Lessons learned from Nobel winner Michael Houghton drive innovation for pharmacy researcher

Originally published by Folio.

Khaled Barakat was starstruck the first time he met Michael Houghton in 2012.

He knew the U of A virologist and director of the Li Ka Shing Applied Virology Institute was renowned for discovering the hepatitis C virus and was likely to win a Nobel Prize (which Houghton eventually did in 2020).

Barakat, a PhD in biophysics, landed an interview for a post-doctoral fellowship with Houghton. Originally from Egypt, where he said nearly 40 per cent of the population had been infected with hepatitis C, Barakat had lost family members to the disease. “It was one of the factors that pushed me to work in this area,” Barakat said.

Barakat was already developing computer programs to mimic how cells work, providing insight into what happens when disease strikes and revealing potential targets for treatments. He thought the approach could work for hep C too, but with his academic background in electrical engineering and physics, he’d never worked in a “wet” research lab like Houghton’s, so he wasn’t sure he’d stand a chance.

“I took all my research posters with me to the interview and tried to explain how I believed my computer simulations could help advance his hep C research.”

Instead of brushing him off, Houghton listened carefully, asked a lot of questions, then gave Barakat the job as part of a multidisciplinary research team.

“I learned at that very first meeting with Michael that to be a visionary scientific researcher, you have to be a good listener, appreciate other people’s work, be interested in what they do and, most importantly, be very humble,” Barakat said.

Teamwork, focus on patients are key

Barakat has never forgotten the lessons he learned during the two years he worked with Houghton before he joined the Faculty of Pharmacy and Pharmaceutical Sciences as an assistant professor in 2014. He now heads his own research group, using supercomputing to solve some of medicine’s thorniest problems.

Back in 2012, Barakat was thrilled that Houghton thought he belonged on his outstanding team. He loved the weekly Thursday meetings between Houghton’s lab and the researchers working for Lorne Tyrrell, another leading hep C researcher and founding director of the Li Ka Shing Institute of Virology.

“Sparkling ideas were stimulated when these two wonderful labs interacted,” Barakat said. “It was like two mountains colliding.”

Barakat noted that Houghton made sure patients were always top of mind for all of the researchers, no matter how technical their work.

“Michael would remind us that patients are waiting for treatments,” he said. “You have to always be thinking that these discoveries that you make on the bench, on the computer, have to be translated into something meaningful for patients.”

Creating heart-safe drugs

Barakat continues to collaborate with Houghton. Their most recent joint research paper represents a breakthrough for patients with chronic conditions who have to take the same drug for many years. Unexpected side-effects, known as cardiotoxicity, can sometimes lead to heart attack, even sudden death, and the drugs have to be withdrawn.

Barakat and his U of A team have created a computer program that drug makers can use before they bring a new medicine to market, to check whether the drug will affect ion channels—proteins in the heart that convert chemical and mechanical messages into electrical signals.

“We built computational models to show how a drug interacts with one of the most notorious ion channels in the heart, called the hERG ion channel,” said Barakat. “Our model can not only tell you if the drug can bind or not, it actually shows you where it binds and how it binds, so you can change the structure of the drug so it doesn’t bind.”

Taking Houghton’s advice to heart, Barakat and his partners have created a spinoff company called ACHLYS to make the program commercially available.

Tackling cancer with the immune system

Barakat, who is a member of the Cancer Research Institute of Northern Alberta, is also working on ways to stop cancer from interfering with the body’s natural immune response, in research funded by the Alberta Cancer Foundation and the Li Ka Shing Applied Virology Institute.

“One way for cancer to invade the human body is to silence the immune system by deactivating T-cells and preventing them from seeing the cancer,” Barakat said.

Cancer patients’ T-cells have too many immune checkpoint receptors, which turn the immune system off. The U of A researchers have hunted down a molecule that will block those receptors.

“The beauty is that this immunotherapy can work in multiple types of cancer,” Barakat said. “Once you reactivate the immune system it will start discovering the problem and go to work to fix it.”

Once again, Barakat said it’s key to have a cross-disciplinary team working on the project, which includes virologists Houghton and Tyrrell, immunologists, chemists, biochemists, toxicologists, oncologists and at least 40 trainees. They have shown the molecule works in purified proteins and cell cultures, and have now formed Heka Therapeutics, named after the ancient god of magic, to develop the drug for human trials.

Searching for COVID-19 treatment targets

Barakat is also turning his focus to COVID-19, working to create a computerized replica of the SARS-CoV-2 virus to uncover drug targets that may have been overlooked.

“If we understand how different viral proteins bind together and work with each other, we can identify future mutations and novel points of attack,” said Barakat. “This worked in hep C research—computer simulations found different binding sites that you can’t see in the crystal structure, and now there have been drugs developed to target these sites.”

The COVID-19 project has not secured direct government funding, but Barakat said his team is committed to continuing to work on it because he feels it holds such promise.

Barakat, like Houghton, pays tribute to his trainees for their pursuit of excellence. On his lab’s website he lists past and present post-doctoral fellows and grad students. Many have gone on to faculty or research positions elsewhere.

“Losing each one has been a disaster to my lab,” he said with a laugh. “But I’m really happy for them, and we can train others.

“As Michael Houghton says, it’s all about spreading the word of science throughout the world. And even though they have moved to other labs, we keep collaborating.”

Barakat believes Houghton’s Nobel-winning vision of using collaborative teamwork to find patient-focused breakthroughs will snowball at the U of A.

“Thanks to the brilliant thinking of Michael Houghton, we will have more success stories emerging from Edmonton,” he predicted. “Venture capital and pharmaceutical companies will come to see what ideas we have here and help turn them into reality faster.”

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