Ken Poss is currently James B. Duke Professor of Cell Biology and Director of the Regeneration Next Initiative at Duke University. His lab aims to understand the mechanisms underlying vertebrate tissue regeneration, focusing on the heart, spinal cord and major appendages in zebrafish, which possess especially high regenerative capacity. Earlier this year, Ken joined the Development team as an Associate Editor, focusing on the field of regenerative biology. We caught up with Ken to find out more about his career, his research and why he decided to get involved with the journal.
So let's start at the beginning – what first got you interested in science?
I think I became interested specifically in biology when I was a kid – I would always search for creatures and critters where I grew up. But what I really liked about biology in particular, in high school and college, was that it seemed to be the only topic where it's very easy to ask an expert a question that they didn't know the answer to; I just thought it was fascinating that there are just so many things that these so-called ‘experts’ didn't know! I then learned very quickly that, just by doing some reading and thinking, you could become someone who knows more about a particular topic than teachers and professors. I guess I just liked the idea that there was this open space and that you could devote time to exploring and making discoveries in this space. I thought science and biology were special because of that. As a professor, I think this is still true – you can't and shouldn't be expected to know all of the answers.
You studied biology as an undergraduate and then, for your PhD, you focused on the enzyme heme oxygenase. Can you tell us a little bit more how you got into that field of research and what that work was about?
Well, it didn't start as a love affair with heme oxygenase itself – I was actually interested in studying learning and memory. At the time, mouse knockouts were really quite new and there were only a handful of labs doing them. At MIT, where I was, Susumu Tonegawa's lab was just starting to make mouse mutants to explore mechanisms of hippocampal-based learning and memory, and I thought this would be great a project to work on. In the late 1980s and early 1990s, there had been a lot of excitement about nitric oxide's role as a gas messenger and, around the time when I started my PhD, there was similar excitement about heme oxygenases. It was thought that these enzymes, which can generate carbon monoxide, might play physiological roles and that carbon monoxide – a toxic gas – could function paradoxically as a messenger during learning. So that's what got me interested in heme oxygenases. But as it turned out, we made the mutants and didn't see any roles for these enzymes in learning and memory. They were involved in all sorts of other processes – iron metabolism, sexual dysfunction and stress defence – so I ended up looking at these instead. It wasn't how I thought it would play out but it was a really valuable experience, as I had to find collaborators who could help me look at and characterise the various different phenotypes.
How did you then become interested in regeneration and, specifically, regeneration in zebrafish?
During the mid- to late-1990s, lots of people were interested in the phenomenon of regeneration. It was one of those topics that everyone knew was important but one that we knew so little about. And so for me, regeneration was – and still is – an area where there's lots of open space and open questions. I guess that just got me excited. I also liked the idea of working more closely with animals and being able to do all the experiments myself; if you're studying learning and memory, you need to know not only the genetics but also the behavioural tests and the electrophysiology, and you often had to rely on experts. I was excited about being able to do everything myself. So it was both the topic and the practical nature of it that attracted me to the field. Looking back, I think that moving into the field at that stage was the best decision I've ever made.
I joined Mark Keating's lab at the University of Utah. He is a cardiologist who was interested in human genetics and cardiovascular disease, but he also had an unpublicised interest in understanding tissue regeneration; when I first met him, he told me that what he was really passionate about was trying to understand how a salamander limb can regenerate. So the lab had no record of regeneration research, and they definitely had no experience of using zebrafish, but I thought it would be a great opportunity to start something from scratch. Luckily, I was in an incredibly talented and well-funded lab, so it was a great place to be starting a new project.
During your postdoc, you showed that the zebrafish heart is able to regenerate. That must have been an exciting discovery at the time – how was it received by the field?
Actually, it was kind of a side project that I worked on towards the end of my postdoc. Back then, the general feeling was that salamanders could probably regenerate their heart muscle, based on what we knew about their regenerative capabilities, and that maybe frogs and fish could do it too. But what we did was to systematically test and show that zebrafish could regenerate their heart muscle, and we also identified some of the underlying mechanistic aspects. So people were really convinced that this could happen – that an adult zebrafish could regenerate its heart. So we basically had a model that you could do genetics with and use to study heart regeneration. At the time, zebrafish were only just starting to become popular, but it was clear that they were going to take off as a model system. It then took a few years for anything else to be published on zebrafish heart regeneration, I guess because it's hard working with adult animals and doing these types of injury studies, but there are now dozens of labs using zebrafish to study heart regeneration, and there's also increasingly rigorous science being done to look at heart regeneration in mammals. One thing that was really encouraging was that the clinical folks – the physician-scientists and pure clinical cardiologists – were also excited and receptive about using zebrafish as a model. That was really important, as we gained support from the people who see patients and who have a big say in where research funding goes. I think it was good for the zebrafish community.
Shortly after that, you went to Duke University to set up your own lab. What's the main question that your group is or has been trying to address?
Actually, I don't know if we have a central question or even a central goal. Our aim is not to regenerate the human heart; of course, it would be spectacular if we could, but we're just most interested in understanding how regeneration really works. And there are many angles to that which we can take, so I don't like having to limit those angles and focus too much on any one question. I also feel that your research should be directed by what the people in the lab want to study and what your postdocs and students are most passionate about. I'm happy to follow their lead, assuming it's a smart project and assuming we're on roughly the same page, which we generally are. Obviously, there are some things that I particularly like and think are important. For example, we (as a field) are developing higher and higher resolution platforms for imaging, to allow us to follow populations of thousands or even 10s of thousands of cells at once and even at the subcellular level. So we're now at a stage where we can hopefully start to really understand how these cells behave during regeneration in a live animal. I also get excited about the idea that we can now understand how regeneration programs are initiated, how they're controlled and how they're shut off – both spatially and temporally. And I really like the idea that we can now identify regulatory elements for key factors in regeneration and, ultimately, work upstream to identify the earliest possible events involved in triggering a regenerative response. So that's what drives me – just trying to understand how and why this all happens as an animal regenerates.
