HomeInVivo Biosystems Blog17 Minutes of ScienceSeventeen Minutes of Science: Creating an Ideal Model – How Judith Eisen Helped Pioneer the Use of Zebrafish in the Lab

Seventeen Minutes of Science: Creating an Ideal Model – How Judith Eisen Helped Pioneer the Use of Zebrafish in the Lab

Tune in weekly to our virtual series "Seventeen Minutes of Science" every Tuesday at 11am PST / 2pm ET where we go live on Facebook with a new guest each week to talk about how science and biotechnology is woven into their lives for (you guessed it) 17 minutes!

For our 31st episode, we are joined by Dr. Judith Eisen to discuss her career working with zebrafish and helping to establish it as the respected and loved model that it is today.

Judith Eisen works at the University of Oregon Institute of Neuroscience, where she uses zebrafish embryos and a combination of cellular, molecular and genetic approaches to study the way in which neuronal diversity is generated during development. In particular, she is interested in discovering how the correct numbers of cells are specified for specific neuronal fates at particular times and in particular locations.

Watch the recording below or read through the transcript to learn more about the early days of zebrafish research and how Judith has continued to shape the field of zebrafish research tot his day.

Transcript:

Sarah Cheesman (Host): [00:00:00] Well, hello, everyone, and welcome to 17 Minutes of Science. My name is Sarah Cheesman. I'm a technical solution scientist at InVivo Biosystems. It's good to be here. I forgot to mention that last week was our 30th episode, so this makes it 31 this week so we're glad if you've been here for some or all of them with us because we just continue to have so many interesting topics. And today my guest is a very special person, Dr. Judith Eisen, and the title of what we're going to talk about today is Creating an Ideal Model, How Judith Eisen Helped Pioneer the Use of Zebrafish in the Lab. So I'm going to say a few words about Judith and then I'll let her say hello and then we'll jump into the questions and just go from there. As you all know, I have a timer and I just started it to try and keep us in our 17 minutes. So now that it's going, we don't have to worry about that. We'll just have fun. So a bit of background on Judith. Judith is an expert in early development of the nervous system, including interactions with host resident microbes. Judith was a postdoc in the laboratory of Monte Westerfield at the University of Oregon. And thereafter she became a professor of biology and a member of the Institute of Neuroscience at the University of Oregon. So Judith is considered a pioneer in establishing zebrafish as a model to study the nervous system and now investigating host microbial interactions that affect that organ system, too. So she was one of the core group of researchers at the University of Oregon that continued the work of George Streisinger after his tragic death in 1984. And George, for those of you who don't know, is sort of recognized as the founding father of zebrafish research. Judith has a long CV, so I'm just going to list a couple of quick highlights and that she is the co-founder and co-director of the [University of Oregon] Science Literacy Program and she's also a member of the American Academy of Arts and Sciences, a fellow of the American Association for the Advancement of Science and a 2010 recipient of a Guggenheim Fellowship. So she has done all kinds of amazing things. We're lucky to have her here today. Welcome, Judith.

Judith Eisen (Guest): [00:01:59] Thank you, Sarah. It's wonderful to be here.

Sarah Cheesman (Host): [00:02:02] Yes. Well, I appreciate you making time to talk with us today because we we love the perspective of people who've been around a field for a long time, and that is certainly you. And so we want to jump in and talk about how there isn't one perfect model for studying diseases. But how do you see different model systems in biomedical research and how do you see the linkage between using these tools?

Judith Eisen (Guest): [00:02:29] So I started out doing this kind of research at a time when there weren't so many models as we think of them now, because mostly we think of models as organisms in which you can do some sort of genetic manipulation. So something like yeast or the worm C. elegans or drosophila or mouse or zebrafish. But when I started, and particularly in neuroscience, first of all, we couldn't do very many genetic manipulations. You could make mutations or you might find mutations, but we couldn't, we didn't really understand most of those mutations. And people were interested in a wide variety of things and didn't really have the thought that genetics was the only way to study them. So people studied many, many different kinds of organisms, and particularly for neuroscience and for developmental biology. For example, in neuroscience, we learned a lot from studies in Aplysia and a variety of snails. Those are certainly not something one would consider model organisms, but we've learned a tremendous amount from them, from the squid giant taxon, from decompiled crustaceans, so crabs and lobsters, from which we've learned a great deal about the circuitry that runs rhythmic processes. And so if you fast forward to now, we really do use primarily the organisms that I mentioned at the beginning as models, because we have a huge amount of ability to manipulate their genetics, which gives you an entire window into addressing certain kinds of questions. But I think the importance of a model is choosing one that allows you to address the question that you're setting out to address. And I think if you think about what's going on now in current research on SARS-CoV-2, for example, that really gives you an idea. Mice, which are a lot like humans, are a great model for some things, some questions you might want to ask about SARS-CoV-2, but they're not such a great model for other things you might want to ask. Ferrets or other animals might be a better model for those things and allow you to address those questions. So you really have to think about what the question is that you want to address. What do you want to learn? What's an organism that's going to let you take a deep dive into that question in whatever way you want to do that, whether that's genetics or electrophysiology or viral transmission. And then when we use the word "model", you know, in some sense we're thinking about what's it a model for, it's a model for humans. So then you have to take that step back and think about how you move from whatever basic process you learned about into generalizing that to other organisms. And so I think there's a real role for comparative types of experiments too. First of all, they tell us a lot about this biology, what's the same and what's different about different organisms as a result of the evolutionary process, but they also give us an idea of how principles work in different ways.

