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Developing best practices for benchmarking: The quiet but crucial work behind sequencing today

The Global Alliance for Genomics and Health publishes new guidelines for comparing a patient’s test results to a reference human genome

Finding the difference between a patient’s DNA sequence and a reference sequence – also known as variant calling – is central to cancer research, but approaches to variant calling differ from lab to lab. Comparing – or benchmarking – one lab’s approach to another lab is important to the development of new sequencing and analysis tools, yet there are no widely-accepted standards for benchmarking variant calls.

To develop these standards and address common benchmarking challenges, a group of stakeholders from government agencies, academic bioinformatics groups, sequencing technology developers and other organizations around the world gathered to create the Global Alliance for Genomics and Health (GA4GH) Benchmarking Team. They’ve recently published their best practices for benchmarking genome sequencing results in Nature Biotechnology.

“Technology is improving rapidly, but we’ve lacked ways to know the strengths and weaknesses of new sequencing and genome analysis methods,” says Dr. Justin Zook, lead author of the study from the National Institute of Standards and Technology. “This paper gives people tools to develop accurate sequencing tests for precision medicine.”

The adoption of these practices – and their continual improvement – can also help facilitate collaboration between research and clinical laboratories while improving the performance of shared tools and methods.

The framework was developed in part by Dr. Paul Boutros and his lab members at OICR, who have used crowdsourcing to develop benchmarking foundations for individual variants as well as broader genetic variation.

Read more about this benchmarking work on Genome Web.

Moving in vivo: A case of navigating through translational research roadblocks

OICR’s Drug Discovery team and Princess Margaret Cancer Centre researchers collaborate to turn a research discovery into a potential cancer breakthrough

For more than three decades, researchers have tried to develop drugs that target the MYC oncoprotein – a protein that can contribute to half of all cancers – but traditional approaches to blocking MYC have not been successful. The structure of the MYC protein makes it ‘undruggable’; it cannot be blocked by a small molecule or a drug, so new strategies to inhibit the activity of this protein are needed.

Dr. Linda Penn, Senior Scientist at the Princess Margaret Cancer Centre, recently discovered a new way of preventing MYC from promoting cancer growth by stopping the interaction between the MYC protein and a ‘druggable’ partner protein, G9a.

Dr. Linda Penn

“We investigated MYC and discovered G9a as a key partner protein. We blocked G9a using both genetic and pharmacological strategies. We saw that inhibiting G9a using an inducible knockdown strategy had the potential to melt tumour cells away,” says Penn. “But for some reason, no matter what we tried, we didn’t see the tumour-fighting effect of the G9a compound inhibitor in animal models. Something didn’t line up.”

A discovery like Penn’s, however, can only be brought to patients if it can first be demonstrated in living experimental models, also known as in vivo. The results of Penn’s in vivo experiments were inconclusive, preventing her from publishing her promising findings in a top-tier journal and advancing this line of research.

Navigating the preclinical minefield

The compound – or molecule – that Penn’s team was using to block G9a in vitro wasn’t doing the same in vivo and they didn’t understand why. Lacking the medicinal chemistry expertise needed to solve this problem, Penn turned to OICR’s Drug Discovery group.

Dr. Ahmed Aman

“All of Dr. Penn’s experiments and all of the published literature implies that the compound should have worked, but unfortunately that wasn’t her observation,” says Dr. Ahmed Aman, Principal Research Scientist in the Drug Discovery group at OICR. “We had to break this problem down and solve it methodically while considering the various factors that could have contributed to these results.”

The Drug Discovery team evaluated the compound and found that it didn’t have the drug-like properties necessary to demonstrate activity in vivo. More specifically, they discovered that the compound would break down in the body before having a chance to inhibit G9a. Although the compound that they tested would not be useable as a drug, Penn’s study was now conclusive. Finding the missing piece of the puzzle allowed her team to publish their discovery in Cancer Cell and proceed with identifying and investigating new compounds to target G9a more effectively.

Collaboration to translation

Penn says that she worked with the Drug Discovery group because of their stellar reputation in the industry, strong track record and unique expertise.

“Without the Drug Discovery team, I really don’t know where I would have gone,” says Penn. “I simply didn’t have established relationships with medicinal and analytical chemists nor private industry to help me solve these chemistry problems.”

