By Şanser Güz, Orkun İrsoy, and Naz Beril Akan

Why do many people practice and advocate systems thinking in biomedical sciences? The human body is a system with strong regulatory mechanisms that maintain the steady state of internal physiological conditions, homeostasis. The regulatory mechanisms of various subsystems of the body emerge from the interaction of feedback signals and provide the body with an internal balancing structure against natural disturbances. But what if the disturbances are far from natural, what if they are chronic or repetitive or interfering with the system itself? Such disruptions in those well-regulated homeostatic systems are the possible leverage points where systemic analysis can add a great deal of value.  These valuable insights can range from deepening inferences about the internal causes to providing alternative methods to alleviate the problem.

Hematological dynamics, in particular, is one of the topics well-covered in the field of System Dynamics, not because of its popularity but due to its inherent delay and feedback-rich nature. Unidirectional thinking falls short in providing successful management of such systems, which attracts the system thinkers. Not surprisingly, including ours, 3 out of 4 articles in the special issue of System Dynamics Review on Biomedical Modeling are related to hematological dynamics.

In our recent study, we take on a hematological disorder called chemotherapy-induced neutropenia (CIN). Along with its targets, the malignant tumors, chemotherapy also damages the valuable stem cell stocks in the bone marrow as a “side effect”. So why are stem cells so valuable to begin with? Stem cells are the earliest precursor cells in the blood cell production chain. When their stock is damaged by a strong disturbance such as chemotherapy, it results in a short supply of blood cells which can only be observed after a certain time. Effectively, we are dealing with a physiological high order supply chain residing in the human body. When the chemotherapy hits the production facility, effects are visible at the consumer level (i.e. blood cells in circulation) after several material delays. 

Aforementioned internal homeostatic regulation is strong, however, for a disturbance that is repetitive.  Having delayed effects such as chemotherapy, endogenous mechanisms may prove to be insufficient to address it. Intensive chemotherapy regimens often result in short supply and oscillations in the leading white blood cells of the immune system, the neutrophils, giving rise to chemotherapy-induced neutropenia (CIN). This is a risky condition for a patient having cancer treatment as it leaves the patient with a vulnerable immune system, against even the simplest of infections. Granulocyte-Colony Stimulating Factor (G-CSF) is the supplementary agent used in the treatment of CIN, stimulating neutrophil production from many stages. However, long delays along the blood cell production chain, susceptibility of stem cells to chemotherapy, and mobilizing effect of G-CSF which depletes the neutrophil reservoir, eventually creates multiple trade-offs inhibiting an easy solution.

In our work, “Dynamic trade-offs in granulocyte colony-stimulating factor (G-CSF) administration during chemotherapy”, we modeled the process in the light of available evidence and previous mechanistic models from other domains of research. With this research, we were able to provide insights on which physiological processes are at play in shaping the patient’s response to treatment and which loops are dominant for the prescription of https://www.papsociety.org/xanax-alprazolam-1-mg/ treatment protocols. Even though the base model was built for a standard patient profile, we see this study as an advancement towards personalized treatments of CIN and plan to build on this subject in future research. We imagine a flight simulator that can be calibrated for individual patients that can be used for generating effective personalized treatment protocols. Following this path has the potential to alleviate neutropenia for people under chemotherapy and improve patient care in a personalized manner.

We started studying the management of CIN nearly two years ago as our bachelor’s graduation project topic.  The work evolved continuously during this time period, with its latest output being this journal article. Our group of three worked on this long enough that System Dynamics and chemotherapy-induced neutropenia became one emerged bilateral entity, and it is only half a joke. As we delved deeper into medical literature and System Dynamics simultaneously, we found astonishing similarities in storytelling on both sides. Our task as modelers was to make a necessary language translation between two mediums and to make an adequate implementation of the method at hand. Because of this very similarity, endogenous feedback structures and systems modeling have been well recognized among the people of medicine. Hence, System Dynamics practitioners like us can use this opportunity to direct their work in this domain of research, where the toolset they use has the potential to systemically analyze, give useful returns, and make a positive change.

Want to learn more about Biomedical Modeling?

Join us for a Seminar on the special issue of the System Dynamics Review! 

June 09 @ 11 am NY

 CALL TO ACTION

• Find Modelers…do you envision a similar project? contact the society to be connected to modelers to help you out (have it go to rebecca@systemdynamics.org)
• Join now for free access to the journal