Sarah Cheesman (Host): [00:06:11] It's certainly something we encounter increasingly in our work at InVivo Biosystems, people come to us because they're seeking help building models and they're using all sorts of tools. And there's a lot of fluidity between people who have a background in using the mouse model system, now wanting to use zebrafish, for example, because, as you say, the question that they're most interested in pursuing is more accessible to them in the fish model, so we see that a lot. And I think it's pretty exciting because it sort of shows how we need to look beyond just the thing we're trained in as well and how to collaborate and work with others. But I'd love to hear you tell us, since you've been in the field for many years, what it was like in those early days of working with fish to try and understand basic questions of biology, as you say at the time, and any sort of fun story you might be able to tell us about those days. We'd love to hear it.

Judith Eisen (Guest): [00:07:07] Well, so you've already mentioned George Streisinger who is really considered the father of zebrafish research. And George was a fish hobbyist and he also was one of the early school of molecular biologists. So we'll say maybe near the end of the first wave of molecular biology when lots of problems, DNA replication and things like that have been solved, there were a number of people who wanted to move forward and and look at organisms. Interestingly most of them had questions about the nervous system. So George Streisinger was interested in and understanding nervous system and nervous system development, and he wanted a vertebrate model. So he chose zebrafish. But there's also Seymour Benzer who chose fruit flies and Sydney Brenner chose C. elegans. And for each of these people, you know, at the beginning, they worked on their own, and that was certainly the case for George. He had his own lab. He worked on his own. It was a small cottage industry in his laboratory. And then that expanded to include Chuck Kimmel, who's another colleague. He was a colleague of George's [and] he's still a colleague of mine at the University of Oregon, who saw that zebrafish had some real experimental tractability for certain kinds of experiments, that Chuck wasn't just looking in the nervous system and then Monte Westerfield and myself and then Jim Weston and John Postlethwait. So, you know, it's still rather a cottage industry at the University of Oregon. But I actually looked this morning and they're now 1,423 laboratories around the world who who work on zebrafish. So if you think about the numbers, there is probably something like ten thousand investigators. So George worked out many of the early tools – mutagenesis, he worked out some ways of doing cell lineage, ways of keeping fish, light cycles, temperatures and so forth, and many of those things continue to be used today. In terms of looking at the nervous system. When I started in the kinds of things that I wanted to do, there were all sorts of things we just didn't know how to do. So in  genetic model organisms, nowadays, we always think of genetically encoded tracers of one sort or another that we can use to look at cell lineage, for example. But such a thing did not exist in the early days of zebrafish. So the techniques for labeling individual cells to look at cell lineage had to be worked out, and that was something that was worked out in Chuck Kimmel's lab and Monte Westerfield and I worked with him a little bit on this. And we would we would look at we were interested in looking at cells in the nervous nervous system that didn't really have a great idea of exactly how to do that. When Chuck was doing these lineage studies, we would all pile into a dark room and watch as the embryo unfolded and cells migrated. And of course, nobody knew the time course of any of this, so you kind of had to watch the whole thing and capture the whole thing at that time on tape. And then we would take shifts so that you didn't have to be there all the time. Different people would be there at different times. It was not quite like the darkrooms now, we were looking at monitors that are probably way smaller than anything that anybody is using to to look at this. And there were four toggle switches with lights and things like that.

Sarah Cheesman (Host): [00:11:36] Sounds like the cockpit of a spaceship.

