Drugs

In less than a month, researchers have used AlphaFold, an artificial intelligence (AI)-powered protein structure database, to design and synthesize a potential drug to treat hepatocellular carcinoma (HCC), the most common type of primary liver cancer.

The researchers successfully applied AlphaFold to an end-to-end AI-powered drug discovery platform called Pharma.AI. That included a biocomputational engine, PandaOmics, and a generative chemistry engine, Chemistry42. They discovered a novel target for HCC – a previously undiscovered treatment pathway – and developed a “novel hit molecule” that could bind to that target without the aid of an experimentally determined structure. The feat was accomplished in just 30 days from target selection and after only synthesizing seven compounds.

In a second round of AI-powered compound generation, researchers discovered a more potent hit molecule – although any potential drug would still need to undergo clinical trials.

The study – published in Chemical Science – is led by the ��߲ݴ�ý Acceleration Consortium Director Alán Aspuru-Guzik, Nobel laureate Michael Levitt and Insilico Medicine founder and CEO Alex Zhavoronkov.

“While the world was fascinated with advances in generative AI in art and language, our generative AI algorithms managed to design potent inhibitors of a target with an AlphaFold-derived structure,” Zhavoronkov said.

“AlphaFold broke new scientific ground in predicting the structure of all proteins in the human body,” added co-author Feng Ren, chief scientific officer and co-CEO of Insilico Medicine. “At Insilico Medicine, we saw that as an incredible opportunity to take these structures and apply them to our end-to-end AI platform in order to generate novel therapeutics to tackle diseases with high unmet need. This paper is an important first step in that direction.”

AI is revolutionizing drug discovery and development. In 2022, the AlphaFold computer program, developed by Alphabet’s DeepMind, predicted protein structures for the whole human genome – a remarkable breakthrough in both AI applications and structural biology. This free AI-powered database is helping scientists predict the structure of millions of unknown proteins, which is key to accelerating the development of new medicines to treat disease and beyond.

Scientists have traditionally relied on conventional trial-and-error methods of chemistry that are slow, expensive and limit the scope of their exploration of new medicines. As COVID-19 has demonstrated, the speedy development of new drugs or new formulations of existing ones is needed – and increasingly expected by the public. AI has the potential to deliver this speed by transforming materials and molecular discovery, as it has done with just about every branch of science and engineering over the last decade.

“This paper is further evidence of the capacity for AI to transform the drug discovery process with enhanced speed, efficiency, and accuracy,” said Michael Levitt, a Nobel Prize winner in chemistry and the Robert W. and Vivian K. Cahill Professor of Cancer Research and professor of computer science at Stanford University. “Bringing together the predictive power of AlphaFold and the target and drug-design power of Insilico Medicine’s Pharma.AI platform, it’s possible to imagine that we’re on the cusp of a new era of AI-powered drug discovery.”

Both Insilico Medicine – a clinical stage company that counts both Aspuru-Guzik and Levitt as advisers – and U of T’s Acceleration Consortium are working actively to develop self-driving laboratories, an emerging technology that combines AI, automation and advanced computing to accelerate materials and molecular discovery. Accessible tools and data will help more scientists enter the field of AI for science, in turn helping to drive major progress in this area.

“What this paper demonstrates is that for health care, AI developments are more than the sum of their parts,” said Aspuru-Guzik, a professor of chemistry and computer science in U of T’s Faculty of Arts & Science and the Canada 150 Research Chair in Theoretical and Quantum Chemistry. “If one uses a generative model targeting an AI-derived protein, one can substantially expand the range of diseases that we can target. If one adds self-driving labs to the mix, we will be in uncharted territory. Stay tuned!”

Studying guppies, researchers find ADHD drugs can affect later generations

Christopher.Sorensen — Thu, 03 Jun 2021 16:12:45 +0000

Studying guppies, researchers find ADHD drugs can affect later generations

Christopher.Sorensen Thu, 06/03/2021 - 12:12

Cutline

U of T PhD candidate Alex De Serrano is the lead author of a study that found the effects of drugs such as Ritalin and Concerta could be detected in multiple generations of guppies, including those with no direct exposure (photo by Helen Rodd)

Sean Bettam

Topic

Breaking Research

Drugs

Ecology & Environmental Biology

Faculty of Arts & Science

Graduate Students

Research & Innovation

By studying guppies, scientists at the ��߲ݴ�ý and Florida State University found that behaviours affected by methylphenidate hydrochloride (MPH) – the active ingredient in stimulants such as Ritalin and Concerta used to treat ADHD – can be passed along to several generations of descendants.

“We exposed male and female Trinidadian guppies to a low, steady dose of MPH and saw that it affected the anxiety and stress-related behaviour of males, but not females,” said Alex De Serrano, a PhD candidate in the department of ecology and evolutionary biology (EEB) in the Faculty of Arts & Science and lead author of a study published recently in Scientific Reports.

