Jared Rutter's group studies the mechanisms by which cells sense their metabolic environment and integrate these signals to influence cell behaviors. Jared completed his PhD at the University of Texas Southwestern Medical Center, USA, where he stayed on to begin his independent research career as the first Sara and Frank McKnight Independent Fellow. He established his own lab at the University of Utah, USA, where he is now Distinguished Professor of Biochemistry and an HHMI Investigator. Jared is a Guest Editor for Development's special issue on Metabolic and Nutritional Control of Development and Regeneration. We caught up with him to find out more about his research, his experiences with translating this work to the clinic and the importance of placing metabolism research in the broader biological context.

Let's start at the beginning, when did you first become interested in science?

I've been interested in science probably as long as I can remember. As a young child, I used to like to watch the nature shows on PBS that included Jacques Cousteau shows and things like that. So, I've always been interested in nature. I don't know that I considered it could be a career choice until I was at university, and started to realize that it could actually be a viable career to do research. But I think I've always been interested in science.

Where did you complete your PhD, and what did your research focus on?

I did my PhD at the University of Texas Southwestern Medical Center, in Dallas, Texas, and my mentor was Steve McKnight. It was a really interesting and exciting time. Steve had previously founded a biotech company, which he had led for several years, and had just recently come back to academia. So, I came into a situation where there was a lot of freedom and flexibility to do new things, because he had adequate resources but there wasn't a bunch of projects already ongoing in the lab. I was therefore able to really explore and be creative, and I had a great experience. The research that I did, which turns out to be, in many ways, conceptually very similar to what my lab continues to do today, was trying to identify molecular mechanisms whereby cells could sense their metabolic environment. We were working on a family of proteins with domains that we hypothesized would be metabolic sensory domains. One of these turned out to be a protein kinase that I worked on quite a bit as a PhD student; this was also the project that my lab worked on initially when I started my own independent laboratory. Other proteins in this domain family turned out to be transcription factors, and we worked on those a little bit, too. That experience really did set the course for my career, both in terms of my personal development and in shaping my thinking about interesting scientific questions.

What was it that initially drew you to the metabolism field?

I think it was a chance thing, to be honest. Of course, we often look back and we infer some logic to the choices that we make. But I think that, if I would have ended up in a lab studying, for example, ion channels, I probably would be fascinated with ion channels; I might still be working on ion channels today and I would think they were the greatest thing ever. I think one thing that was clear, and continues to be clear, is that there's a lot that we don't know about how metabolism and metabolites signal to control cellular behaviors and cellular decisions. However, I think there are a lot of unanswered questions in most fields, so I don't know that there was anything particularly unique about it other than that's the lab I ended up in, and I found a lot of exciting things to do and so I was therefore excited to keep doing it.

There's a lot that we don't know about how metabolism and metabolites signal to control cellular behaviors and cellular decisions

I understand that you became an independent fellow straight after your PhD. What was that transition like, and what did you work on during this time?

I had completed my PhD, or was about to, and I had gone out interviewing for postdoc positions. I was excited about a number of opportunities and great labs that I'd interviewed at. I went back to Dallas, and I was talking with Steve about what my options were. It turned out that he had decided to endow an independent fellow position in the name of his parents and, in the end, I became the first one of these independent fellows. In many ways, it was fantastic. I basically moved down the hall to a separate lab space, I had the money to hire a technician and I didn't have a boss so I could do whatever it was I wanted to do. Steve was also generous enough to let me continue to work on the project that I had worked on as a PhD student. But it was also hard, really hard; I didn't realize it, but I had become very dependent on the lab environment and being able to just lean over to a friend and ask them their opinion about something. Steve was also a very inspiring mentor and I had grown dependent on that. So it was hard to now show up at work every day and walk into an empty lab with a young technician who was just looking at me waiting for me to tell them what to do. But, on the plus side, I think I already made some of that difficult transition to independence during that period, rather than when I started my own lab at the University of Utah and became an Assistant Professor. So, it was a great experience – it was hard for me, probably more emotionally than anything else, but I'm very glad I did it. When I did then start my own lab at the University of Utah, I think I was probably more effective as a result.

What research questions did you initially set out to address when you established your own lab?

As I alluded to previously, I think everyone in my lab, for the first few years, worked on this family of protein kinases that had this domain that we believed to be a metabolic sensory domain. We were trying to understand how, maybe through direct metabolite sensing, this kinase might be able to couple the metabolic state of the cell to signaling. We studied this question in yeast, mammalian cells and mice, and we made some interesting observations. I have a former postdoc who continues to work in this area in his own lab. Toward the end of this project, we actually started a company and found an inhibitor of this kinase that went into clinical trials. Unfortunately, we identified some unexpected toxicity that ended the program, but it was a great experience to see the drug discovery and therapeutics development side.

How has the focus of your lab shifted since you started it?