Judith Eisen (Guest): [00:11:38] It was! If you go to the Smithsonian and you look at the old rocket ships with all the manual toggle switches. Yeah, except ours had lights on and I'm not sure that those old ones had lights on them. But I remember the first time I watched the axon of a neuron grow out and you could actually see this in real time, it went pretty slow, but you could see it in real time. Because we were taping it, we could speed it up later and we actually put up acrylic sheets and we had marker pens of different colors and we would tape them on the monitor and we would trace those so we didn't have to go back to the tapes all the time because tape is a terrible medium for finding out exactly the place that you want to go back to. But we had these drawings which journals accepted back then. And I remember watching this and it was astonishing. Nobody had ever actually in real time in a living embryo of an organism watched nerve cells grow their axons out before. And these were these were cells that were labeled manually with fluorescent dyes to follow lineage. And some of them turned into neurons. And we could watch that. We could see muscle fibers form. We could see all of these things. It was really completely astonishing to be able to watch this and realize this is a way that one could start to study these early developmental processes.

Sarah Cheesman (Host): [00:13:17] I think you're describing that thrill of science that keeps us coming back for more!

Judith Eisen (Guest): [00:13:23] Yeah!

Sarah Cheesman (Host): [00:13:23] That sounds gorgeous, because that's one of the things I love about zebrafish, is just how beautiful they are to look at. And your whole career has centered around visualizing so many of these gorgeous cells. I would like to turn to what you're doing more recently, because I'm sure visualization continues to be important to you, but you're also thinking about things you can't see. So we were discussing your long history of working the nervous system, but in recent times you've turned towards thinking about the contribution of the microbiome to neural development. I'm curious if you could say a few words about how you landed on that idea and in our last couple of minutes.

Judith Eisen (Guest): [00:13:59] So a colleague of mine, Karen Guillemin, came to the University of Oregon and she was interested in host microbial interactions. She didn't know anything about zebrafish, but she thought this would be a good organism to use for these studies. So she worked very closely with people in my lab and when I started seeing how important resident microbes are for the normal unfolding of the developmental process, I have to say I was shocked because as a developmental biologist you learn mom's genes package the package of what's in the egg or provide the sustenance for for development in utero and then zygotic genes. And that's what it takes for development. And of course, we knew from studies done in the nervous system by Hubel and Wiesel in the 1960s and 1970s that there are critical periods in the nervous system for environmental factors, for example, light. So animals who can't perceive light during a critical window will never learn to see properly (mammals at least). And so this was the first time that it looked to me like there's something besides mom's genes, your genes, and photons that are important for the animal unfolding and that's all these other creatures and all their genes and all the gene products that the developing animal is being exposed to over time and that interplay and I just figured there must be some important role for this in the nervous system and there might be feedback. So the nervous system might also influence the structure of these microbial communities. So those are the two things that we're really working on in my lab today.

Sarah Cheesman (Host): [00:16:06] That is such an interesting intersection. And no doubt, when you were pondering these questions, that it is such an open field because there's so many different things to explore regarding how microbes affect all aspects of our physiology and development. Yeah, I'm sure most people wouldn't have connected those two things at the beginning, thinking about what's in your guts and then what ultimately is protected inside, deep inside your tissues. That is fascinating. And I know you have a big grant on that so we're going to stay tuned about where that work leads you. In our last minute, because that's what happens on this show, it goes so fast! You have been so successful in your career and were elected to the Academy of Arts and Sciences a couple of years ago. And so what advice would you give to young scientists on the beginning of their journeys?

Judith Eisen (Guest): [00:16:59] Be excited about what you're doing. I think that's even more important than planning out your career goals. Be excited about what you're doing. If you're in a situation where you're not excited about what you're doing in the laboratory. Think about why that is. Is it Because you're not interested in the topic? You don't work well with your mentor? But it's very hard to pursue things that aren't of real interest to you, and I just think that's of paramount importance and where that's going to take you in your career, you just don't know. I mean, so many really successful people, they stumble into something! They hear about it in a talk, they read about it, they hear something off hand, they see a microscope slide or the digital equivalent and they say, "I wonder what that is?" and it really turns them in a different direction. So I think it's I think it's really important to seize that moment and be really excited about it.

Sarah Cheesman (Host): [00:18:13] Well, that is a great way to end, and I was going to make a comment about how when I hear you talking like that, it also always underscores for me, I don't really like the phrase "basic biology" because I feel like it somehow diminishes the body of work. And I don't feel that way at all. But just being able to explore the questions you're interested in, I mean, there's something very fundamental about that and you never know where it's going to lead. And we've seen so many great examples of that. And no doubt where you're headed with microbial neuro interactions is going to reveal that story. Thank you so much, Judith, for taking time this morning to talk to us. It's been a treat to hear about stories old and new and wish you well and be safe. Be well at home.

Judith Eisen (Guest): [00:18:57] You too, Sarah. Thank you very much. It's been really fun.

Sarah Cheesman (Host): [00:19:01] We'll see everybody next week. Take care.

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