“Because of this male-specific effect, we investigated the effects of MPH through the paternal line and observed the same behaviours in several generations of their descendants not directly administered the drug.”

The findings add to growing knowledge about paternal effects on offspring, as well as the capacity for those effects to span multiple generations – of which even less is known.

From one month of age and through adolescence and into adulthood, first-generation guppies were exposed to MPH via the water in which they lived. The researchers then compared their behaviour against a control population exposed to non-treated water and observed that the males exposed to Ritalin were less cautious when placed in a new environment, compared to those not treated with the drug.

“The Ritalin-treated males showed less inhibition than expected when moved to a new environment,” said De Serrano. “Under natural conditions, guppies would be expected to freeze if they found themselves in such a situation, as this allows them to assess their new surroundings for predators and other threats.”

De Serrano then produced three generations of offspring from these individuals to see if the behaviour of their descendants differed from descendants of those not exposed to the drug and observed behaviours similar to those of first-generation males exposed to the drug.

“It suggests that Ritalin has the potential to cause changes that persist across several generations,” De Serrano said.

The study’s findings contribute to a growing understanding of paternal effects on offspring, as well as the capacity for those effects to span multiple generations (photo by Alex De Serrano)

The researchers say the paternal effect of behavioural change may be transmitted to descendants via non-genetic modifications to the sperm of male ancestors exposed to Ritalin. Such molecular changes that don’t affect DNA are a potential mechanism for males to transmit information about their environment – including exposure to drugs or pollutants – to future offspring.

“In many species, including guppies, males do not interact with offspring beyond contributing sperm, so it was traditionally thought that paternal effects would be limited to species where fathers provide some type of care to offspring or other resources to mothers,” said Helen Rodd, a professor in the department of ecology and evolutionary biology who is De Serrano’s supervisor.

“As of now, most known examples in animals of paternal effects and transgenerational effects – effects that span several generations – come from rodents, so our findings add to the handful of studies that have found paternal, transgenerational effects in other species, though the actual mechanism remains unclear.”

It has been suggested that Ritalin could cause transgenerational effects because MPH has been shown to affect the sperm cells of male rodents. Further, paternal effects have been observed in descendants of rats exposed to drugs with a similar mode of action. Despite these concerns, the transgenerational effects of paternal exposure to MPH in humans are unknown.

“I was surprised to learn that no studies had investigated whether a drug so commonly prescribed to adolescent boys to treat ADHD affects the behaviour of their offspring,” said De Serrano. “Because reduced caution in new situations has been associated with increased drug-seeking behaviour in rodents and humans, our results suggest that long-term exposure to Ritalin could increase the propensity for drug abuse and other affective disorders in males and their descendants.”

However, the researchers note that, as with all comparative studies, their results only hint at general processes that might be occurring in humans and are not directly translatable to human populations.

“More research is required to determine the mechanism that caused this altered behaviour to persist across generations,” said De Serrano. “And in order to extend these results to humans, longitudinal studies following individuals taking Ritalin and their offspring are needed.”

Support for the research was provided by the Natural Sciences and Engineering Research Council of Canada.

Virtual 'spotting' could help keep drug users safe during COVID-19, U of T researchers say

Christopher.Sorensen — Mon, 26 Apr 2021 13:29:09 +0000

Virtual 'spotting' could help keep drug users safe during COVID-19, U of T researchers say

Christopher.Sorensen Mon, 04/26/2021 - 09:29

Cutline

Carol Strike, a professor at U of T's Dalla Lana School of Public Health, and Natalie Kaminski, a research assistant, are studying a remote supervised-consumption model known as "spotting."

Topic

Dalla Lana School of Public Health

Drugs

Research & Innovation

A group of researchers at the ��߲ݴ�ý and the Canadian Association of People Who Use Drugs are studying a remote supervised-consumption model known as “spotting” to understand its benefits among people who use drugs during the pandemic.

The research team coined the term because the model involves a “spottee” consuming drugs in a safe location such as their home while a friend, family member or an acquaintance – the spotter –monitors them virtually.

“Before someone consumes a drug, they call their spotter on the phone who will be there on the call with them as they use,” says project lead Carol Strike, a professor at the Dalla Lana School of Public Health. “The spotter stays on the line with the spottee for another five to 15 minutes to ensure they are safe or call for help if needed.”

So far, Strike says the researchers have found that spotters and spottees view the model as a way to be safe during the pandemic.

“If the spottee overdoses, the spotter will call a neighbour, friend or an ambulance to come and help,” says Natalie Kaminski, a research assistant on the project.

The plan for overdose response is created by both parties before the spottee consumes a substance.

While people who use drugs have spotted each other in person for a long time, the study is exploring how it is being used amid COVID-19, Kaminski says.

Research team members with lived experience of drug use recruited 30 participants from their personal networks in Nova Scotia and Ontario to take part in the study. The participants reported an increase in their safety and said they appreciated the privacy and stigma-free environment that spotting offered. Spotters, meantime, reported an improved connection with their community and a sense of accomplishment when working with spottees.

