The Goals of Science

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Dr. Herington began by recounting his writings on the overall goals of science and how these goals should shape research practices and external safety regulations. He told us about two conflicting views of science: the traditional vision, in which science is purely epistemic and value-free, and the increasingly popular modern view that science is, in addition to its mission of acquiring knowledge for knowledge’s sake, also inherently a moral exercise. Science and the values that shape it have real effects for the public, even when they are not direct recipients of any research products. Dr. Herington gave the example of inductive risk, in which considerations of the costs of false positives and false negatives dictate significance thresholds across scientific disciplines.

Technology as a Mechanism for Meeting Basic Needs

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We then asked Dr. Herington about his climate insecurity article entitled, “Climate-Related Insecurity, Loss, and Damage,” in which he argues that, “one of our goals in determining climate policy ought to be mechanisms which ensure the security of basic goods" [15]. He told us that technological solutions like ours can be helpful for meeting the public’s basic needs as humanity anticipates and adapts to the inevitable effects of climate change. Our project could make the process of obtaining valuable chemicals cheaper, less resource-intensive, and less destructive, reducing the amount of arable land required to produce medicinals. These are all great implications! However, he pointed out that many current technological ‘solutions’ to similar supply issues fall short in that they maximize convenience, efficiency, and output of a good in the short term, while destabilizing its availability in the long run or increasing the vulnerability of the supply chain. He said there could be instability in resource availability or increased supply chain vulnerabilities due to complex interactions such as geopolitical conflicts, natural disasters, climate change and global reliance on single-source or just-in-time inventory practices. This instability and vulnerability can lead to disruptions in the production and distribution of essential goods and services, causing economic hardship, price volatility, and even social and political unrest. To address this issue in the long term, organizations and governments must prioritize supply chain resilience, diversify sourcing options, invest in technology and infrastructure, and implement effective risk management strategies to ensure continued availability of critical resources and stronger supply chain systems. He warned us against falling into this same pattern of placing profit before planning as we design our project.

Science and Policy

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We asked Dr. Herington why he felt that public policy and external government regulation should supplement or replace traditional approaches to risk management in research, which typically involve ethics regulations on an institutional or organizational level. He pointed out that scientists are placed under an immense pressure to produce results, publish papers, and obtain grants, and it can thus be against their personal interests to impose ethical constraints on themselves and their fellow researchers which limit what they can accomplish in the laboratory. An external incentive in the form of governmental regulation is necessary to ensure that proper safety procedures are being followed, however Dr. Herington also stressed that there must be a close collaboration and dialogue between scientists and public officials in creating these legal guidelines in order to bridge the understanding gap between them. He stated that policymakers themselves must ultimately make these value judgements, though, as they represent the public who will ultimately be affected by science and its regulations or lack thereof.

Accessible Design

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Dr. Herington wrote in his article, “The Social Risks of Science” that the risks and rewards of scientific research are often unjustly distributed, with affluent countries, communities, or people of a certain race, sex, or ethnicity disproportionately reaping the benefits while marginalized groups are placed at a proportionally greater risk of harm [16]. Our team asked for Dr. Herington’s recommendations on project design elements that would transform our 3D bioprinter system into a solution to distributive injustice in terms of essential plant molecules, rather than a contributor to this issue. He replied that, in order to ensure that our project reaches those who would benefit the most from it, we should consider accessibility in our project design and implementation over profit. This may involve leaving our biosynthesis open-source, rather than placing it behind a patent wall. In addition, we should consider how much infrastructure is required for its implementation (electricity, refrigeration, sterile laboratory areas) and whether or not it exists in the areas where our technology would be most useful. Finally, he said that while our project itself should be cheap to create, we should also avoid using expensive precursors wherever possible, such as pricey bio-inks.

Risks of Our Project

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When we asked Dr. Herington about the potential social risks that our project posed, he responded that biocontainment is the most commonly referenced hazard for genetic engineering experiments, however it is already well accounted for by existing policies, the iGEM competition’s safety regulations, and our hydrogel containment system. He felt that a much more serious risk imposed by our project was that of misuse, as a biosynthesis system such as ours which is designed to be cheap, open-source, and easy to use could create illicit drugs or biological weapons if placed in the wrong hands. He pointed out ricin as an example, a highly potent plant-based toxin that our project may be able to synthesize more efficiently than existing biomanufacturing techniques.

