Elly Tanaka is a senior scientist at the Research Institute of Molecular Pathology in Vienna, Austria. Her lab's research uses the axolotl – which possesses impressive regenerative capacity – to understand the molecular and cellular mechanisms underlying limb and spinal cord regeneration. We met Elly in her office in Vienna on the occasion of the recent SY-Stem symposium (see Meeting Review by Porrello and Kirkeby in this issue) to talk about what drew her to regeneration research and the axolotl, the challenges of working in this field, and how she and her colleagues at the Vienna BioCenter are trying to support the new generation of stem cell researchers.

Let's start at the beginning: what got you interested in biology?

When I was younger, I really wasn't sure what I wanted to do. At college, I started out in chemistry, and then I thought about comparative literature, and then I thought about going to medical school. But I took a biochemistry course from Nancy Kleckner and Michael Green, and that was really inspiring. And so from then on I decided to major in biochemistry. In terms of doing biology research, I worked on my undergraduate thesis with Larry Goldstein at Harvard. I started to study Drosophila genetics, and this was one of the first attempts to do reverse genetics on a known gene. And I just really loved the genetics – how the phenotypes segregated, the concept of balancers and so on – I thought it was super cool and I guess this is what made me decide to continue with research in this area.

Your PhD work at The University of California San Francisco (UCSF) with Marc Kirschner focussed on growth cone dynamics in cultured neurons. What drew you to that topic?

I think it was the visual beauty of the biology. At that time, Marc was working on the cell cycle and on cytoskeleton. Actually, when I was first considering his lab, I was really interested in the cell cycle but he told me I should work on cytoskeleton! But then I got hooked on the topic – something that really appeals to me is the idea of polarity: how cellular or organismal polarity organises (or self-organises) the cues that are given to instruct cell behaviour and how either intracellular structures or cells respond to those cues.

And to what extent has that cell biology training influenced your approach to what you now study, regeneration?

That's a good question because I think it that had a huge effect on my science. Being in Marc's lab was amazing because not only was he working on cell cycle and cytoskeleton, but he was also interested in development. He used many different approaches in his lab – expression cloning, biochemistry, imaging and so on – and so we got exposed to this incredible diversity of ways to understand biological systems mechanistically. Marc is someone who is attracted to complex systems, and his way of trying to reach a conceptual understanding while also innovating new experimental approaches to complex problems was certainly very influential for me. So, for example, my cell biological and imaging background was really important when I set up my lab to try to lineage trace neural stem cells during spinal regeneration by doing live imaging of animals.

What was the drive to move into regeneration, and why did you choose Jeremy Brockes’ lab for a postdoc?

At UCSF we were taught that when you define a project it shouldn't just be the next experiment, you should choose a big question, and it should be something that's unknown. Limb regeneration seemed pretty understudied, and Jeremy's approach was very appealing because again, he had a cell biological and biochemical viewpoint for understanding regeneration so I felt that there was a real affinity there in terms of the mind-set for how to study the problem.

In Jeremy's lab, you used the newt system to study muscle regeneration, but when you set up your own lab, you started to work with axolotl. What are the main differences between these two salamander systems and why did you choose axolotl?

The newts that Jeremy was using, Notophthalmus, were caught from the wild at that time (they couldn't be bred in the lab), and so they had parasites, and you never knew how old they were – and old ones regenerate slower than young ones – and so it was a very difficult-to-control system. When I was there, I did some animal studies but actually most of my work was in vitro, because the system was very difficult to work with.

Jeremy had chosen the newt because, unlike the axolotl, it was clearly post-metamorphic. He was worried that regeneration might be a feature of the axolotl's neoteny, or perhaps more that other people might think this. But when I set up my lab, I just went for the system that I thought was going to be experimentally accessible. With axolotls, you can breed them in the lab, and you can get hundreds of eggs quite easily. One of my aims was to do transgenesis, so I really needed those features. In the meantime, people have developed ways of raising Notophthalmus in the lab: their natural cycle is two years, but I think this has been shortened to make it a more viable system. I just didn't know that that could be successful at that time.

The fact that the axolotl can regenerate what looks morphologically like a fully formed limb is very significant and something above and beyond development

And do you think that the axolotl's neoteny is a factor in explaining why it's so good at regeneration – because it's in a ‘juvenile’ state?

It's hard to know, but I don't think that the developmental aspect of neoteny can explain everything. For example, a chick limb stops being able to regenerate well before it looks like a limb. So I think that the fact that the axolotl can regenerate what looks morphologically like a fully formed limb is very significant and something above and beyond development.

But I do think that there are things about axolotl, perhaps not so much the neoteny, but the fact that they seem to show a slow rate of turnover, or very slow growth, over long periods of time, that might make the initiation of regeneration a bit easier than in a newt for example.

Your lab has done a lot of technology and resource development in axolotl – genome sequencing, transgenesis and knockout methodologies and so on. Do you enjoy this part of the work, or is it just something you have had to do to allow you to get on with the question-driven research?

No, I do really enjoy this. Being trained in Marc's lab, I got the sense that a lot of questions are unsolved because there's some technical limitation that stops us from working on them. So this gave me a feeling for the importance of technology development in allowing you to tackle interesting problems, and I like the challenge. And of course I also see this as a really valuable thing to do for the community.