“Also, given COVID, they can consume at home instead of coming to the safe injection site,” says Strike.

The researchers say such tactics are needed amid reports of a growing number of fatal opioid overdoses in Canada during the pandemic.

However, the spotting model isn’t foolproof. For one thing, some spotters fear help may not arrive in time to revive spottees.

“There are also concerns about police intervention if 911 is called, especially among people who use drugs who are racialized,” says Strike, pointing to recent headlines about over-policing and criminalizing of racialized people.

The research team has produced recommendations to improve spotting programs – notably the development of guidelines for spotters and spottees, awareness programs for spotting services in the community and trauma support for spotters.

They are also presenting results to conferences and will submit their findings to an open-access journal. Strike and her team are poised to receive additional funding to create educational materials such as animated videos and tip sheets. The team hopes to do more research about app-based supervised consumption and the recently-launched National Overdose Prevention Service – a service funded to provide spotting 24 hours a day, seven days a week.

“The primary goal of this project is to improve options for overdose prevention,” says Kaminski. “We’re hoping to make spotting safe for more people – in particular, those who don’t have access to supervised consumption sites.”

The study was made possible through funding from the Dalla Lana School of Public Health.

U of T expert on how drug ads leave Canadians in the dark about safety risks

noreen.rasbach — Wed, 05 Sep 2018 04:00:00 +0000

U of T expert on how drug ads leave Canadians in the dark about safety risks

noreen.rasbach Wed, 09/05/2018 - 00:00

Cutline

The failure of TV ads to explain the safety risks of over-the-counter drugs can leave people in the emergency department with liver damage or psychosis (illustration by Shutterstock)

Topic

When you watch Canadian television, it’s almost inevitable that you’ll come across advertisements for over-the-counter (OTC) drugs – the ones that you can buy without a prescription.

The ads are more than happy to tell you about the benefits – how your pain will be relieved, your skin cleared up, your allergic symptoms vanquished. Safety information in these ads, however, is virtually non-existent.

If you’re quick and have really good eyesight, you might catch a message in small print at the bottom of the ad that runs for two to three seconds. It says that to make sure that the drug is right for you, you should read the label. Missed that message? The other night I missed that message in three different ads.

One of the results is that in the emergency department in Toronto where I work, we see alcoholics who have further damaged their liver because they took too much acetaminophen.

We see people with psychotic symptoms because they took too many antihistamines.

There was no warning about these safety problems in the ads. Some of this information was in the label, but any message about reading the label was highly likely to have been missed.

Health Canada relinquished responsibility

It wasn’t always this way. Up until the end of February 1997, Health Canada was directly responsible for clearing the scripts for TV ads for OTC drugs. A 1993 review found that approximately one third of these scripts failed to comply with regulatory requirements.

TV ads for over-the-counter medicines tout their health-promoting benefits but explain none of their risks (photo by Shutterstock)

At the start of March 1997, the responsibility for clearing consumer-directed broadcast advertising for OTC drugs was transferred to Advertising Standards Canada (ASC), a national industry association.

Crucially, the role of ASC was only to review the ads, not to regulate them.

Health Canada continued to set minimum standards, but at the same time also stopped adjudicating complaints about ads.

After this transfer of responsibility, there is no public record of any evaluation of the adequacy of the new system in complying with Health Canada’s regulations.

Agencies regulate themselves

Despite never having done an evaluation, in August 2006, Health Canada announced its intention to further loosen control over this type of advertising.

Under the new proposed system, Health Canada would no longer endorse specific agencies performing these pre-clearance activities. Rather, it would let agencies self-attest that they had the ability to meet these criteria.

In other words, agencies would regulate themselves and the public would have to rely on them being honest.

The equivalent would be for students to “self-attest” that they had not cheated on an exam and for teachers to trust them.

Instructions on an over-the-counter pill bottle are shown in Toronto: Trying to decipher dose instructions written in small print on prescription medication labels can also be a daunting task for people with vision impairment or dimming eyesight due to age (photo by Graeme Roy/The Canadian Press)

ASC itself pointed out the weaknesses in what Health Canada was proposing. It noted that the new system “could…result in the mistaken belief [that agencies possess the requisite knowledge, expertise and systems to perform this function]. This lack of understanding and expertise could lead to review errors that compromise consumer health and safety.”

Virtually unreadable messages

Another part of the move to change the oversight of OTC promotion was a 2006 invitational roundtable, sponsored by Health Canada, on the inclusion of risk information in advertising.

At the roundtable, a wide variety of opinions were expressed as to how much safety information should be included in ads. Some participants wanted more detailed information provided, some advocated for “black box” warnings for certain drugs, others felt that labels and inserts should be more user friendly.

