The immune system quickly responds to stroke and turns on many different cells and processes to guide the body’s response
Barr TL1, Conley Y, Ding J, Dillman A, Warach S, Singleton A, Matarin M. Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling. Neurology. 2010 Sep 14;75(11):1009-14. doi: 10.1212/WNL.0b013e3181f2b37f.
Barr TL, VanGilder R, Rellick S, Brooks SD, Doll DN, Lucke-Wold AN, Chen D, Denvir J, Warach S, Singleton A, Matarin M. A genomic profile of the immune response to stroke with implications for stroke recovery. Biol Res Nurs. 2015 May;17(3):248-56. doi: 10.1177/1099800414546492. Epub 2014 Aug 14.
This study resulted in two primary publications and created the foundation for my research program and most of the technologies we are working on at Valtari Bio. So I would probably call this my seminal work and one that I am very proud of because it also brought me my PhD!
As a graduate student and practicing nurse I became acutely aware that our ability to quickly and accurately identify and treat stroke and brain injury patients was shockingly poor. Even in a large academic medical center I found that we often missed or downplayed patients who presented with ambiguous symptoms, we didn’t start life-saving treatments on time because of problems figuring out when the patient’s symptoms actually begin and we always gave patients and family members a non-descript overview of what their recovery would look like, rather than making it personal. As an internally driven and motivated person, I found this completely unacceptable.
With the help of my mentors and many conversations with clinicians and patients, our team created this study to ask whether we could identify that a person was having an acute stroke using an unbiased method of monitoring RNA expression in the blood. I was convinced that this approach could work because of seminal studies being published in other laboratories solidifying the method and my goal was to validate the method and create proof of concept for future studies to develop a better diagnostic for stroke. I wanted to find a way to aid clinicians making hard decisions in emergency situations and ultimately improve the patient and family experience. However, the scientific field wasn’t very supportive of the method and at the time of this study development (late 2006) there was only two other laboratories in the world who were trying to do this. I reached out to both of the investigators in those labs and learned a great deal from them in passing conversations and watching their science evolve over the course of the next few years as I implemented my study. We were all at the forefront of something great, we just knew it and had to prove it to the world.
When the study was complete and we were in analysis mode, Andy (one of my mentors) made us re-run the statistics numerous times because he couldn’t believe the results—we had validated the work of the other labs and found some of the same biomarkers in our profile that scientists had been studying for years. Albeit in a completely different patient population and technology platform. This method worked.
Our data discovered the expression of 9 RNA biomarkers in the blood could identify stroke from non-stroke in the first 0-24 hours from stroke symptom onset. We still had a long time to go to make that relevant for clinical care, but it was an absolute first step in the process and one that we have worked to optimize over the past 10 years. The most interesting part of the findings were that we found the expression of immune related genes to be very highly expressed in our stroke patients, suggesting the immune system quickly responds to stroke and that can be seen in the RNA profiles. Some work had been done previously to characterize this immune system response, but not much if anything related to RNA, so this finding was exciting. We followed this up by looking at the changes of expression between 24-48 hours following stroke and found a very different pattern in the blood. In the first 24 hours following stroke the immune system responds by a very general inflammatory response (innate immunity). By 48 hours this changes to a more coordinated respond that starts shaping recovery (adaptive immunity). We can monitor these immune changes in the blood to tell us whether or not a patient is actually having a stroke and when that stroke may have begun. At Valtari Bio, we have worked to find a way to leverage this powerful immune system response to increase the accuracy of acute stroke diagnosis and ultimately hope to use this information to guide patient treatment. Our technologies will undoubtedly lead the way in personalizing stroke care and this critical study set us on this path.
I would like to close this blog post by honoring the life of a beautiful woman I met along this journey. Study implementation for this project was tough; I spent countless hours in the hospital, in the laboratory and running back and forth to make this happen and when I look back at this period in my life it is a bit of a blur. We didn’t have a dedicated research team to collect this type of data, so it was mostly me, our awesome stroke team and my patient’s day after day making this happen. She was a patient, in her early 60’s who came in alone, scared and not doing so well. I approached her for study participation and she smiled and eagerly agreed. I had a hard time getting a blood sample from her, so I had to follow her around the ER, the neuroimaging suite and finally up to her room until I could try again. Over the course of this time, her symptoms progressively got worse. After about 3 hours of waiting with her, I remember looking at the clock and thinking I can’t believe I will have been here for 14 hours in 10 minutes, I just want to go home. I was frustrated and angry. Once things settled down with her, we tried her blood samples again, and after multiple attempts we just couldn’t get anything worthwhile, so she could not be enrolled in our study. I left disappointed. As I was walking to my car that evening I saw a good friend who immediately could see I was frustrated. She took me by the arm, gave me a hug and said, “Taura, you weren’t there to get her enrolled in study; you were just there for her”. These words have stuck with me and when I came back to the hospital the next day, I found out that the patient had progressed to the point of being in a coma and later died. At their core, our research projects are so much more than research projects, they are an opportunity to make a difference in the lives of our patients every day, with the ultimate hope of creating new futures for patients to come. My work is personal and I carry every patient encounter with me when I go into the lab to create new and innovative diagnostic technologies or when I’m speaking to others about my work. This is what drives us at Valtari Bio, and why we are already making a difference.
For additional information check out:
How to improve stroke patient triage, assessment, care and transport: http://www.ems1.com/stroke-care/articles/63248048-How-to-improve-stroke-patient-triage-assessment-care-and-transport/
A Revolution in Stroke Care: http://www.emsworld.com/article/12061567/prehospital-stroke-care
Stroke genomics clinician scientist, Frank sharp: http://www.ucdmc.ucdavis.edu/neurology/faculty/sharp.html
Overview of the Immune System: https://www.niaid.nih.gov/topics/immunesystem/Pages/overview.aspx
The Immune System in stroke: https://www.sciencedaily.com/releases/2016/04/160415081701.htm