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Human Practices

An alarming amount of global deaths are the result of sepsis.

When considering the area of our 2021 project, we wanted to find a project that reached a lot of people. Almost 20% of global deaths are sepsis-related every year¹. Sepsis is the overreaction to any infection, including bacterial, fungal, and viral. Because of this, the impact of SARS-CoV2 virus (COVID-19) has drastically increased the onset of sepsis. While our solution is only applicable to sepsis conditions caused by bacterial infections, there is still a need to lessen the global burden of this condition. Dr. Eric Adkins, an intensive care unit physician, estimated that about 50% of ICU cases are sepsis-related. This data supports a need for a more effective treatment plan for sepsis.

An increase in awareness of sepsis is needed.

55% of Americans say they are aware of sepsis in a 2016 survey². This percentage does not include an understanding of sepsis nor an ability to identify the symptoms of sepsis. Many sepsis fatalities could have been avoided if the public knew what symptoms to recognize and watch out for. Because of the disparity in the awareness of sepsis, we have dedicated a portion of our project to influencing target audiences. With the Rochester iGEM team, we have created a children’s book on sepsis that will introduce children and their parents to sepsis in an understandable and creative medium. We also attended and presented at a symposium hosted by the Rochester iGEM team during sepsis awareness month. We got to spread awareness on our project idea, we also got to hear firsthand accounts from a sepsis patient and healthcare provider. Both agree on the importance of sepsis awareness, and were interested in our project idea.

Below we have included a summary of sepsis that provides an understanding of the disease from a patient perspective.

Download the file here.

Phage therapy as an option for combating sepsis.

Phage therapy is an uncommon treatment against bacterial infections due to the benefits of antibiotics. However, with the rise of microbial resistance, an alternative to antibiotics will need to be used. Phage therapy is a potential candidate with promising results. We met with Dr. Strathdee and Dr. Patterson in July. Dr. Patterson was the first person in the United States to successfully undergo intravenous phage therapy. From this conversation, we learned of the benefits of phage therapy, and where phage therapy stands in the regulatory process in the United States. The public may be apprehensive about phage therapy, but with understanding and legislative approval, it could become more widespread. To aid in legislative approval in the United States we have proposed a strategy and guidelines for phage therapy. The document can be found here.

Researching legislation and policy

There are no regulations for approved phage therapy usage in the United States. Exceptions have been made for those that are receiving end of life care. We talked with many professionals with firsthand experience dealing with regulations such as Dr. Strathdee who dealt with receiving the necessary approval of phage therapy under a time crunch due to her husband’s accelerating condition and Brooke Zentmeyer who gave insight on how we could propose regulation to encourage the more widespread use of phage therapy.

Gaining perspective from physicians

Sepsis impacts many intensive care units across hospitals worldwide. To gain a healthcare provider perspective on how our project would impact their work was important to us. From the physician's we discussed with, sepsis is very prevalent in hospitals and a solution is needed to reduce the physical and financial burden on the often-fatal condition. They would also be accepting toward engineered phage therapy if it had the necessary regulatory approvals and was effective. One cautioned us on how to communicate phage therapy to the public due to how unfamiliar it is.

Increasing accessibility to synthetic biology education and sepsis awareness

We recognize that awareness of complex issues such as sepsis and phage therapy start with education. This is why we created a children’s book to educate both children and their parents of the warning signs and potential treatment for sepsis. We also chose mediums such as a crochet pattern and DIY-lab protocols to increase the accessibility to synthetic biology.

Gaining feedback regarding practicality and functionality of the project-- Infectious Disease Institute at The Ohio State University.

