Return to the audio for How to Science Episode 1, with scientist Trisha Wittkopp.
Monica Dus: I want to ask you a question that became evident as I was looking through your website. You have a lot of pictures with your lab, you have a Lab Olympics, there’s a picture where you’re holding a giant turkey when you had your lab over for Thanksgiving dinner. And it’s really clear from these pictures that you guys have a lot of fun in the lab, and you seem to take the idea of science done as a team as a core principle in the lab. Can you tell us a little more about that?
Trisha Wittkopp: Sure, absolutely. As much as anything can be by design, as a group of people come together over the years, the desire to make science fun and the lab atmosphere fun was actually really fundamental from the beginning.
Before starting my position, I read a lot of advice books about how to set up the lab, and they talked about having a lab motto. The one I came up with was, “Science is fun.”
Science should be fun. I mean, that’s what brought me into science. That’s what I think brings us all together, is this passion for knowledge. And the more we can have fun along the way, the better. I think that doing things like the Lab Olympics, where we get a chance to compete on these rather esoteric skills that we’ve honed day to day in the lab; or an annual canoe trip; or Whirlyball; and various lab gatherings allow the people in my group to build the personal relationships that really support their science and make it easier for them to ask each other for advice, or help, or to speak more freely when something’s not going right. I think it helps reduce the competitiveness in the lab.
There’s so much, I would say, competition in science, and also critical assessment of your work that happens thru the review of papers and grants. And there’s lots of negativity sometimes, which comes through that. The hope is that the lab environment becomes sort of a safe space for exploring your scientific interests, but also where you can take a risk intellectually and be supported by those around you.
In many ways, it’s not a common thing in science—the idea that a lab would be fun was almost a taboo, because it’s almost like you don’t take your science seriously, which we know now is not true. So how does each member of the lab—especially because we have people from all different cultures and countries—how does that play into making this atmosphere fun and unique?
TW: I would say, certainly everyone’s individual strengths are welcomed and supported. Most of our lab gatherings are a potluck of some sort, so everyone’s bringing various dishes. One of my first graduate students was from Turkey, and I remember she made this lentil soup that was amazing.
It’s a great metaphor, I think, for the way the lab works. Each one bringing their own expertise in something they love, and everyone else being open to and celebrating that. In fact, we have a lab cookbook now, or a sort of recipe book, that we’ve assembled to share all these recipes, because it’s a great way to experience new things. And we find new foods that we love.
So now, I have this habit to make lunches easier when life is busy: I make a big pot of soup, and I freeze all these individual packages. One is the lentil soup I mentioned—so every time I make it, I think of Gizem, my first grad student. In addition to good food for me, it’s sort of the memory and the reflection on people that make the lab what it is.
I do want to be careful to say that where this idea and philosophy came from was actually my own graduate lab, so I’ll give a shout-out to Sean Carroll. It’s interesting that you said sometimes you might have the view that if you’re having too much fun, you’re not taking your science seriously. Sean, my grad advisor, was the most down-to-earth person. He quoted Animal House at lab meetings; he always had his feet up on the desk to think. He was a Howard Hughes investigator; he’s now the vice president for education outreach at Howard Hughes. He’s undeniably very successful and takes his science very seriously. But yet, the atmosphere in the lab was always one of fun and support.
One thing that we did there, that now I do in my own lab, is we celebrate various successes scientifically, as well. So one at the smallest scale is our donut result. When somebody has a significant step forward on a project—something that might make a figure in a paper or something—they bring in donuts, and we all enjoy the donuts and celebrate. And then the larger milestones—like a grant, or a fellowship, or someone’s first first-author paper—those get recognized with champagne. We have a collection of champagne bottles as a visual reflection of the lab’s accomplishments.
I think that having that experience—living in a lab that was fun myself, and wanting that for my own group—helps. And I have to be very, very quick to say that ultimately, it’s the people in my lab who make that a reality. That’s not something you can dictate—to say, “Lab must be fun!”
I think the best I can do is create an environment that allows it and supports it.
Was the lab culture in the Carroll Lab something that attracted you to it? This might be a good time to ask you how you got to graduate school.
TW: Sure. Maybe I’ll back up quite far, which is to say that I was not a kid that grew up chasing bugs or thinking about science.
It was a really good high school teacher that got me hooked on genetics. I was raised by a single mother who didn’t have a college education, so I was just looking forward to going to college and trying to find a way financially to do that.
I didn’t know that grad school existed. The idea that you could get a Ph.D.—again, I didn’t know what that was, or be a scientist as a career—was not at all on my radar. That was so not in my family’s worldview.
