian researchers, says Scherer, because the vast landscape of interconnected scientists in this country, could one day produce the next landmark genetic research of grand scale. Scherer is director of U of T's McLaughlin Centre and a senior scientist at the Hospital for Sick Children (SickKids).

“It showed the capacity of scientists around the world to work together,” says Scherer. “We hope Canadian funding agencies might decide to fund population-scale cohort studies, instead of us shipping our samples and data to the USA. Toronto can and should be a central hub for this kind of work going forward.”

For the current study, international consortia pooled their data to examine the genetic patterns across 25 psychiatric and neurological diseases. Because each genetic variant only contributes a tiny percentage of the risk for developing a given disorder, the analyses required huge sample sizes to separate reliable signals from noise.

The researchers measured the amount of genetic overlap across the disorders of 265,218 patients and 784,643 controls. They also examined the relationships between brain disorders and 17 physical or cognitive measures, such as years of education, from 1,191,588 individuals.

The final results indicated widespread genetic overlap across different types of psychiatric disorders, particularly between attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia. The data also indicated strong overlap between anorexia nervosa and obsessive-compulsive disorder (OCD), as well as between OCD and Tourette syndrome.

In contrast, neurological disorders such as Parkinson’s and multiple sclerosis appeared more distinct from one another and from the psychiatric disorders – except for migraine, which was genetically correlated to ADHD, major depressive disorder, and Tourette syndrome.

According to the researchers, the high degree of genetic correlation among the psychiatric disorders suggests that current clinical categories do not accurately reflect the underlying biology.

As a hypothetical example, a single mechanism regulating concentration could drive both inattentive behavior in ADHD and diminished executive function in schizophrenia. Further exploration of these genetic connections could help define new clinical phenotypes and inform treatment development and selection for patients.

Additionally, within the cognitive measures, the researchers were surprised to note that genetic factors predisposing individuals to certain psychiatric disorders – namely anorexia, autism, bipolar disorder, and OCD – were significantly correlated with factors associated with higher childhood cognitive measures, including more years of education and college attainment. Neurological disorders, however, particularly Alzheimer’s and stroke, were negatively correlated with those same cognitive measures.

“We were surprised that genetic factors of some neurological diseases, normally associated with the elderly, were negatively linked to genetic factors affecting early cognitive measures,” says Verneri Anttila, a postdoctoral researcher at Harvard’s Broad Institute, the paper’s first author. “It was also surprising that the genetic factors related to many psychiatric disorders were positively correlated with educational attainment. We’ll need more work and even larger sample sizes to understand these connections.”

The consortia have made their data accessible online.

With files from Karen Zusi, Broad Institute of MIT and Harvard.

More than 300,000 Canadians enrol in multi-decade research initiative to monitor disease trends

noreen.rasbach — Mon, 18 Jun 2018 04:00:00 +0000

More than 300,000 Canadians enrol in multi-decade research initiative to monitor disease trends

noreen.rasbach Mon, 06/18/2018 - 00:00

Cutline

From left, Dr. John McLaughlin, executive director of CPTP, Cindy Morton, chief executive officer of the Canadian Partnership Against Cancer, and Dr. Philip Awadalla, national scientific director of CPTP

Topic

Dalla Lana School of Public Health

Faculty of Medicine

Genetics

Global

Research & Innovation

Subheadline

U of T is national co-ordinating site of Canadian Partnership for Tomorrow Project

Over the past 10 years, more than 300,000 Canadians have volunteered to be part of the Canadian Partnership for Tomorrow Project (CPTP), a research platform that tracks the development of cancers and chronic diseases in the population over several decades to better understand risk factors.

Researchers from across Canada and the �ؿ�ζSM published a manuscript in the Canadian Medical Association Journal last week, marking a culmination of effort from hundreds of Canadian researchers to build the project with support from multiple national and provincial funders.

“This project is a living population observatory that enables researchers – in Canada and across the globe – to tap into a rich population health database of genetic and environmental factors associated with chronic disease development,” said John McLaughlin, CPTP’s executive director, co-author of the manuscript, and professor of epidemiology at the Dalla Lana School of Public Health.

The paper describes how 307,017 participants aged 30 to 74 were recruited with informed consent from the general population within eight Canadian provinces. Most participants provided a blood or other type of sample and about a third completed a physical assessment. All the data in the CPTP are de-identified, but it will provide researchers with a platform for assessing the effects of genetics, behaviour, environment and societal factors on health.