I'm also open to looking at regeneration in lots of different contexts. When people join the lab, they tend to have a passion for a certain question or tissue, and each of these tissues has an important technical advantage or attraction. For some people, the thing that drives them is knowing that, by understanding heart regeneration in zebrafish, they can better understand human cardiovascular disease. However, for people who are more interested in quantitative developmental biology, the zebrafish fin is a better model; it's tough to image the beating heart inside an animal (plus heart regeneration is really slow), whereas the fin is just a wonderful system for imaging. You can make really fine measurements of just how well regeneration is progressing (e.g. in a wild-type animal or in a mutant or transgenic line) and you can follow the same animal easily over hours, days or weeks. So this system has real advantages for addressing issues such as patterning and positional memory. And zebrafish spinal cord regeneration is just a spectacular process in which you really see the functional output of regeneration: initially, you see an animal that's paralyzed but in 6 weeks or so they're swimming like they've never been injured!
By studying all of these systems, we also end up developing and accumulating tools that can be used in different ways. I actually think the most fun part of science is the accidental discoveries. There have been times when we've been studying one type of regeneration that exposes something really new and unexpected about another type of regeneration. Or we end up with a tool that wasn't so effective for one tissue but turns out to be revealing for another.
We're also interested in looking at other models. There's definitely still a lot to do in zebrafish – and I'd be perfectly happy working in zebrafish exclusively – but I think if you're really interested in regeneration you want take your findings and apply them to a system that that doesn't regenerate as well. For example, can we take our discoveries in zebrafish to see if they can be instructive for regeneration in mice? That is, to use some of the factors that we've identified in fish to tweak a regenerative response in mice? And, of course, genetic technologies are opening lots of other animal species up to experimentation. But I think the rate-limiting step to understanding regeneration is making genetic and other tools, so zebrafish will always offer huge advantages.
Surely, any biologist has to be excited about the stage we're in right now and the technologies we currently have access to!
You recently joined Development as one of our Associate Editors, where you'll be handling papers that focus on regenerative biology. Can you tell us why you decided to get involved with the journal?
Development has always been my ‘go to’ journal. In fact, my first bit of funding was a Development Traveling Fellowship back in 1998. My first important paper in the field was published in Development; as part of my postdoc, I cloned a gene that is required for zebrafish fin regeneration and this was published in the journal. And then my first paper as a PI was published in Development. Actually, I just checked and it turns out that in one in four papers that I've ever published has been in Development. So I really like the journal!
I'm also really happy that the journal has always dedicated some attention to regeneration studies, so I'm hoping that I can help the journal to continue to attract good regeneration papers. I think there's an opportunity for a journal like Development to be the ‘centre’ for these types of papers. As I mentioned above, I've always found that studying different contexts of regeneration can be enlightening, so I think that it would be great to see studies of regeneration in different organs and systems in one place. So, people who study liver, pancreas and skeletal muscle regeneration, some of whom would normally submit to a disease community, could come together with people who work on regeneration in Hydra, planarians, zebrafish and salamanders; we could build a development and regeneration community.
I also think that, certainly when I was starting in the field, a paper on regeneration that was published in Development was considered to be a landmark paper. Admittedly, there weren't a lot of regeneration papers being published back then, but I think it would be great for trainees to want to submit their best papers to Development and to know that this would help them progress. In my lab, this is pretty well established, but it would be great if, more generally, Development is the first journal that people think of when they have a great regeneration story.
What particular areas of research do you think are exciting right now?
Well what's not exciting? I could mention a whole bunch of things but I think it's hard not to be excited about genome editing. I know that seems like an easy answer but the idea that you can make these chimeric Cas9 enzymes, in so many different flavours, and you can direct them to a short sequence of DNA and get them to perform at that specific sequence – that's something I never could have imagined could be done 20 or even 10 years ago! I really like the idea of being able to regulate gene expression surgically using that approach. The possibility of turning on and controlling the level of a gene in a reversible way in specific cell types is very exciting. And the idea of being able to study tissue regeneration with that level of experimental control is super exciting. Surely, any biologist has to be excited about the stage we're in right now and the technologies we currently have access to!
And what kind of papers would you like to see more of at the journal?
I'm pretty confident the field will come up with a great selection organically. I'd love to see tools applied in clever and innovative ways. I also think it's really important that regeneration papers not only use tried and tested methods, but that they involve making or trying something new, such as a new mutant or transgenic strain, or an unbiased screen that directs the story.
I should also emphasise that I think the term ‘descriptive’ is a compliment for a study; sometimes it's important to do the very careful landmark studies to document what's going on and set the stage for the mechanistic question. It's a mistake to ask someone to go through prescribed hoops to identify a ‘mechanism’ when the observation itself is much more important.
I think the term ‘descriptive’ is a compliment for a study; sometimes it's important to do the very careful landmark studies to document what's going on and set the stage for the mechanistic question.
Moving on to career advice: what's your advice for someone who's starting out in the field of developmental and/or regenerative biology?
I'm very optimistic about the field – the questions are there and are just waiting to be answered. But when you're thinking about what to study, you've got to be thinking 10 to 15 years in advance. So I guess my advice is to look for open spaces – I think there are many of them – and to follow what you are passionate about. It should be something that you see as having many questions for many, many years to come.
Finally, is there anything that our readers would be surprised to find out about you?
I have an unbelievably fantastic sense of humour.