Karolin Luger: Leading Ladies in Epigenetics Research

Karolin Luger Interview

EpiGenie: We know you have a lot going on in your lab, but if you had to pick one or two areas of research that you’re the most excited about, what would they be?

Luger: It’s really hard to answer that question because there’s always something exciting going on. Right now we’re mostly interested in nucleosome and chromatin dynamics. Nucleosomes aren’t these monolithic structures that everybody thought they were. They disassemble and assemble constantly, and we’re looking into the mechanism. Our lab is a bit unusual because we use a lot of structural and biophysical approaches to this problem, and there aren’t that many groups who do that.

The other thing that I find really exciting is we’re branching out into a lot of additional methodologies. We’re starting to do a lot of in vivo work, and to me, a structural biologist, it’s pretty fascinating to actually work with living cells. It’s fun to do research that runs the gamut from looking at atoms in a structure to saying, let’s see what that particular interaction does in a yeast cell or in a whole fly.

EpiGenie: The chromatin field has really exploded in recent years. What do you think has been one of the most interesting findings?

Luger:  Again, there are so many that it’s going to be a very personal answer! When I entered the field in 1989, which is a long time ago, it was a somewhat stagnant time for chromatin. And I actually thought it was super-boring, too. I’d come from enzymology in my graduate work, and histones didn’t do anything. The opinion was that they just sat there and made a nuisance of themselves. I basically wanted to learn crystallography, and chromatin kind of grew on me with time.

I think that the realization that histones are very active participants in regulating a lot of cellular processes was definitely one of the most exciting finds in modern biology. I also think the new tools that have come along are really amazing, such as whole-genome analysis where you can actually look at an entire yeast genome and see precisely where every nucleosome preferentially sits. There’s a lot of information available, and we have to make sense of it. So I think it is a really exciting time.

What I think is really, truly fascinating is that when HATs [histone acetyltransferases] and other enzymes that modify histones were first discovered, we thought it was a very ordered and black-and-white process?certain modifications turn genes on, and certain ones turn them off. Not surprisingly, it’s not nearly as straightforward as we thought. There are polymerases in areas where they have no business being, and there’s heterochromatin marks in areas where there is activity.

EpiGenie: Part of your lab’s research looks at the interaction with and impact of small molecules on chromatin structure. Since EpiGenie covers areas like non-coding RNA and DNA methylation, has your lab investigated the consequences of trans-acting RNA on chromatin and/or the impact of DNA methylation signatures on nucleosome structure or chromatin dynamics?

Luger: We have not looked at transacting RNAs, but I think that’s a really fascinating interconnection. I still haven’t really wrapped my brain around that? it’s a very complicated finding. We do work on methylation, in a roundabout way. We work with chromatin architectural proteins that recognize methylated DNA, and so we started to get into methylation that way. I think in terms of chromatin structure per se, if you just look at the methylated versus the unmethylated state of normal nucleosomes, that’s not going to be very exciting. Many factors will be able to recognize the methyl site in the context of the nucleosome. That’s one of the foci of my lab. We look at the interaction of chromatin architectural proteins on methylated and unmethylated nucleosomes because DNA methylation is still to this date the only true heritable epigenetic modification that we know of. The histone modifications, as far as we know, are not heritable.

EpiGenie: What was it like to be the first author on a truly groundbreaking paper in the chromatin field, your 1997 Nature paper on the structure of the nucleosome?

Luger: I was 34 years old at the time. A lot of my colleagues already had real jobs, and I was still a measly post-doc, and the reason is, it just took soooo long! It took me 8 years of my life to get that structure, and of course there were several of us working on this together—it was very much a team effort. I want to make that clear. To be honest, when it was finally done, I was exhausted, and I was just glad it was over.  There really wasn’t much of a party. But I had stared at it for so long, you know, in various stages. I built the whole thing from scratch, one amino acid and one nucleotide at a time. It is a very large structure, and the data really were borderline for seeing atomic detail, so we were pushing the envelope in every respect. You have to have to have a lot of tenacity and mental strength, and you have to be a glutton for self-punishment. But it was also fun to see the structure grow before my eyes—you look at it and say, ‘Yes, of course, this makes total sense.’ Nature is clever in so many respects.

But about 3 weeks before the structure was published, my post-doc mentor let me present it at a large Cold Spring Harbor symposium meeting, which I was so grateful for. It was a great opportunity. So I just put this slide up there?back then, we still had slides?and there was this collective gasp going through the audience. That was really cool because I’d stared at the structure for so long that I really thought it was no big deal. But for somebody who’d never seen it before, I guess it was kind of nice to look at. And so that kind of almost made it worthwhile. Not quite, but? [laughs]

EpiGenie: In many regards, women in science have come a long way, but women PIs are still very much a minority. What do you think could be done to decrease the attrition rate of women from the graduate to PI level?

Luger: I’m on a lot of hiring committees, and we really try very hard to get women to apply. And they do apply, and we get some excellent women. I really don’t see much of a bias against women anymore, if they apply. I hear other stories from colleagues, though. I think the problem is to get more qualified women interested in this career track in the first place. So, you know, we can’t just blame only the system.  I think part of the problem is that some of these women don’t have enough female role models. They still think the PI is this white, middle-aged, male nerd, and they don’t want to fit into that mold. I think that’s going to change. As more women become prominent scientists, more women will get encouraged, saying, well, this is really the career for me.

