Stem Cells, Leukemia and a Cutting Edge


Guy Sauvageau is a stem cell researcher who specializes in hematopoietic (blood) cells. As director of the Institute for Research in Immunology and Cancer at the University of Montréal, he’s one of a handful of Canadians who is pushing the boundaries of this area of research, unraveling the mysteries of blood disorders such as acute myeloid leukemia and aplastic anemia. Sauvageau’s particular interest is the regulatory pathways of these diseased cells – essentially, what is the cellular signature of disease and how can such knowledge be used to find new ways to relieve or cure the disease.

Currently, one of the standard methods of treatment for blood disorders is autologous hematopoietic stem cell transplantation (ASCT; commonly known as bone marrow transplant), but limitations in our ability to scale up hematopoietic stem cells mean that ASCT is not a viable treatment option for many patients with the most devastating blood disorders. Sauvageau is also working on this problem, and is considered to be a pioneer in this field.

I know a bit about Sauvageau’s work; I’ve met him on a couple of occasions and heard him speak at the 2009 Stem Cell Network annual meeting, where he received the Till & McCulloch Award. I know, for instance, that he received notoriety in 2004 when he and Keith Humphries identified the role of the TAT-HOXB4 protein in the formation and expansion of hematopoietic stem cells. I know that Sauvageau can trace his research lineage directly back to James Till and Ernest McCulloch, who famously identified stem cells in the blood system back in 1961. (They too were working on ASCT, then a relatively new technique whose mechanism for reforming the blood system after radiation therapy was poorly understood.)  I also know that Sauvageau has some new, as yet unpublished, data that has some people buzzing about the implications.

And I’ve been told that he generally prefers not to talk to media, which I fear is exactly the category I’ve been lumped into.

I arrive at the Institute 15 minutes ahead of our scheduled meeting and dump my wind-destroyed umbrella into the trash. My clothes are sodden and plastered uncomfortably to my legs. This, I realize, is my reward for trying to catch a cab in downtown Montréal during lunch hour in the rain. When I present myself at Sauvageau’s office, however, I am kindly told that he’s been called into another meeting for at least the next hour. Thankfully, I am met by two of his lab personnel, who would be pleased to show me through the labs and allow me to do some filming in the meantime.

Jalila Chagraoui, research associate and Iman Fares, PhD candidate are members of the Sauvageau team working on a new translational grant focused on identifying small molecules and proteins for hematopoietic stem cell expansion. It’s a week before the holiday break and everyone is busy. You can see it as soon as you step foot in the lab, where some students are focused on bench work, others are discussing a particular research protocol and a technician is busy with the high throughput screening equipment.  It’s not unlike many other labs I’ve visited, but here there is a certain energy behind it all.  I’d like to call it determination, but there’s more to it: enthusiasm; intensity, and a sense of camaraderie.

Fares, a relative newcomer to the lab (some, like Chagraoui, have been there for upwards of 10 years), has just finished dissecting some mice for a current experiment and offers an animated account of her role in finding a new and very promising drug target for stem cell expansion. Fares’ passion and excitement are infectious and with good reason – there is real potential here – this is the work I had heard whispers about, but Fares delicately suggests that I should talk to Sauvageau about it in more detail.

What strikes me in the lab tour and through my conversation with Chagraoui and Fares is the incredible speed with which this research has been accomplished. Since adopting the rapid screening (high throughput) technologies most commonly used in the pharmaceutical industry, many branches of molecular and genetic biology have made astounding leaps in a very short time.  The key is the ability to mix functional experiments (such as RNAi testing combined with deep screening through the high throughput machines) to dissect entire networks that are involved in a single cellular behaviour.

I leave the lab with greater understanding, but even more to ask about. Back down at the office, however, I am regretfully told that Dr. Sauvageau will be unavailable until very late in the afternoon. I debate the merits of canceling my return train to Ottawa in order to wait, but in the end, I head back into the storm (sans umbrella) with my list of festering questions and the promise of another meeting time.

It’s a good thing persistence pays off.

