Synthetic Mammalian Circuitry for Graded Treatment of COVID-19 Cytokine Storms

Cytokine Storm GIF

Why COVID-19 cytokine storms?

The COVID-19 pandemic, caused by SARS- CoV-2, has afflicted millions of people, with one prominent feature of its lethality being an overactive immune response, or cytokine storm. We aimed to design a synthetic mammalian network to alleviate cytokine storms using powerful, switchlike endoribonucleases. By sensing changes in concentration of two biomarkers indicative of cytokine storms, our system will respond with graded output of a cytokine-sequestering single-chain variable antibody fragment in order to differentially treat patients with varying levels of disease severity. We computationally constructed a cellular and plasma-level immune response to COVID-19 through an ODE-based SimBiology model to inform the design of our sensor specifications, network topology, and tailored treatment response. This engineered system, once experimentally verified in vitro, can be used to further our current understanding of COVID-19 immunopathology, with a particular focus on IL-1.

What is a cytokine storm?

COVID-19 has affected millions in the world by storm–that is, a cytokine storm. Cytokines are a family of secreted small proteins used in cell-cell signaling; of this family, uncontrolled levels and signalling of interferons (IFNs), interleukins (ILs), chemokines, and tumor-necrosis-factors (TNFs), result in an immune system overreaction often worsening patient outcome–this is a cytokine storm, the phenomena linked to lethality in COVID-19 (Ragab et al.).

Why a computational model?

Much of COVID-19 pathology is still being unraveled; remotely, through the power of computational experimentation, we saw the opportunity to contribute with minimal risk. We thus studied literature pointing to unique biomarker patterns found in COVID-19 cytokine storms (CCSs), as well as underlying mechanisms of other overactive immune disorders, such as rheumatoid arthritis and psoriasis. Based on statistical analyses by Yang et al., IP-10 and MCP-3, two cytokines secreted by the IFN-γ cascade, when present together in elevated concentrations, served as promising biomarkers for severe CCSs.

Why did we see synthetic biology as a means to combat the COVID-19 cytokine storm?

Quantifiable levels of cytokines and other immune signatures vary greatly between patients’ unique health profiles. Here, we realized a critical need: mitigation of the inflammatory response, catered to the individual patient’s immune response to SARS-CoV-2 infection. This challenge was one we believed synthetically engineered mammalian cells were well suited for: their ability to continually monitor state, implement dosage-feedback regulation, and utilize native biological parts pose many advantages over traditional pharmaceuticals.

Synthetic biology requires the engineering of nonlinear biology into predictable, digital behaviors; our goal was to employ effective digital molecular mechanisms to construct an analog, or “graded”, response which is tailorable to individual patients using already available synthetic biology-designed tools. Such an approach would ensure maintenance of systemic immune homeostasis.


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