Assistant Professor of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics Britt Adamson was named a 2020 Searle Scholar for her project entitled “Mapping the Processes of Genome Editing in Human Cells.”
Established in 1980, the Searle Scholars Program “makes grants to selected universities and research centers to support the independent research of exceptional young faculty in the biomedical sciences and chemistry.”
Adamson is one of 15 recipients of the honor in 2020. Her lab will receive $300,000 in funding over three years as part of the award.
Adamson’s work focuses on genome editing and biological mapping in order to understand how somatic cells (cells not involved in reproduction) respond to DNA damage and mutations. Adamson’s lab hopes to achieve a more holistic view of how DNA damage affects cells as a whole, as opposed to past approaches that focused on individualized mechanisms of cell responses.
Adamson spoke with The Daily Princetonian to discuss her award and future research plans.
This interview has been lightly edited for clarity and concision.
The Daily Princetonian: To start off, how would you describe your research interests to someone without a background in biology?
Britt Adamson: I suppose I study many things, but all of the projects in my lab and with collaborators share a common theme: We are trying to understand how the products of human genes control the inner workings and inner mechanics of cells — the basic systems that make cells live and grow.
Recent advances have produced some spectacular tools for doing this work. These tools allow us to turn specific genes off, down, or up and then measure the effects of those perturbations on cells.
We can ask, for example: How well do cells grow after we turn off one particular gene? If the answer is worse or better, we have learned something about the role of that gene. Excitingly, we can then scale up this type of analysis and ask: Out of all human genes, which ones are important for a particular process, like growth? This gives us insight into how basic cellular processes work.
DP: Based on your page in the Department of Molecular Biology, you have a variety of research interests. You were named a Searle Scholar in relation to your work with genome editing — can you tell us more about that, and what were your goals regarding this effort?
BA: Genome editing is a technology for changing the DNA sequence of living cells. Right now, we can “edit genes” by using designer enzymes [specialized proteins] to surgically break DNA at specific spots and, depending on how we break the DNA, coax cells into installing mutations at those locations.
But how does this work? Well, what we know is that after damage, cells use their own DNA repair mechanisms to fix the broken DNA and, in doing so, sometimes introduce mutations. These mutations are the “edits” of genome editing, and of course, once you understand this, you can see that “genome editing” is, at least conventionally, more or less a passive process: We break the DNA, and then we wait for the cell to install sequence changes.
Now, fundamentally, this “cut-and-wait” process of editing is something that researchers in the field have known how to do for decades, albeit with increasingly accessible and versatile enzymes, but from an engineering perspective, this process has problems. One big problem is that cells have many ways to fix DNA, and because each of these mechanisms can install different mutations or none at all, when we try to edit a population of cells, we often end up with a bunch of cells carrying different edits or no edits.
Our work is aimed at understanding how cells make each of these changes, with the larger goal of discovering new ways to improve genome editing. Of course, this is a very active area of research, but what makes our approach unique is that by using some of the genetics tools I’ve already described, we are attempting to study the system as a whole, or as much of a whole as we can, rather than one mechanism at a time. We think this will give us new insight.
DP: Getting more into your work with genome editing, what were some of the challenges you faced in designing the project, and how have you worked to overcome them?
BA: The wonderful thing about the Searle Scholar Award is that it is structured as a research grant, which means that the program is giving money to the lab for work we haven’t finished yet — they are helping to fund our future studies. Of course, this means that there are probably some big challenges lurking ahead that we haven’t even anticipated.
That said, one of the challenges that we are currently facing and will continue to face is that it is incredibly hard to design an assay [a test] — well, a tractable assay, anyway — that allows us to study all editing outcomes at once. What we want to do is measure how perturbation of many genes affects the frequencies of every edit made during our experiments.
In our current strategy, we do the best we can, and we probably capture most outcomes, but because of technical limitations, we know that we don’t observe 100 percent of them. For example, we miss very large deletions. As we adapt our platform and as technologies improve, we will get better at this, but interestingly, we will still have to address the even more basic question of how to know when we are done —when to say, “Okay, this data set contains all possible outcomes.”
DP: What got you interested in genomics and the study of stress responses in cells?
BA: It wasn’t one thing or one experience. As an undergrad, I was premed. Naïvely, I thought that because I enjoyed studying biology, the only logical thing to do would be to go to medical school. But once I started working in a research lab, everything changed.
From there, I followed a path of working on “the most interesting next thing” through both graduate school and a postdoc, picking up genomics and cell biology as I went. Then one day, I woke up at Princeton — at least, that is how it feels in retrospect.
Ultimately, I think everyone’s career ends up being the summation of many experiences and influences, some small and some big, some that we choose and some that we would rather not have endured. So far, I have been extremely lucky, and at each step in my career, I’ve been able to choose a direction based on what I thought would be the most interesting next thing.
DP: We can agree that this is a particularly interesting time for biomedical researchers. As a researcher that focuses on cell stress responses and genomes, what role, if any, do you think that genome editing could play in our general understanding of disease?
BA: Genome editing has already had an enormous impact on medical research. As an example, disease modeling is perhaps one of the most straightforward: Many diseases have known genetic components — differences in our DNA that contribute to disease processes, causing or predisposing individuals to — or protecting them from — certain health conditions.
By using genome editing to model these changes in cells, or better yet, to model organisms, we can learn about those conditions. Notably, another area to pay attention to with regard to genome editing will be therapeutic applications. Several clinical trials are now ongoing for treating genetic disorders.
DP: Looking more into your research, what are you interested in studying in the future, after being named a Searle Scholar?
BA: I am really excited about the general idea that we can use genetic technologies to study complex cellular processes as coherent systems, not just piecemeal as many individual parts. We’ll be focused on genome editing for a while, but we are also beginning to use similar tools to understand how cells respond to less targeted forms of damage.
DP: Is there anything else you would like to add, either regarding your research or something you’d like University students to hear during this time?
BA: I think perhaps the best sentiment to end with is the same advice I keep wanting to hear myself right now: Hang in there!