Health Canada’s position was that there should be a verbal cautionary statement in TV ads, but it was willing to accept visual disclosures – provided they were “clear, visible and of a sufficient duration to be effectively read and understood by consumers.”

What we got was self-attestation with virtually unreadable messages.

People deserve to know about the safety risks of medicines that they buy. It’s time Health Canada took back the regulation of OTC advertising.

Joel Lexchin is an associate professor of family and community medicine at the ��߲ݴ�ý, professor emeritus of health policy and management at York University, and an emergency physician at the University Health Network.

This article was originally published on The Conversation. Read the original article, including his disclosure statement.

Rethinking psychedelics: U of T study looks at the practice of microdosing to ease anxiety and sharpen focus

noreen.rasbach — Thu, 26 Jul 2018 15:04:20 +0000

Rethinking psychedelics: U of T study looks at the practice of microdosing to ease anxiety and sharpen focus

noreen.rasbach Thu, 07/26/2018 - 11:04

Cutline

LSD blotter tabs on top of a U.S. quarter: Microdosing LSD and other psychedelic drugs is the subject of a new U of T study (photo by Paul J. Richards/AFP/Getty Images)

Topic

Research & Innovation

��߲ݴ�ý Mississauga

��߲ݴ�ý Scarborough

Tune in, turn on…and boost your focus? A new study from the ��߲ݴ�ý reveals fascinating insights into how and why people use small doses of psychedelic drugs for therapeutic effects.

Microdosing is the practice of taking drugs like LSD or psilocybin (the key ingredient in magic mushrooms) in amounts too small to produce a high but large enough to quell anxiety, boost mood, or improve focus and creativity, according to anecdotal reports. The practice has become well-known after the recent publication of a book on psychedelics by bestselling author Michael Pollan.

Because the drugs are illegal in many jurisdictions, microdosing remains an underground practice and, until recently, was not subject to close scientific investigation. That has changed with a new study that examines how and why people microdose and its reported effects.

According to study co-author Thomas Anderson, it is the first study of its kind.

Anderson is a PhD candidate and cognitive neuroscientist with the Regulatory and Affective Dynamics (RAD) Lab of Norman Farb, an assistant professor of psychology at U of T Mississauga. Anderson's main research focuses on attention and meta-awareness, but his interest in the study of microdosing was sparked by a professional literature review group where he noticed there were plenty of anecdotal reports but a dearth of scientific research into the practice.

“There’s currently a renaissance going on in psychedelic research with pilot trials and promising studies of full-dose MDMA (ecstasy) use for post-traumatic stress disorder and of psilocybin use within healthy populations or to treat depression and end-of-life anxiety,” says Anderson. “There hasn’t been the same research focus on microdosing. We didn’t have answers to the most basic epidemiological questions – who is doing this and what are they doing?”

In 2017, Anderson launched a collaborative investigation with Rotem Petranker, a graduate student studying social psychology at York University, U of T Scarborough psychology PhD student Lê-Ahn Dinh-Williams and a team of psychiatrists from Toronto’s Centre for Addiction and Mental Health. Anderson and Petranker targeted microdosing communities on Reddit and other social media channels with an anonymous online survey that queried participants about the quantity and frequency of their psychedelic use, reasons for microdosing, effect on mood, focus and creativity, and the benefits and drawbacks of the practice.

The survey, which ran from September to November of 2017, drew more than 1,390 initial responses, with 909 respondents completing all questions. Two-thirds of the group were practicing microdosers, or had some past experience.

“We wanted to ensure the results produced a good basis for future psychedelic science,” Anderson says.

The data yielded interesting results, including important information about how much of the drug participants were taking, which had previously been unknown.

“Typical doses aren’t well established,” says Anderson. “We think it’s about 10 mcg or one-tenth of an LSD tab, or 0.2 grams of dried mushrooms. Those amounts are close to what participants reported in our data.”

The data also revealed information about frequency of use. Most of the microdosers reported taking the drug once every three days, while a small group microdosed once a week.

Qualitative data from the survey revealed that microdosers reported positive effects of the practice, including migraine reduction, improved focus and productivity, and better connection with others. In quantitative results, microdosers scored lower than non-microdosing respondents on negative emotionality and dysfunctional attitude.

Microdosing respondents also reported a number of drawbacks. “The most prevalently reported drawback was not an outcome of microdosing, but instead dealt with illegality, stigma and substance unreliability,” says Anderson. “Users engage in black market criminalized activities to obtain psychedelics. If you’re buying what your dealer says is LSD, it could very well be something else.”

Anderson adds a standard caveat about safety. “We wouldn’t suggest that people microdose, but if they are going to, they should use Erlich reagent (a drug testing solution) to ensure they are not getting something other than LSD.”

Dose accuracy was another issue. “With microdoses, there should be no ‘trip’ and no hallucinations,” says Anderson. “The idea is to enhance something about one’s daily activities, but it can be very difficult to divide a ½-cm square of LSD blotting paper into 10 equal doses. The LSD might not be evenly distributed on the square and a microdoser could accidentally ‘trip’ by taking too much or not taking enough.”