Our conversation with Dr. Herington provided many valuable takeaways for our project development and human practice initiatives. Firstly, he reminded us that because science is steeped in value judgments that greatly impact the public, we must allow public policy and the needs of our community to shape our scientific process in order to avoid harm and maximize the good we can accomplish. Constraints on our research should not be viewed as a loss, but as a means to assure the safety of our stakeholders. Secondly, in order to create a viable and long-term solution to the mounting problem of botanical shortages, we realized that we must balance issues of convenience and efficiency with those of sustainability and integration into existing supply chains as we design and market our biosynthesis system.

We also realized that, in terms of biosafety, we must research whether there are any harmful molecules whose ease or accessibility of creation will be improved by our project, such as illegal drugs or potent toxins. We should acknowledge and plan for the possibility of our project’s misuse, both through design elements and correspondence with policymakers. Specifically, Dr. Herington prompted us to consider how policy can interact with and regulate the use of biosynthesis systems such as ours to mitigate some of the safety risks associated with misuse of our project. We must ask ourselves: how can we keep our project accessible while preventing the types of misuse that Dr. Herington theorized may occur? This interview sparked the idea to research and explore how external policy and internal regulation can intersect to minimize the potential harms of our project.

Finally, based on the recommendations that Dr. Herington gave us for reaching a global user base with our project, our team made modifications to both our existing business plan and our design elements. The human practices team had initially planned to apply for a patent on our biosynthesis technology, however we weighed the financial sustainability of our project in the long-term against the barriers that a patent may pose on those who wish to replicate and refine our technology in order to supply essential medicines and other compounds to their communities. In addition, the human practices team must coordinate with our hardware team to determine the minimum infrastructure required to operate our printer, and both the financial and physical difficulties of producing our bio-inks.

During our meeting, Dr. Morehouse mentioned that global warming is threatening existing agricultural practices. He told us, for instance, that many companies in the Netherlands are buying farm land at higher elevations and building more greenhouses in order to better control the climate at which their plants are being grown. Dr. Morehouse said that our project has importance as another method of climate adaptation. Currently, plants are becoming extinct due to their specific geographical growing limitations and climate tolerances, which cannot evolve quickly enough to accommodate global warming and its impacts on the environment. The Lamiaceae herbs such as rosemary, lemon balm, oregano, and sage from which rosmarinic acid is derived primarily grow in Mediterranean climates. The Mediterranean climate type is characterized by hot, dry summers and cool, wet winters, and is located between 30^。and 45^。latitude north and south of the equator. This climate type is mainly located on the western side of each coast due to ocean currents, and is a unique ecosystem that is now being threatened by increased risk of fire.

Dr. Morehouse also placed the Human Practices team in contact with Dr. Carlos de la Rosa, the President and CEO of the Center for Plant Conservation, which is a California-based nonprofit organization invested in the seedbanking and preservation of endangered North American plants. While Dr. de la Rosa could not meet with us to interview, in our correspondence he offered us additional insights into the endangered valuable plant species that grow in mediterranean-type ecosystems worldwide and the threats that these plants face due to increasing wildfire frequency and overharvesting of plants such as sagebrush and some ornamental orchids and succulents, and asked us questions which aided us in articulating our vision for how our project could aid in solving the agricultural supply chain issues created by the climate crisis.

Dr. Morehouse is in favor of using laboratory methods to produce plant-derived chemicals without growing plants themselves in order to reduce the carbon footprint of the chemical manufacturing process and provide a more stable source of chemicals for countries that are experiencing agricultural issues and land loss due to global warming and rising sea levels. During our interview and subsequent correspondence, both he and Dr. de la Rosa offered us more information on conservation issues facing plants in similar climates to that which Salvia rosmarinus is native to. These facts that they provided helped us to better conceptualize the growing severity of the climate crisis and its impact on plants, and thus the growing importance of technological adaptations such as ours to help humanity satisfy its ever-growing need for plant compounds in the face of this crisis.

