Team:Virginia/IS

Manifold

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Human Practices
“The potential for synthetic biology and biotechnology is vast; we all have an opportunity to create the future TOGETHER.” - Ryan Bethencourt
Human Practices
CHAPTER 3: IMAGINE SOLUTIONS
2A) Brainstorm Ideas
From our earnest conversations with experts, stakeholders and end-users, Team Virginia acquired a new understanding to inefficient chemical manufacturing, that beneath this global problem was a spectrum of underlying problems facing different communities. Scientists struggle to optimize biosynthesis for large-scale chemical manufacturing. Stakeholders accept wasteful synthesis methods, even though emerging technologies yield higher quality products and reduce costs. Patients pay an abnormally large amount of money for life-saving medications, while others don’t even have access to prescription drugs at their local pharmacy. With our newfound understanding of the perspectives of scientists, stakeholders and end-users, we returned to the drawing board with an important question. Now that we have greater insight into the chemical manufacturing, how could we modify Manifold, such that it solved all these scientific and stakeholder problems, while overall benefiting the end-user?


ALEX ZORYCHTA

HOW DO WE USE THE CREATIVE PROBLEM SOLVING PROCESS CORRECTLY?

Introduction: Alex Zorychta is a renowned public speaker that has inspired hundreds-of-thousands of people to use the creative problem solving process to answer the emerging challenges we face today. Currently, he works as the Head of Product for Zealot Interactive and travels across the United States providing mentorship to upcoming student entrepreneurship. As a former translational researcher in point-of-care rapid diagnostic tools for bacterial infections, Alex Zorychta was the perfect contact to discuss how creativity could be used in scientific research like Manifold.

Discussion: Our team first met with Alex Zorychta, a long-time mentor for University of Virginia undergraduates in creativity, during one of his public speaking events hosted by the nanoSTAR Institute. From this opportunity, our team had the amazing opportunity of talking more about the creative problem solving process and how our team could best use it. Although Zorychta discussed the importance of being unfiltered when generating solutions or encouraging conversation when seriously reflection on those solutions, his greatest advice to Team Virginia was acting out the creative problem solving process through the example of “How would someone get a Hippopotamus out of a bath tub?” Using this thought process, we employed the same creative problem solving process to generate modifications to our Manifold design.

Reflection: Our team began brainstorming modifications to the Manifold design to address our new understanding of inefficient chemical manufacturing through the scientific, stakeholder and end-user perspectives. Team Virginia employed Zorychta’s “Creative Problem Solving Process” to break down our global problem, generate ideas and evaluate those ideas for feasible solutions. First, each member of Team Virginia was given sticky notes and a distinct colored marker. Second, our team captain displayed the prompt, “How might we modify our synthetic biology project Manifold such that we build a more sustainable solution?” onto a projector. Finally, team members were then timed thirty minutes and told to write down any solution that came to mind. From a mere thirty minutes of brainstorming, the members of Team Virginia produced over 112 modifications that ranged anywhere from making the protein shell soluble in water to expressing multiple layers of protein shells on top of one another. But out of the wild ideas that our team came up with, one sticky note stood out, “Standardization and Modularity”. From this idea, we immediately knew that this was the direction we needed to take.

2B) Question Assumptions
From our brainstorming session, we recognized that amongst the 112 solutions that we came up with, the sticky note labeled “Standardization and Modularity” was the answer to inefficient chemical manufacturing. But before continuing onwards, the countless reviewing of sticky note after stick note, prompted an odd question amongst the members of Team Virginia. Why Synthetic Biology?

Temporarily pausing our reflection, Team Virginia approached the guidance of synthetic biologist Dr. Kozminski, because of his experience as the principle investigator for past University of Virginia iGEM teams. From our thought-provoking conversation with him, we understood that besides introducing sustainable and economically viable manufacturing practice to an industry that has largely accepted the problems with chemical and plant synthesis, Team Virginia was advancing the broader synthetic biology field by showcasing how synthetic biology can uniquely solve global problems unlike traditional scientific disciplines. At that moment, members of Team Virginia were humbled by the important role we served in synthetic biology research. This awareness eventually led our team to developing the “Guide for Synthetic Nanoreactors” and instructional videos to inspire future researchers to build upon Manifold and advance synthetic biology. Furthermore, we added “Research Transparency” to our team values, encouraging us to return to experts, stakeholders, and end-users that we’ve interviewed and share the improvements that came from conversations like this.
2C) Reflect on Solution
Through weeks of reflecting on one, singular sticky note labeled “Standardization and Modularity”, Team Virginia engaged in serious debate and reflection to narrow down our project towards a more sustainable and socially good project. With countless of team meetings focused around the engineering design cycle, our team would finally come up with a new direction for Manifold’s design.

