Structural Genomic Consortium

A new model for innovation? How Elizabeth and Aled Edwards are driving an open science revolution

rahul.kalvapalle — Mon, 07 Nov 2022 15:38:12 +0000

A new model for innovation? How Elizabeth and Aled Edwards are driving an open science revolution

rahul.kalvapalle Mon, 11/07/2022 - 10:38

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Elizabeth and Aled Edwards say an open science approach promises to accelerate key discoveries that will help address everything from the next pandemic to climate change (photo by Johnny Guatto)

Rahul Kalvapalle

Topic

Our Community

Open Science

Temerty Faculty of Medicine

Structural Genomic Consortium

Cell and Systems Biology

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Molecular Genetics

Research & Innovation

When the COVID-19 pandemic struck, scientists, corporations and governments around the world scrambled to share research data and ideas to advance the understanding of the disease and produce life-saving vaccines and therapies in record time.

For many, it was a crash course in “open science” – the practice of freely sharing research information and, often, eschewing intellectual property protections on early-stage inventions for the sake of accelerating discovery.

But for the ��Ƶ’s Elizabeth and Aled Edwards, it was little more than a well-publicized example of an approach for which they’ve long been advocates (and an example Aled argued should have been extended by making access to COVID-19 vaccines more equitable globally). Over the course of their careers, the two researchers – who are married – have attracted numerous industry partners to open science initiatives in medicine (Aled) and engineering (Elizabeth), helping establish U of T as a hotbed of what could be described as a new model of innovation.

Each has been made an Officer of the Order of Canada for their industry partnership work. Elizabeth received the honour in 2020 for her contributions to bioremediation, while Aled was honoured earlier this year for his efforts in advancing Canada as a leader in open science research through his leadership of the Structural Genomics Consortium (SGC), which he founded in 2003.

“Society’s big problems – such as how AI can help drug discovery, how we’re going to create bio-manufacturing capabilities that can provide medicine to the world affordably, how we’re going to tackle climate change and how we prevent the next pandemic – can’t be solved by any single actor,” says Aled, a professor in the departments of medical biophysics and molecular genetics and the Temerty Nexus Chair of Health Innovation and Technology in the Temerty Faculty of Medicine. “They require spaces to focus purely on innovation – the science, engineering and other research – in which ideas are freely shared and worries about patenting are set aside.

“We believe that universities in general, and U of T specifically, are ideally positioned to host these spaces.”

While some critics fear a sharing-first approach will dampen incentives and scare off industry, SGC’s open science policy, which expressly forbids patenting on its research, has so far had precisely the opposite effect. Over the past 15 years, the expansion of SGC’s open science remit has only served to bring more industry partners to the table.

A more recent SGC project – Critical Assessment of Computational Hit-Finding Experiments (CACHE) – was organized with several partners from Big Pharma and aims to accelerate development of AI methods in drug discovery. It invites experts to participate in “challenges” around predicting which small molecules bind to specific target proteins implicated in diseases including Parkinson’s disease and COVID-19, and placing the drug starting points in the public domain. In an interview for the CACHE website, Alexander Hillisch, vice-president and head of computational molecular design at Bayer AG in Wüppertal, Germany – one of the companies supporting CACHE – said the incentive for companies lies in being able to access quality experimental data and get to know the most skilled scientists for potential future collaborations.

Beyond his stewardship of SGC, Aled has founded and led numerous companies including the more traditional Affinium Pharmaceuticals, a venture-backed company that developed and sold a new antibiotic, and the more unusual M4K Pharma, which is developing new, but affordable, therapeutics for rare children’s cancers using an open science business model.

Aled sums it up: “To me, in my work, open science is not an end – it’s a business tactic to reach an end, which is to help us understand more about the human genome and human biology, and to allow this knowledge to be translated as rapidly as possible to drive new treatments.”

Elizabeth, meanwhile, traces her early forays into open science to when she worked with industry partners to develop a microbial culture, KB-1, that can dechlorinate pollutants in groundwater. That invention led to the creation of the spinoff company SiREM.

Since KB-1 was a collaborative discovery, patenting it became more of a headache than it was worth.

“When we started working together, we weren’t thinking about IP – it wasn’t even on the radar,” says Elizabeth, a University Professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Sciences & Engineering who is cross-appointed to the department of cell and systems biology in the Faculty of Arts & Science.

“So, we just negotiated a royalty and have kept working together ever since, with students going back and forth.”

