Feature: In your bones - Professor Sara Rankin
5 October 2011. By Chrissie Giles
A couple of hours in a lab as a teenager was all it took to make Sara Rankin decide to be a scientist.
"I didn't come from a family of academics and I knew nothing about scientific research, but I loved science at school. I got the chance to visit a lab in the Bristol Radiotherapy Centre, which was supported by the charity where my mother volunteered. Dr Ann Light showed me HeLa cells in a dish and talked about trying to cure cancer by doing experiments on them. that was enough to make me want to do research."
Now Professor of Leukocyte and Stem Cell Biology at the National Heart and Lung Institute at Imperial College London, Sara is repeating the favour, hosting workshops for school students to experience real research in Imperial's purpose-built Reach Out Lab. She's also passionate about developing early-stage researchers, supervising several PhD students and postdocs in her lab and mentoring those in others. Running through all of this is her work researching bone marrow and the stem cells within. She currently has a particular interest in mesenchymal stem cells, which have the potential to turn into different body components, including cartilage, fat and bone. As part of her work, she is investigating how to use drugs to trigger the release of these cells from the bone marrow into the blood so they can help repair and regenerate the body.
Earlier this year, she was named as one of the Wellcome Trust's first Senior Investigators. Hearing the news, she says, was incredibly exciting. "Applying was a very rigorous process, and I enjoyed writing the application because it was very different to what we're normally asked to write. usually, applications are about the minutiae of experiments, but for this grant the focus was on the individual and their vision. It came at just the right time - I know exactly where I want my work to go."
Stimulating stem cells
The timing is apposite in terms of history, too, coming in the 50th anniversary year of the first experimental demonstration of stem cells. In 1961, Canadian biophysicist Dr James Till and former physician Dr Ernest McCulloch were examining the effects of radiation on mice when they showed that bone marrow cells could give rise to colonies of other cells, in effect proving that stem cells exist. The cells they had identified - haemopoetic stem cells - divide and differentiate into the red and white cells and platelets that make up our blood.
"These are the stem cells that everybody knows about," Sara says. They can be released into the blood by treating with G-CSF, or granulocyte colony-stimulating factor, a protein made in the body that stimulates bone marrow to release stem cells. This treatment has been used for the past 30 years as the basis of bone marrow transplants.
Another kind of stem cell is found in the marrow, although this kind is much rarer. It is these mesenchymal stem cells that Sara and her team are targeting, to understand better what they are, where they are, and how they work.
The ultimate aim is to find drugs that can stimulate these cells (or a subset within them) to leave the bone marrow and travel to a site of injury or wear in the body to help repair it. Sara's group was the first to show that it is possible to selectively release mesenchymal stem cells into the blood, a finding that led to a patented therapy.
"When mesenchymal stem cells were originally discovered, it was thought that their main function was to provide what's called the stem-cell niche for haemopoetic stem cells, the environment in which they live," Sara says. "People started showing that if they grew these cells in culture they could get them to differentiate into different cell types, so it was thought this could be another function."
Mesenchymal stem cells can develop into some of the cells that make up bone, fat, muscle and cartilage. As well as playing supporting actors to the bone marrow's haemopoetic stem cells, mesenchymal stem cells have recently been shown to have a wider influence. They secrete a variety of chemicals, such as growth factors, signalling proteins called cytokines and anti- inflammatory factors. these chemicals act on nearby tissues to have two main effects: to promote regeneration and to dampen the immune system.
There is a lot of interest in the potential of mesenchymal stem cells to treat disease. Clinicaltrials.gov, a database of clinical trials in humans, lists 174 trials involving these cells, to explore their regenerative and anti-inflammatory potential. The diseases under study include cardiovascular disease, brittle bone disease and several respiratory conditions, such as chronic obstructive pulmonary disease. Also of interest are therapies to treat acute graft-versus-host disease, a major reason for the failure of some bone marrow transplants.
"In all these clinical trials, researchers isolate stem cells from a tissue in the patient or donor, grow them by cell culture and inject them back into the patient," Sara says. "For example, it's been shown in large animal models that this can promote regrowth and suppress the remodelling of the heart that happens after a heart attack. these cells are thought to be regenerative in the context of heart disease."
Building up the whole heart again would be unlikely, she says, but an aim might be limiting damage and promoting repair to keep the heart working. There are, however, many practical and technical hurdles to overcome to develop that kind of therapy in humans. "It's going to be expensive, and will be an invasive procedure," says Sara.
As a pharmacologist by training, she has a different idea. "What we're trying to do is to bypass that process by being able to give somebody a medicine or a therapy that would release these cells from the bone marrow into the blood, allowing them to be recruited to the damaged tissue or organ."
