By John McLaughlin
Thomas Gregor is a biophysicist and Professor at Princeton University. His Laboratory for the Physics of Life uses both Drosophila melanogaster and Dictyostelium discoideum as model systems to understand developmental processes from a physical perspective.
Could you briefly describe your educational path from undergraduate to faculty member at Princeton?
TG: As an undergraduate, I studied physics in Geneva, and then moved into theoretical physics and math. I came to Princeton, initially for a theoretical physics PhD; I switched during my time here to theoretical biophysics and then realized that it makes sense to combine this with experiments. I ended up doing a PhD between three complementary disciplines. My main advisor was Bill Bialek, a theoretical physicist. My other two were David Tank, an experimental neuroscientist, and Eric Wieschaus, a fly geneticist. So I had both experiment and theory, from a biological and a physical side. I then went to Tokyo for a brief post-doc, during which I continued in that interface. But I changed model organisms: I switched from a multicellular, embryonic system to looking at populations of single cells [the social amoeba Dictyostelium discoideum]. As a physicist you’re not married to model organisms. When I came back to start my lab at Princeton in 2009, I kept both the fly and the amoeba systems.
What is the overall goal of your lab’s research program?
TG: Basically, to find physical principles behind biological phenomena. How can we come up with a larger, principled understanding that goes beyond the molecular details of any one particular system? I mostly look at genetic networks and try to understand their global properties.
Do you think the approaches of biologists and physicists are very different, and if so are they complementary?
TG: I’m driven by the physical aspects of things, but I’m also realistic enough to see what can now be done in biological systems, in terms of data collection and what we can test. To find the overlap between them is kind of an art, and I think that’s where I’m trying to come in.
Do you have any scientific role models who have shaped how you approach science?
TG: The three that I mentioned: Bialek influenced me in the types of questions that speak to me; Tank had a very thorough experimental approach that taught me how to make real, physics-style measurements; and Wieschaus brought a lot of enthusiasm and knowledge of the system.
Your lab has been studying developmental reproducibility and precision, in the patterning of the fly Drosophila melanogaster. In a 2014 paper1, you showed that levels of the anterior determinant bicoid mRNA vary by only ~9% between different embryos. This is a very similar value to the ~10% variation in Bicoid protein levels between embryos, which you demonstrated several years earlier2. So it seems that this reproducibility occurs even at the mRNA level.
TG: Before going into this, the general thought in the field is that things were very noisy initially, and as the developmental path goes along it becomes more refined and things become more precise. This paper basically asked whether the precision is inherited from the mother, or the embryo needs to acquire it. Because the fluctuations in mRNA, from the mother, completely mimic the fluctuations in protein that the zygote expresses, that told us that the mother lays the groundwork, and passes on a very reproducible pattern. So there’s no necessity for a mechanism that reduces fluctuations from the mRNA to the protein level.
Continuing on the theme of precision: in a separate paper from the same year3, your lab showed that the wing structure among different adult flies is identical to within less than a single cell width. Did you have any prior expectations going into this study, and did the results surprise you?
TG: Before looking at the wing, I had kind of made up my mind. I had first seen single cell precision in patterning of gene expression boundaries in the embryo. But I also knew that it’s always better to make a measurement first, and it seems that things are much more precise and reproducible in biology than we think, given the idea of “sloppiness” that we have.
Do you think that a high level of reproducibility is a general feature of development, or varies widely among different types of species?
TG: It’s a philosophical question in a way, because I haven’t looked. I think what we found in the embryo is not special to the fly; specific mechanisms for getting there might be unique to the fly. For instance, we have also shown in a recent paper from 2013 that transcription is just as noisy in flies as it is in bacteria, hugely noisy. So, physical mechanisms like temporal and spatial averaging seem enough to reduce the high ubiquitous noise that transcription has to the very fine, reproducible patterns that you see in the fly. The specific mechanisms that reduce noise will be very different from species to species, but I think overall the fact that development is precise and reproducible is something we may one day be able to call a principle.
If you could make any changes to scientific institutions, such as the current funding system, journal peer review, etc. what would they be?
TG: One thing that might be nice is if we didn’t have to fund graduate students for the first five years of their career; it would be nice to have more streamlined training grants, not only for U.S. but also international graduate students. And so, graduate students wouldn’t have to worry. They should be free to choose a school based on their scientific interests.
For peer review in journals, the problem is the sheer volume of output is becoming so high. One way to keep a peer review system, is either to pay the reviewers money, or to put everything on the bioRxiv [bio archive is a pre-print server for the life sciences] and let some other means determine how to evaluate a paper. I don’t read papers from looking at the top journals’ table of contents every week, I read them because I see people talk about it on Twitter, or my colleagues tell me I should look at that paper, or because I hear about the work in a talk and decide to see what else the guy is doing.
A lot of people are advocating the new metrics – citations, citation rates, H-index – which are so dependent on the particular field and not necessarily a good measure of impact. In 100 years, are we going to look more at those papers than the ones that currently get very few citations? We don’t know. I don’t think the solution is out there yet.
Do you have any advice for young scientists – current PhD students or post-doctoral fellows – for being successful in science?
TG: My advice would be to focus on one very impactful finding. If it’s very thorough and good science, it will be seen. Also, nothing comes from nothing. You need to put in the hours if you want to get a job in academia. And I think that’s one of the ways to measure a good scientist, because knowledge in experimental science comes from new, good data.
What are some future goals of your lab’s research?
TG: We’ve been looking at the genetic network in the fly embryo, trying to understand properties of that network. Medium term, we want to incorporate a slightly different angle, which is looking at the link between transcriptional regulation and the 3D architecture of the genome. In the living embryo, we want to look at how individual pieces of DNA interact, and how that influences transcription and eventually patterning. In the longer term, I don’t know yet; I just got tenure, so I need to sit back. Everything is open. That is what’s nice about being a physicist; you’re not married to your biological past so much.
In your opinion, what are the most exciting developments happening in biology right now, whether in your own field or elsewhere?
TG: It’s definitely the fact that so many different disciplines have stormed into biology, making it a very multidisciplinary science. I think it makes the life sciences a very vibrant, communal enterprise. Hopefully the next decades will show the fruits of those interactions.
This question is asked very often: How do you balance your lab and family life?
TG: When you start thinking about having a family in science, things become much more complicated. Since I’ve had children, my workload went down a lot. My wife is also a scientist, and for her it’s much harder because she’s not yet tenured. As much as people look at the CV and see how many high-profile papers you have, they should also look at it and see your family and life situation. And for women in science, despite all the efforts that have been made, I don’t think we’re there yet.
- Petkova, MD et al. Maternal origins of developmental reproducibility. Current Biology. 2014. 24(11).
- Gregor, T et al. Probing the limits to positional information. Cell. 2007. 130(1).
- Abouchar, L et al. Fly wing vein patterns have spatial reproducibility of a single cell. J R Soc Interface. 2014. 11(97).