So when I got to the University of Michigan and knew that I wanted to study genetics, I had to figure out what that meant. I gradually learned that there may be a way to do this as a career, and then was told, “Well, you need some research experience.”
So, like many undergraduates, I went through all of the webpages of the faculty—of the biology department at the time—and looked for anyone who had the word “genetics” on their page and sent them an email. I got a response from one person. This was a new faculty member, whom I jokingly say probably didn’t know he didn’t have to respond to all those messages. But fortunately for me, he did. And he invited me to come in and learn about what he was doing.
This was a man named Greg Gibson, who’s at Georgia Tech now. He’s still one of my cherished mentors, I would say, to this day.
What he was studying, as he described it, was how cells become different. All the cells in the body have the same DNA, and it’s fascinating to think about how you create different structures. Why is an eye cell an eye cell, and a heart cell a heart cell, and a blood cell a blood cell—when they all have the same DNA?
As I learned about gene regulation, I thought that was really cool. And then one moment in that lab crystallized for me that I wanted to go to grad school.
I was doing the experiment that Greg told me to do, to be blunt. Obviously, with undergraduate students who don’t have a lot of research experience, there’s a lot more guidance in those early projects. So he had asked me to cross flies together with different types of eyes and decide how rough the eye looked on a scale of one to ten.
I was doing that, and keeping all my careful notes, and I was noticing that the eye colors weren’t exactly what I expected them to be. At the same time, in parallel—and maybe this is a good example of research and coursework merging—I was learning about things like dosage compensation in my classes. And I came up with this idea that if the gene I was studying, instead of being on an autosome, was on the X-chromosome—that might explain all the weird eye colors.
I went to Greg, and I said, “You know, I think maybe this could be going on. I’ve been keeping track of eye colors, too, and this is what I see.”
He said, “Trisha, I think that that’s an interesting hypothesis. I think that the people who determined where that gene was are experts in the field, and I don’t think they would make the mistake of putting it on the wrong chromosome.”
And the X-chromosome has such different inheritance patterns. He said, “But if you want to test your idea, this is how you do it.” He showed me how to do a fluorescence in situ hybridization. And I did it. And I was right.
And in the grand scheme of science, it’s not very important. But for me and my career, that ability to observe something that I just noticed myself, come up with a hypothesis to test it, and to have the validation that I could do that was just…I mean, “addicting” is the word that comes to mind. There was nothing else I wanted to do with my future at that point.
And so that was the moment that I knew I wanted to go to graduate school.
Fortunately, having Greg as a mentor—somebody who was in the lab with me, sitting next to me at the microscope, day in and day out, and we would talk about science and all of that—those conversations actually led me to apply to the University of Wisconsin and to work with Sean Carroll. Greg had crossed paths with Sean at a meeting, I found out later, and had mentioned me to him. So Sean was sort of looking out for me.
And within a few days, going back to the genesis of the question you asked about the atmosphere…Yeah, it just felt like home. That’s all I can say. Within a week or so, I knew that that was the right place for me.
It was an environment that was filled with about 20 people who were all very smart, very kind, very funny, who all had different training, and were brought together to work in this interdisciplinary science. It was this environment where, like I said, there was a sense of community, culture, openness, and sharing, with a mix of expertises (I’m not sure that’s a word) that created a combination of freedom and support that was really great for me.
And it seems like it’s almost the ideal science experience, because I can see how going through the process as an undergrad teaches the way that science works. That it’s okay to challenge things that you thought were the case. To ask new questions and to rewrite maybe a new dogma that gets challenged again.
TW: Yeah. I mean, looking back on it, I think that the way Greg handled it, in saying, “I don’t think so, but here’s how you figure it out,” and giving me the freedom and the tools to test that—
I’m not sure everyone would have said that. I think that was really just a pivotal moment for me, which put me on a track to where I am.
There are still moments…Now, I’ve been a professor here at Michigan for 12 years, and I’ve had an opportunity to visit many different places in the world, different institutions, invitations for talks at meetings, and seminars. And there are moments when I look around and think, “How did I get here?”
I visited Harvard, actually, and they put me up in the Harvard Faculty Club, as they do seminar speakers, and I looked at the guest book. It was people like Colin Powell, and it was just one of these moments of…This girl who grew up in a very blue-collar city, raised by a single mother… How am I here?
And it feels normal, because it’s step by step, and day to day, I don’t have those reactions. But every once in a while, when you step back, it’s…I don’t know; I have a hard time putting it into words.
