C150 research chairs break new ground on human health

Our understanding of both the earliest and latest stages of human health have deepened thanks to the Canada 150 Research Chairs (C150) Program. The $117.6 million Government of Canada initiative helped bring two dozen renowned scholars from around the world to Canada to mark the country’s 150th anniversary and build on its reputation for research excellence.

Two C150s are Miguel Ramalho-Santos, a Portuguese-American cell biologist who researches embryonic development, and Donna Rose Addis, a neuroscientist from New Zealand who researches memory and aging. Both moved their labs across borders and time zones to the University of Toronto in 2018.

Canada has long been a research hub for cell biology and for memory research, which Ramalho-Santos and Addis have built on as chairs. As the seven-year program draws to an end in 2025, Ramalho-Santos and Addis shared their experiences, and why they intend to continue pursuing their research here in the years to come.

Miguel Ramalho-Santos: “We’re really driven by our curiosity”

Ramalho-Santos completed his PhD at Harvard University and established the Santos Lab at the University of California San Francisco, before moving it to the University of Toronto and Mount Sinai Hospital as the C150 in Developmental Epigenetics.

“C150 was an attractive opportunity, because it was offering long-term support to take the leap and land in a fantastic community in Toronto,” Ramalho-Santos says. “What better place to research stem cells and development than where a lot of the key findings were made, where stem cells were discovered?”

His team has spent the last seven years working to shed new light on how external events shape embryo development, and the long-term impacts these events have on adult health.

In 2019, Ramalho-Santos published an article in the journal Nature showing that vitamin C is important for activating genes in female fetuses that help form egg cells, meaning maternal vitamin C levels may impact the fertility of the next generation. In addition to the reproductive health implications, these findings also generated interest among cancer researchers.

“Vitamin C actually has a direct facilitating impact on the activity of enzymes that are fundamental for the cells to remain doing what they normally do, function normally, differentiate normally, and not turn into undifferentiated cancer cells,” Ramalho-Santos explains. “People read our work and realized that, if vitamin C does that to those enzymes in the embryo, it probably does that to the enzymes in leukemia. And indeed, it does.”

There are now several clinical trials underway where patients are taking vitamin C intravenously in combination with their chemotherapy treatment.

“The vitamin C discovery opened up a number of thought processes in our lab,” says Ramalho-Santos. “If embryos are attuned to the levels of vitamin C, what else are they attuned to?”

One related avenue the Santos Lab embarked on was to study the phenomenon of developmental pausing, whereby embryos go into a reversible “suspended animation” state when not enough nutrients are available. When Ramalho-Santos spoke to cancer biologists at the Princess Margaret Cancer Centre about this, their interest was piqued, because cancer cells can similarly enter a “dormant” state that allows them to survive chemotherapy and give rise to new tumours.

In 2021, a group of University of Toronto labs, including the Santos Lab, reported in an article in Cell that dormant cancer cells indeed highjack the same cellular pathways that regulate developmental pausing to evade therapy. The study points to new ways to target cancer dormancy, using insights gained from how embryos do it.

“This project really emerged from coming here,” Ramalho-Santos says. “There’s such a strong base of cancer biology in Toronto that these conversations with partners here just started happening.”

He predicts there are even more “really interesting offshoots” to come.

Donna Rose Addis: “This is an amazing place for memory research”

Addis completed her PhD at the University of Toronto, followed by postdoctoral studies at Harvard University. She was running the Memory Lab at The University of Auckland when she learned about the C150 program in Canada.

She was thrilled by the “amazing” opportunity to return to Canada to become the C150 in Cognitive Neuroscience of Memory and Aging at the University of Toronto. She joined interdisciplinary research teams at both the University of Toronto and the Rotman Research Institute at Baycrest.

“I love working here,” Addis says. “It’s so collegial. It’s so stimulating. It’s a great memory research community.”

Addis has unique insights into how the human brain enables us to remember past experiences, imagine future events, and construct a coherent sense of self. She made the groundbreaking connection in 2007 that imagining the future engaged the same neural network as remembering the past. The discovery was named a top 10 breakthrough by Science that year.

Given Canada’s aging population, increased research on memory’s role in maintaining a sense of self and preventing cognitive decline is both timely and urgent.

In Toronto, Addis has access to the most advanced equipment for creating images of the brain and observing brain activity.

“Baycrest has not only state-of-the-art MRI imaging, but also a magnetoencephalography (MEG) scanner,” she explains. “There’s not that many MEG scanners in the world, but one of them is here.”

Like Ramalho-Santos, Addis has joined forces with Canadian colleagues to explore new areas of interest. Amid the COVID-19 pandemic, she partnered with Shayna Rosenbaum at York University to understand how people make decisions in a public health crisis, for example by imagining near-term rewards (which is easier) or more distant rewards (which is harder).

Addis wants to take this research to its next level by investigating how the power of our imaginations could help shift decision-making for better collective outcomes.

“It taps into some other work I had been doing with a student,” says Addis, “looking at if you imagine helping people, does that change your intentions to help people? Does imagining it change your future behaviour?”

In her own future, Addis foresees many more collaborations with Canadian researchers and institutions. She plans to apply for Canadian citizenship as soon as she’s eligible.

“I really feel like I’ve found my people,” she says.

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Keywords

• Embryonic development
• Memory
• Aging
• Developmental epigenetics
• Stem cells
• Cancer biology
• Public health
• Cognitive neuroscience
• Clinical trials
• Decision-making