About UEBT

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Issues of conservation and of preventing negative effects of mass commercial plant harvesting on communities and ecosystems have been addressed long before our project’s conception. In order to help us determine how our project would integrate with existing solutions to the unethical environmental practices of corporations and individuals, Ms. Oliva first told us more about them.

The Convention on Biological Diversity (CBD) is the international legal instrument for "the conservation of biological diversity, the sustainable use of its components and the fair and equitable sharing of the benefits arising out of the utilization of genetic resources" that has been ratified by 196 nations [18]. The United Nations’ Convention on Biological Diversity outlined these principles for sustainable utilization of the world’s biodiversity to guide use of natural resources by a range of stakeholders, organizations and countries. More companies have since become interested in implementing these ideas into their supply chains.

Ms. Oliva told us that the central goal of her organization, The Union for Ethical Biotrade, is to take these biotrade principles established by the CBD and develop them into an official ethical biotrade standard. The standard lays out guidelines, a verification process for compliance, and permits use of a special label on UEBT-certified products. Companies sign up to improve their biodiversity practices and implement the standard in their operation process and overall supply chain, but they prioritize certain supply chains based on strategic importance, volumes, and risk.

The Current Market for Botanicals

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Most of the companies that Ms. Oliva works with primarily focus on botanicals. They have roles in creating products such as beauty, food, fragrances, and flavors. These products are important streams of revenue, but are often associated with vulnerable landscapes. The species required for production may themselves be threatened, and these botanically-derived products are also often associated with vulnerable populations in places with high levels of poverty. Some producers fail to respect worker's rights and do not provide their employees with liveable incomes.

Ms. Oliva gave the example of sourcing vanilla from Madagascar. Many issues including ensuring fair wages and labor conditions for workers, maintaining consistent product quality, and establishing transparent supply chains can arise in this sourcing process when working with producers, and there are also biodiversity issues surrounding vanilla, such as the potential for deforestation and habitat destruction as vanilla cultivation expands, and the need for sustainable farming practices to protect local ecosystems and rare species.

The Demand for Synthetic vs. Natural Plant-Derived Products

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“Would it be easier just to say stop using natural vanilla? - It depends.” In the 1800s, a German company successfully synthesized vanillin, a chemical which is the primary component of the extract of the vanilla bean. Currently, most of the world uses synthetic vanillin as a cheaper and more readily available alternative to natural vanilla extract for flavoring. But there’s still a high demand for natural vanilla extract and paste, which is the higher quality vanilla for flavoring purposes because it tastes richer, more complex, and less artificial. Ms. Oliva concluded that, based on trends such as these seen with natural flavorings, colorants, and medicinal herbs, synthesized chemicals such as those our project produces will likely not interfere with local agriculture practices, as we are targeting different markets from those that small-scale farmers of medicinal and aromatic plants sell to.

Our Project's Place in Biodiversity Preservation Efforts

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Ms. Oliva commented that our project and other synthesis systems for botanically-derived chemicals would likely aid in conservation, and in the Union for Ethical Biotrade’s mission: “Some plants are endangered in the wild. We are looking to reduce the pressure on these plants from overharvesting, and being able to produce something off-site would reduce the pressure.”

She warned us, however, that the burden of proof was on us to demonstrate our product’s contribution to preserving plant diversity and helping humanity weather the effects of climate change on our supply of essential plant-based chemicals. She said that it is important for companies like this to show or to measure that they are making some positive contribution to climate change before making a product claim to this effect.

“There’s definitely a space for this…Biotech companies are not replacing substances, but they are generating new substances. What comes out of green biotechs are not exact replicas of raw plant materials, but isolated chemicals found in plants that have specific properties which are useful for incorporation into cosmetic or pharmaceutical products.”

“This is not, in any way, replacing traditional plant materials,” Ms. Oliva said of our project and the initiatives of other biotechnology companies. “In the previous example I gave, there is always a market for natural vanilla. Culinary professionals will always want to have the actual vanilla because it tastes much nicer. So your product is not replacing natural rosemary; you are complementing it.”