Oh, it's completely shifted a few times since then. Much of my lab has now come back to the same question that I had as a graduate student, which is: how do cells monitor their metabolic environment? How do they know what nutrient, metabolic and energetic resources they have? And then how do they integrate that information to make decisions about their behavior or their fate? That is probably very similar to how I would have described my research as a third-year graduate student. I've allowed the people that come to my lab to develop their own questions, and so the interests of my lab have evolved as people in my lab have made discoveries or established platforms and new technologies. New people coming to the lab have then often gravitated toward those developing areas, and so my lab has quite substantially changed directions multiple times. But I think it's been great. We've always learned from the things we've done in the past and tried to incorporate those ideas and technologies into our new topics and the new questions we're asking, and so I think it's been good to continually evolve. We also try to be creative with the questions we're asking, and aim to focus on significant areas where there's inadequate understanding and where I think we have the capabilities to make a difference.

What technologies are you using to address your research questions? Have you had to develop any of these yourselves?

One of the core technologies that we use has been in development in my lab over the last several years. Recently, it was really brought into practice by a postdoc, Kevin Hicks, who now has a faculty position at the University of Utah and is currently looking for independent faculty positions. His approach allows us to identify metabolite–protein interactions with very high sensitivity, and it has been a transformative technology for us. Several people in the lab are either using that technology or studying discoveries that were made using that technology. We think there will continue to be more and more development related to that.

Your lab has also developed software that is freely available to other researchers in the field, such as Metaboverse. Is open-source science important to you in general?

I have to say, I must give credit where credit is due here. I barely have the capabilities to send emails with a computer, so I am not the one writing that software! I've been fortunate to have a couple of graduate students with those talents: Cameron Waller and Jordan Berg. Between the two of them, they developed a few software packages that are useful for studying metabolism. And yeah, I think open-source science is very important. I feel that one of the important developments that has happened in the field over the last several years is pushing more toward transparency and open-source availability of data and the published results of our research. I think it's important that everyone has access to the work that we do. Many of us are using money that comes from taxpayers, and I think it's really important that we take that stewardship seriously and try to do research that actually will benefit people someday. At a minimum, the public should have access to the results of the research that we do. Whether or not they can fully understand that research and all its implications, they should at least have access to it.

I noticed that the Metaboverse paper was initially made available as a preprint. How do you think preprinting is impacting your field?

I'm a fan of preprinting. We preprint essentially every paper that we publish, and I think it's good because it just gets it out into the field earlier. There were predictions that this would ruin science because non-peer reviewed studies would now be out there and the scientific world would implode as a result. That obviously hasn't happened. Overall, I think that the negative effects some people predicted haven't happened, or have rarely happened. I also think, to some extent, that the positive effects probably haven't been as dramatic as some would have hoped. In most circles, a paper that is on a preprint server is not viewed with the same authority as a paper that is published following peer review. For better or for worse, that is the case. So, I'm in favor of it, although I think it hasn't been the revolution that some people thought it would be.

I'm also interested in the revolutionary ideas that are being proposed in the publishing world to try and decrease some of the pain that authors face in trying to get through the peer review process. This is a common source of frustration for everyone that does research and tries to publish it. So, I'm interested in the results of the experiments that are being done to explore other publication models. And I'm hoping that, in the end, we devise a system where those who are doing research spend the vast majority of their time doing the research that they think is the most impactful, not the research that some reviewer thinks is the most impactful. Or, even worse, doing experiments that are dumb, because some reviewer thought that they were important and didn't really understand the nature of the research or the nature of the field. I'm optimistic that the system will continue to evolve and end up in a better place than it is now.

Why did you accept the invitation to become Guest Editor for this special issue on Metabolic and Nutritional Control of Development and Regeneration?

One of the reasons that I did it is because I like and respect the other people who are involved. Both Irene [Miguel-Aliaga] and Lydia [Finley] are great, and I really like the work that they do, so that was a big plus. I also think this is an interesting area. As I said, the fundamental interest of my lab is understanding how metabolism influences cell behaviors, cell fate decisions and so forth. In a way, this is right on topic for what I consider to be one of the most important questions facing the metabolism community, which is how to take the metabolism research we do and put it into context. I think the intersection between metabolism and developmental biology is just one nice example of that. There are other ways to think about this special issue, and we will have papers that don't really get at this one specific aspect of the topic, but I am largely thinking about it in terms of questions such as: how does metabolism influence development? How does the metabolic status of a stem cell influence how that stem cell develops? How does metabolism affect the rate at which a stem cell develops and how the progeny of that cell behave? I think this is a really important field with a lot of very important disease impacts. One could argue that many cancers are at least partially the result of failure to make this connection between metabolism and development and to actualize that connection in the proper way.

What does the role of Guest Editor involve?

My role is basically to edit some subset of the papers submitted to the special issue and to try to shepherd them through the review process. For those that are appropriate, I help to get them published efficiently. Of course, thinking about whether individual manuscripts that are submitted are within the scope of the special issue is also a part of it, and I also publicize the existence of this special issue and encourage people to submit their papers there.

What have you enjoyed most about helping to curate the special issue?