On the move
Sara didn't begin her career working on stem cells. When she moved to Imperial College in 1995, supported by a Wellcome Trust Career Development Award, she joined Professor Tim Williams's lab, investigating how white blood cells move from the bone marrow into the blood and subsequently to the lungs in a model of asthma. The team identified the molecules involved in mobilising eosinophils, a type of white blood cell, from the bone marrow into the blood and eventually to the lung.
"I then started looking at a number of different models of inflammation to see if that paradigm existed in other models of inflammation, and indeed it did," says Sara. "There were different factors that were generated, dependent on the type of inflammation, and they basically signalled to the bone marrow to release specific subsets of white cells (neutrophils, eosinophils, monocytes) so that they could be recruited into body tissues. That's the basic model."
At the same time, interest in stem cells was growing among researchers. Collaborating with a biotechnology company, Sara's team was involved in studies showing that plerixafor (a drug that blocks a protein receptor called CXCR4 and was originally developed to treat HIV) could be used to stimulate the release of haematopoietic stem cells from the bone marrow. Industrial collaborations are also important to Sara, who wants to find ways to translate her findings into novel regenerative medicines in the future.
"It was a very logical progression to start looking at stem cells," says Sara. "I basically hypothesised that, in the same way that you can selectively release different subsets of white cells from the bone marrow, you'd be able to do the same thing looking at different subsets of stem cells. And that was essentially what we were able to demonstrate experimentally."
The focus of her Investigator Award will be the study, at the level of the bone marrow, what the molecular mechanisms of mobilising these stem cells are, developing therapies that could most effectively mobilise them.
She and her team will also try to understand the mixture of cells that make up mesenchymal stem cells. "We think that some of the cells may be better at forming one particular type of tissue, such as cartilage, so we might use a specific drug regimen to activate the cells that we're interested in," says Sara.
They will also be investigating the impact of age on mesenchymal stem cells. "As I get older, I realise that it's taking longer for my body to repair itself. If my children fall over, the next day you can hardly see a scar," she says. "We want to understand at the molecular level what's going on and if age makes a difference to the mesenchymal stem cells, in terms of how many there are, how they function and their ability to mobilise."
Getting wasted
In between the labwork, Sara is part of a collaboration called 'Wasted' with artist Gina Czarneck. "We met in 2008 and we started a project that is still evolving and really interesting. these artworks provide a way of engaging with a completely different audience. Fundamentally they're about getting people to think, to make links and to ask questions." They produced 'Pixiedust', a film that looks at limb regeneration. It was shown at the 2010 Winter Paralympics and on the BBC Big Screens, which broadcast in 20 cities across the UK.
They are now working on a series of sculptures, including two supported by a Wellcome Trust Small Arts Award. "These are sculptures made of body parts that are generally wasted: liposuction fat and femoral hip joints removed during hip replacements. these body parts are usually regarded as clinical waste and incinerated, but they're actually rich sources of stem cells," says Sara.
Sara's priority is her research, but she sees outreach and art projects as another way to focus on her science. "It's an important part of my professional identity to do these other activities, but I couldn't do them unless the research was excellent," she says.
Sara always wanted to do outreach, and she and her lab regularly welcome primary and secondary school groups. "Stem cell science is one of the areas where you can do something a bit inspirational to get people interested, while also delivering what's required in the curriculum," Sara says. "After all, for one person the trip could be a life-changing event."
Sara on...
...mentoring
"I currently mentor four postdocs in other people's labs. It can be time-consuming, but it is rewarding. Generally it's about being a sounding board, providing objective career advice and suggesting paths for personal development but it can also be, for example, about the practicalities of balancing a scientific career with motherhood."
...early careers in science
"I think it's definitely getting harder for young people to stay in science. To move from a postdoc into that first position can be really tough. I was lucky as I obtained a Wellcome Career Development Award, which was critical for allowing me to develop as an independent researcher."
...being a supervisor
"You always want the people that come into your lab to develop and go on to do great things. In the past, career success as a scientist meant becoming a respected academic, but careers today are much more flexible, less linear, and cross-disciplinary. More and more it's about identifying people's key skills and directing them to areas in which you think they'll excel. Past students now have successful careers in academia but also in the pharmaceutical industry, as science communicators and as scientific software developers."
This feature also appears in issue 68 of ‘Wellcome News’.
Top image: Sara Rankin. Credit: Wellcome Images
References
Jones CP, Rankin SM.
Bone marrow-derived stem cells and respiratory disease. Chest 2011;140(1):205-11.
Martin C et al.
Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003;19:583-93.
Pitchford SC et al.
Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4:62-72.
Rankin SM.
The bone marrow: a site of neutrophil clearance. J Leukoc Biol 2010;88:241-51.
