Rare disease research inspired by patient care, with Anna Greka

In recognition of Rare Disease Day, Anna Greka, an institute member at the Broad Institute, an associate physician at Brigham and Women’s Hospital, and an assistant professor at Harvard Medical School, shares part of her journey as a physician-scientist studying rare kidney diseases and highlights the deep impacts of patient involvement in research.

Susanna M. Hamilton, Broad Communications
Credit: Susanna M. Hamilton, Broad Communications


Hi. I’m Lisa Girard, director of scientific communication for the Broad Institute, and this is BioLogic, the logic behind the science: conversations with Broad researchers exploring what they do and why they do it.

This podcast episode is produced as part of our recognition of Rare Disease Day, an international event held on the last day of February to raise awareness about the impacts of rare diseases. In the United States, diseases are considered “rare” when they affect fewer than 200,000 people. There are estimated to be about seven thousand rare diseases affecting roughly one in ten Americans.

Anna GrekaAnna Greka

Broad Institute member Anna Greka joins me for this episode of BioLogic. Anna is also an associate physician at Brigham and Women’s Hospital and an assistant professor at Harvard Medical School. The research in her lab focuses on understanding the fundamental mechanisms of calcium ion channels, and applying that knowledge to developing therapies for rare kidney diseases. I asked Anna to tell us a little bit about how rare diseases can affect patients and families, and how genomic tools have advanced these fields.


There are estimated that there are probably more than seven or eight thousand rare diseases out there. We do not have a diagnosis or the ability to diagnose many of them. And so, with the advent of genomics, we can certainly begin the work of identifying, at the very least, the causal variants or mutations that lead to these diseases, many of which also affect children — even very young children.

But we can’t stop there, and that’s, I think, one of the wonderful things about being at the Broad, that we can harness this incredible collaborative environment here to partner with genomics superstars who can help with the identification of the causal variants and provide a diagnosis for these patients with rare diseases — and their families, of course. I mean, imagining a parent with a child with rare disease, and not even knowing what the cause of it is, is of course devastating.

But now, using our interdisciplinary approaches here at the Broad to go beyond that, go beyond the ability to simply find the causal variant, into actually thinking about ways that we can then treat these diseases, having a good understanding of the molecular underpinnings of the disease offered by genomics. And so I think what we are now poised to do — of course, it will take a lot of hard work and will not be possible simultaneously for all those thousands of rare disease, but one at a time as we move forward, and together collectively with colleagues around the world — we can go after, you know, understanding the gene that is involved, trying to understand the mechanisms and the cellular pathways and functions that may be affected by the mutation, and ultimately developing the assays and the programs that would be necessary for these functions and perturbations to be reversed in a way that we can restore health. And so, ultimately, treatment based on our molecular understanding and definition of these diseases.


That treatment doesn’t always have to come from a new drug, either. Sometimes, there’s already one on the market that could help treat a rare disease, once clinicians and researchers understand the mechanisms behind it.

Diving into the lab for a moment, Anna shared one experience finding a new purpose for a previously developed compound. In 2013, she and her colleagues discovered that an existing arthritis drug might also help patients with a rare kidney disease called focal segmental glomerulosclerosis, or FSGS.


The Mundel laboratory was a laboratory next to mine when I started out my lab. So, I was a very junior faculty at the time, just barely getting started. And in interacting with Peter Mundel, the PI of the lab, he was able to share some data that, at the time, was at the basically fundamental science level. They had done incredible work, in cells as well as in mice, to demonstrate that this particular target called CD80 was actually relevant in a very surprising way in podocytes.

Peter is a basic scientist, and so as we were conversing about these data, I asked him if he was aware of the fact that there was a treatment that had been approved by the FDA for this target for a different disease, for rheumatoid arthritis. And he said he was aware of it but didn’t know how to harness that. And I said “Well, from my clinical experience,” which is how this came to bear, “I know that there are patients with FSGS who have no treatment options, and so all we are really doing is basically waiting for their kidneys to fail,” which is a horrible thing. Many young patients find themselves in that predicament. And I wondered whether this FDA-approved, and therefore safe, treatment that is used for a different disease might be possibly repurposed based on the evidence that Peter’s lab had generated.

And so ultimately this is what led into both me giving this drug to a patient in my clinic, but also other colleagues doing the same. This is a rare disease, so it's hard to find patients, but we ultimately were able to get a total of five patients who had an incredible response to this drug. And actually my clinic patient, who I still follow, is five years out and only taking this drug, she’s 30 years old and doing incredibly well on this treatment.

And as a follow-up to this study, I’m now involved in a 25-center study across the United States to do a randomized control trial to really test the efficacy of this approach for patients with FSGS. The study’s ongoing so we don’t have the results yet but it's incredible that one can go from a study that was published in 2013 to now, just a few years later, being able to have an ongoing randomized control trial as another treatment option for these patients who otherwise have very few, if any, treatment options.