Anderson and Petranker recently presented their findings at the Beyond Psychedelics conference in Prague, which drew researchers, physicians, mental health practitioners, policy-makers, and technology and business participants from around the globe. The team will publish results from the survey in three upcoming research papers that will cover the survey results, psychiatric diagnosis analysis, and the benefits and drawbacks of microdosing.

“The goal of the study was to create a foundation that could support future work in this area, so I’m really excited about what these results can offer future research,” says Anderson. “The benefits and drawbacks data will help ensure we can ask meaningful questions about what participants are reporting. Our future research will involve running lab-based, randomized-control trials where psychedelics are administered in controlled environments. This will help us to better characterize the therapeutic and cognitive-enhancing effects of psychedelics in very small doses.”

The study is being supported by the Natural Sciences and Engineering Research Council of Canada and the Social Sciences and Humanities Research Council.

U of T researchers turn to baker’s yeast to develop new drugs

ullahnor — Wed, 26 Jul 2017 19:53:53 +0000

U of T researchers turn to baker’s yeast to develop new drugs

ullahnor Wed, 07/26/2017 - 15:53

Cutline

Yeast cells labeled with colourful fluorescent markers (photo credit: Wiki Commons)

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Breaking Research

Donnelly

Drugs

A team of Canadian, U.S. and Japanese scientists are enlisting baker’s yeast in a hunt for better drugs.

A new method developed by U of T researchers and international collaborators has the potential to accelerate drug discovery with help from yeast cells. They are simpler versions of human cells and better understood when it comes to basic cellular processes – helping researchers better link a drug to a particular bioprocess.

Even with cutting-edge technology, it can take years to untangle how drugs interfere with cells. In fact, one of the hardest parts of drug discovery is pinning down how a medicine actually works in the body. For example, it took nearly 100 years to uncover the molecular target of aspirin. But to develop medicine that targets disease effectively and is safe – with no side-effects – these molecular insights are key.

The study, published this week in the journal Nature Chemical Biology, tested how nearly 14,000 compounds, hundreds of which were previously unexplored, affect basic cellular processes so drug makers can become aware of chemicals that are most likely to target a particular disease.

The data pointed to about 1000 chemicals, many of which are natural products derived from soil microbes as a rich source of potential drugs against a range of diseases, from infections to Alzheimer’s and cancer.

The research teams led by Charles Boone, a professor of molecular genetics at U of T’s Donnelly Centre for Cellular and Biomolecular Research, Chad Myers of the University of Minnesota-Twin Cities and Professors Minoru Yoshida and Hiroyuki Osada from the RIKEN Centre for Sustainable Resource Science in Japan developed a new chemical genetics approach to link a drug to a cellular process it acts on.

Boone and Myers are also fellows at the Canadian Institute for Advanced Research where Boone is a senior fellow and co-director of the Genetics Networks program.

Despite modern technology, drug discovery still largely rests on guesswork. To find a drug that kills cancer cells, scientists sift through libraries containing thousands of chemical compounds, the majority of which will have no effect at all.

“There are many different types of libraries to choose from. A lot of the time you choose a library based on its availability or its cost, not any sort of functional information, and so it becomes a shot in the dark,” says Jeff Piotrowski, a lead author on the paper who was a postdoctoral researcher in both the Yoshida and Boone labs and now works at the Boston biotechnology company, Yumanity Therapeutics, which uses yeast cells to find drugs for neurodegenerative diseases.

With their chemical genetics platform, Piotrowski and colleagues were able to show which parts of the cell are targeted by thousands of compounds from seven different libraries, six of which have been extensively explored and includes collections from the National Cancer Institute (NCI), the National Institute of Health and the pharmaceutical company GlaxoSmithKline. The seventh and largest collection, from RIKEN in Japan, harbours thousands of virtually unexplored natural products from soil microbes.

“By annotating these libraries, we can tell which library targets which bioprocess in the cell. It gives us a head start on linking a compound to a target, which is perhaps the most challenging part of drug discovery,” says Piotrowski.

The data revealed, for example, that the RIKEN library contains compounds that act in many different ways: from microbe-fighting chemicals that could be used to treat infections to drugs that target cellular trafficking in Alzheimer’s and Parkinson’s diseases, to those that interfere with cell replication and might be used against cancer. In fact, the RIKEN library turned out to have many novel compounds with anti-cancer potential.

“It’s long been thought that natural products are more functionally diverse, that they can do more things than purely synthetized compounds and that certainly seems to be true from our data,” says Boone.

And because natural compounds were shaped by evolution to act on living organisms, they are better candidates for future drugs than synthetic compounds that often do not even get into the cells. For example, aspirin, penicillin and the cancer drug taxol come from nature.

The data also revealed chemicals that influence more than one process in the cell. These compounds are more likely to cause side-effects and are best avoided.