“The CMAJ paper points researchers to this national scientific asset, and how CPTP can be used,” said Philip Awadalla, co-author of the paper and national scientific director of CPTP.

“We’re at the beginning of a new phase for the CPTP as we move from building the platform to creating new evidence that is relevant to Canadians,” said Awadalla, who is also a professor of population and medical genetics in the Faculty of Medicine’s department of molecular genetics and director of computational biology and senior investigator at the Ontario Institute for Cancer Research.

Earlier this spring, U of T was named CPTP’s national co-ordinating site, led by Awadalla and McLaughlin in partnership with the Ontario Institute for Cancer Research. Recognized as Canada’s premier health research initiative, the CPTP research platform is unlocking the answers to why some people develop cancer and chronic diseases while others do not.

“The complexity of cancer is such that massive data sets are required to identify common risk factors on a national scale, which may open the door to new pre-diagnostic techniques and prevention strategies,” said Dr. Stephen Robbins, scientific director of the CIHR Institute of Cancer Research..

On the CPTP research platform, any researcher can submit a proposal to access portions of the data. More than 80 scientific programs have already begun research with CPTP, and received independent funding from national and international funders. A study published earlier this year in Nature Communications showed how environmental exposures interact with our genomes to impact health. The CPTP scientists involved in the study will also use the cohort to answer questions about why cancer rates vary across the country (B.C. has much lower rates of certain types of cancers compared to Atlantic Canada).

Awadalla and colleagues have received funding from the Canadian Institutes of Health Research to examine metabolic syndrome, which includes a range of conditions like high blood pressure, Type 2 diabetes, glucose intolerance and cardiovascular disease. The study seeks to understand how environmental factors, including air pollution and green space, interact with genetics to impact rates of metabolic disease nationally.

Funding for this program is a partnership across many national and provincial organizations including: the Canadian Partnership Against Cancer, Heart and Stroke Canada, Genome Quebec, Ministère de l'Économie, de la Science et de l'Innovation, Ontario Institute for Cancer Research, Cancer Care Ontario, Public Health Ontario, Alberta Health Services and Alberta Innovation.

Read here for more information about the CPTP and its regional partners (CARTaGENE, Ontario Health Study, BC Generations, Atlantic Path, and the Alberta Tomorrow Project) and details about accessing the data.

Gut feelings: family history influences what's in our intestines, U of T research shows

lavende4 — Wed, 05 Oct 2016 16:15:26 +0000

Gut feelings: family history influences what's in our intestines, U of T research shows

lavende4 Wed, 10/05/2016 - 12:15

Cutline

Colon biopsy of chronic ulcerative colitis, Active Phase (Photo by Ed Uthman via flickr)

Topic

inflammatory bowel disease

What triggers the difficult and painful set of conditions known as inflammatory bowel disease? How can we understand the influence of genetics as well as the environmental factors?

Those questions are at the heart of Professor Kenneth Croitoru’s gastroenterology research with the Genetics, Environmental, Microbial (GEM) Project, a major international study led by Croitoru at the �ؿ�ζSM and Sinai Health System to determine the cause of inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis.

Read National Post story on Prof. Croitoru's research into stool transplants helping obese people lose weight

That work took a step forward recently with a study published in Nature Genetics, which showed that one-third of the naturally occurring bacteria found in participants’ guts – known as the microbiome – had a heritability factor. In addition, four specific genes were found to have links to specific bacteria types within participants’ gut microbiome. This suggests that our genetics influence what types of bacteria may inhabit our gut.

The study holds promise for the use of stool transplants to combat obesity, according to the report in the National Post.

Professor Ken Croitoru (photo from Sinai Health System)

“As an inflammatory bowel disease specialist, I have seen a consistent pattern of heritability of this devastating disease," said Croitoru, who is a professor of medicine at U of T. "This study sets the stage to define how our genetic makeup and its relation to our gut microbiome may explain disease. The challenge ahead of us is to explore the impact of that genetic link, and how we can use this new information to prevent and treat disease.”

Croitoru is also a clinician-scientist in Sinai Health System’s Zane Cohen Centre for Digestive Research and scientist with the Lunenfeld-Tanenbaum Research Institute. The GEM Project is collecting data from healthy family members of patients with IBD to track those who develop the disease. The data from GEM was used in this microbiome study.

