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Even from the start of our efforts to design a system for targeting antimicrobial resistance, we had to consider very specific details about human health and safety.
While any project that intends to be eventually implemented in a real world setting should make these considerations, we had to tackle a unique set of design restrictions.
These restrictions stem from our end goal of creating a foundation for therapeutics that would enter human systems.
We could not have reasons to believe that our proposed phage delivered CRISPR-Cas antimicrobials would target human cells or cause damage outside of its intended function.
One way we achieved this specificity was by using bacteriophages as a scaffold.
However, to build an even better idea about how our project can suit our society's needs and gain support from medical practitioners and the public, we hosted three separate interviews with individuals from different backgrounds and areas of expertise.
Thus we were able to develop a holistic perspective on how our research would potentially be used and perceived by the public in order to help guide the progression of our project.
Firstly, our project considers human health by being designed not to infect human cells nor the native microbiome.
Even if bacteria in the microbiome had antibiotic resistance genes, they either wouldn't be expressing them to be subjected to the trans cleavage activity of Cas13, or the disruption to cellular systems wouldn't be close to the damage commonly induced by antibiotics, especially after prolonged use [1].
Our phage system is also non lytic meaning that no phages are reproducing and no contents of bacteria are released to potentially trigger a dangerous overactive immune response [2].
This further provides us with dosage control, which might be received better by patients as opposed to medication wherein the phages would reproduce and potentially rise in concentration.
One critical perspective we were excited to listen to was that of a pediatric nurse practitioner from the Dayton Children's hospital.
Her experiences in the medical field ranged extensively, which, along with her current work with children, served an important role to shape and inform her views on antibiotic resistance.
In fact, she has to consider this global issue in her work everyday.
She is very careful about when she prescribes antibiotics and has to evaluate the susceptibility of the infection to different treatments, the strength of the antibiotics, and any preexisting health conditions of her patients.
She and her co-workers are also concerned about a day where they no longer can rely on their current knowledge about which types of antibiotics generally work for common infections.
In other words: a day when the majority of pathogens will be multidrug resistant.
In addition, most 'last resort' antibiotics are not recommended for use in pediatric care because of the intense side effects they cause, which further narrows treatment options.
As these concerns grow closer to being realized, our interviewee believes it is more important than ever to promote better education about antibiotic use and has seen first hand how misinformed expectations about treating illnesses in western culture can perpetuate this global problem.
For instance, she regularly has to meet the disappointment and outbursts of parents when she has to explain that she will not prescribe any antibiotics because a particular illness is caused by a virus.
In a stroke of brilliance, however, her team eventually created a system of providing patients with care packages during the flu season that contained helpful items for at-home care such as ibuprofen, thermometers, vitamins, cough syrup, etc. to avoid leaving patients empty handed.
We were also pleased to hear that our interviewee was excited about the prospects of our project for improving human health.
However, there are still limits to our current design in its functionality.
We would need to better integrate thorough diagnostics concerning what species the infection consists of and assays for determining what phage modification would make our system work best.
The latter improvement gave us another reason to use sortase because we can attach a variety of antibodies for alternative targets or even multiple antibodies for multistrain infections.
In addition, to build strong public relations we would need to be informative and clear about how the method works differently from traditional antibiotics.
It was overall a great opportunity to think more about how our research, once developed into a functional therapeutic, would potentially be implemented in a clinical setting.
Another interviewee our team was fortunate to meet with was a pharmacist from a local CVS, a drugstore chain with locations throughout the United States.
While we provided a synopsis of our goals and project, we learned much more from her about the circumstances that guide widespread misuse of antibiotics.
One major issue with how antibiotics are currently prescribed is abuse of the “trial and error” approach where if one antibiotic doesn't work, a patient is simply given another medication to try.
This practice reinforces the selective pressures for resistance against potentially multiple drugs and facilitates the spread of resistance mechanisms across different strains.
Our interviewee further described an interesting hypothetical of where education fails and people in dire circumstances may feel pressured to undergo unsafe practices.
More specifically, she referred to individuals sharing antibiotics that they don't finish with friends or family without health insurance.
This was disheartening to hear, but it would be naive to think that this and other similar situations were rare.
Class disparities exist within the U.S healthcare system, and future applications of our project are not immune from its effects [3].
After discussing these dangers, and additional information about the biology behind antibiotic resistance, our interviewee asked several important questions about how our project could address the antibiotic resistance problem and about better practices, we as a society, could adopt.
She eventually expressed how inspired she was knowing the role she has as a pharmacist to promote careful use of antibiotics.
As part of this role, she also told us she wants to make more time for counseling patients about the medications they have been prescribed and the best way to use them.
Our final outreach effort was with a local retirement community. We chose to meet with them because at an advancing age, the immune system grows less robust and support from various medications is often required.
Additionally, if hospitalization is required for any age-related health conditions or complications, they may contract hospital acquired infections, which are highly likely to be antibiotic resistant [4].
It was not only critical, therefore, that these individuals understood the antibiotic resistance problem, but that they could also openly share their perspective, which had the chance of influencing how we approach the problem in a lab setting and how we present our research.
After our presentation, we were able to proceed with discussions in a casual atmosphere as we sat and enjoyed coffee and pastries with the residents.
In a world with instant access to endless streams of information, addressing common misconceptions about antibiotic use was important for us to build public trust in our research.
We received several questions about how doctors make decisions about antibiotics, where phages originate from, and how our system works differently from traditional medicine.
Most importantly, however, we were able to address why our design was safe.
At the same time, our proposed therapeutics can still be redesigned to further assure the public about its harmlessness.
Some ideas we're considering include a method to limit the longevity of the phages and CRISPR-Cas technology as well as co-option of our delivery system to deliver anti-inflammatory agents.
While these are improvements that would require many more months to attempt, we enjoyed the opportunity to consider our project from a consumer's perspective.
Moving forward, we were inspired to continue searching for feedback from nonscientific communities and to combine both technical and human-based reasoning in our decision making.
We continue to spread the message of iGEM in both the Miami University newspaper and in classrooms of freshman and sophomore students.
In fact, we were invited to present in our previous PI's introductory Microbiology class about synthetic biology and our personal experiences.
Overall, understanding the communities most likely to be impacted by future applications of research heightened the passion of our entire team to change the world through synthetic biology!