KB-1 has since been deployed at some 900 sites around the world by organizations ranging from Fortune 500 companies to NASA, with SiREM continuing to collaborate with Elizabeth and her students to develop cultures that can degrade other contaminants.

Elizabeth Edwards gives a tour of U of T’s BioZone research centre, which has freely disseminated nearly all of its research (photo by Nick Iwanyshyn)

Elizabeth is also the founding director of BioZone, an interdisciplinary research centre that is dedicated to developing biotechnologies that address sustainability challenges. Nearly all of of BioZone’s past research output has been disseminated freely, and all new industry partnerships are being pursued using the no-patent, open science approach – including Elements of Bio-Mining, which aims to harness microbial science to stabilize waste tailings from mining. Industry partners include mining giant Vale and commodity trader Glencore.

The U of T open science industry partnership roadmap is also driving similar projects across Canada. That includes “Open Plastic,” led by Queen’s University assistant professor and U of T alumnus Laurence Yang, which focuses on the discovery of enzymes that can break down plastics in the environment – and has attracted partners including chemicals giant DuPont; Star Produce, a distributor of fruits and vegetables; and Carbios, the first industrial-scale foray into enzymatic PET recycling.

Elizabeth says the long list of corporate partners that have collaborated on open science ventures proves that IP isn’t the main motivating factor for companies looking to work with universities. With the help of student interns from the Faculty of Law, Elizabeth, Aled and colleagues at BioZone rebutted common misconceptions about industry partnerships in an article titled “Could open science stimulate industry partnerships in chemical engineering university research?” published in the Canadian Journal of Chemical Engineering.

“The people who work in companies read the same literature as professors do, and they’re just as smart and capable – but they have a different mandate,” she says.

“If something interesting happens in their labs but it’s a little bit sideways, they’re not allowed to pursue it because they have a core business to stick to. So, these companies love [open science partnerships] because it helps them find out more about the things they wish they could do, but don’t have time for.”

Aled agrees.

“Industry loves the clarity of the policy; they know exactly what they’re going into the collaboration for – to talk science, to engage with brilliant young people, to do science they would not have the time to do internally, and to get excited about the latest scientific developments,” he says.

“Elizabeth and I see the university’s role in the innovation economy as being a vehicle for industry to ask far-out questions, while allowing them a way to engage and attract students to their problems – and students really enjoy tackling real-world problems.”

He adds that U of T’s support of his and Elizabeth’s open science initiatives has placed the university in a leadership position in industry engagement worldwide.

“In supporting us to explore this radical way to innovate, U of T has painted a picture of how the Canadian university of the future can work with the private sector and others to tackle big problems and more effectively move ideas from the lab to the market.

“It’s an innovation on innovation, and we hope U of T continues to lead the way.”

'We need a cultural change': Aled Edwards on why equity matters when planning for the next pandemic

Christopher.Sorensen — Mon, 14 Mar 2022 17:49:46 +0000

'We need a cultural change': Aled Edwards on why equity matters when planning for the next pandemic

Christopher.Sorensen Mon, 03/14/2022 - 13:49

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A vehicle with a COVID-19 vaccination team crosses a flooded bridge in Zimbabwe (photo by Tafadzwa Ufumeli/Getty Images)

Jim Oldfield

Topic

Our Community

COVID-19

Temerty Faculty of Medicine

Structural Genomic Consortium

Equity

Global

Molecular Genetics

Aled Edwards is of two minds about the medical community’s response to COVID-19.

On one hand, he notes, we developed life-saving vaccines and therapies less than a year after the discovery of SARS-CoV-2. On the other, more than six million, and possibly as many as 18 million people have died, and global access to advances that can prevent and treat severe disease remains highly inequitable.

“We need a cultural change in how we view access to new medicines,” says Edwards, a Temerty Health Nexus Chair in Innovation & Technology and professor of molecular genetics and medical biophysics in the ��Ƶ’s Temerty Faculty of Medicine. “Are they commercial assets that we leave to the private sector to develop and tacitly endorse the fact that this means they will be priced at levels unaffordable by most? Or is access to new medicines a right to which all should have fair access?”

Edwards, who is also the founder and CEO of the Structural Genomics Consortium, a public-private partnership dedicated to the discovery and sharing of new medicines, recently published a review paper with colleagues in the journal Science about COVID-19 vaccines and therapies.

He spoke with writer Jim Oldfield about how society could better prepare for future pandemics.

You write that a foundation of basic and applied research, years in the making, enabled effective medicines for COVID-19. What do you mean, exactly?

Some folks are concerned about the novelty of the COVID-19 vaccines, but they were not invented from thin air.