It makes sense, because the day-to-day can sometimes be overwhelming. And then one day, you find yourself with a major accomplishment. And sometimes it’s just easy to focus on all the little things that went wrong, than just to look back and say, “Oh, wait. I am here today.” And that’s why it’s so important to celebrate accomplishments with donuts.
TW: I think the nice thing about the donut result is that each person decides what’s a donut result for them. I don’t decide. It’s not my judgment. It’s not anybody else in the lab deciding when you’ve accomplished enough to earn donuts.
Sometimes it’s something that objectively maybe doesn’t advance the project that much, but has been technically so challenging. The cloning you beat your head against the wall about for nine months, and it finally works. Or our first transgenic flies, or things like that.
I think it’s just a way to celebrate the short-term successes in a way that is independent of anyone else’s assessment. There’s not a reviewer saying, “No, you can’t have donuts for that.” It’s your own sense of accomplishment.
So what was it like to be in the Carroll Lab? What did you do there, and how did that make you grow even more as a scientist?
TW: I think some of his unique qualities that have made him as successful as he is, and that I hope I have learned some of, are a clarity of thought and communication. The ability to synthesize information. The ability to see through the forest of possible experiments to find the one tree or the one approach that is actually going to answer the question. And then to put all your energies into that one thing.
I think that, combined with being down to earth and not really having much of a hierarchy in the lab. Everyone’s individual opinions and viewpoints were valued, whether you were an undergraduate researcher or a senior postdoc in the group, there was respect for everyone’s thoughts and ideas. To some degree, the freedom that he allowed—that there wasn’t a lot of handholding.
To be blunt, that wasn’t the best fit for everyone. There were a number of graduate students who came and ultimately decided to leave the lab. For me, personally, there was that freedom and independence that I was allowed to do something that maybe he didn’t even know I was doing. Sometimes it worked great, and other times, maybe it didn’t! And that was okay. The lab and the atmosphere could support that.
Your project was on fruit flies.
TW: Yes. Actually, going back to that first question that Greg asked me: “How do different cell types become different?”
Over the course of my career, that’s expanded to: “How do individuals of the same species become different, and how do different species become different?” All those levels.
And again, that geneticist core in me says, “What’s the genetic basis of that?”
The answer to the cell type question comes down to gene regulation. Each gene has what I describe as something like a dimmer switch that will control your lights. It can be on, off, or on to different degrees. And that’s true for every individual cell. So the combination of cells that turn on a gene, and how much of that gene they produce, are largely what gives a cell its properties. And changes in the switches underlie differences between individuals of the same species and between species.
As a graduate student, I chose pigmentation in Drosophila as a case study to study that.
Pigmentation is one of the most variable traits in most plant and animal species, and one of the advantages that allows is: Number one, it’s not usually essential for life. So you can manipulate it without hurting the organism. You can still raise them in the lab. And there’s a lot of natural variation for it, so you can study the genetic mechanisms underlying it.
What I learned was that, actually, it’s often different due to changes in gene regulation. I’ve phrased it here as going in looking at gene regulation, but really that was what came out of the genetic analysis.
So with all of these positive experiences in academia, was your aspiration to become a professor? Or did you consider different kinds of naturalist careers?
TW: Definitely not the naturalist piece. I joke with my husband, who ended up being a high school biology teacher for a while and now is an academic advisor here. He was also a biology undergraduate major here at Michigan with me, and he took all of the “ology” courses, if you will.
And if we go on a walk, he’s the one who can identify a tree, and what type of frog it was that croaked. And I joke that I’m just lucky if I can say that’s a grass, or a bush, or a bird—that’s got wings. Well it’s not always a bird, but…
But I can tell you about how that flower was patterned in its meristem as it grew.
TW: That’s right. And I think the geneticist at the core is what drives me.
Pretty much from the time I decided I wanted to go to graduate school, being a professor was really the only thing I was focused on. And I’m not sure that’s…Well, that is what it is. That was my reality. That was what I wanted to do.
So was your postdoc still in pigmentation?
TW: No. For my postdoc, I had taken the advice to go and do something different, which I remember when thinking about postdocs was really super stressful. I felt like I was being told two things: The first was that you should go learn something new as a postdoc. And the other reality was that what you do as a postdoc is what you’ll do in your lab for the rest of your life for the next 20 years or something.