The OhioState iGEM team presented our project during an Infectious Disease SCOPE meeting at the Ohio State Battelle Center. The team presented our project pitch in April and our project progress in October. During these meetings, the OhioState team detailed our current progress and welcomed feedback from the audience of law students, research scientists, virologists, microbiologists, and computer program modelers. During our April project pitch, the audience understood the complexity, but also appreciated our willingness to address the issue of sepsis. The general consensus was the project would be engaging and feasible for the scope of iGEM. A few key points from our October presentation were they appreciated our simple communication of complex scientific topics through graphics. They highlighted the importance of being able to communicate our work to a broad audience. This supports our awareness work to simplify the topic and engage more of our community with sepsis and synthetic biology education. They were interested in our summer camp protocols and asked how they could implement more science education into their work. This shows our end goal being put into effect: increasing synthetic biology education. Even if our protocols are not used directly, they still encourage others to do similar projects with students and young kids.

Integrated Human Practices

We further found support for our efforts involved with policy, education and overall project goals through our discussions with professionals in the field. We chose to prioritize elements that are directly related to our project. Due to time constraints we had to stop pursuing the catheter design proposal, and we were unable to create a complete business plan that involved how phage therapy could be manufactured as a treatment. We chose to pursue more educational based efforts instead of the business model because we valued the awareness of sepsis and phage therapy based on our initial interests and research understanding how unaware the global population is of sepsis.

Understanding the experiences of professionals and patients involved with sepsis and their thoughts on phage therapy is an important aspect in our project. Here we present summaries and pieces of our conversations with those we networked with that were influential for our project. These suggestions and comments were either integrated into our project or shaped the direction of our project.

March

Dr. Steve Abedon

Principal Investigator at OSU.

This was our first conversation we had on the feasibility of our project idea. Dr. Abedon gave us insights into paths we should stay away from as well as questions that we should be careful to answer and think about.

Project Impact: Compiled a list of anti-lipid A proteins

June

Dr. John Gunn

Professor of Pediatrics and Microbiology and Principal Investigator, Nationwide Children's Hospital.

During this conversation we discussed the viability of our various anti-lipid A proteins. Dr. Gunn recommended not to pursue the majority of the eukaryotic proteins except for the small sequence of lactoferrin. He also suggested that the pathways involving phosphate modification might have the highest chance for success.

Project Impact: Wet lab condensed their list to 8 proteins to test.

Austin Cool

Biophysics GRA at The Ohio State University.

We learned general information about docking and the inputs and outputs of the computational system. He offered several programs that we could use such as Auto Vina. Auto Vina would output a docking score and a pose. It is possible to compare docking scores between a single substrate and multiple molecules.

Project Impact: Research a model based on docking to support the success of our proteins

July

Dr. Eric Adkins

Intensive care unit physician at Wexner Medical Center in Columbus.

Dr. Adkins estimated that 50% of ICU cases are sepsis. And acknowledged the need for better detection, protocol, and an effective treatment. We asked him if he would use our proposed engineered phage therapy to combat sepsis. He responded saying that if phage therapy had a successful proof of concept, and FDA approval he would have no hesitation in using it. During this time of the project we were looking into how we could incorporate a catheter design to improve sepsis prognosis. He emphasized that indwelling catheters are a huge risk, and considering how to limit biofilm formation both inside and outside the catheter would decrease the harmful effects.

Project Impact: Continue to build on the phage therapy policy proposal, continue to look into incorporating a catheter design proposal.

Dr. Dan Mandell

CO-FOUNDER AND CHIEF EXECUTIVE OFFICER OF GRO BIOSCIENCES, INC.

He stated that docking may not be helpful because it is a function of the approximations of the inputs. Instead of comparing the binding or modifying abilities of our enzymes computationally, it would be better to just get experimental data since that will be much more reliable. He spoke highly of our children’s book idea and thought it was a good way to appeal to adults. Another modeling option we were pursuing at this time was a bacteriophage evolution model. To help determine the parameters and structure, he suggested a normal distribution of mutations throughout the genome. In regards to our regulations work he suggested we talk to someone at the FDA and incorporate a cost analysis of sepsis to further demonstrate the impact of sepsis. Incorporating business model aspects such as phage therapy delivery and packaging could also help our regulations proposal.

