Basic Science Lays the Foundation for Clinical Breakthroughs

Even the longest journey begins with a single step; creating new treatments for complex diseases is no different

Media love to hype the latest scientific achievements in human health – new blockbuster medications, surgical devices and procedures and, as COVID-19 has demonstrated, novel vaccines routinely make headlines around the world. Rarely, however, do the sensational stories trace the roots of a clinical breakthrough back to its origins in basic science, often decades in the making.

OIRM sat down with Dr. William Stanford, Canada Research Chair in Integrative Stem Cell Biology, Senior Scientist, Regenerative Medicine Program at the Ottawa Hospital Research Institute and Professor at the University of Ottawa, for his take on the need for continual investment in basic science – and how his lab is using that investment to solve important stem cell challenges.

If you had to pick one, what is the most pressing question you are trying to answer in your lab?

Dr. Stanford: Every cell in your body has the same DNA; a cell’s identity is ultimately defined by the epigenome, which provides instructions to turn certain genes on or off to produce specialized cell types. The effects of aging and various diseases such as cancer arise from changes in the epigenome and the subsequent loss of epigenetic inheritance from a cell to a daughter cell, resulting in a loss of homeostasis. This is called epigenetic drift, and it is often thought of in the literature as a stochastic, or random, process. I hypothesize that it is really driven by the cell’s response to DNA damage in a non-random way.

How are you testing that hypothesis?

Dr. Stanford: We’ve been studying vascular smooth muscle cells and other cell types made from induced pluripotent stem cells generated from patients living with progeria, which is a rare rapid-aging disease. These individuals tend to get vascular disease and die from heart attacks and strokes in their teenage years. We analyzed vascular smooth muscle cells isolated from progeria-induced pluripotent stem cells to determine whether they undergo degeneration similar to atherosclerosis. Working with collaborators Mike Hendzel in Edmonton and Jeff Dilworth in Ottawa, we have demonstrated that the progeria vascular cells demonstrate transcriptional profiles overlapping with atherosclerotic cells, an altered DNA damage response, and reproducible patterns of loss of histone acetylation.

So far, everything strongly suggests that our hypothesis that epigenetic drift is not random is correct. We’ve identified a lot of players that are already known to be involved vascular disease, and we believe this work will also identify novel players, as well. Ultimately, we want to identify potential therapeutic strategies to treat vascular disease, which is the number-one cause of death globally.

Basic science is often chronically underfunded, yet it plays a crucial role in understanding diseases and developing new therapies. What success story can you share?

Dr. Stanford: Every major therapeutic discovery is rooted in basic science. I can point to one of our projects to really elucidate this. Around 15 years ago, we wanted to understand the molecular wiring of stem cells and the initiation of cell differentiation, so we began to make transcriptional networks and gene regulatory networks using mouse stem cells. We identified several interesting novel players in stem cell fate, and one in particular – MTF2 – that is involved in the epigenetic regulation of the genome. We manipulated MTF2 in mouse embryonic stem cells and found that it regulated the ability of cells to differentiate versus self-renew, so we then wondered if it would play a role in other types of stem cells. To answer this question, we made a MTF2 knockout mouse that demonstrated MTF2 is required for blood cell development.

This led us to collaborate with Caryn Ito and Mitchell Sabloff to determine whether MTF2 plays a role in leukemia. We found that a significant population of acute myeloid leukemia (AML) patients have low levels of MTF2. Strikingly, MTF2-low patients have reduced survival compared to AML patients with normal levels of MTF2.

Next, we mapped out the gene regulatory network involved in these leukemic cells and discovered that MTF2 plays a central role in regulating the DNA damage response in response to chemotherapy, and the loss of MTF2 in normal hematopoietic cells renders them chemoresistant. Importantly, we found increased activity by the E3 ubiquitin ligase protein MDM2 in MTF2-low AML cells, leading to repression of p53-driven apoptosis in response to chemotherapy.

With our collaborators in the U.S., we have already begun to translate these findings with two phase 1 clinical trials to treat AML using an MDM2 inhibitor with different standard chemotherapy regimens.  So, we’ve gone from very basic questions about cell fate in mouse embryonic stem cells all the way to clinical trials. That took 15 years, but now that we’ve mapped these gene regulatory networks, new discoveries will come much faster – but we would not be here without support for basic research. Unfortunately, Canada seems to support it less and less, as the most recent federal budget suggests.

Beyond funding, what else does it take to make impactful research happen? What does Ottawa’s regenerative medicine ecosystem have to offer researchers like you?

Dr. Stanford: First and foremost, having access to cell and tissue samples is vital to doing meaningful patient-oriented and translational research, and so we are grateful to patients who sign up to donate samples or agree to be an organ donor. Excellent core facilities from next-generation sequencing to high content imaging that support our research has been incredibly important to our success as has been patient-led philanthropy.

Ottawa is a great place to do combined fundamental and translational research. I think this is due in part because we have fewer silos between disciplines and institutions. We can all walk straight from The Ottawa Hospital to the Faculty of Medicine at the University of Ottawa, so it’s a great environment for collaborating with different scientific disciplines and clinician-scientists. We lag behind in biotech start-ups compared with Toronto, but I think that will change once some planned new incubators round out the ecosystem here.

The key point is, it takes continual investment to make this happen – you’ve got to keep watering the garden you’ve planted if you want to reap the rewards.

Photo: OHRI