“With our map, we can see these promiscuous compounds earlier and focus on the good ones,” says Piotrowski.

The study followed earlier research by Boone, Myers, and Donnelly Centre Director Brenda Andrews, which mapped out how thousands of genes interact with each other to drive fundamental processes in the cell.

The research was supported with funding from the Canadian Institutes of Health Research, Canadian Institute for Advanced Research, National Institute of Health in the US and National Science Foundation of Japan.

U of T's Deep Genomics applies AI to accelerate drug development for genetic conditions

ullahnor — Wed, 03 May 2017 21:10:58 +0000

U of T's Deep Genomics applies AI to accelerate drug development for genetic conditions

ullahnor Wed, 05/03/2017 - 17:10

Cutline

U of T Engineering Professor Brendan Frey is the founder and CEO of Deep Genomics, a startup company applying deep-learning techniques to revolutionize genomic medicine (photo courtesy of Deep Genomics)

Marit Mitchell

Author legacy

Marit Mitchell

Topic

Global Lens

Artificial Intelligence

Vector

Brendan Frey

Entrepreneurship

Faculty of Applied Science & Engineering

Startup

Drugs

Faculty of Arts & Science

Donnelly

Faculty of Medicine

Subheadline

U of T spinoff company combines leading research in both machine learning and genomic science to accelerate development of highly tailored medical treatments

Genetic mutations are the cause of countless diseases and disorders, from cancer to autism to cystic fibrosis.

Now, startup company Deep Genomics is applying decades of research into machine learning and genomic science to develop genetic medicines – accelerating treatments that address the root causes of these conditions.

“If you have smoke billowing out of the tailpipe of your car, you don’t just put a filter on the tailpipe – you have to look under the hood and address the original problem,” says Brendan Frey, the co-founder and CEO of Deep Genomics, and a U of T engineering professor with cross-appointments in the department of computer science and the Donnelly Centre for Cellular and Biomolecular Research. “That’s what we’re doing: applying our platform for the discovery-phase development of medicines that address genetic problems.”

Developing new drugs is expensive, slow and inefficient – when researchers identify a protein involved in a disease, pharmaceutical companies often use a ‘guess-and-test’ approach to see whether any of the known drug molecules in their arsenal is a match to the protein’s unique shape. Often, thousands of molecules need to be screened in order to generate a match.

Frey’s team at Deep Genomics is looking at the first biological step in the process: at the genes that contain the blueprints for proteins and instructions on how and when to produce them.

“There are many ways a protein could be causing a problem, resulting from different changes to the genome. We can see those changes at the level of individual genes,” says Frey. “Instead of focusing on proteins, we’re focusing on the genetic mutations that are the source of the problem.”

Learn more about entrepreneurship and startups at U of T

U of T researcher launches startup to help find new smart drugs

ullahnor — Mon, 24 Apr 2017 17:03:11 +0000

U of T researcher launches startup to help find new smart drugs

ullahnor Mon, 04/24/2017 - 13:03

Cutline

Professor Igor Stagljar's new startup ProteinNetwork Therapeutix will be based in Toronto

Chris Sorensen

Author legacy

Chris Sorensen

Topic

Subheadline

The lab’s technology maps cell membrane protein interactions for hundreds of diseases like cancer, Parkinson’s, Alzheimer’s, diabetes and cardiovascular disease

Igor Stagljar likens the process of commercializing his ground-breaking research into cell membrane proteins – which has yielded hundreds of new targets for drug-makers seeking cures for cancer and other deadly diseases – to building a highly automated Tesla factory.

But there’s a key difference: ProteinNetwork Therapeutix will be based here in Canada, not south of the border.

Stagljar, a professor of biochemistry and molecular genetics at the ��߲ݴ�ý, initially considered setting up his new venture in Silicon Valley. But he and business partner Ivan Plavec ultimately decided Toronto was a better option.

“The technology is here and the know-how is here,” says Stagljar, citing U of T’s large pool of research talent and a growing cluster of venture capital investors on or near the university’s downtown campus. “Maybe some people from my lab will even go to work for the company.”

Read about his latest research findings for Parkinson's

Helping to seal the deal: a $1 million grant from CQDM’s Quantum Leap program. The grant, co-funded by the Brain Canada Foundation, targets research with “very high potential impact” within the biopharmaceutical industry. It’s only the second time the program has funded a Canadian researcher. The other was U of T’s Andrei Yudin, a professor of chemistry.

Stagljar’s research certainly qualifies as having a potentially big commercial impact.

With the help of his 17-person lab, he developed a new genetic technique that allows researchers to map the interactions between proteins in a cell’s membrane, a process previously made difficult because of the proteins’ fragile, transitory states. The interactions play a key role in determining whether a cell stays healthy or becomes diseased, and are therefore of huge interest to pharmaceutical companies seeking a new generation of precision drugs to cure deadly diseases like cancer.