Together, Penn and the Drug Discovery group are continuing to investigate G9a and how to block it from interacting with the MYC protein. They are using another reported G9a inhibitor, which has been prepared in-house by the Drug Discovery team that Aman says should be able to work much more effectively in vivo.

“Our collaboration with the Penn group is a great example of how we hope to leverage our drug discovery capabilities to support investigators across Ontario and advance their research efforts,” says Dr. Rima Al-awar, Director and Senior Principal Investigator of OICR’s Drug Discovery group.

Learn more about OICR’s Drug Discovery services and capabilities through the Collaborative Research Resources directory.

New step-by-step protocol for common omics analyses fills 10-year gap in training resources

Expert group develops comprehensive guide for the interpretation and visualization of gene lists, replacing outdated, decade-old protocols

The importance of understanding biological pathways – or how our genes work together – is becoming increasingly evident, but pathway analysis remains a major challenge for many basic and biomedical researchers. Current computational tools can help simplify this analysis, but there is no established guide or standard for using these tools in practice.

To fill this gap, a team of experts from OICR and the Bader Lab at the University of Toronto recently published a comprehensive, step-by-step guide to pathway enrichment analysis that brings together their highly-recommended tools into one protocol. The complete protocol, which is now published in Nature Protocols, can be performed in less than five hours and can be used by researchers with no prior training in bioinformatics or computational biology.

“These days, almost every omics study needs to include pathway enrichment analysis, but it has been over a decade since a comprehensive protocol for these analyses has been published,” says Dr. Jüri Reimand, Principal Investigator at OICR and co-lead author of the protocol. “Our new methods are designed to guide researchers through their analyses and serve as a practical resource for their studies.”

Each step of the protocol is supported with detailed instructions and valuable troubleshooting information, which were designed in large part by Ruth Isserlin, co-lead author and Senior Bioinformatics Analyst in the Bader Lab.

Recently, the methods were used to identify a therapeutic target for ependymoma, a prevalent type of childhood brain cancer that is notoriously difficult to treat. The pathway analysis, as described in Nature, led to a better understanding of why most ependymoma treatments are not effective and revealed a new treatment option that could stop the progression of the disease.

“Future cancer research discoveries rely on our understanding of biological pathways,” says Reimand. “This protocol provides a resource from which we can build our understanding and explore previously uncharted relationships between our genes.”

Op-ed in The Globe and Mail hails innovation strategy that resulted in record-breaking investment by Celgene

Rima Al-awar showing the structure of WDR5 at podium.

In a contribution to The Globe and Mail titled “For Innovation, open science means business”, E. Richard Gold and Max Morgan point to the recent investment by U.S. pharmaceutical giant Celgene into a potential treatment for leukemia developed by OICR researchers, as an example of how Canada can successfully commercialize its scientific discoveries. The authors note that the uniquely Canadian approach employed by FACIT and OICR working together will, unlike other strategies, keep the intellectual property (IP) in Canada longer and see research and development, clinical trials and other outcomes, benefit Canada and Ontario.

Gold and Morgan point out that it was an open science collaboration between OICR and the University of Toronto’s Structural Genomics Consortium (SGC) that allowed for the initial scientific discovery behind the new potential drug to take place rapidly, since traditional concerns around IP weren’t a factor. This approach allowed FACIT and OICR to move towards targeted drug development much earlier than possible under other models, enabling them to create a patented drug candidate. Gold and Morgan call on Canadian governments to replicate the open science to IP model, which Celgene’s investment shows is a viable path to commercialization in Canada. 

E. Richard Gold is James McGill professor, McGill Faculty of Law; senior fellow, Centre for International Governance Innovation; former technology lawyer. Max Morgan is chief policy officer and senior counsel, SGC; corporate secretary and legal consultant, M4K Pharma Inc. OICR has provided funding to M4K Pharma Inc. through its Cancer Therapeutics Innovation Pipeline initiative. SGC and OICR are long-term partners.

