Dr. Demet Araç, currently an associate professor of Biochemistry and Molecular Biology and of Neuroscience Institute at the University of Chicago, has been conducting research on cell communication, specifically on the cell-surface receptors that mediate intercellular adhesion. With an inspiring career as a structural biologist, she has been the forefront of ground-breaking work in understanding regulation of adhesion GPCRs and advancing their engineering to better understand this family of proteins.
Dr. Araç is visiting us on March 24th. Prior to her visit, we had the opportunity to have a zoom meeting to talk about her research, her intellectual journey and personal reflections on life within and beyond science.
What originally inspired you to pursue a career in science? Were there other career paths you considered along the way?
I’ve actually always been interested in science, as far as I can remember. Thinking of my time at middle school, I was already interested in science but watching documentaries about animals or the big ideas of biology, chemistry and physics, really sparked my curiosity. Then, when I entered science high school, everything just deepened and expanded on my interests.
You have conducted research at many institutions including in Turkey as well as at UT Southwestern, Stanford and the University of Chicago. How have these different scientific environments shaped your approach to research?
As you can probably guess, science in Turkey is not the best. Coming from Turkey and seeing many different places allowed me to have a broader perspective on how people, scientists, and the world can do, or cannot do, science as they wish. So, basically, this shapes my perspective. Here in the US, or other advanced countries, we have everything we need to do science. Especially in most big institutions. It is important to appreciate what you have and make use of it. Lots of other people in the world want to be in our institutions and do science here. We should appreciate it and use the resources and the opportunities we have to the best possible level. That is what I have learned.
Is there any specific experiment or discovery that you are very proud of?
I think the discovery of the GAIN domain is the one I’m most proud of. Adhesion GPCRs were very understudied, and people often avoided working on that field. While there was research on them in the past and scientists figured out a lot of things, the field was at a bottleneck when I first started working on them. Nobody really suspected this discovery. Nobody even looked for a domain; everybody was convinced that there was no domain in the location where the GAIN domain is.
I realized this through bioinformatics analysis. Although I was trained as a structural biologist, when something doesn’t make sense, I like going and learning other things to figure it out instead of rushing. Through bioinformatics analysis, I realized there were secondary structure elements there that didn’t look unstructured like everybody else was sayingSo, I went against the whole literature, and finally, we identified this domain. It turned out that it exists in all adhesion GPCRs, and it is really important for their activation. I’m proud of this because it probably would have been done 10 to 15 years later if I had not looked into this. Nobody was looking at it, so that’s the one.
Is there an example of a setback and how you learned from it?
I guess being in Turkey was a setback. I tried to come to where better science is being done. One other setback has been the pandemic. When the pandemic hit, it was a big setback for me. I guess everybody had a setback at that time for multiple reasons. I have two kids and they were at home for a year. Because there was no childcare, that was a setback. And now, the setback is kind of related to the NIH. What’s happening at the NIH now is becoming a setback for everybody. I guess I didn’t have too much of a big personal setback but whatever setback everybody had is the same. What I learned is to keep going. We should keep going and do our best.
What are the most exciting ongoing projects in the lab?
Adhesion GPCRs are very interesting and exciting molecules. My lab studies cellular communication, with a large focus on adhesion GPCRs. Specifically, we want to understand how they work, their mechanisms, and how they can be modulated and engineered. We also want to develop tools to pharmacologically target them because adhesion GPCRs are really important for many diseases.
But beyond adhesion GPCRs, my lab’s focus is also on understanding how cellular communication happens through adhesion. Other than adhesion GPCRs, we are looking at other cell-surface receptors like teneurins. Basically, the transition from cellular adhesion to cellular communication is very important for the rise of multicellular organisms from unicellular ones. So, we also want to investigate the rise of multicellularity.
This is very basic science: understanding how these receptors evolved early on to switch cells from taking another cell to active communication. Cellular communication is important throughout the body, from the brain to the heart. These are the important and exciting projects we are working on.
What are your interests or hobbies outside of science?
Outside of science, I used to read a lot of books. Now, my main hobbies are music, movies, and books. Although recently I don’t have much time, I still really enjoy listening to music. I also like making bread at home with a bread maker. Specifically, I make sourdough bread, it’s more like Italian sourdough than traditional Turkish bread. I don’t know how to make authentic Turkish bread, but I do know how to make sourdough.
What are the big questions you hope to answer in next decade?
My current focus is on the application side. G protein-coupled receptors are major targets in pharmaceutical development; over 35% of current drugs target conventional GPCRs. However, adhesion GPCRs remain largely untargeted. My goal is to conduct basic science that raises our understanding to a level where pharmaceutical companies can effectively target them.
Currently, the pharmaceutical companies have explored adhesion GPCRs somewhat but have largely abandoned them because they are difficult to work with. There are still so many unknowns. So, they are waiting for the academic scientists, which is where I have spent the last 10 to 15 years. Historically, there were no downstream G-protein signaling assays, it was unclear how they coupled to G proteins, and pharmacological tools like agonists and antagonists were missing. Furthermore, no full-length structures existed.
My lab has focused on developing these tools: we have established assays, identified which G proteins they couple to, and developed antibodies and small molecules targeting them. We have significantly advanced the field, though much more is needed. Recently, we determined the first and only true ‘holoreceptor’ structure, capturing both the extracellular and transmembrane regions simultaneously. While a few other partial structures exist in the literature, ours provides the necessary orientation and combination of these regions.
Looking ahead to the next decade, we also aim to identify the natural ligands that activate adhesion GPCRs. Currently, there are only a few known proteins that bind them, but we want to find the ligands for the 33 different types to understand how they are involved in cellular and physiological events.
As I mentioned, we also want to study multicellularity. We plan to look at early organisms like Choanoflagellates as model systems. We know that families like latrophilins and teneurins are present in these early organisms, though not all adhesion GPCRs are. We want to study this evolutionary aspect of multicellularity and communication. Well, those are the things we want to do in the next decade.
What is your advice for young scientists starting their career?
I think the timing is not the best for starting a career in the US. But, as I said, the US is not the worst place at all. There are still amazing opportunities. So, don’t be discouraged by any news. Just go for what is in your heart and what you want to do.
Also, be prepared for failure. Failing a few times happens to everybody, so don’t ever get discouraged. Keep working hard. That’s my advice to new trainees. I should also say that my lab’s success totally depends on my trainees. It was enabled by my students and my postdocs. They worked with such care for science. They have done all these discoveries and all these great pieces of science that came out from our lab. Basically, it’s not mine but it is their success. And there are still so many resources and so much to do. You should just keep doing what you like.
Links:
@demet_arac