Understanding genomic ecosystems
New group leader joins the MPIMG
Zachary Smith received his B.S. in Biology from M.I.T. in 2008 and later worked with Alexander Meissner at Harvard. He obtained his PhD in 2019 and became an Assistant Pofessor in Yale in September 2020. He will establish his lab at the MPIMG in December. We talked with him about how growing up next to the ocean shaped his view on genetic phenomena, how he plans to use modern technologies to make connections between different fields, and why, to him, science is a humbling endevaour.

Zack, you are joining us from Yale University, where you worked on embryonic and fetal development. What will be the focus of your lab at the MPIMG?
Our lab has always been really curious about the concept of “epigenetic regulation,” which broadly refers to changes in phenotype that don’t require changes in sequence-specific information. To me these concepts are best studied in the context of developing embryos. We work really hard to develop and apply new technologies to look at embryo development with as high a resolution as possible, be it at the level of single cells or genes, and to then connect those observations to the “whole” of the organism.
Your earliest publications already deal with epigenetic modifications and early development. What got you interested in this field, and what fascinates you about it that you stuck with it?
I grew up right next to the ocean in a place with lots of different ecosystems, salt marches and tidal flats, and for some reason living and working there inspired an appreciation for the environment as a driver and shaper of living things. Given that point of view, the concept of epigenetics has always felt more like “genomic ecology” – epigenetic modifications and regulators seem to act like organisms that interact and interpret genetic information to drive distinct outcomes, they flock or swim or school around distinct loci to create local ecosystems, compete with one another to change those ecosystems, and sometimes swing past their normal functions to create “toxic” disease states. The intuitions developed from early training as a naturalist seem to lend themselves to my sense of purpose within the field.
What do you think are the big open questions in the field?
I don’t think there are any solved questions, honestly. As scientists we’re very much driven to reduce our findings to simple rules that we can articulate and memorize, but as we’ve collected more data, we’re mostly just realizing how over-fixated we’ve become on that methodology. To me, the nice thing about some of our approaches is that they allow us to approach really foundational concepts in developmental biology with an open mind, and lets us follow the resulting data in an unbiased fashion towards what’s actually going on.
What do you hope to achieve in the next ten years?
I think that’s a very tricky question as we don’t really think of our work as approaching some clean “now we can rest” kind of answer. I think that the 20th century ended up creating a lot of very impressive but diverse subfields –biochemistry, genetics, evolutionary biology, developmental biology, etc. In contrast, the 21st century really has been about creating and applying new technologies that allow us to study and explore these concepts with unprecedented precision and resolution. To me, the ten-year plan is to see how well we can use these tools to begin unifying all of the different subfields.
For example, we have a reasonable understanding of what lots of epigenetic regulators look like in terms of their structure and how they function biochemically, but how we take those principles and connect them to their actual biological function has proven really challenging, particularly within the context of the developing embryo.
When our work is going well, we’re seeing phenomena that allow us to make connections between these different disciplines – for example, how epigenetic regulators act in ancient versus evolutionarily new cell types, and how those behaviors might reflect changes to their biochemistry or interactions. Our goal is to make those connections.
What do you enjoy most about being a scientist/doing science?
Science is very humbling, to me anyway – it’s one of very few professions where, if you do it properly, you’re directing questions to some seemingly simple aspect of nature about how it works. Most times you don’t get an answer you understand, but there are occasional, often brief, moments where suddenly you feel you’ve made some new connection with an organism as it lives on earth. It’s a privilege to be able to do that, as well as to try and train younger scientists to develop their own intuition and appreciation for how life works.
What kind of qualities are you looking for in potential members of your lab?
I’ve been very fortunate to recruit really diverse students, each with their own passions and points of view, and find it somewhat humbling to take on the responsibility of training and positioning them towards their future goals. Really, I just ask that they take the opportunity to do science seriously and to see the fun and freedom in trying to ask hard questions. It’s unfair to ask for anything more than that.
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