Please describe the research questions of your lab.
My research program is primarily focused on understanding the immune mechanisms contributing to the development and severity of Acute Respiratory Distress Syndrome (ARDS). We incorporate genetic approaches to understand inter-individual variation in immune responses towards a goal of developing precision approaches for patients. For example, we have focused on genetic variation in Toll-like receptor 1 (TLR1) which has been associated with the development of respiratory failure in patients with sepsis. We have found that genetic variants in TLR1 account for almost 35% of the population variance in response to TLR1 agonists. We have also used molecular and cellular techniques to understand how these TLR1 genetic variants modify T cell responses.
What genetics/genomics techniques do you utilize in your lab?
We have experience with genome-wide association studies. In collaboration, we also use gene expression data and/or protein biomarkers in combination with genomics to draw causal inference. Another “omics” technology we are using is mass cytometry to study single cell proteomics.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
It’s hard to pick any one technique or instrument in the lab. Recently we have been gaining novel insights with mass cytometry. The high dimensionality of the data requires a different analytical approach than standard flow cytometry. The more unbiased analysis has allowed for detection of novel cell populations/proteins that change in patients with ARDS that we may not have detected otherwise.
At what point in your life did you decide you wanted to be a scientist/physician?
I developed a strong interest in science in high school at first with a particular affinity for chemistry. Over time, my scientific career has slowly transitioned with small steps along the way. I was a biochemistry major in college and then really enjoyed working in immunology labs during my training. Ultimately, medicine made sense for me because I appreciated the ability to join science with clinically relevant questions. I really enjoy being in the “translational” space between bench and bedside.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
I think the work in Cystic Fibrosis has really been impressive. Identifying the various genetic mutations and now having targeted therapies based on genotype is inspiring. The work in complex diseases and/or syndromes is not there yet but I think the role of genetics in distilling heterogeneity will provide for more targeted therapies in the future for other clinical populations.
Briefly describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
I really enjoyed working on the genome-wide association study to understand Toll-like receptor 1 (TLR1) responses (PMID:23151486). We knew that variants in TLR1 were associated with important clinical outcomes in sepsis like mortality and respiratory failure using a candidate gene approach. We wanted to take a more unbiased approach to identify variants that account for differences in TLR1 responses. To do this, we performed a GWAS where we stimulated whole blood 360 healthy subjects with a TLR1 agonist to identify genetic loci associated with cytokine responses. After all of the important quality control, the first analysis showed a significant association right at the TLR1 gene locus with a p value of 1x10-27. For those who have performed or read GWAS studies, it is very rare to get such a significant hit in a study this size. This has allowed us to really use this going forward to perform mechanistic studies in humans based on haplotype of TLR1.
What is your favorite aspect of ATS?
ATS has been a great place to meet with collaborators and to develop new connections. As a junior investigator, the AII assembly and the Section on Genetics and Genomics have been a way to meet people within the larger community. The section meeting at ATS for SGG attracts many people working on diverse aspects of pulmonary and critical care medicine and also has had many interesting invited speakers. The ATS also provides grant opportunities for early stage investigators. I received an ATS Foundation unrestricted grant in pulmonary medicine that allowed me to pursue a project in sarcoidosis.
How could your research assist scientists and clinicians in other assemblies at ATS?
Particularly in genetics and genomics, collaborative science across disciplines is a key ingredient. We are enrolling critically ill patients at Harborview Medical Center to study genetic factors and biomarkers associated with development of organ failure. We also continue to pursue mechanistic studies that connect genetic variation to immunologic phenotypes. These are likely to have implications not just for critical care but across disciplines. Ideas for future collaboration are always welcome.
Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?
I would certainly be open to collaboration with GG or non-GG scientists. We don’t at present have any openings in the laboratory but I would be happy to talk to trainees or post-docs about future opportunities.
Carmen Mikacenic (CMikacenic@medicine.washington.edu)
