Q&A with Dr. Salla Keskitalo: Challenges and Opportunities in Studying Rare and Ultra-rare Autoimmune Diseases

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Dr. Salla Keskitalo is a Senior Research Scientist at the University of Helsinki and a recent winner of NanoString’s Autoimmunity Grant Program. She made time to speak with us about her work studying rare and ultra-rare autoimmune diseases.

NS: Tell us about your research background.

SK: My scientific path has not been traditional. I started as a biochemist then moved to cancer research, studying vascular endothelial growth factors. This work led me to pursue another degree in pharmaceutical sciences. Through the course of my studies and research I was recruited to a team studying Alzheimer’s disease—a completely different field. While working with the new Alzheimer’s team, I joined another group at the Swiss Federal Institute of Technology in Zurich where we studied the organization of cellular networks using mass spectrometry. After completing my studies at ETH Zurich, I moved back to Finland to combine my experience in cancer research with my recent proteomics work.

NS: Who in your field do you most admire and why?

SK: It’s hard to name just one person from the whole field of great researchers. From the perspective of the Finnish population; however, one name stands out—Leena Peltonen-Palotie, the mother of Finnish disease genetics. She identified fifteen genes involved in Finnish heritage disease. We take her work for granted now but at the time it was groundbreaking.

NS: In your grant proposal, you mentioned that Finland has a high incidence of primary autoimmunodeficiency diseases. What are the reasons for this?

SK: Basically, Finland is a very isolated population. So, there is partly the Scandinavian genetic influence and inheritance but there is also a very special thing called Finnish heritage disease. This is characterized by the geographical isolation of populations within Finland. Only after bicycles became more common did we see a mixing of the Finnish population. You can still see that there are areas in Finland where immunodeficiencies are more common and with a common genetic background. I’m sure there will be future studies to see if this genetic background is coming from one individual, isolated, original site. At the moment that’s what the data point to.

NS: What led you to apply for the NanoString Autoimmunity Grant Program?

SK: Our research focuses on proteomics and we have a lot of collaborations around the Helsinki area. The physicians in this area are also active in research. We were contacted by some physician scientists in the hospital who had some interesting patients displaying severe symptoms. There were only a few of these patients but they wanted to learn more about the underlying biology. We designed an initial set of fifty target genes to characterize these patients. When we saw the grant program we thought it would be an excellent opportunity because most of these patients have an unknown autoimmune disorder. The opportunity to look at not just fifty genes but 800 genes with the NanoString panel was wonderful!

NS: What are the goals of your project specific to the grant?

SK: The ultimate goal is to try to better understand the biology of these individuals and their mutations. Many of these patients have very severe symptoms but there isn’t a standard clinical care protocol and no one knows how to treat them.  We want to link the mutation to the biology and the symptoms and then develop a targeted, personalized medical treatment plan.

NS: How do you plan to use the data from the NanoString Autoimmunity Discovery Consortium Panel?

SK: We have the patients’ genomic data, data from RNA sequencing, as well as the protein-protein interaction data. The Autoimmunity Discovery Consortium Panel will give us a broader understanding of what is happening at the RNA level and help build a model of what is happening in the cell, kind of like a multi-level atlas.

NS: How did you first learn about NanoString?

SK: We had a manuscript with a lot of great data ready to submit to a high impact journal. We sent it to our collaborators for a final review and they suggested we try a NanoString panel. When we looked at the technology we realized it was a perfect fit. Luckily, our institute already had the instrument, trained personnel, and experience running samples. We had everything set for the panel and analysis!

NS: Some articles suggest that early exposure to pathogens in childhood help set up the immune system to mitigate autoimmune diseases later in life. Is this something you have observed in relation to your research into autoimmune disorders in the Finnish population?

SK: In Finland, we talk about this from the perspective of the allergy hypothesis—exposure to farms as a child, playing in the dirt and such, basically does help protect you from allergies later on. I think it’s completely true.

NS: NanoString has recently come out with a gene expression panel for chimeric antigen receptor T cells (CAR-T). Have you seen anyone developing adoptive cell therapies to combat autoimmunity?

SK: I’m not aware of any work at this time. In consultation with one of our clinical physicians we discussed that designing the target for this in the context of autoimmunity would be very challenging. Basically, what we have in primary autoimmune disease is that all of the cells in the body are affected. If you try to combat that I think you would inadvertently mess up the whole system. Maybe in time this will be possible but at the moment this technology is better suited for cancer cells and somatic mutations within a specific tissue.

NS: Personalized medicine will be critical to patient care for some of these rare diseases. Do you know how the autoimmunity field is benefitting from the development of targeted immunotherapies in the oncology field?

SK: We do need to do personalized medical care for these patients and this follows the models developed by the cancer field. We do have replacement therapies for CTLA-4 and we can inhibit different signaling pathways. I would say we are definitely taking advantage of what immuno-oncology has developed. Our greatest challenge in autoimmune disease research remains the complexity of these diseases that affect so many different cell types and signaling pathways. Additionally, the mutations that give rise to the disease are present in all cells of the body.

NS: What do you think are the most pressing challenges facing researchers in autoimmunity?

SK: From my perspective, it’s the patient numbers. Basically, we are working with rare and ultra-rare diseases. In Finland, we may have only three cases of one type of autoimmune disease. This means there are fewer funding opportunities. In the case of ultra-rare diseases, we may have only one person in Finland or a total of five patients within Europe. These individuals with very severe but very rare diseases are not of interest to most pharmaceutical companies. And without funding, it’s hard to do anything.

NS: What are the benefits of using the NanoString nCounter over other genomic methods?

SK: Performing NanoString experiments is extremely easy. It’s not time consuming at all and the results are very reliable and reproducible. The most crucial thing for us is that it’s a multiplexed assay for direct quantification of RNA. We don’t have a lot of patient material to waste and need to gather as much information as possible from one experiment. So far, we’ve already been able to identify pathways in these patients that we can now target with existing medications. It has already helped us start treating these individuals.

Click here to learn more about Leena Peltonen-Palotie (1952-2010)

By NanoString
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