Again, probably interacting with the people – I really like the people who are involved. And I've been doing science for quite a while, but I actually don't have that much experience as a journal editor. I have a lot of experience as a reviewer of papers, but much less as an editor. So that's been interesting, to experience that side of it and see the challenges involved. Going back to the publishing situation, every academic scientist in the world, I'm sure, feels like they're constantly overwhelmed with tasks. And then journal editors come at them and say: ‘OK, now can you add one more thing to your task list and review this paper?’ I've always tried to be responsible as a reviewer and take on as many reviewing tasks as I can, myself. But I think having this experience helps me see a little bit more clearly what it's like for the editor, who's asking a lot of people in the hope of finding two or three that will review a paper. And so I'm a little more sympathetic to editors, I think, than I was before.

What do you think are the biggest challenges for researchers working at the interface of development and metabolism?

Oh, there are many challenges. The way that we measure metabolism, typically, is we grind up a tissue, extract it with an organic solvent and then shoot it into the mass spectrometer. This, of course, completely eliminates any spatial information because we're taking a homogeneous mixture of some biological sample, whether it's tissue, or cells in culture or whatever. And I think that is massively problematic if you're thinking about, for example, a developmental situation where you have a stem cell and stem cell niche, and you're trying to understand what's happening metabolically in that stem cell, in the cells that make up the niche and maybe even in the differentiated progeny of that stem cell. The way we do metabolomics, all of that is going to end up in the same tube, and we're going to lose all the specific localization information. So, I think one of the most important frontiers of our field is figuring out how to measure metabolism in a spatially resolved way, such that we don't lose all that information. The ultimate goal is to be able to do assays that say: ‘This is what the metabolism of the stem cell is, this is what the metabolism of the niche cell that's right next to it is and this is the metabolism of the differentiated progeny which is a few cells away.’ As of today, our ability to do that is very limited. There are a lot of really smart people that are working to develop technologies to address that problem, and I'm excited about the future. Coming from my perspective, that's one of our most important challenges, and it's going to require either new technologies or the massive improvement of existing technologies. So, I'm excited about that. I think it's a really important area, not just for development, which is how I've described it, but for every other biological situation as well.

I think one of the most important frontiers of our field is figuring out how to measure metabolism in a spatially resolved way

You are also actively involved in translating your lab's findings to the clinic. What has this experience been like, and do you have any advice for other researchers looking to branch into this area?

It's been a great experience for me. There have been many cases where the commercialization of technologies or ideas that have come from our lab has ended up coming back and informing and improving some of the things that we do in our lab. So, this has not been a one-way street where we do things and throw them over the wall for somebody else to catch them and take them forward, because it's actually been mutually beneficial a number of times. And, again, I actually think it's our responsibility as academic researchers to at least do our best to do research that will in some way, at some point, impact the human population. So, I would say this area is important for me personally. I think I have also, at least for several years, been open to the possibility that the research we do might have a translational aspect or translational opportunity associated with it. And exploring that has been fun, it's been interesting. It's a different world, and I've learned a lot. Running a good academic lab doesn't necessarily prepare you to fully understand what it takes to make a commercial entity and to be successful in that, but I think it's been a great experience for me, even though I don't yet have an approved drug that's come out of something from my lab, which I think would be the ultimate positive outcome. I hope that will happen in the future, but it hasn't happened yet. There's another drug that came out of my lab that is in clinical trials now, and I'm optimistic for that project as well.

In terms of advice to other people, I actually think that it's pretty simple: choose scientific problems that are impactful, and where there is the potential that what you discover could be impactful for human disease. I don't believe that this has to mean that you are using patient samples in your research, that you're doing clinical research on humans, or even that you're using animal models of disease. Most of my lab has never done those things; just a small fraction of my lab's effort has been in those areas. I think that what's more important is to try to do experiments and ask questions that are relevant to the human condition. And the second piece of advice, which probably goes without saying but I think is the most important thing by far, is to do good science. I think if you work on important questions, and do a really good job of answering those important questions, there will be opportunities to translate your research. I do think that, in general, academia is not very good at translating our research, and so it is a very inefficient process. So, I should say that there is more to it than just doing good and impactful research because there is a gap there that still exists, and we as an academic community need to do better at figuring out how to take the most appropriate research and translate it. But what we can do as individual scientists is choose important problems and solve those problems with good science with high rigor and with creative use of technology.

Finally, what do you enjoy doing outside the lab?

I like to play golf, and I like to ski. I have to say, amongst all the bad things that came from the COVID pandemic, many of which were of course tragic, it did give me a lot of time to play golf more than I had in the previous 20 years. I had the opportunity to play with my family, and so that's been a lot of fun and I've tried to carry that on. I think it's important that we, even as scientists who are very passionate about what we do, find a way to have passions outside of the laboratory. For me, that's mostly my family, but also having a little bit of fun golfing or skiing is a good way for me to do it as well.

Jared Rutter’s contact details: Department of Biochemistry, University of Utah School of Medicine and Howard Hughes Medical Institute, 15 N. Medical Drive East, Salt Lake City, UT 84108, USA.

E-mail: [email protected]

Jared Rutter was interviewed by Laura Hankins, Reviews Editor of Development. This piece has been edited and condensed with approval from the interviewee.