This type of connection between the lab and the clinic is a hallmark of Anna’s career as a physician-scientist. And when it comes to rare diseases, patients are often more than just observers. Anna touched on some of the effects that she sees when her patients have the opportunity to contribute their information and samples for research.


The ability of patients to engage directly, I think, is incredibly empowering to patients. Having interacted over the past many years with patients and their families in the rare disease space, I know what an incredibly engaged community they are. And I think that patients, as I see patients coming into my clinic — patients, who come from all over the country to see me for the particular rare diseases that I specialize in, tell me that they are absolutely interested in being engaged, in offering help in the form of offering their information, of being engaged in registries where you can go back again and again and collect information that will allow us to characterize the natural history of these rare diseases, which is very important. And ultimately to be counted in for contributing their samples for genomics, contributing their samples for other types of analyses, for example, for things like us developing appropriate biomarkers to be able to see whether we can impact their disease in a positive way if we come up with a particular treatment.

I think the patients just really — and their families, their parents in many cases — wish to be actively involved and updated. And what I often hear is the last thing they want is to participate in something and never hear again, but rather that they would like to be bugged, again and again, about the progresses that we’ve made, the difficulties that we find along the way, I think patients are very attuned to the fact that science is not a smooth way forward and that there will be hurdles and there will be setbacks. But they are, I think far and above all the people that I have interacted with, are very interested in being part of that journey alongside the scientists. Not to influence the journey, but simply to participate and understand as much as they can.

The other thing about direct-to-patient involvement and approach in various projects, as we have already done here at the Broad, is what one patient advocate recently told me, which is democratizing in some ways the process of involving patients into what academic centers are doing, because there are many patients out there who do not live, as we have the opportunity here in Boston, who do not live close to a major medical center. And yet, not only do they suffer from a rare disease, but they’re also quite isolated because it’s hard for them to find other patients with the same disease, or to find specialists who are able to tell them more about their disease and to ultimately have hope that someone out there is working on this.

So the ability to use the internet — anyone who can have access to the internet can have access to this information that we would be able to provide, and engage with patients in the direct-to-patient approach. And so as, you know, as I sometimes say, if you have a mailbox and internet, you can be part of all of this. This is incredibly democratizing. It allows all patients to participate, to be involved, to have knowledge and the power of knowledge — and the power of hope, therefore, that something can come that can impact their disease. So we are very excited to do this for kidney disease, and it’s ongoing for many other rare diseases, and I think it can be incredibly powerful.


This participation doesn’t just benefit the patients, of course.


I think that it can also be incredibly inspirational for the scientists working in the lab. Many people who work in my lab who are not clinicians — I have people who are also clinically involved as fellows in the lab, but there’s also scientists who do not have the interaction with patients directly — who tell me how incredibly inspiring it is to them to have the opportunity to either meet with patients or see the degree of patient involvement by patients signing up on websites and registries and becoming involved. And I think that being able to offer the opportunity for them to be our partners in this, it can be empowering for both sides.


Anna chose this mix of lab and clinical duties early in her career, following the example set by her physician-scientist parents. She first came to the United States to study biology, and then completed an MD/PhD program at Harvard Medical School and MIT. I’ll let her tell you more about her journey and her inspirations.


You know, I grew up primarily in Greece, I went to an American high school, so I always had this idea that I would come to the States. And one of the reasons for that was that I admired the people here who were physician-scientists and who were able to combine their roles as doctors who are inspired by taking care of a particular subset of patients, in many cases, and then bring what they were learning from those patients back into the laboratory so that the one can inform the other, you know. We have often used these terms, you know, but from the bedside to the bench and from the bench back to the bedside. And that seemed to be to me incredibly powerful.

So I think that I always knew that I wanted to have this career that is inspired by patient care, recognizing that that would have to be a small percentage of my time if I really wanted to pursue science, which is really at the heart of what I always wanted to do.

And, you know, as I think of my lab and my research activities, we definitely do a lot of classical basic science work, but my team is always thinking about ways that that fundamental understanding, the single cell assays that we pursue in the lab, how they may influence our understanding of disease pathways. And so that’s always in the back of our minds as we even do the most fundamental scientific experiments in the lab. All of this work is likely to be of great benefit to humankind at large, as we, again, understand the molecular definitions of particular rare diseases, and we then harness that information for developing therapies for more prevalent diseases.

And I like that approach to science. And I think it’s been fruitful so far, and very rewarding, and again I feel lucky and blessed to have the opportunity to have this kind of career, at the interface of medicine and science.


You can read more about Anna’s work, and other research on rare diseases, at broadinstitute.org. You can also find other episodes of BioLogic at broadinstitute.org, as well as through SoundCloud, iTunes, Pocket Casts, and other podcast distributors. For the Broad, I’m Lisa Girard. Thanks for listening.