Unlike what a lot of people say, I think a scientific career is very compatible with having a family because you are pretty flexible. I can work wherever and whenever because most of the stuff I do is writing nowadays, and so I can do that at home at night, or whenever.

I think a lot of the problem is that the PI life is portrayed as this dog-eat-dog kind of world with a lot of pressure, and you need to very tough and aggressive to be successful. A lot of women are smart that way?they say, ‘Well, you know, I don’t need this. Why would I do this to myself?’ We need to change that perception because it’s simply not true. So I think it’s maybe the image of this career track that has to be changed and that will then encourage more women to come in. Because this job is like any other job where you have a leading position. You have to stand up for yourself, but you don’t have to fight all the time. In fact, a lot of people really don’t like to scoop their colleagues or be scooped by them, and a lot of the younger-generation scientists go a long way to avoid it.  There is a lot of science to go around. I wish the same were true about funding. The shortness of funding puts a bit of a damper on the warm and fuzzy feelings, I believe.  Nevertheless, a lot of us are very collegial—we are all trying to make a living and advance science.  I have experienced myself the incredible generosity of more senior scientists (women and men) in advancing my career by providing advice, invitations to speak at meetings, letters of support, ideas . . . I am trying to pass that on.

I think what happens often is that women get short-changed once they are in the assistant professor position because they don’t say no. They’re on a lot of committees. They’re being very nice and collegial in collaborations. They don’t stand up and say, ‘Hey, you know, I should be last author on that paper,’ but they say, “Yeah, whatever,’ and move on. Then they’re perceived to be less successful in the sciences than men, and so they perpetuate that stereotype. I’m speaking in stereotypes, but I find that to be true more often than not, actually. In that way, we do get short-changed. Also, there are a lot of committees that desperately need women, and so you can’t complain about the system and then not be on the committees. It is a bit of a catch-22.  I think as more of us are getting into these leading positions, it’s going to get easier, hopefully, but I’m pretty sure it’s not something that you can force. I think the gender disparity at the PI level is going to even out?I don’t think it’ll ever be 50/50, but I think it’s going to be a lot better.

And remember, I’m from Europe, and when I come here, I don’t even see that much of a problem, to be honest, because Europe is just a little bit further behind in the timescale.  There’s probably a little bit more discrimination, subversive discrimination, going on there, but I have seen that change very fast.

Also, I think a lot of it is just cultural. Women often follow their husbands, it can be as simple as that, and that can kill it right there, you know? You don’t do that post-doc that you really could do, but you go somewhere where your husband has a wonderful opportunity, and you do something else. Then it’s really hard to get back on track. I don’t want this to come across wrong, but I think we shouldn’t only blame the system. I think we have ourselves to blame, also.

EpiGenie: What’s it like having a young daughter and being a researcher?

Luger: I’m actually very deliberately taking my daughter to some scientific meetings, especially when she was an infant. Some organizations have this bizarre language in the conference announcements ?‘children are not allowed on the conference site.’ There was a meeting, and I brought my daughter with me openly, and I just didn’t care. Then the second day, there were two more babies, and the third day, more?they were all hiding them! And I thought that was so sad. So I’m doing this to provoke, to a certain extent, because I think we can reconcile these things, and also because I hate to be separated from my family. Nobody was disturbed by it, and if they are, then just come talk to me. But I have certainly gotten ‘stingier’ with my time, especially travel. I do less of it in general, and more red-eye flights so that I have fewer days on the road.

So you can reconcile it, but there’s something to be said for having a job and then going home and being done, which is not ever the case for scientists. So I think there are two sides to the coin, and it’s a decision every woman has to make. But you shouldn’t just say, ‘Oh, you know, I want a child, so I cannot be a scientist.’

EpiGenie: What advice do you have for women scientists who are trying to balance the demands of a research career with family life?

Luger: Well, there’s really no good time or bad time to have children. I think it’s harder for women than men just because of the hormones, the biology. I think the biology tells us if we have a child, you stay home with your child. At least that was the case with me, you know. It was very hard for me, and I have a relatively good situation. I didn’t have to leave her with strangers, and that was nice.

But you know, don’t think it to death, and you cannot be perfect at everything?the earlier you realize that, the better. And you have to learn how to say no. You have to prioritize. You have not as much time in the lab as you used to before having children, and so you have to lose the micromanagement. You have to not sweat the small stuff, and just do what you do best, which is keeping the ship running and not obsessing over which Eppendorf tubes to buy because you can hire a lab manager to do that. There’s no question that you just have to give up control to a certain extent, but that may be a good thing for the grad students and post-docs.

I think the hardest part is that when you’re in the lab, especially in an operation as large as mine, you wear about 17 different hats on any given day. So you write papers, you deal with editors, you talk to a student whose cat has died and another who is obsessing about an A– in an exam, and you try to recruit faculty. There are 5 million things going on. Then you go home, and you wear the hat of a parent, which is about seven hats, really. So by the end of the day, you’re exhausted.

You have to lose the guilt. If you’re taking a day off because you feel you need to spend time with your daughter, you can’t feel guilty about not being in the lab, and vice versa. But I think the most important thing for women in faculty positions, especially if you have a family, is to not be afraid to say no. When you don’t have tenure, and your chair asks you to do certain things, our temptation is always to be accommodating. That’s just the female thing?yeah, we’ll do it, and we’ll work harder. So they catch on to that pretty fast, who to ask who never says no. Try saying no a couple of times, in a nice way, to some selected things and still be a good colleague, and that will make things easier.