Both biomedical science and computer science have made huge advances in the last three decades so it makes sense that combining these two fields will lead to productive research.
The OSU College of Veterinary Medicine, with funds from the Provost Matching Program, is further enhancing their mission to create an interdisciplinary workforce with the hiring of Stephen Ramsey as a new Assistant Professor in the Department of Biomedical Sciences at CVM.
Recent improvements in the speed and cost of using genome sequencing in biomedical research have provided investigators with a valuable tool to study organisms, but it also creates massive amounts of data that need analysis. That workload is handled by computers, but computers are useless without software. That is where Ramsey comes in; he has the computational skills and computer software design experience needed to marry information technology and biology in a productive way.
Ramsey began his academic career in physics. His Ph.D. dissertation tackled the problem of simulating matter during the earliest moments after the Big Bang. “In those extreme conditions, it’s very hard to solve a Physics problem using pen and paper; you have to use computational methods,” he says. That sparked an interest in high-performance, scientific computing.
How did he get from physics and computers to biomedical science? Serendipity.
Soon after receiving his doctorate, Ramsey’s wife, bioengineer Elain Fu who is also new faculty at OSU, began working in the University of Washington genome center. “This was in the heyday of the human genome project,” he says. “Elain was a graduate student at the genome center and saw the need for someone who could grapple with masses of measurements and their huge mapping challenges.” She suggested Ramsey go talk to the center director and the rest is history. “He brought me into his lab and that is what changed everything. It got me on a life-sciences trajectory.”
Most recently, Ramsey has been working at the Institute for Systems Biology using mice to understand the innate immune system. His focus has been on the role of macrophage — cells that attack foreign substances through destruction and ingestion — in chronic inflammation and coronary artery disease. “I’ve been working with mouse models of arthrosclerosis where we look at large datasets of measurements of macrophage gene expression under different conditions.”
Funded by the NIH, Ramsey’s study focused on how macrophages respond to oxidized LDL, the ‘bad’ cholesterol. “We modeled a chronic exposure situation where, over time, macrophages in the walls of our arteries take up too much oxidized LDL,” he says. He found that this over-exposure can cause cell death and inflammatory responses. “That’s bad because then you get this positive feedback loop that causes inflammation of the vessel wall and is a key part of what drives the pathogenesis of atherosclerosis.”
Ramsey developed a specific set of computer programs to figure out what is controlling the whole process. “There are transcription factors, proteins that bind DNA and regulate gene expression, that are activated and deactivated in response to the macrophage stimulation by oxidized LDL,” he says. His software looks for patterns in these gene expressions and seeks to identify specific factors that are orchestrating the harmful response. “Ultimately we want to take those transcription factors and figure out their specific functions. Then what we try to do is disrupt them in the most realistic model systems that we can.”
In conjunction with the computational tools, Ramsey and his collaborators used a mouse strain that is genetically deficient in a transcription factor called ATF3. They were able to breed that mouse with another mouse strain that is susceptible to atherosclerosis. “Now you have a tool that you can use to study what is the effect of the loss of that transcription factor in the context of atherosclerosis,” he says. They were able to show that there was a significant increase in the disease burden in the animals that were deficient in ATF3.
Ramsey notes that the tools he used to model atherosclerosis could also be used in animal models of other health issues like tuberculosis infection or response to vaccination, and is looking forward to collaborating with other researchers at CVM. “These methods could also be used in the study of canine diseases,” he says. “I’d like to see if computational approaches might be helpful to some of the clinical studies in the CVM.”
Ramsey has a 70% appointment with CVM and 30% with the Department of Electrical Engineering and Computer Science. He is part of an initiative by the Provost’s office to hire interdisciplinary scientists who will work with the OSU Center for Genome Research and Biocomputing (CGRB). “I credit Provost Randhawa and CGRB Director Brett Tyler with having the foresight to see that this is an area where investment now will pay big dividends in the future by stimulating collaborations and new methodology, translating quantitative sciences and math into life sciences and systems biology.”
