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John M. Higgins, MD
Associate Professor of Systems Biology, Harvard Medical SchoolAssistant Pathologist, Massachusetts General Hospital
Center for Systems BiologyMassachusetts General HospitalRichard B. Simches Research Center185 Cambridge StreetRoom 5.222Boston, MA 02114Phone: 617-643-6129Fax: 617-643-6133Email: email@example.com
I study the dynamics of human pathophysiologic processes by developing mathematical descriptions of complex human disease phenotypes and how they change over time. The research combines medical insight, dynamical systems theory, and experiments utilizing microfluidics, video processing, flow cytometry, simulation, and large-scale analysis of medical databases in pursuit of two goals: (1) advancing fundamental understanding of human pathophysiologic process and their dynamics, and (2) improving patient diagnosis, monitoring, and treatment.
Pathophysiology may be described at the molecular, cellular, tissue and organismal levels and may show clinically significant variation over time scales ranging from less than a second to more than a decade. Using clinical laboratory data and experiments with clinical specimens, we can develop detailed descriptions of pathophysiologic states in terms of clinically relevant and measurable quantities. We can then propose mathematical models describing the interrelationships between these state variables and how those relationships change when perturbed by disease. Models must be consistent with both existing basic research and clinical experience, and once validated will enable the estimation of dynamic parameters. Personalized estimates of parameters often quantify unmeasurable aspects of biological processes, revealing new insight into pathophysiology and providing opportunities for novel approaches to diagnosis and patient monitoring. Recent work has focused on population dynamics of cell characteristics in anemia and inflammatory states, blood flow in sickle cell disease, and immunologic response to transfusion.
I am developing a mathematical model of vaso-occlusion in sickle cell disease by combining theory from fluid mechanics with experiments using patient samples flowing in microfluidic devices under controlled conditions. With collaborators, I have developed a way to stop and start the flow of sickle cell blood in a network of silicone polymer channels by changing only the oxygen concentration. I hope to understand the physical determinants of in vitro vaso-occlusion and to explore their relevance to clinical management and intervention.
I am also developing a probabilistic model of alloimmunization following red blood cell transfusion. By analyzing several large-scale patient databases, my collaborators and I have identified robust patterns of immunologic response which suggest that only a subset of transfusion recipients are at risk of alloimmunization. We hope to determine if these patterns have implications for human immune response in general and to apply any insights to the improvement of blood bank practices.
View a complete list of Dr. Higgins' publications on the Center for Systems Biology website.
Patel HH, Patel HR, Higgins JM. Modulation of red blood cell population dynamics is a fundamental homeostatic response to disease. American Journal of Hematology. 2015; 90(5):422-8. Di Caprio G, Stokes C, Higgins JM, Schonbrun E. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(32):9984-9.
Wood DK, Soriano AO, Mahadevan L, Higgins JM, Bhatia SN. A biophysical marker of severity in sickle cell disease. Science Translational Medicine. 2012; 4(123):123ra26.
Higgins JM & Mahadevan, L. Physiological and pathological population dynamics of circulating human red blood cells. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 20587-20592. [See commentaries in New England Journal of Medicine 2011; 364(4):376-7 and Nature Medicine 2010; 16(12): 1386.] .
Higgins JM and Sloan SR. Stochastic Modeling of human RBC alloimmunization: evidence for a distinct population of immunologic responders. Blood. 2008 ; 15;112(6):2546-53. [See Blood editorial commentary: Blood. 2008; 112(2): 2180-1.].
Massachusetts General Hospital
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