It felt really hard for me to figure out how to choose something that I know I’m going to like to do when I haven’t done it. Like, explicitly, I haven’t done it. And that’s why I have to consider it. With the hindsight I have now, I would say that was way too much pressure and not true. That’s not the way it works.
But I decided to go and work with a guy named Andy Clark at Cornell. I started out on a project that was part of a larger collaboration he was involved in, looking at human genetic sequence data. There’s nothing on my CV that would ever reflect this. I spent probably a good six to eight months learning to program. At the time, it was a Perl programming book—learning to work with the command line and getting the skills to handle large datasets.
One day, I was at a seminar, and the talk was about—I don’t even remember. Something with mouse genetics. And something that he said about RNAi [RNA interference] triggered a thought for a project idea I’d had in graduate school.
In graduate school, I considered doing this experiment where you could cross two species together and use RNAi—which is RNA interference—to knock down one allele or the other. My thinking was that you could sort of march across the genome and find genes that had changed between the two species in this way.
I never did the experiment. I don’t think it’s doable. But what it made me think about was the allele specificity. What I realized in that moment during that seminar was that, if you cross two strains together and make these hybrids…
I mentioned the gene expression being controlled by switches. There’s really two components to that: One—maybe we should take the analogy further—would be the switch on the wall. And the other would be the hand that needs to turn the switch. So the switch on the wall would be the cis-factors and the hand would be the trans-factors. The switches get inherited with the gene.
In hybrids, you can look at the RNAs that come from one allele or the other. If there’s a sequence difference between them, you can figure out which actual molecule came from which copy of the gene. If those two switches are not working the same, you can get different amounts of RNA coming from each of the alleles. If you had a way to measure that, you could directly test for cis-regulatory differences.
When a gene changes expression, where in the genome are the changes that cause the change in expression? Are they in the switches—the cis-regulatory sequences—or the things controlling those switches?
As a graduate student, answering that question for one gene took me three years of a lot of work.
And in the second half of the seminar, I realized that if we had a way to just track which transcripts came from which allele, we could do this quickly and easily.
And in Andy Clark’s lab, he had a tool called a pyrosequencer that was used for genotyping DNA. I realized that we could adapt it to look at RNA levels and the relative expression of the two alleles.
So you were working on something completely different.
Learning how to code.
In front of a computer, away from your fruit flies. And then you went to a seminar. Maybe you might’ve never gone that day. Sometimes you have to; sometimes you go because you can’t do any more coding. And then, as you’re listening, something that’s not related to your research triggered a thought that you had a few years back, and…
TW: …changed the course of what I was doing, yeah. Within that second half of that talk, I remember the whole idea forming.
That sounds like a donut moment! Not for data, but for ideas.
TW: Yeah, the person sitting next to me at the time was a fellow lab member—Brian Lozaro—and I was like, “Brian! I think if we did this, we could do that…” And he’s like, “Yeah, I think that’ll work…”
And I remember running upstairs to the lab, and Andy was there—my postdoc advisor—and Andy’s pretty quiet, and I was pretty charged. So I was like, “Andy I think, and we could use the pyrosequencer, and we could measure this, and we could sort out cis and trans differences, and we could do this for lots of genes, and it would happen quick, and—”
And I remember him going, “Yeah, I guess you can try that…”
And I would be very careful to say here that both of those labs—Andy’s and Sean’s—allowed me freedom, because they were well funded. They were large enough, established enough, that they could let people in the lab take risks without really compromising the stability of the lab as a whole.
So with the green light, I did this. It worked out; it ended up being published in Nature. Now this approach is being used by lots of people in different fields, and it definitely changed the focus of my postdoc. It became one of the first things I used in my own lab, to get it up and running. And it was inspired in part by my experience in Sean’s lab of taking a project idea wherever it leads.
We’ve adopted a new model system with yeast—new to us, I should say. It’s a classic genetic model system. But what adopting that system has done is allow us to systematically study the effects of new mutations, which are changes in DNA that underlie all variation, and look at how these new mutations affect gene expression. Which is, again, not only important for genetic variation and evolution, but also diseases like cancer, which are purely driven by new mutations, many of which affect gene expression. So I view that part of our current work as basic biology: How do mutations affect gene expression?
Although we often frame it as: How does this create raw material for evolutionary change? We compare the effects of these new mutations to the effects of variation in natural populations. That allows us to tease out what contribution selection has had versus mutation, which is a fundamental question in evolutionary biology.
