December 17, 2020
Dr. Jared Simpson and collaborators develop new nanopore-based methods to investigate two understudied aspects of disease biology
Studying DNA modifications may offer new insights into cancer – and the tools to read these changes are now in our hands.
In a recent publication in Nature Methods, OICR Investigator Dr. Jared Simpson and collaborators at Johns Hopkins University describe a new method to investigate two key aspects of disease biology, methylation and chromatin accessibility, simultaneously. These aspects can help describe how genes are organized and switched on and off in a cell, which may enable future progress in cancer research and discovery.
The group’s new method, coined nanoNOMe-seq, is built for nanopore sequencing – a fast, portable way to read long molecules of DNA. nanoNOMe serves as an additional tool that extends the utility of nanopore sequencing technologies.
“Our collaborators developed the lab protocols and we developed the analysis software to determine where DNA modifications occurred,” says Simpson. “Now, with this method, other researchers can investigate how DNA is modified within a cell to give an extra layer of information that the community can decode into new insights and discoveries.”
Dr. Michael Molnar, Scientific Associate in the Simpson Lab at OICR, led the development of the analysis software behind nanoNOMe.
“At times, it seemed like it might not be possible to develop a statistical model that could make sense of all the data,” says Molnar. “But we were able to persist and develop the nanoNOMe software, which showed a high degree of accuracy. We hope this method will enable others to discover long-range patterns and make new connections in sequencing data.”
nanoNOMe was first released as a preprint, which has already been cited in other scholarly articles including a tool for methylation pattern visualization, an analysis of human chromosome 8, and a published review on long-read sequencing among other publications. Simpson and Molnar’s collaborators plan to further investigate methylation and chromatin accessibility in human cancer cells with nanoNOMe.
“If you’re interested in understanding how methylation relates to open chromatin, then you can use this protocol,” says Simpson. “This is opening a new space for the community to explore interactions between chromatin and DNA methylation.”
November 21, 2019
International research group unlocks the promise of nanopore native RNA sequencing
Studying RNA may offer new answers to cancer – and the tools to read RNA directly are now in our hands.
An international research consortium, led in part by Dr. Jared Simpson at OICR, has developed new laboratory protocols and a suite of software tools that will allow the research community to exploit the promise of direct RNA sequencing.
These techniques, published recently in Nature Methods, represent the first large-scale exploration of human RNA using nanopore sequencers – the advanced handheld sequencing devices that can read long strands of RNA.
“Unlike traditional sequencing devices that read copies of RNA strands that are cut into little pieces, nanopore sequencing allows us to study long strands of RNA directly without losing important information in the copying and cutting process,” says Paul Tang, Computational Biologist at OICR and co-first author of the publication. “Our methods combine the power of reading RNA directly with the power of long-read sequencing, enabling an entirely novel way to study cancer biology.”
In collaboration with researchers at Johns Hopkins University and the University of California Santa Cruz, Tang and Simpson developed the software methods that could decode the output data from a nanopore sequencer. Their methods used a machine learning technique, called a Hidden Markov Model, to determine the letters of code within an RNA strand.
“With these methods, we’ve shown that you can leverage nanopore RNA sequencing to gain a lot of valuable information that we couldn’t have otherwise,” Tang says. “We’re very happy to see this work published because we are enabling others to study a new aspect of cancer biology and we look forward to the research discoveries to come.”
These new methods have been integrated into Simpson’s already-popular nanopolish software suite which is routinely used by the nanopore community around the world.
September 18, 2019
Dr. Ina Anreiter joins OICR as a Schmidt Fellow, bringing her background in behavioural genetics to bioinformatics
While writing her doctoral thesis, Dr. Ina Anreiter realized that there was a missing piece to her research. What she didn’t realize was that this missing piece would lead her into a prestigious postdoctoral fellowship in an entirely new scientific discipline. For decades, scientists have known that RNA – often referred to as DNA’s cousin – undergoes chemical modifications before running its course. These modifications, like RNA methylation, have an important effect in cancer cells, but without the tools to study RNA modifications, progress in this field had stalled for many years.