Your research programme now focusses on limb and spinal cord regeneration, which seem like hugely complex problems to be tackling. How do you approach such a multifaceted question as ‘how does an animal regrow a leg?’

At least for limb regeneration, I guess I've chosen to break it up into temporal phases: how is regeneration initiated, how do you grow a blastema, how do you start regenerating different cell types and so on. And we've made a lot of progress on the early stages: we've developed a lot of tools to answer the question of how regeneration starts and have been able to identify at least some of the source cells for regeneration so we could understand how cells transit to becoming a blastema cell. That line of research will continue, but I always like to keep pushing on, and for me the pushing on means studying the late phases of regeneration and asking questions like how the regenerating limbs know when to stop. And because we can actually watch all these phases of regeneration, it's a really accessible system for looking at each of these steps, and I'm very excited by what we still have to learn.

To what extent are you motivated by the hope of providing insights that might translate to human regenerative medicine, as opposed to just finding the problem of regeneration an inherently fascinating one?

When I started, I was certainly way out on the extreme of only being interested in the biology. But being able to make progress in the system, and understand how this complex process is controlled, has actually made me more optimistic that what we study here could perhaps be used more translationally, and it's an interesting problem to try to apply it to the human setting. We definitely think a lot in the lab about why it is that mammalian regenerative capacity is so much lower – is it that mammals never had the tools to regenerate in the first place, or have we evolved barriers to regeneration? Considering how important the conserved morphogens and things like that are in regeneration, my guess is that a large part of the problem is that there are various blocks in place in mammalian systems – like the induction of the fibrotic response – and it's interesting to start to look at what those are and if and how we might overcome them.

You've said that to study regeneration you need patience because it takes many weeks for regeneration to complete. Given the competitive nature of academia, does this make working in this field a more daunting prospect – particularly for young scientists?

Actually, the competition is, I would say, less of an issue in this field, because one is not really limited by the speed at which one works; rather, it’s an issue of taking approaches that answer the question with satisfactory resolution and thoroughness. The experiments do tend to take some time and we tend to tackle questions that require quite a bit of development to come to a satisfactory end answer. The people in the lab have successfully published, sometimes taking some years to come to the publication – although I think that is the case for many ambitious projects independent of the system. I think that being aware of publishing good intermediate milestones is a good strategy, and it is important to be aware of any time-sensitive career steps in the science culture that you eventually want to end up in. I am strongly against funding agencies and universities establishing age limits for certain career steps. Some people/projects take longer than others to do creative science.

And you've also started to work with embryonic stem cells. How does this complement your in vivo work, and is part of the attraction that it can give you results faster?

Yes it is. That's not really why we got into it, but it's definitely an advantage. We started working with stem cells because we were interested in the self-organisation of tissues, which I think is an intrinsic part of regeneration. So we wanted to apply some of the ideas we were getting from regeneration to a mammalian stem cell system and I thought it would be interesting to try and engineer a 3D tissue (the spinal cord) in vitro. I think the two systems complement each other very well and, although at the moment we're mainly learning from the in vivo situation to do our in vitro experiments, I hope that in the future it will work the other way as well.

I think that a very important recipe for success is to find an institution that supports you and recognises that what you want to do is valuable.

We're here at a meeting you're co-organising, which is focussed on ‘the next generation of stem cell researchers’. It's exciting but quite rare to see a meeting where most of the invited speakers are junior PIs (and even senior postdocs) – what was your motivation for putting on such a conference and what do you hope it will achieve?

I'm really excited about this – all of the organisers (Juergen Knoblich, Ulrich Elling, Sasha Mendjan, Chukwuma Agu and myself) really wanted to organise the meeting in this way. Obviously, there are a lot of senior people who really helped shape the stem cell field and continue to have an important guiding role. But of course these prominent researchers have amazing people in their labs, who go on to establish their own labs. This meeting is really exciting because it allows these next-generation people to have their own forum for communication, and to become a little more prominent. I think this is very important – to give these more junior people a voice, and an opportunity to interact with each other, so that we help build the next generation of leaders for the field. We hope to make this a regular series of meetings to continue to support this community.

Do you have any advice you would give to young researchers starting out in their careers?

At least for me what worked was to work on something fairly adventurous. I'm sure that there's a huge amount of pressure now to publish quickly, and in a high-impact journal. But I think there's still room to think about less explored areas, and to develop such an area. People have said to me that they're anxious about doing something like this because they're worried about the timescale in publishing. Rather than give up on your idea, I think that a very important recipe for success is to find an institution that supports you and recognises that what you want to do is valuable.

Then, hopefully, you'll have the opportunity to develop the system and publish the initial papers that characterise that system without necessarily having to aim for the really ‘big’ story as your first publication.

Finally, what might readers of Development be surprised to find out about you?

Well… I guess the thing that springs to mind is that my kids call me weird! When I go home, I just want to relax and have fun with them, and so I think I'm much more immature than they are. So we have a rule at home where if you stick your tongue out on a weekday, you have to pay 50 cents into a kitty. And I'm probably the one who has to pay the most money!