Anna Greka, MD, PhD
Associate Professor at Harvard Medical School; Associate Physician in the Renal Division in the Department of Medicine at Brigham and Women’s Hospital; Founding Director of Kidney-NExT at Brigham and Women’s Hospital and Harvard Medical School; Institute Member and Director of the Broad Kidney Disease Initiative at the Broad Institute of MIT and Harvard
Can you tell us more about your lab’s interests?
My lab is focused on general cell biological questions at the most fundamental level. In my graduate school days, I worked on ion channels and the signaling pathways that they mediate in hippocampal neurons. When I started my lab, we initially continued on that arc of discovery, but in a different organ, the kidney, because we became particularly interested in functionally different ion channels and how they might interact to regulate the cytoskeleton in the kidney filter. It turned out that two ion channels in particular were involved in important processes, as also supported by human genetic mutations. We, therefore, uncovered fundamental mechanisms about the critical process of kidney filtration in specialized cells called podocytes. These are fascinating cells, because, like neurons, podocytes are terminally differentiated and it turns out that calcium signaling is critical for their regulation and survival. We ultimately solved the puzzle and found that the ion channel TRPC5 is responsible for injury-driving mechanisms in podocytes. As a consequence of all of this basic science work, TRPC5 inhibitors were developed for the treatment of kidney diseases, and remarkably, they are now in Phase 2 trials in the clinic!
This scientific trajectory reinforced in me the idea that understanding fundamental mechanisms can ultimately lead to therapeutic insights. Since then, my lab became increasingly interested in basic cell biological questions, and so in more recent studies, we identified connections between BRAF signaling and lipid peroxidation, which is new and exciting work. We also used single-cell genomics to define the reproducibility and faithfulness of human iPSC-derived organoids. Finally, we became interested in human mutations in the glycoprotein mucin 1 and how they affect the kidney. Solving this decades-old scientific puzzle led us to a completely unexpected discovery about protein quality control for secretory and membrane proteins that is potentially generalizable across many different cell types and tissue, and may have implications for as much as 30% of the entire human proteome.
Overall, our scientific journey so far has been fascinating. We are completely driven by science, and follow it wherever it takes us!
Such an interesting path! Can you talk to us more about this transition from studying neuronal physiology of hippocampus cells to kidney physiology?
It goes back to the idea of following the science without being afraid to go to unfamiliar places. I credit David Clapham, my PhD mentor, for teaching me this lesson, to focus on mechanisms and pathways no matter where they are and whatever cell type or tissue. Of course, to some extent, it is scary to go into unfamiliar fields, but it’s also thrilling and incredibly rewarding! Actually, if you look at the careers of scientists who we all admire, the pioneers, the people who have made really significant contributions to our scientific knowledge, they are often scientists who took learnings from one area and applied them to another area in a way that people looking at a field more narrowly could not see. As is often the case, when someone comes from outside, they begin to ask questions in ways that lead to new insights.
From a translational perspective, many significant contributions have changed your field over the past years – what are you most excited about?
In my view, the fundamental principle, also based on what I said earlier, is to do the science and be led by the scientific, mechanistic work to potential clues about therapeutic strategies. So the goal is not to go after a specific strategy but rather let the science lead us to what makes the most sense therapeutically. I think the word translational is being used now in so many different ways that I don’t know at this point what it means to different people. To me, the way to really get to actual therapeutic strategies that might work for patients really comes from taking a deep dive into the underlying cellular mechanisms. I’m excited about the contributions that have come out of our work for kidney disease because treatments for these diseases have been lacking for many decades. Also, it has been tremendously rewarding to follow up on our recent findings related to a fundamental biological process that we have uncovered called cargo quality control, and to see how this knowledge can be harnessed for therapeutic insights, not only for kidney disease, but far beyond that, in a whole host of different tissues including the brain, and the eye, where we are learning that our work may one day make a difference for certain forms of blindness. I am recognizing that we are probably years away from being able to really fulfill this promise, but extremely excited about the potential. I always say this, if you had interviewed me two years ago, I would have said this is the most exciting year in my lab, and now I am going to say this is the most exciting year in my lab — maybe it’s good to have this kind of excitement all the time, but I really truly do think that we are in a very exciting moment right now!
You have been actively involved with many outreach initiatives that also include hosting Greek students in your lab. Can you tell us more about them?
This program arose organically a few years ago when my lab was still very young. I came up with the idea of hosting students from Greece, which at the time was plunged into a terrible economic crisis that has been going on for a long time now, resulting in fewer opportunities for students to learn what real research is about. When I was growing up in Greece this was not something that I had the opportunity to experience either, so I thought that it would be a tremendous idea to be able to bring one or two students every summer to the lab, and just really do nothing other than just let them experience what medical research is about, here in my lab at Harvard and the Broad Institute. So I reached out to my high school in Thessaloniki, as a small gesture of paying it forward if you will since this was a school where I thought I had gained and learned so much from. Since then, basically every year (except this year because of the pandemic), I host in my lab one or two students who are interested in learning more about scientific research. From what I have been hearing from all these tremendously talented and bright young people, their time in my lab was an eye-opening experience. I am also incredibly proud of all of them, because, through their talents and their hard work, each and every one of these students got scholarships to attend US universities, like Harvard, Columbia, Duke, Brown, Hopkins, Northwestern, and Princeton! I hope after the pandemic is over, we will continue this program. Needless to say, it has been really enriching for my lab as well. The Greek program, together with another program hosting high school students who are under-represented minorities has brought a great feeling of renewal to our lab every summer: just seeing science through the eyes of these young people brings a new level of passion and enthusiasm for our research!
Interviewed by Chara Koutsioumpa, PhD candidate, Harvard Medical School