“There’s about 500 proteins that we know of nested in the cellular membranes that are involved in the onset of various human diseases,” says Stagljar, citing cancer, Parkinson’s, Alzheimer’s, hypertension, diabetes, cardiovascular disease and even migraines. “There are approximately 500 diseases that can be tackled with this technology.”

But studying protein interactions in the lab is not the same as systematically evaluating them on a commercial scale. So Stagljar is in the process of retooling his laboratory at U of T’s Donnelly Centre for Cellular Biomolecular research, tapping a local Ontario company to design and build robotics that can handle hundreds of screens per day.

Everything should be up and running within the next 12 months. Stagljar’s focus at U of T will be on “druggable” membrane proteins related to three types of cancer: lung, breast and pancreatic. His company, meanwhile, will use similar technology and equipment to focus on other diseases in partnership with pharmaceutical partners.

“We’re already leading very serious talks with well-known drug companies,” Stagljar says. “Two out of the five biggest pharmaceutical companies are interested in our technology.”

How long until ProteinNetwork expects to see results?

“I think in the next two or three years, we will learn about new drug targets, which, when neutralized by drugs, would lead to cures for these cancers,” says Stagljar. “But before these drugs would appear in clinics is a long process, from nine to 12 years.

“Our focus right now is to build a high-throughput, high-grade technology for biomedical research.”

Learn more about entrepreneurships and startups at U of T

U of T immunologist's new drug shows promise in treating Ebola

ullahnor — Wed, 22 Mar 2017 15:57:09 +0000

U of T immunologist's new drug shows promise in treating Ebola

ullahnor Wed, 03/22/2017 - 11:57

Cutline

Two women in Liberia walk in front of a billboard enocuraging people to take steps to fight Ebola (photo by Emmanuel Tobey/UNMIL via Flickr)

Topic

A pilot study of a class of drugs used to treat hepatitis and some forms of multiple sclerosis has been shown to ease symptoms of Ebola patients and increase their chances of survival.

The study, entitled, “Interferon ß-1a for the treatment of Ebola virus disease: A historically controlled, single-arm proof of concept trial,” was recently published in PLOS ONE.

Interferons are a family of naturally occurring proteins, produced in response to viral infections. They have widespread potential as therapeutic agents for the treatment of viral infections, and are currently used for chronic hepatitis B and C infections and some forms of multiple sclerosis (MS).

They inhibit viral infection by preventing viral entry into target cells and by blocking different stages of the viral replicative cycle for different viruses. And because they are already in use, researchers know that they have a favourable safety profile.

Since there is no vaccine or specific approved treatment for Ebola virus disease (EVD), there is a “moral obligation” to collect and share all data generated, to understand the safety and efficacy of any intervention and to evaluate promising interventions to inform future research, says Eleanor Fish, the senior author of the study and a professor of immunology at U of T.

Eleanor Fish (fourth from left, bottom row) trained 11 Guinean health-care workers to do clinical trials during the pilot study (photo courtesy of Eleanor Fish)

To date, no treatments or post-exposure prophylaxis are available for Ebola. Clinical trials for several vaccines are in various phases, with promising published results in humans.

Nine individuals with Ebola virus were treated with Interferon ß-1a, and compared retrospectively with a matched cohort of 21 infected individuals receiving standardized supportive care at a treatment centre in Guinea, Africa, from March 26, 2015 to June 12, 2015.

When compared to patients who received supportive treatment only, 67 per cent of the Interferon-treated patients were still alive at 21 days. In contrast, 19 per cent of the supportive treatment patients survived at 21 days. Additionally, the blood cleared of the virus faster in patients treated with Interferon. Many clinical symptoms such as abdominal pain, vomiting, nausea and diarrhea also disappeared earlier in the Interferon-treated patients.

An additional 17 patients in other Guinean treatment centres who matched the Interferon-treated patients based on age and the amount of Ebola virus in their blood were included in the analysis. These patients, who did not receive Interferon, more than doubled their risk of dying as a result of not being treated with the drug.

“Despite the limitations of a single arm, non-randomized study, we infer from these data that Interferon ß-1a treatment is worth further consideration for the treatment of Ebola virus disease,” said Fish, who is also senior scientist at the Toronto General Hospital Research Institute, noting that the decision to undertake the clinical trial was based on previous preliminary scientific data and the fact that currently no approved antivirals exist to treat Ebola.

In earlier work on human cells led by Fish, researchers compared how eight different drugs, in different combinations and at different doses, were able to inhibit the Ebola virus. As a result of using a mini-genome system to rapidly evaluate drugs, the most potent inhibitor of Ebola turned out to be Interferon.

Fish also pointed out that the on-site team for this pilot study was composed of 11 Guinean health-care workers who received, for the first time, relevant training in all aspects of conducting a clinical trial according to international standards. This team is now working with Fish to monitor Ebola survivors and the impact of treatment with Interferon.