Already in 2019, thanks to decades of research on vaccine technology and coronaviruses, mRNA and adenoviral vaccines showed strong promise in models of other deadly coronaviruses.

The main question was whether these technologies would work in people in the real world. And no one could know. Indeed, in early 2020, the WHO said if vaccines were 50 per cent effective in people, we should be doing high-fives – nobody imagined efficacy like 90 per cent.

To give you sense of how it might have gone, we’ve been trying to make vaccines for HIV and hepatitis C since the 1990s and have been spectacularly unsuccessful. So, the COVID vaccines have been a great news story, although of course we clearly need broader-spectrum vaccines that work against SARS-CoV-2 variants, and also against the next virus that might jump from animals to humans.

You also write that in addition to scientific innovation, we need better vaccination implementation?

Yes. We need to increase capacity to produce billions of doses for global demand, particularly in low- and middle-income countries. There are certainly technical challenges, but we should be able to overcome them either by reducing the quantity of active components in vaccines – by limiting the number of doses needed for immunity, or by using vaccine adjuvants or other methods.

But the greater challenge is in the social and political realms. It’s critical that we provide more equitable access to vaccines globally. We saw both in Canada and in other rich countries a very selfish, me-first approach to vaccine distribution. We should have had a discussion as Canadians and decided what fraction of the vaccines we purchased should stay in Canada or be given away to the less fortunate. We did not. Now we are left trying to convince Canadians to help others only because it's in our best interests, and not because it’s the right thing to do. That argument really disappoints me.

How should we shift our approach in Canada?

We need a cultural change in how we view access to new medicines. Are they commercial assets that we leave to the private sector to develop and tacitly endorse the fact that this means they will be priced at levels unaffordable by most? Or is access to new medicines a right to which all should have fair access?

Affluent countries like Canada lean more toward the asset view because our economic systems are entangled in the development of medicines, and, of course, because we are rich. But if you’re from a developing country, you lean toward them being a right.

It’s a hard question, obviously, and you can’t ignore that distribution may be better done by the private sector, and that money is a motivator. But I think we, particularly at public universities, should do our best to create a system in which access to medicines is the guiding principle. Indeed, greater equity is the driving principle behind open science, and it’s what we’ve been trying to do at the Structural Genomics Consortium for two decades – first with drugs for neglected diseases and more recently with antivirals. And I’m convinced that, if given a choice, it’s what many people at the university would want.

You also say that addressing misinformation is crucial for pandemic planning. Can you explain?

Well, social media has spread mis- and disinformation far and wide, and that has spurred vaccine hesitancy and undermined public health interventions. I’ve seen it in friends and family. Ironically, older generations have been less influenced by misinformation. I think it’s because many of them remember polio and measles, for example. They’ve seen the power of vaccines with their own eyes and have no hesitation to get vaxxed. Look at Mitch McConnell [Republican U.S. Senate minority leader] – he had polio, and that fear will always be with him – he’s pro-vaccine. But many young people have never seen these diseases and it’s harder for some to imagine their danger.

Early education programs on the science and history of vaccines would be a great start on this problem. And universities should take the lead on that. U of T in particular can play a role here – we’ve published more COVID-19 papers than any other Canadian university, and over 15 per cent of them are in the social sciences and humanities. Misinformation is not a science problem per se, and it won’t be solved by nerds like me in labs.

Antiviral therapies have emerged as a potent way to halt COVID-19 progression. What did we do right with those?

Both antiviral drugs and antibody drugs have been effective. When the pandemic hit, we saw huge efforts to repurpose drugs approved for other diseases that might work for COVID-19. Most repurposing efforts to identify antivirals failed, but those that succeeded started from drugs that act on other RNA viruses – it is a good strategy to “to fish where there are fish,” as we put it. So we must start casting our lines in this pool to finds drug starting points for the other 15 viruses of pandemic potential – and we should start now, while we have time. Our goal should be to identify oral, broad-spectrum antiviral pills likely to protect against these emerging pathogens. The science is there, it’s whether there is a will. Fortunately, the Americans are beginning to invest heavily in the prospective development of new antivirals. Canada has not yet decided what it will do.

As for antibody drugs, like the one discovered by the Canadian company AbCellera and developed by Eli Lilly, they offered one of the first treatments for COVID-19 – in part due to their safety profile. It took just five months for the first monoclonal antibody to enter trials. There are more than 100 similar treatments in development.