When I do get the chance to speak with Sauvageau many days later, I start by commenting on the ease with which all his trainees and technicians worked in the space and asking him about his perceived role as a mentor and leader.

Sauvageau quickly gives the credit to his team. “I’m surrounded by a bunch of really good people, and I’m not saying this just to be nice to them. They choose one another when we interview them, and they train one another. They ensure the stability and the passage of the know-how between postdocs and students and I think that’s a key point.”

But Sauvageau worries that this crucial element of his lab culture may be in jeopardy.  This is the reality of a research system where less money is available to increasing numbers of researchers and it has led some funding agencies to place caps on their grants.

“It’s a deep, profound trend we’re seeing now and I feel badly for the funding agencies that are just trying to please as many people as possible,” says Sauvageau. “One thing I love about research is that it’s based on merit. You fund people who propose the most original work, but once you start spreading the money around and trying to please everyone I don’t think you’re accomplishing what science is all about.  It’s sad the way the system is evolving.”

Sauvageau contends that labs that have larger infrastructures may have difficulty surviving in a system where there is a maximal amount of money in the lab.

For his own work, infrastructure is critical. The lab includes more than just sophisticated equipment; it includes people with specific skills – bioinformatitians and statisticians, for example, in addition to the more traditional complement of lab personnel.  These diverse skills are essential to the success of the sophisticated research being conducted. “You need to be aware that you can make a mistake and for this you need to be sitting beside someone who knows what you don’t,” he explains.

“Scientific culture has to be maintained at the highest level so I would argue that as a country we need to invest in places where unique resources are available on site.”

Until that fateful day arrives, there’s work still to be done. In fact, this is the reason Sauvageau can be hard to pin down for people like me. Contrary to the rumours I had heard, I don’t think it’s because he doesn’t want to talk about science to the media or the public – he is gracious, eloquent and clearly passionate about the work he does. He’d just rather be doing it than talking about it.

“I think we’re in a very privileged moment in scientific history right now where we have the means and the technology to understand things very deeply. For example, when people like ourselves are interested in the self-renewal of cells, we now have chemical tools, high throughput technology that allows you to do genome-wide experiments and really identify the determinant that regulates the process. When things go awry such as in leukemia, you can use these technologies to completely see the genetic anomalies that are involved and you can even start to put people together who will try to get at the bottom of this and come up with new strategies for cure.”

As I’m talking with him, Sauvageau has a new set of data in front of him that he’s quite excited about – a follow up to the work Fares spoke about earlier.

“I’m working on a bunch of leukemia that we sequenced recently and it took our bioinformatic team only a few months to really get the necessary tools together for understanding the basis behind this disease,” he explains in reference to the data. “This table illustrates the complete set of genetic anomalies in human acute T  lymphoblastic leukemia. It’s beautiful!”

The genetic mutations are not identical from patient to patient – there were 565 anomalies among 12 patients to be exact – but what this data shows is that the pathway is exactly the same. It gives strong evidence to support a deeper investigation of this pathway for therapeutic targets. The fact that the Sauvageau lab has already identified two possible chemical compounds, among many thousands, only intensifies the excitement.

There are so many numbers and combinations at play – to me it seems incredible that they would be able to narrow it down so precisely. So I ask him if he believes in luck.

“I believe in data analysis. If you do a lot of experiments and don’t analyze them properly, you’ll never find the gold mine hidden within. And in the era of high throughput, where people generate so much data, you must be careful about not trashing it too quickly, because sometimes it is the method of analysis that allows you pinpoint a critical pathway.  For example: in this sequencing project you can see the twelve leukemias that we sequenced and the hundreds of anomalies, and if you look at them on your spreadsheet they make no sense. But if you bring this data into programs that allow you to find networks, you suddenly see that it’s all the same groups, and then your data makes sense.”

“It’s extremely exciting and I predict to you that unless the system collapses, which is not impossible, we’re going to see major things in this country in the next ten years.”

All the more reason to work hard and talk less. Given the possibilities, I wouldn’t mind spending more time in the rain.

This article is appearing simultaneously on Numéro Cinq, a literary magazine that keeps an eye on science.