An original outbreak of Ebola virus disease that began in West Africa in December 2013, mainly affecting Guinea, Liberia and Sierra Leone has now ended, but the risk of sporadic cases remain.

More than 11,000 deaths occurred as a result of that outbreak, with a high mortality rate of the disease estimated at around 60 per cent. The World Health Organization (WHO) declared the outbreak in 2014-15 a public health emergency of international concerns, and it is the largest outbreak to date.

This pilot study was funded by the Canadian Institutes of Health Research and supported by the European Mobile Laboratory, a partner of the (WHO) Emerging and Dangerous Pathogens Laboratory Network and the Global Outbreak Alert and Response Network.

U of T study provides new hope for Parkinson’s as elusive proteins come to light

ullahnor — Thu, 16 Mar 2017 18:01:08 +0000

U of T study provides new hope for Parkinson’s as elusive proteins come to light

ullahnor Thu, 03/16/2017 - 14:01

Cutline

Research reveals a breadth of new drug targets for neurological conditions and opens the door to a greater understanding of the way in which common medications work

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Ever take antihistamines? Or heartburn medication?

Along with drugs used for a variety of conditions like diabetes, high blood pressure and depression, these common household drugs work by targeting the same class of protein molecules in our cells. They are only the tip of the iceberg. A ��߲ݴ�ý study reveals a large swath of new therapeutic opportunities for these drugs, including ones that could lead to a better treatment for Parkinson’s disease.

Despite representing about a half of prescribed medications worldwide, these compounds target only a sliver of one of the largest – and most elusive – classes of human proteins, called G protein coupled receptors (GPCRs). Tapping into this vast unexplored therapeutic potential has been difficult because available tools weren’t up to the task of surveying the GPCRs on a large scale.

Enter Professor Igor Stagljar of U of T’s Donnelly Centre.

“Our cells are made of proteins, which also do most of the work in them. But no protein acts alone and that’s why we have to look at interactions between proteins to understand what’s going on in the cell,” says Stagljar, who is also a professor in the departments of molecular genetics and biochemistry.

Stagljar’s new study, which is on the cover of the March issue of Molecular Systems Biology, is based on technology developed in his lab, called MYTH.

The technology allows detection of membrane protein interactions as they occur in their natural setting – on the surface of cells. Using MYTH, Stagljar’s team was able to capture almost 1,000 interactions between more than 600 proteins for almost 50 clinically important GPCRs (see inset).

The largest survey of GPCRs to date, it revealed new associations among proteins involved in neurological disorders like motor neuron disease, schizophrenia and neurodegenerative disorders, as potential targets for new drugs.

One association that stood out involved a G protein coupled receptor targeted by Parkinson’s disease drugs, called ADORA2A. By binding to ADORA2A, the drugs stimulated the release of dopamine, which helped communication between nerve cells to ultimately reduce tremor in patients with Parkinson’s.

Stagljar’s team found that ADORA2A associates with another Parkinson’s disease associated receptor (GPR37), in a way that affects movement in a mouse model of disease, suggesting that a combination of drugs targeting both receptors may work better in patients.

The work on Parkinson’s was done in collaboration with Professor Francisco Ciruela’s team at the University of Barcelona in Spain, which will continue to investigate the clinical potential of the enhanced combination therapy involving ADORA2A and GPR37.

“High-throughput studies like ours are going to be major contributors in future drug development,” says Jamie Snider, a senior research associate in the lab and a lead author of the study. “You can look at the cell in the ways we could not do before. We can understand how proteins interconnect better to identify possible reasons why certain drug compounds might be causing side effects and also to predict which targets might potentially be valuable for treating disease.”

To appreciate just how pervasive the 800 or so human GPCRs are, you only need to take a deep breath and look at yourself: nestled inside the eye, these proteins detect light and help us see, those in the nose detect scents, while the ones in taste buds let us taste chocolate, sweets and bitter foods.

But these proteins also detect glucose and hormones in the blood, neurotransmitters, or chemicals that help our brain cells communicate, as well as hold cells together, ensuring that tissues don’t fall apart. It’s no surprise then, that when GPCRs go awry, this can lead to brain disorders, diabetes, cancer and a host of other diseases.

In the past, scientists would either focus on the GPCR parts that are easily accessible, such as those sticking out on either side of the cell.

Or, to study the GPCRs in entirety, they would remove the surrounding membrane, which changes the proteins’ properties. Either way, researchers weren’t getting the full picture of how these proteins work. Stagljar's technology has revolutionized the study of membrane proteins, attracting interest from the pharmaceutical industry.

Read here about Stagljar’s work on proteins playing a role in cancer

“Our previous limited knowledge of the GPCRs had already helped us to tremendously improve human health,” Stagljar says. “Think of what we might be able to do if we mapped all these proteins and their interactions and then understand the biological importance of those – this would be a huge step forward for biomedicine.”

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