Recently, the study of these modifications – also known as the field of “epitranscriptomics” – has garnered new attention as the research community develops new methods to study RNA. These methods, Anreiter says, still rely on common chemistry lab techniques and cumbersome procedures that make studying RNA methylation difficult, especially in application to diseases like cancer.
“I found myself in need of a tool,” says Anreiter. “I needed a way to easily analyze RNA methylation across large datasets and found that nothing existed – well, nothing existed yet.”
From fruit flies to machine learning
Anreiter’s doctoral research focused on the behaviour of fruit flies, specifically how inherited characteristics and environmental factors influence their feeding patterns. While searching for a way to study RNA methylation, her background led her to a unique idea.
Anreiter knew of nanopore sequencing – a relatively new type of sequencing technology that could decode DNA and RNA as it passes through a tiny channel. By directly reading a strand of RNA, Anreiter says, nanopore sequencing has the potential to revolutionize how we study RNA modifications. To this day, however, there are no algorithms or tools that can accurately find RNA methylation patterns in the output data of a nanopore sequencer.
Anreiter had also heard of Dr. Jared Simpson’s breakthrough methods for detecting DNA methylation using nanopore sequencing. His computational methods allowed the nanopore community to sequence the entire – highly-methylated – human genome in 2017, and since, he has been working in part to study RNA modifications, like RNA methylation, using nanopore sequencing.
Anreiter pitched her idea to Simpson.
“RNA methylation occurs in normal fruit flies, but not in a certain type of mutant fly,” says Anreiter. “I had a crazy idea that we could sequence both of these types, and use the datasets to develop a machine learning algorithm that could find RNA methylation on its own.”
The potential of her idea would win her the prestigious Schmidt Science Fellowship and a $100,000 USD stipend to work with Simpson for a year.
From machine learning to cancer patients
Anreiter recently began her year-long postdoctoral fellowship in the Simpson Lab at OICR where she is working alongside a team of computational biologists to turn her idea into an algorithm. She is cross-appointed with the University of Toronto’s Department of Computer Science.
“At this point, we’re working on a preliminary dataset, but I’ve already learned so much. The team has been very welcoming and supportive and we’re working together to make better tools to understand diseases.”
The Schmidt Fellowship, which was co-founded by the former CEO of Google, is awarded to exceptional, early-career researchers making a “pivot” in their work. Anreiter saw the fellowship as an opportunity to immerse herself in a completely new field.
“If we can develop this tool, it would allow us to study human diseases in a new way,” Anreiter says. “When we look at a problem in a new way, we don’t know what solutions we’ll find, but this angle could lead us to new cures.”
April 23, 2019
OICR’s Dr. Jared Simpson and collaborators at the University of Oxford create a new method that allows researchers to explore the fundamental, but hard-to-study biological process of DNA replication
How DNA replicates in a cancer cell is difficult to understand, in large part due to the limitations of current technologies. Nanopore sequencing – a fast, portable way to read very long molecules of DNA – could allow researchers to detect DNA replication patterns. Experts in DNA replication from Oxford University, led by Drs. Carolin Müller, Michael Boemo and Conrad Nieduszynski, teamed up with OICR’s expert in nanopore sequencing, Dr. Jared Simpson, to tackle this challenge.
Together, they developed D-NAscent, a sophisticated laboratory protocol and computational tool that together allow researchers to detect and study how DNA is replicated. Recently, the group’s techniques were published in Nature Methods.
“Traditional methods of studying DNA replication have limited resolution – how finely we can see these patterns,” says Simpson, an Investigator at OICR, who helped develop the computational methods used in the study. “With our methods, we can now look at DNA replication on individual, long molecules of DNA at high throughput. This gives us the ability to look for biological patterns that we were once unable to see, for example, in repetitive areas of the genome.”
In the study published today, the group used their methods to study yeast cells, which have a simpler and smaller genome than human cells. Now, the group will apply D-NAscent to study the DNA replication dynamics of human cancer biology. They’ve released their software freely to allow other researchers to do so as well.
“We’re very excited to apply D-NAscent in human cancer cells,” says Simpson. “The potential of this technology is what excites me. We’ve opened up an entirely new way to look at genomic diseases – one that can potentially turn an unexplored aspect of biology into new cancer research discoveries.”