So one thing that is cool to me, as I listen to you tell your story, is that you’re really in love with genetics. Throughout your career, when you weren’t really using it as much as you wanted, you found a way to do it. And you were an undergrad at Michigan. To go back and be the person that’s teaching genetics instead of taking genetics, and what your love for that subject meant, and how that drove you to change it…
TW: Yeah, absolutely. As you say—correctly—genetics is really what drew me in to science in general. It’s what drew me through my Ph.D. It’s still at the core of everything I do in my research program.
So I was really excited to teach genetics when I came here, which is not the reaction that most people have. At the time, I think they really needed to find somebody to teach genetics. That may have factored into my hiring, I would suppose. But it was my first year. It was the first time I had taught, so I had not had much teaching experience.
I will credit being married to a high school teacher. We had a lot of biology teaching magazines lying around the house that the societies put out, and I could bounce ideas off of him—and I did, for ideas for the class.
At first, it was a little surreal. As you say, I was an undergraduate—I took this exact class in the same room, and now I’m standing up there teaching it, about seven or eight years later. It was very surreal.
I was co-teaching the class with Steve Clark, who was very generous in sharing all of his materials, which formed the beginning of all my lectures. The first time through a class, I think you take all the help and support that you can get, and take advantage of previous efforts. So that was also a little surreal—from being a student in Steve’s class to now teaching with him.
The course pack of problems that we had at the time that we gave to the students was the same course pack of problems I had as a student. So in teaching that class, I had some of my own memories of what it was like to be a student in that class, and that helped me to shape a little bit more how we taught it. And I would say one example of that is including a lot more problem solving into the lecture itself. Modeling some of the thinking that goes behind how you know which formula to use, or which information is important or not important in a problem.
By stopping and asking them to work on a problem before I worked thru the solution—giving them time to sort of think through it—helped me, helped them, and seemed to be one example of one of the changes I made to the course. And I should say very carefully that those course changes we made in genetics were in collaboration with Gyorgyi Csankovszki, who inspired a lot of it.
You said when you were in Greg’s lab that part of you identifying the pattern of inheritance was because of the coursework. Not quite as great as being in the lab doing an experiment, but with that many kids, that’s the next best thing. It’s kind of similar to trying to put together the applied versus the lecture materials. So what about trying to engage that many students? I liken it to a gladiator amphitheater, where you’re at the bottom and there’s 400 people listening to you talk.
TW: Yeah, so I’ve refined my approach to that over the years. I’m not somebody who I think is naturally outgoing, but I’ve come to terms with my role in the classroom.
One of the moments that I dislike the most in that large—I think gladiator amphitheater is a great description—is those first few minutes of class. Students come in, and their mind is on other things, and they’re talking with their friends about what they did last weekend, or they’re shuffling through notes or something, and then you need to get 400+ students to be quiet and focused and ready to think about genetics.
One of the tools that I’ve adopted for doing that is short, one- to two-minute video clips. These might be something from the local news media, or something more professionally produced by the HHMI [Howard Hughes Medical Institute], or a silly YouTube video about the science of the day. Hopefully it’s engaging and interesting material. It’s also a very clear sign that class is about to start, and it gives me a way to connect the more basic principles to something that’s more real-world applied.
The more I can get from them, the better job I can do teaching them. So I definitely view teaching in general as an experiment. Every time I try something new. So I need to collect data and feedback and then refine it and try it again the next year.
The first time I taught genetics, I did something that my husband—again, who was a high school teacher at the time—described as masochistic. I decided that I wanted to know from students, for virtually every topic and every lecture, what was working and what wasn’t. So I wrote this completely anonymous survey asking, “What the hardest thing was to understand today? What was the most interesting? How was the time spent on these various topics?” The first time I taught, there were 300 students.
Wow. I learned what I was not doing right, quickly.
It was not fun, I have to say, to get a lot of negativity twice a week, when at the time, I was putting 30 hours into developing one lecture.
As a junior professor trying to start your lab…
TW: My first year. It was painful.
The truth is that the reason I put a lot of time and energy into my teaching, and tried to refine it, and found things that worked, is because I wanted to do a good job. So I started with that, and I did what I thought was a good job. I solicited the feedback that made it clear that some of that was not working. After I got past the pain, I found ways to be more constructive and more effective as a teacher. So a lot of my investment and time and energy was to avoid my own pain of going through that.
Each semester, each lecture, I continued soliciting feedback to those surveys for the first two or maybe three years. After a while, the response rate went down, and the comments I got were pretty positive. That’s how I knew—maybe we’re okay. Maybe I have a strategy that’s working.
Return to the audio for How to Science Episode 1, with scientist Trisha Wittkopp.