From the Globe and Mail (subscription required): For Innovation, open science means business

Updates and highlights from Global Alliance’s 6th Plenary Meeting

The Global Alliance for Genomics and Health (GA4GH) held its 6th Plenary Meeting in Basel, Switzerland earlier this month. The meeting brought together more than 430 participants from 25 countries, making it the biggest GA4GH event yet. Attendees of the meeting learned about GA4GH Connect – a strategic phase focused on connecting GA4GH development work to the immediate data sharing needs of the community.

Peter Goodhand, CEO of GA4GH, introducing GA4GH Connect

At the meeting, Peter Goodhand, Chief Executive Officer of GA4GH, announced a call for new real-world genomic data initiatives – Driver Projects – with a specific focus on global collaboration and scientific merit. The Steering Committee will announce the accepted Driver Projects in February 2019.

Also at the meeting, Dr. Marc Fiume, Chief Executive Officer of DNAstack and OICR Associate, presented on the recent progress of the Beacon Project – an international collaborative initiative that has developed a realtime discovery platform for genetic mutations. The Beacon Project has released Beacon API V1.0.0 on Friday – the first genomic data interoperability standard from the GA4GH 2018 Strategic Roadmap.

“It was a fantastic meeting and an eye-opening experience to learn about how the field of precision medicine is linking genomic tools with clinical databases and patient outcomes to drive a patient-centered, learning healthcare model,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “GA4GH continues to play a critical role in establishing standards for genomic data acquisition, quality, interpretation, integrity, security, and sharing that many national genomic health initiatives are beginning to embrace around the world.”

Access highlights and updates from the Plenary Meeting online, or read a PDF of the meeting report here.

Researchers find common cell process key to therapy resistance

Ottawa researchers discover a new way to make cancer cells more susceptible to virus-based therapies

Over the past decade, researchers have made significant progress in designing oncolytic viruses (OVs) – viruses that destroy cancer cells while leaving healthy tissue unharmed. However, some cancer cells are resistant to this type of therapy and their resistance mechanisms remain poorly understood.

Researchers at the The Ottawa Hospital and University of Ottawa, under the leadership of Dr. Carolina Ilkow, have discovered that a common cellular mechanism, RNAi, allows cancer cells to fight back against cancer-fighting viruses. Their findings, recently published in the Journal for Immunotherapy of Cancer, show that blocking RNAi processes in tumours can make cancer cells more susceptible to OVs.

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Ontario centre attracts national attention for probe research, development and commercialization

Centre for Probe Development and Commercialization

The Centre for Probe Development and Commercialization (CPDC) awarded $10.5 million to expand molecular imaging probe work in Ontario

Translating new scientific discoveries into products and moving those products to the market is a challenging process. This is especially the case for highly-regulated medical products such as radiopharmaceuticals – a special class of drugs that are used to accurately diagnose and treat diseases. Over the past decade, the CPDC in Hamilton has been bridging the gap between the innovation and commercialization of radiopharmaceuticals in Ontario and, in turn, reaping benefits for patients and the province’s economy.

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Viral protein identified as one of the main drivers of virus-induced stomach cancers

The Epstein Barr virus in false Colour

Some common pathogens, like the Epstein-Barr virus (EBV), can turn healthy cells into cancer cells, but it is not well understood how they do so. Better understanding how such pathogens work allows researchers to find new ways to target the pathogen’s disease-causing mechanisms and ultimately find new treatments for certain virus-induced cancers.

Dr. Ivan Borozan, from Dr. Vincent Ferretti’s Lab at OICR, and Prof. Lori Frappier at the University of Toronto are working together to better understand EBV and how it triggers the transformation of normal cells to cancerous cells, also known as oncogenesis. Together, they have identified that a key protein expressed by EBV, BKRF4, is one of the likely drivers behind EBV-induced stomach cancers.

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FACIT Appoints Biotech Veteran Dr. David O’Neill as President

Entrepreneur adds US oncology management experience to Ontario commercialization

David o'NeillTORONTO, ON (June 13, 2018) — The Board of Trustees announced the appointment of David O’Neill as the President of FACIT. Dr O’Neill joined FACIT in 2013 as Vice President, Business Development, bringing cancer drug development expertise as well as an extensive business network in pharma and biotech. As Acting President for the last year, he has elevated the profile of the organization and enabled FACIT to continue to deliver critical commercialization financing to innovative start-ups in the growing Ontario market.

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