August 3, 2018
OICR researchers have contributed to major open source projects available to the global research community in order to accelerate cancer research. Click the link below to read about more of OICR’s open source software projects.
August 1, 2018
In the effort to bring better disease prevention and treatment to patients faster, cancer researchers are thinking more creatively about ways to conduct high-quality scientific research. Concerns about the quality, efficiency and reproducibility of research have motivated the open science movement – the growing trend of making data, methods, software and research more accessible to the greater scientific community.
Open source software (OSS), a major component of open science, enables research groups to reduce redundant efforts in software engineering by sharing software code and methods. In addition to improving efficiency, OSS promotes high-quality research by enabling collaboration, and helps make research easier to reproduce by making it more transparent.
January 29, 2018
A new nanopore technology for direct sequencing of long strands of DNA has resulted in the most complete human genome ever assembled with a single technology, scientists have revealed.
The research, published today in Nature Biotechnology, involved scientists from the University of Nottingham, University of Birmingham and the University of East Anglia in the UK; UC Santa Cruz at the University of California, Genome Informatics Section of the NIH and the University of Salt Lake City in the USA; and the University of British Columbia and the Ontario Institute for Cancer Research in Canada.
Using an emerging technology – a pocket sized, portable DNA sequencer – the scientists sequenced a complete human genome, in fragments hundreds of times larger than usual, enabling new biological insights.
January 25, 2018
The Canadian Data Integration Centre receives new funding to help cancer researchers translate findings to patients
Toronto (January 25, 2018) – The Canadian Data Integration Centre (CDIC) has received $6.4 million in funding from Genome Canada to help the research community translate the biological insights gained from genomics research into tangible improvements for cancer patients.
CDIC is a “one-stop shop” service delivery platform for cancer researchers, helping streamline research by providing coordinated expertise on a broad range of services, including data integration, genomics, pathology, biospecimen handling and advanced sequencing technologies. It is an international leader in genomics, bioinformatics and translational research, supporting some of the world’s largest programs in genomic data analysis, genomic and clinical data hosting, cancer data analyses and access, and the development of algorithms for advanced sequencing technology.
February 23, 2017
Digital Detection Tool Will Be Shared Freely Over the Web
Toronto, ON and Baltimore, MD (February 23, 2017) A research team from the United States and Canada has developed and successfully tested new computational software that determines whether a human DNA sample includes an epigenetic add-on linked to cancer and other adverse health conditions.
January 13, 2017
What does a beaver’s genome look like? And how can understanding the beaver genome help us to improve human health? A group of Canadian researchers led by Drs. Stephen Scherer and Si Lok at The Centre for Applied Genomics and The Hospital for Sick Children today published the sequenced genome of the Canadian beaver in order to answer these questions and others (and just in time for Canada’s 150th anniversary, no less).
Dr. Jared Simpson led a team at OICR who provided their bioinformatics expertise on the project. We spoke to Simpson about his team’s role in the study and how their findings could contribute to a better understanding of cancer.
September 15, 2016
On September 13 the Government of Canada, through Genome Canada, made a $4 million investment in Canadian big data research to help improve real world challenges such as infectious disease outbreaks, managing food crops and combating cancer.
Of the 16 projects funded across Canada, three are based at OICR. Led by OICR Principal Investigators Drs. Paul Boutros, Vincent Ferretti, Jared Simpson and Lincoln Stein (Stein is also OICR’s Interim Scientific Director and leader of the Institute’s Informatics and Biocomputing Program), the projects are developing ways to make genomics and health data more manageable, securely accessible and easily understood. Together these projects will help to facilitate cancer research and assist in the adoption of more precision medicine. As well, they have applications in other fields of genomics research beyond cancer, such as agriculture and energy.
June 16, 2016
Photo: University of Birmingham
Scientists from the University of Birmingham in the U.K. have established a mobile DNA sequencing lab in Brazil to help that country track the spread of the Zika virus. The lab, based inside a minibus, is travelling through the areas of Brazil that have been most affected. A central part of the technology they are using is the small, USB-powered MinION genome sequencer. OICR’s Dr. Jared Simpson, an Investigator in the Informatics and Bio-computing Program, developed the software used to sequence samples on the device.
Read the news release: Mobile laboratories help track Zika spread across Brazil