Project Description

The Issue

Sepsis is a life-threatening condition caused by the immune system’s severe response to an infection (WHO, 2023). This dysregulated inflammatory response can cause damage to a patient’s tissues and organs, and ultimately result in death. Individuals with chronic health conditions, over the age of 65, pregnant women, and neonates are at greater risk of contracting sepsis. Approximately 48.9 million sepsis cases were reported and 11 million deaths resulted from sepsis, contributing to 19.7% of deaths worldwide in 2017 (Rudd et al., 2020).

Furthermore, those who survive are often left with chronic symptoms that affect their long-term well-being. Post-sepsis syndrome (PSS) is a condition that affects up to 50% of sepsis survivors and can have numerous chronic symptoms such as insomnia, hallucinations, memory loss, disabling muscle pain, and reduced organ function (Sepsis Alliance, 2022). These consequences of sepsis make it difficult for survivors to go back to their routine and complete everyday tasks. Many studies have proven that PSS is associated with a reduced lifespan and the current 5-year mortality rate ranges between 44% to 82% (Van Der Slikke, 2023). This condition has a vast impact, significantly harming and impacting many people in our society.

The University of Florida (UF) is home to the UF Sepsis and Critical Illness Research Center (SCIRC), the United States’ first center committed to studying sepsis (University of Florida, n.d.). By working with the UF Shands Hospital surgical and trauma intensive care units, the SCIRC is able to research progression and long-term outcomes in sepsis patients. UF Health treats about 3,300 septic patients annually (Doctor Gator, 2016). The combination of sepsis prevalence and accessibility of research resources uniquely situated at the University of Florida heightened our team’s interest in studying sepsis.

Understanding Sepsis

Currently, little is known about the mechanisms of disease and inflammation in human bone marrow. All cellular components of the blood are formed through hematopoiesis in the bone marrow, derived from hematopoietic stem cells (Jagannathan-Bogdan & Zon, 2013). Sepsis elicits a response from the bone marrow by activating hematopoietic stem cells, altering cell differentiation, and inducing myelopoiesis. Understanding in-depth how sepsis affects hematopoiesis may be the key to understanding how the dysregulation of the immune system in sepsis progresses.

Rodent models are the current standard for sepsis research (Cai et al., 2023). However, the differences in the immune system and process of hematopoiesis in humans and rodents make it difficult to gain insight from the bone marrow in murine models (Cai et al., 2023; Parekh & Crooks, 2012). Organoids, 3D in vitro models of organs, derived from human cells are promising platforms to investigate biological processes as an alternative to animal testing (Zhao et al., 2022).

Inspiration

Due to the local and global relevance of sepsis research, the UFlorida team sought to study sepsis through synthetic biology. Our team was inspired by our advisor Dr. Jing Pan’s vision to study sepsis in a bone marrow organoid. UFlorida’s project is a continuation of our work last year (UFlorida, 2023). This year, our team designed the implementation of the research project, as we sought to study sepsis through biomanufacturing and computational modeling.

Our iGEM team is composed of a diverse group of undergraduates, with majors ranging from engineering to public health. As we recruited members for the 2024 iGEM competition, we found members passionate about the broad aspects of our project, from its foundational biology to its future clinical and industry potential. A guiding passion for creating animal testing alternatives drew many members to the 2024 team, which led to a greater emphasis on bioethics in our team’s work.

Our Approach

To further the global understanding of sepsis, our team developed an in silico bone marrow organoid model to predict and quantify the immune system's response to pathogenic stimuli. Additionally, our team improved the biomanufacturing of bone marrow organoids in the Wet Lab by optimizing iPSC culture and organoid production techniques. Our in silico model provides insight into cellular behavior as a bone marrow organoid develops and responds to an infection. This model will inform future experiments utilizing our in vitro bone marrow organoid.

Through computational modeling and tissue engineering, we are fabricating an ex vivo platform to provide an in-depth understanding of the cellular changes triggered by sepsis in human bone marrow. Our project offers new insights into human bone marrow pathophysiology in a septic state.