This approach shows a lot of promise, but cost and logistics are significant barriers – currently they are too expensive for all but rich countries. Canada should think carefully about investing only in these products because currently this is an investment in medicines that will be available only to rich people. I do not think this is a good message to the world. We absolutely must develop a strategy that prioritizes fast, fair and global access.

Indeed, as a university and as a country, we’re at a key point. It’s like the Robert Frost poem: The Road Not Taken. Are we going to take the easy road, stay the course and contribute to the development of medicines that will likely never be available to all? Or take the hard road and do something different here at U of T to prioritize the public good first and develop medicines with a priority on access?

Taking the rough road flies against the current policy thinking of how drug discovery is “supposed” to work, but there is a precedent for that at U of T, all the way back to insulin and diphtheria vaccines, where university scientists pushed for access over profit. Medicines for the public good is part of our past, and it could also be our future, if we’re willing to risk walking-the-talk.

U of T Engineering team manufactures coronavirus ‘parts’ for COVID-19 research

Christopher.Sorensen — Thu, 07 May 2020 16:05:39 +0000

U of T Engineering team manufactures coronavirus ‘parts’ for COVID-19 research

Christopher.Sorensen Thu, 05/07/2020 - 12:05

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The COVID-19 Protein Manufacturing Centre at U of T aims to produce and distribute large quantities of SARS-CoV-2 proteins, including the ones that make up the spikes on the now recognizable renderings of the novel coronavirus (photo courtesy of CDC)

Liz Do

Topic

Our Community

Coronavirus

Structural Genomic Consortium

Faculty of Applied Science & Engineering

Faculty of Medicine

Molecular Genetics

Research & Innovation

The structure of SARS-CoV-2 is now all too recognizable, resembling a soccer ball covered in spiky protrusions. Now, a team of ��Ƶ researchers are replicating these spikes – and all the other proteins that enable its deadly attack on the human body – in the hopes of speeding up COVID-19 research around the world.

“There are about 25 of these viral proteins. We can make all 25 in our labs,” says Peter Stogios, a senior research associate at the Faculty of Applied Science & Engineering’s BioZone who’s bringing his team’s expertise in producing proteins to the newly launched Toronto Open Access COVID-19 Protein Manufacturing Centre, which received support from the Toronto COVID-19 Action Fund.

The centre is led by Aled Edwards, a professor of molecular genetics and medical biophysics at the Faculty of Medicine and director of the Structural Genomics Consortium (SGC), which aims to speed-up scientific discovery involving the human genome by sharing research. The Protein Manufacturing Centre aims to produce and distribute large quantities of viral proteins in rapid fashion, at no cost.

SARS-CoV-2 proteins are essential in understanding the virus’s biology, developing antibody testing, antiviral drug discovery and, potentially, vaccine discovery.

Antibody tests, for example, rely on detecting antibodies in the bloodstream that can neutralize the virus. The way these antibodies work is by recognizing the component proteins – such as the spikes or internal proteins that wrap up the virus’ genome – and blocking their action on the human body.

“To develop these tests and to look for the antibodies in the bloodstream, you need to have proteins available,” says Stogios.

Viral proteins are already on the market for research and testing, but for-profit companies are selling them at upwards of $10,000 for quantities measured in milligrams, according to Stogios.

“If you’re an academic researcher, or a small company in Canada or anywhere in the world, this is cost-prohibitive,” he says. “We’re hoping that through this centre, we’re alleviating that barrier and expediting important research.”

Manufacturing proteins is nothing new. Researchers can genetically program bacteria to produce any protein from any organism, from humans and animals to other bacteria – and, in this case, a virus.

“We grow bacteria in the lab, crack them open and fish out the protein we’ve engineered the bacteria to produce. And then we go through a purification process, where the end product is a high-quality sample of the protein,” says Stogios.

With the BioZone lab back up and running, Stogios and his team have purified eight SARS-CoV-2 proteins. Stogios says that, if all goes to plan, BioZone and SGC will have all 25 proteins produced within a month or two. The speed at which they’re producing proteins, he says, is in the spirit of COVID-19 research being conducted at U of T and around the world.

“I’ve never seen researchers come together so fast and work so collaboratively than in this situation,” says Stogios. “This open-science approach proves that, in any public health situation, we have the power to quickly and freely come together to solve important problems. I hope we can use this approach with other crises, beyond this pandemic.”