“The genetic analysis of the microbiome from healthy subjects gives us important insight into the possible interplay between our genetic makeup and microbial factors that influence health and disease,” said study co-author Andrew Paterson, a senior scientist at the SickKids Research Institute and a professor at U of T’s Dalla Lana School of Public Health. “Understanding these possible interactions may have implications for many diseases associated with altered microbiome.”

Funding for this study was provided by the Canadian Institutes of Health Research (CIHR), Crohn’s and Colitis Canada (CCC) and The Leona M. and Harry B. Helmsley Charitable Trust.

Mikko Taipale has the second-best job in the world: finding cures for genetic diseases

lavende4 — Tue, 04 Oct 2016 18:52:50 +0000

Mikko Taipale has the second-best job in the world: finding cures for genetic diseases

lavende4 Tue, 10/04/2016 - 14:52

Cutline

Mikko Taipale: “We want to democratize research in rare diseases because most of them are completely neglected” (Photo by Julia Soudat)

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Professor Mikko Taipale believes cures for genetic disorders already exist. We just have to find them.

“I have the second best job in the world. The first is being an astronaut,” says Taipale, an assistant professor of molecular genetics at the �ؿ�ζSM’s Donnelly Centre. With his feet firmly planted on the ground, Taipale is finding cures for genetic diseases.

Taipale, 39, has won an inaugural $100,000 CIFAR-Azrieli Fellowship. It’s awarded to 18 scientists worldwide, who are less than five years into their first academic appointments, by the Canadian Institute for Advanced Research (CIFAR). Among the other winners are U of T professors Natalie Bau (economics) and Luyi Yang (physics).

“This group of phenomenal young investigators is the future of research,” said CIFAR President and CEO Alan Bernstein in the institute’s announcement.

Taipale joined the Donnelly Centre in 2014 after a post-doctoral fellowship in the lab of Professor Susan Lindquist at the Whitehead Institute for Biomedical Research and MIT, where he studied how proteins – the end products of genes – fold into three-dimensional molecular machines. At Donnelly, he has expanded his research to a number of cellular processes that ensure proteins are properly made and working, in order to understand what makes cells healthy and how changes in protein biology cause disease.

One of Taipale’s projects sets out to investigate rare and debilitating – but often overlooked – disorders.

“We want to democratize research in rare diseases because most of them are completely neglected. Developing a new drug costs $1.2 billion and you cannot recover those costs if you only treat thousands, or even hundreds of patients in some cases,” says Taipale.

A rare genetic disease occurs when a particular gene is mutated so that the protein it encodes no longer works. For example, mutations that impede the function of proteins encoded by the genes CFTR or dystrophin will cause cystic fibrosis and muscular dystrophy, respectively. Such harmful mutations run through family trees but only wreak havoc in a small number of people. That’s because we carry two copies for every gene, one inherited from each parent. If one copy of a gene is broken, its harmful effects are masked by the other working copy of the gene. It’s only when someone inherits both bad versions of the gene that they get sick.

Unlike complex diseases such as cancer, which are caused by mutations in many genes, rare diseases are an easier problem to solve. If you could find a way to restore the broken gene’s function, you might be able to alleviate symptoms or cure the disease altogether. Still, a relatively small patient population means that the pharmaceutical industry has little incentive to invest in these diseases.

But what if drugs already existed? What if they lurked among thousands of compounds that have already been approved or are being developed for other conditions?

“We’re trying to completely change the way in which we study rare genetic diseases. Traditionally, these diseases are studied one at a time with multiple methods, and we want to study one thousand diseases all at once, with one or two methods” says Taipale.

To do this, he has a collection of 1000 mutant proteins – each carrying a mutation known to cause a genetic disease. The plan is to run a battery of tests on these damaged proteins, side-by-side with their healthy counterparts. “These experiments will help us understand the underlying molecular causes of disease. Then we can use FDA-approved drugs to fix the damaged proteins. We are trying to find a disease for a drug and not a drug for a disease,” says Taipale.

Taipale cites an example of lonafarnib, a failed cancer drug that was repurposed to treat progeria – an extremely rare condition where aging is accelerated so much that patients die of old-age complications in their teens. The drug works by reigning in the rogue progerin protein, which is the underlying cause of the disease.

“Even if you hadn’t known anything about the molecular biology of progerin, and done a screen with FDA-approved drugs and drugs in clinical trials, you probably would have found the same compound. I have a hard time believing that out of 7000 rare diseases this would be the only one that has an existing drug that could work. Maybe we’ll be able to make a difference for one of these 1000 diseases that we study, but I have no idea which disease it will be,” said Taipale.