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Profile feature – Kieran Jones
9 November 2012
From an undergraduate degree at the University of Bradford to a first paper in Nature in just six years, Kieran Jones compares lab life in the US and the UK researching stem cells under a BBSRC PhD studentship.
How does it feel to have a paper in Nature?
It was an amazing experience when it first came out. When I first started a lot of people said they worked their entire career to get one, and some never do, so I feel extremely privileged to work in this group and actually achieve this. The whole review process took such a long time. We weren't sure it would get through or what the reviewers would say. So when we finally got the acceptance email there was a massive relief throughout the entire lab.
We've also had experience with the media and with press releases and such going on. So far it's great, and definitely exciting.
How did you come to work on the project?
Kieran Jones has co-authored a Nature paper aged 25. Image: Jas Grewal
It was part of a collaborative project with Albert Basson's lab at King's College and Andrew Brack's lab over in Boston. For my PhD I'd spend 1-2 years working with Albert Basson and then went to Andrew's, still working on the same gene, but in a different tissue stem cell system.
When I got there Joe Chakkalakal, the first author on the paper, had some pretty interesting findings that aged muscle stem cells [also known as satellite cells] proliferated more than younger ones. Andrew thought that was quite interesting so he wanted me to start working on the project with Joe.
What made you want to want to work on stem cells?
I was interested in working on adult stem cell biology mainly because of the great implications it holds for tissue regeneration. Repair of skeletal muscle is an incredibly important process, and one that would not take place if the skeletal muscle stem cells were not functioning properly. Understanding the mechanisms which control skeletal muscle stem cell proliferation and differentiation will allow us to better understand, and even stop muscle-wasting diseases.
What did your paper show?
As you age, your ability to regenerate muscle after injury declines. We've shown that this is in part because of a decrease in the number of muscle stem cells and also impairment of their function.
As you age your muscle fibres produce a growth factor, Fgf2 (fibroblast growth factor), and this causes satellite cells to divide which causes a depletion of the stem cell pool. Our current model to explain this is that these cells might only be able to undergo a limited number of divisions before they die or differentiate.
And this contributes to ageing?
We think this is what ageing is – a depletion of the stem cell pool. So if you injure the muscle in an aged mammal you don't get as efficient regeneration.
How is this different in healthy adulthood?
Under normal adult homeostasis (in healthy balance) Fgf2 is not produced, only as you get older is Fgf2 produced by the muscle. This is because in normal adult homeostatic conditions you don't want your satellite cells to proliferate, only when you're injured so they can repair the damage.
Three light micrograph images show muscle stem cell, indicated with white arrow, on a muscle fibre using the DAPI stain (to show nuclei) and Pax7 marker for stem cells. Image: Kieran Jones
Theoretically, if you can keep up a supply of stem cells could your muscle regenerate forever?
Yes, you should technically be able to. The problem is the muscle stem cell is depleted with age.
Why does the body produce Fgf2 then?
We don't know why Fgf2 is produced by muscle fibres. The hypothesis is that aged muscle accumulates minor damage, and so Fgf2 is released to repair it but this causes activation of satellite cells when they should be quiescent (at rest). They usually only proliferate with injury to repair damage.
How hard was it to demonstrate this stem cell-activating role for Fgf2?
And so the story went a step further. We decided to play around with the Fgf2 signalling cascade using genetic tools developed by Albert Basson. We focused on a negative regulator of Fgf2, called Sprouty1, which normally inhibits Fgf2 signalling. When we deleted Sprouty1 from satellite cells, we observed further depletion of the stem cell pool in aged animals. But when we removed Sprouty1 in normal (non-aged) adults we do not see any phenotype effects because there is no Fgf2 around - it's only in aged muscle stem cells that we see the effect.
Could this lead to new drug therapies?
From a pharmaceutical standpoint there's a drug, its name is SU5402, which like Sprouty1 is an inhibitor of the Fgf signalling. When we inject this drug into a mouse we can inhibit some of the detrimental effects of ageing.
This "proof-of-principle" experiment gives some hope in thinking that a pharmacological rejuvenation of skeletal muscle in aged people might be possible in the future.
Did you have any insights or 'eureka!' moments yourself?
My 'eureka' moment came when we developed something we call a 'purified myofibre extract'. Essentially we were able to isolate all of the proteins associated with the microenvironment of the satellite cell, allowing us to expose an adult satellite cell to an aged environment, and conversely an aged satellite cell to an adult environment. It was a great day in the lab when we saw that adult satellite cells lose quiescence after being exposed to an aged environment, further proving that the aged muscle fibre produces Fgf2 and causes satellite cells to proliferate.
Would this all have been possible without funding from BBSRC?
Oh yeah if I didn't receive the funding I probably wouldn't have been able to do a PhD to be honest. I currently receive a fully funded BBSRC Doctoral Training Grant which pays all my fees and I get a stipend as well.
Are you following up this work in the UK?
For the rest of the PhD I'm back at King's College and I'm working on neural stem cells in the brain, which support learning and memory formation; I'm specifically looking at chromatin remodelling (how DNA is packaged on a chromosome) in adult neurogenesis (nerve cell formation). Although this may seem like a complete switch of projects, there is a link because I can look at chromatin remodelling in muscle since we have the mice and the reagents here for that.
Have you picked up new skills along the way?
Oh definitely, the actual skills set I obtained from this project is remarkable. Working with Andrew in Boston taught me efficient stem cell culture techniques, and how to isolate the muscle stem cells; working here is teaching me epigenetic profiling, working with neural stem cells culturing those… a lot of skills in that respect.
How would you compare working in a US lab compared to the UK?
The lab in the US was pretty similar to the lab here in the UK, but one of the main differences I found was the working schedule. The labs at Harvard put a lot more pressure on you and so I worked much longer hours. However, on the other hand there was more freedom to go for the more expensive experiments that might not work, but would give incredible results if they did.
The Boston skyline. Image: Kieran Jones
And how did you take to life in the US overall?
Boston is definitely a great place to be, both for scientific and recreational purposes. The thing I enjoyed most about it was being able to travel 30 minutes away and be in a completely different area, such as hiking on a mountain, relaxing at a beach, or going skiing, whereas with London it will take a lot longer to get out of the city. I would definitely recommend it to anyone considering a PhD or postdoc abroad. Bring a few coats though – it gets incredibly cold during winter!
Were you always interested is science?
It wasn't there my whole life to be honest. When I got to sixth form I still didn't really have much of an idea of what to do. For 'A' levels I just chose a broad range of subjects. However from biology 'A' level it got a lot more interesting and I wanted an undergraduate degree in biomedical science and take the path there. It then became a lot more embedded in me and, in particular, research was what I wanted to go into.
Where did you go to university?
I went to the University of Bradford and did biomedical sciences there. It was really good actually. I was very laid back in applying to choosing universities; I decided to apply for a course that would give me a good background in biology with a focus on human diseases. It was a three-year course and then I applied for PhDs and was accepted for the four-year BBSRC Doctoral Training studentship with Albert Basson at King's College.
What's next for your career?
I'm in the final year of my PhD now so my first priority is to finish experiments on adult neurogenesis and write up the work on muscle stem cells. I think the next step will be to find a post-doc and continue through the research career path, but I haven't made a final decision about which area I want to pursue in the future. I have developed a great interest in adult stem cell biology throughout my time as a PhD student so far, and so further research in to the mechanisms which regulate stem cell function would be my main aim.
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