'A molecular Swiss army knife': U of T researchers uncover versatility of ancient DNA repair mechanism

Christopher.Sorensen — Fri, 06 Dec 2019 21:43:47 +0000

'A molecular Swiss army knife': U of T researchers uncover versatility of ancient DNA repair mechanism

Christopher.Sorensen Fri, 12/06/2019 - 16:43

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U of T researcher Cheryl Arrowsmith and Levon Halabelian, a research associate at the Structural Genomics Consortium, collaborated with U.S. researchers on the study (photo by Arij Al Chawaf)

Topic

Breaking Research

Structural Genomic Consortium

Faculty of Medicine

Global

Research & Innovation

If a bone breaks or a tendon snaps, you know to seek treatment immediately.

But your most fragile and precious cellular commodity, chromosomal DNA, breaks with astounding frequency – some estimate as many as 10,000 times a day per cell – usually without consequence.

That's because legions of DNA repair proteins prevent genomic catastrophe by repairing DNA damaged by chemical or physical mutagens or just normal cellular wear and tear. Proteins dedicated to these tasks are common to all species. In fact, life as we (or bacteria) know it cannot exist without proteins that are dedicated to DNA repair.

Now, new research from Cheryl Arrowsmith, a professor in the ��Ƶ’s department of medical biophysics in the Faculty of Medicine, reveals a previously unrecognized activity for one DNA repair factor that has been highly conserved through evolution.

“Our research revealed how a molecular Swiss army knife has multiple ways it can repair damage to our DNA,” says Arrowsmith, who is also chief scientist at the Structural Genomics Consortium (SGC) and senior scientist at Princess Margaret Cancer Centre.

“Our collaboration with colleagues in the U.S. provides a greater understanding of processes relevant to cancer and the function of immune cells.”

In a study published in July in the journal Nature Structure and Molecular Biology, Levon Halabelian, a research associate at the SGC, showed how the repair protein (known as HMCES and prounounced Hem'-sez) can recognize and trap several types of broken DNA strands.

Now in a second study published in Molecular Cell, Arrowsmith and collaborators including Anjana Rao at the La Jolla Institute for Immunology, and L. Aravind at the National Institutes of Health, show a new role for HMCES in which it helps a type of immune cell, called B lymphocytes, recombine their DNA to make certain classes of antibodies.

This finding means that HMCES, in addition to its role in repairing nicks in single DNA strands, also participates in what is called alternative end joining.

As the name suggests, alternative end joining is a secondary strategy used by mammalian cells to rejoin severe cuts across both strands of the DNA’s double helix. These and other recent reports suggest that a humble DNA repair factor whose history likely dates back several billion years performs multiple tasks to guard cells against genomic instability.

"When activated, normal B lymphocytes snip out a segment of their DNA that encodes antibodies called IgM and then reconnect the strand in order to make other more potent classes of antibodies," says Vipul Shukla, the study's first author, describing a DNA editing trick immunologists call class switch recombination (CSR).

"People have known for decades that immune cells use this kind of gene editing as a way to make potent antibodies. We found that HMCES not only recognizes these double strand breaks but helps reseal them."

The Rao and Arrowsmith labs, which both study DNA-modifying epigenetic enzymes, became interested in HMCES because it had been reported to bind to DNA chemically modified by one such enzyme called TET.

Crystal structure of HMCES in complex with 3’ overhang DNA in green and orange (PDB ID: 6OEB). HMCES surface color indicates electrostatic potential ranging from −7kT/e (red) to +7kT/e (blue)

Reasoning that HMCES and TET proteins might be engaged in similar biological tasks, the Rao lab genetically "knocked out" the HMCES gene in experimental mice, predicting that animals would display blood cell defects or even cancer – similar to outcomes caused by TET gene mutations. Surprisingly, that didn't happen: The new paper by Shukla and the other researchers reports that blood cells from HMCES-deficient mice were normal and showed little disruption in TET-dependent DNA modifications.

However, there is abundant messenger RNA coding for HMCES inside normal, activated B lymphocytes, prompting the group to compare immune responses in HMCES-deficient versus normal adult B cells. Following antigen stimulation, normal B cells predictably "switch" their antibody repertoire from IgM to IgG antibodies. By contrast, lymphocytes from HMCES-deficient mice were less-efficient at making IgG antibodies, presumably because the CSR machinery that "recombines" DNA to convert IgM to other IgG isotypes is operational to a lesser extent without HMCES.

"In this study we used lymphocytes as a model system to identify a new role for HMCES in a lesser-known pathway of DNA double-strand-break repair," says Shukla, referring to alternative end-joining. "But that pathway is not only active in immune cells. The kind of DNA double-stranded break repair we describe here likely occurs in response to DNA damage in any cell of the body."

The research was supported by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and the Structural Genomics Consortium, among others.