Donnelly

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

Fighting global diseases: U of T researchers tackle parasites

ullahnor — Tue, 11 Apr 2017 20:28:13 +0000

Fighting global diseases: U of T researchers tackle parasites

ullahnor Tue, 04/11/2017 - 16:28

Cutline

Researchers help identify anti-parasitic drugs by using C. elegans, a worm grown on a lab dish (photo courtesy of Wikimedia Commons)

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Andrew Fraser and Peter Roy lead research into identifying new drugs that can fight parasites infecting the gut, lungs and livers of two billion people globally – many of whom live in poor and marginalized communities.

The researchers, who are both professors in the department of molecular genetics, work with pharmaceutical companies to identify promising drugs.

“Drugs already exist for some parasite infections, but resistance is always evolving – we need new ways to attack these complex creatures,” says Fraser, who signed a deal last month to work with Janssen, a branch of the pharmaceutical giant Johnson & Johnson.

“The best anthelmintic drug today, ivermectin, was developed in the 1970s as a partnership between an academic lab and a major pharmaceutical company. It’s a great cooperative model to help solve these huge global health problems.”

Roy says there is also a potential for the agriculture industry to play a role in developing new treatments.

“Most of the meat we eat has been treated with anthelmintics, drugs that kill parasitic worms,” says Roy. “If novel anthelmintics are shown to be useful for cows and sheep, then they might become therapies for humans.”

As their main research tool, the professors rely on a harmless type of worm widely used in labs called C. elegans. Unlike parasites, which cycle between living inside the body and outside, lab worms grow on a dish and are easy to work with.

But to mimic what is taking place in the body – many parasites live in places within the body with little oxygen – U of T PhD students Samantha Del Borrello and Margot Lautens found a way to trick the worm, C. elegans, which needs oxygen to survive, into behaving like a parasite.

“The way worms survive in low oxygen is extremely unusual, humans don’t use this process at all. That’s the key. It means that if we can target this unusual metabolic pathway, we should be able to kill the worms without having any impact on the human host,” says Fraser.

In Del Borrello's case, family history led her to researching parasites. Her grandmother's childhood in 1940s rural Italy was plagued by intestinal worms that ravaged her health to the point doctors thought she would die.

“It is crazy to think that I may not be here because of a parasite, and now here I am working on preventing the parasites from hurting people,” says Del Borrello.

Using a different strategy, Roy’s team has already uncovered a treasure trove of potential anti-parasitic compounds. Two years ago, postdoctoral researcher Andrew Burns was part of a team that uncovered 275 chemical compounds that killed C. elegans. These worm active compounds, dubbed wactives, were then tested on fish and human cells to identify which ones could potentially harm the host.

That team is now teasing apart how wactives work. A new study in PLOS Neglected Tropical Diseases describes how a compound called wact-86 works by blocking an important enzyme in the worm. The next step is to explore whether wactives can clear parasitic infections in larger animals.

Another potential avenue is to work with a pharmaceutical company from the start. To do this, Fraser is working with BIO Ventures for Global Health (BVGH), a Seattle-based non-profit that boosts research in neglected tropical diseases through partnerships between academic labs and the pharmaceutical industry. The organization, among other roles, helps academia and industry share reagents, says Ujwal Sheth, associate director at BVGH.

Last month, Fraser signed a deal with Janssen, granting his team rights to the company’s drug collection – a potential chemical gold mine with 80,000 diverse compounds. If they find a medicinally promising compound, Janssen could decide take it on, said Sheth. Or, the BVGH could help connect Fraser with other partners with capacity to develop new medicines, she added.

Donnelly

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

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

Read more about startup by Frey's student using AI to analyze protein data

Learn more about entrepreneurship and startups at U of T

Fighting global diseases: U of T researchers tackle parasites