Like last year’s team, our team sought to engineer bacterial microcompartments with enzymatic binding sites attached to interior DNA scaffolds to localize enzymes needed for a specific biosynthetic pathway. These bacterial microcompartments are expressed in the safe chassis of Risk Group 1 Escherichia coli, where chemical manufacturing companies simply grow these bacteria in bioreactors and isolate the product. However, our vision for Manifold substantially differed from last year’s iteration, because of its emphasis on modularity and standardization. Recognizing that existing chemical manufacturing involved different procedures, different machinery, extensive purification, transporting chemicals into and out of solution as described by the stakeholder perspective, current pharmaceutical manufacturing needed to be drastically simplified. Thus, instead of entirely designing Manifold for manufacturing a specific chemical like last year’s team, the 2021 Virginia iGEM Team would build an industrially-standardized version of Manifold that allowed chemical manufacturers to swap any enzyme along the DNA scaffold through simple molecular cloning procedures. These characteristics allow any chemical manufacturing company to easily adopt and modify our device, allowing any chemical of interest to be manufactured in a streamlined and optimized fashion.


How Does Our New Design Support the United Nation’s Sustainable Development Goals?
1. Standardization and Modulation of Biosynthesis Optimizes Production for Pharmaceutical Companies By employing the resource efficiency and chemical specificity found in cells, Manifold optimizes the pharmaceutical manufacturing process by drastically cutting the costs invested in lengthy reaction-purification cycles, plant growth and infrastructure. Additionally, Manifold improves on current production rate capabilities, by allowing any pharmaceutical company (whether a startup, an emerging leader, or existing company) to easily engineer multiple version of Manifold and manufacture multiple drugs in parallel. This results from the standardization and modulation of Manifold. The overall effect is that pharmaceutical companies can supply more medications, like hormones, anticoagulants, and steroids, at significantly lower prices, which allows patients to have greater access to life-saving drugs and improve quality of life.
2. Feasibility Promotes Development of Sustainable Cities Throughout the World Implementing Manifold into any chemical manufacturing process follows a simple, three step procedure. First, transformed bacteria are placed in bioreactors, where technicians set external variables like temperature, pH, growth medium. This allows our bacteria to optimally, continually and precisely synthesize our desired chemical. Additionally, because our DNA scaffolds occur within a diffusible bacterial microcompartments, our product can continuously be produced in our protein shell and diffuse to the cytoplasm, allowing for continuous synthesis of the product in the protein shell. Second, antimicrobial agents are used to kill the bacteria. And finally, simple organic chemistry procedures can extract our desired chemical from the debris. With a standardized process of synthesizing chemicals and an optimized bioreactor setup, the possibility of making 100% self sufficient chemical plant that recycles the cells becomes possible (similar to Affinity Chemical). This translates into chemical manufacturers producing pharmaceuticals, construction materials, textiles, industrial enzymes, and many more chemicals that are environmentally waste free. This supports the development of sustainable industries and sustainable cities.


3. Separating Biosynthesis from the Environment Promotes Positive Climate Action Because Manifold is contained within a Risk Group 1 organism and grown inside bioreactors, our design entirely sequesters all biosynthetic processes from the environment. Further, by coupling our solution with an optimal bioreactor setup, the possibility of recycling cells and excess feed entirely removes the production of chemical waste that could end up in bodies of water, landfills and local habitats. By adopting this synthetic biology platform, we promote a global shift away from the excessive waste-producing process of industrial chemical synthesis and take action against climate change and pollution.
Where Did We Go From Here?

From our meticulous review of the scientific, stakeholder and end-user perspectives, our team finally agreed on a new direction for Manifold’s design that emphasized standardization and modularity . From there, we methodically compared our design with our “Team Values” document to examine if Team Virginia could maintain philanthropy and a people-centered focus while engineering our solution through wet-lab and modeling research. Ultimately, the debate stemmed to weeks of discussion, with a particular emphasis on the economic impact, the ethics surrounding increased drug supply, and our implementation approach. In the end, the members of the 2021 Virginia iGEM Team unanimously voted that our project design did not violate our team values and we were ready to move on to engineering our solution. Yet, with particular contention around some aspects of Manifold, we further promised to gain greater insight into the economic impact, the ethics and implementation strategy of Manifold.

Beginning our wet-lab and modeling research, we wanted to take last year’s concept for Manifold and entirely reengineer it to be modular and standardized across all forms of chemical manufacturing. Hence, last year’s project design needed to be changed, resulting in our team applying as a Phase I team in the iGEM competition. Yet, recognizing the power of integrated human practices brought hope to our team, encouraging everyone that the creation of this modular and standardized version of Manifold was wholly possible. We knew that the expression of structures within bacterial microcompartments was feasible from current literature. All we needed to do was carefully design our parts as that was the key to the modulation and standardization of Manifold as encouraged by the scientists we interviewed.

With a little more than 3 months before the Giant Jamboree, Team Virginia was now ready to build our device.
Manifold
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