Project Project Impact: Discontinue the docking model idea, continue working on the children’s book, assume a normal distribution of mutations in our evolution model, include upscaling and a cost analysis in our regulations work.

Dr. Tom Patterson and Dr. Steffanie Strathdee

Authors of the book “The Perfect Predator”.

From the conversation with them we learned that a model that would decide which phage should go together in a single cocktail for treating different types of infections. She also said it would be interesting if we were to look at the synergy between phage and antibiotics to see which ones should be combined. We could incorporate different standards such as endotoxin levels, synthetic vs. natural phage, etc. For the database, it would be good if we also included the receptors each phage targets so that we can see which ones might work best together. They said that they think if they got phage therapy right away then he could have walked out of the hospital instead of having so many more problems because of the delay in the treatment.

Project Impact: Encouraged our overall project efforts, consider different model aspects based on feasibility, consider including the receptors of each phage targets if available.

August

Dr. Anik Debnath

Co-founder and CEO of Tenza.

Further discouraged the pursuit of a docking model. He suggested we include an evolutionary phage model instead. He also recommended the database should be ordered by the most common or popular bacteria in regards to resulting in sepsis.

Project Impact: Not pursuing the docking model, researching an evolutionary model, ordering the database by most common bacteria.

Dr. Vatsan Raman

Assistant Professor at the University of Wisconsin Madison.

He gave us insight on how to further develop our project, by defining why we chose to focus on lipid A and why we are using engineered proteins instead of lysing proteins. He also asked what are the modalities for phage therapy and future goals for our project. Along with Dr. Debnath and Dr. Mandell support the phage-bacteria evolutionary model and changing environmental conditions.

Project Impact: Define the reasoning behind our project choices, continue to pursue the evolutionary model.

Brook Zentmeyer

Graduate student at Moritz College of Law at The Ohio State University.

She recommended targeting a United States agency since they are given delegative authority by congress. She also suggested convincing the FDA to make a new regulation which would be an easier route than passing a law. Some additional ideas included explaining in our proposal that it is not as radical as they might think it is.

Project Impact: Organize our regulations work in a petition format including a requested action and a statement of grounds, research similar proposals and petitions.

Dr. Kevin Bosse

Director of the research of regulatory affairs at Nationwide Children’s Hospital.

Once we finished up the majority of our document, we decided to meet with Dr. Kevin Bosse from Nationwide Children’s Hospital to discuss our regulations. In this meeting, Dr. Bosse gave us a presentation on the general regulatory process for the different products that FDA regulates. He looked over our document and gave us helpful feedback, mentioning that we should elaborate on the need for alternative treatments and to be thorough with our data collection for a higher chance of product approval. Dr. Bosse noted that from his experience, we are most likely currently in the “research and development” phase of our project from an FDA-approval standpoint.

Project Impact: Added to our section on the need for alternative treatments, framed our document as more of a resource for other researchers/iGEM teams rather than as a proposal.

October

Professor Parasidis

Professor at the Ohio State University

We then met with Professor Efthimios Parasidis, who we were connected with by Brooke. Professor Efthimios contributed to our project by advising us to get a patent for our work and by giving us feedback on our document. Professor Parasidis mentioned that we should include information about the ethics of clinical trials and to make sure we look into animal studies as a means for getting data for FDA approval for human subjects.

Project Impact: Added more information to our section on ethical implications. We also started working on getting a patent for our project.

Dr. Jim Rathman

Professor at the Ohio State University

As we hit snags in our population model, we reached out to Dr. Rathman. As a modeling professor, he was familiar with MATLAB and what we were generally trying to do. He suggested ways to get around our roadblocks. In the end, his help allowed us to move on with our model instead of being stuck behind one error.

Project Impact: Suggested mass matrix method of handling S prime and P prime in the model ODEs. This allowed us to move on from the prime terms, search other avenues to negate them from our model, and eventually finish what is now our final model.