The stem cell fraction

Author: Lisa Willemse, 04/24/12

An interview with Till & McCulloch Award winner, Dr. Aaron Schimmer, whose paper, entitled 
“Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia,” published in Cancer Cell, November 2011, was selected by committee as the most important stem cell publication by a Canadian in the past year. Dr. Schimmer will present the Award lecture on April 30, 2012 at 2pm as part of the Till and McCulloch Meetings in Montreal. Interviewed by Lisa Willemse, blog editor.

Lisa Willemse: Congratulations on winning the award. I understand that this comes as a bit of a surprise to you because you’ve only been working with stem cells for a relatively short time.

Aaron Schimmer: Yes, this is correct. If you look back five or six years ago, I wouldn’t say I had a focus on stem cells. But it is thanks in large part to Stem Cell Network members such as John Dick, David Kaplan and John Hassell that we acquired the ability to extend our work to stem cells. They’ve made an effort to allow others to enter the stem cell field. John Dick has done this particularly well — he has directed a large amount of resources to making these platforms accessible to the broader community.

So it’s really an honour to get this award, but it’s particularly touching because it is due to this group that we’re actually working on stem cells.

LW: How much of your work today is focused on stem cells?

AS: We’ve always had a focus on developing novel therapeutic strategies for leukemia, but now we are able to look not only at the bulk leukemia cells, but we are also able to target the stem cell fraction which is so critical. If you were to ask me five years ago, I would have said that perhaps 20 per cent had relevance to stem cells, but now stem cells account for roughly 80 per cent of my work.

LW: Why the switch for you? Aside from that door being opened by John Dick in terms of access to techniques and other supports, was there a shift in your understanding or belief in this area of research as a potential way to tackle leukemia?

AS: I think it was a combination of two things. Clearly it was having the people like John and David and John that we were able to extend our assays into the stem cell platform, but it really came from the observations on the clinical side. When you treat patients with leukemia, you can kill off 99 per cent of their leukemic cells with just about anything, and yet, 80 per cent or more of patients relapse. So when we examined this in a really objective way, the question was not how to kill off those bulk cells – we already knew how to do that — but are we really missing a critical component of what we should be targeting? And when you look at it, more and more studies continue to validate that new therapeutic strategies are going to have to account for the stem cell fraction.

LW: Specific to the compound, tigecycline, that you detail in this paper, can you give a summary of how it was identified as a possible target and the timelines involved?

AS: The assay itself was done over a period of 2-3 weeks, during which we screened through a few thousand compounds. We were able to go from the hit from the screen to the first patient treated in a phase 1 clinical trial in under two years. What’s interesting about the high throughput screening approach using approved drugs is that because of what’s known about the pharmacology and toxicology of tigecycline, we can move rapidly from the lab to the clinic as a way to test proof of concept very early in clinical trials. What we can learn through the early human studies can help validate the therapeutic strategy so that greater resources can be placed into developing those second-generation compounds or formulations that will have improved anti-leukemic and anti-leukemic stem cell activity. This agent will likely be most effective in combination with other standard or other novel agents and ultimately it’s where I think the development of this drug will go.

LW: What is it about this agent that makes it work on leukemic stem cells and can it be broadly applied to all patients?

AS: In our studies, tigecycline appeared to work by essentially shutting down the energy supply of the leukemia cells and stem cells, which occurs in the mitochondria through oxidative phosphorylation process [the process of electron transfer using oxygen within the mitochondria of a cell]. Leukemia cells appear unique in their reliance on mitochondrial oxidative phosphorylation. Essentially it is like producing a selective power outage in leukemia cells but not normal cells. Most cancers get their energy from glycolysis but there might also be other malignancies that are unique in their reliance on this process. Not all leukemia cells respond to this drug in culture and we have been able to relate this response to mitochondrial mass and oxygen consumption, with those leukemic cells with the highest mitochondrial mass demonstrating the greatest response to the drug. So theoretically, if this holds up in clinical trial, in the future it could be possible to identify those leukemia patients whose cells and stem cells have high mitochondrial mass and would most benefit from this therapeutic strategy.

LW: In your dual role as a clinician-scientist, what do you enjoy most?

AS: You end up with the best of both worlds. There’s the aspect of patient care — when you’re treating leukemia, it is a very devastating disease, and there’s an opportunity to make an impact and contribution on a very personal level. And one balances that with the lab-based career where one tries to be a part of advancing therapeutics, but on a much bigger level. What’s also nice is to be able to translate the findings from the lab into the clinic and to really try to address some of the problems that patients are experiencing.

LW: In your career, what has given the most satisfaction thus far?

AS:  Every so often, we’ll have a patient that’s enrolled in one of our phase 1 studies where nothing else has worked, and they’re enrolled in a phase 1 agent where the expectations of success are low. And yet, that patient will enter remission and that’s really what validates all that one is doing. So, the reason one is a clinician-scientist, caring for patients and advancing the latest therapies to them, and recognizing that that therapeutic the patient ultimately got was the combination of work, not just in our lab, but in labs everywhere. This is why we are doing this – whether it was the drug that I made or that someone else had made – the idea that it’s all building, and it’s those moments where you say, “this is what it’s all about.”

The following two tabs change content below.
Lisa Willemse

Lisa Willemse

Lisa is a science communicator with 15+ years' experience in the fields of regenerative medicine, child development and technology. She launched this blog (first as the Stem Cell Network Blog) in 2009, and served as co-editor until April 2015. She is currently the Senior Communications Advisor for the Ontario Institute for Regenerative Medicine and has recently contributed to Motherboard, Science Borealis and the Genome Alberta and Canadian Blood Services blogs. Follow her on Twitter and Medium @WillemseLA.
Tags: , , , , ,

Leave a Reply