Her Advice for Implementation

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Ms. Oliva also works with the International Union for Conservation of Nature (IUCN) group to develop new synthetic biology policies, where she collaborates with a group of scientists and examines potential challenges such as the misuse and potential unexpected effects of synthetic biology. UEBT recognizes that the “green solution,” in which some European companies are developing technologies to sequester or reduce the emission of greenhouse gasses, is of interest to biotech companies, and she has attended several trade fairs in Europe where biotechnology was heavily represented. For her, the question is not whether solutions to problems of climate change and biodiversity employing synthetic biology are “good” or “bad” as ideas; she would be more interested in when and where these initiatives are being implemented and how they are being deployed.

Our project could potentially help to preserve biodiversity in areas rich in medicinal and aromatic plants, and Ms. Oliva suggested that we further qualify and develop our sustainability claims in our project marketing. According to one of her biodiversity reviews [19], we must prove that our project implements applicable United Nations Sustainable Development Goals in order to make substantiated sustainability claims. She told us that we could certainly make the connection between our project and plant conservation, and that by proving that our system can help to reduce the pressures on endangered plant species, we can make our project stronger and satisfy these criteria laid out by the UN for improving our world. There are SDGs relating to science, technology, infrastructure, ecosystems, and public health that we should aim to achieve with our project [21].

Our meeting with Maria Oliva provided us with foundational knowledge of biodiversity conservation efforts in the biotrade sphere, and of concerns raised by synthetic biology technologies such as the potential for misuse or unintended consequences, intellectual property and patenting issues that may hinder access to essential technologies, and the need for robust regulations and oversight to ensure responsible research and application, allowing us to better understand the issues we aim to tackle in our project. We learned that climate change is severely impacting biodiversity, but addressing it holds great promise for the green industries. Another important takeaway is that our project will likely not affect local medicinal and aromatic plant farmers as we are targeting different markets, and there is always a market for natural ingredients. This information reduces the severity of this ethical concern that we initially proposed. In terms of demonstrating our project’s stability, we believe that we can satisfy Ms. Oliva’s criteria and substantiate our claims by comparing the waste products, resource requirements, and environmental impacts of our synthesis system with those of standard chemical manufacturing, extraction, and bioreactor fermentation techniques.

Dr. Chen told us that although rosmarinic acid has strong antioxidant properties, RA cannot currently be used as a therapeutic drug. Compared to other drugs with specific indications in clinical trials, RA does not have an advantage. Compared to synthetic drugs, rosmarinic acid's effects may be less potent, and it might require high doses or specific formulations for efficacy. Additionally, its bioavailability can be poor, and it lacks the precise target specificity often required for treating complex medical conditions. Much global research regarding RA has ceased for clinical trials. However, there are some research groups who have modified the structure and specific targets of the RA to improve its therapeutic effects [24], which has thus far been promising. However, they are still at the very early stage of the clinical trials and therefore do not have any significant results yet.

Aside from clinical trials, rosmarinic acid’s supposed anti-aging and antioxidant properties have good supplemental and cosmetic applications, as this ingredient is incorporated into health and wellness products such as skin and hair-care oils. In beauty and wellness industries, these unsubstantiated claims about rosmarinic acid’s benefits can still increase the compound’s marketability. For example, there are currently bio-supplements such as the NMN products that are popular and renowned in China for their anti-aging properties. NMN stands for nicotinamide mononucleotide, is a precursor to a crucial compound known as NAD+. Studies have revealed that this molecule not only supplies the energy required for our bodily functions, growth, and maintenance but might also play a pivotal role in mitigating the aging process [25].

Dr. Chen suggested that, because RA does not have a very complicated structure, manufacturers could use chemical methods to synthesize it and obtain a very high purity. However, many of the requirements for supplements and cosmetics require the products to be natural or made by biological methods. Therefore, he believes our project could have great promise in the industrial sector using synthetic biological methods to optimize the yield of RA.

In response to the interview with Dr. Chen, our team learned more about the chemical and biological manufacturing market in China and around the globe and realized that our project may have great promise for industrial applications. We decided to emphasize our system’s production of rosmarinic acid for use in the supplement and cosmetic industries and our novel synthetic biological method in general when marketing our project to the public. Dr. Chen recommended that our possible future directions of research could include modifying the structure of RA (making changes to functional groups, altering the scaffold, modifying stereochemistry, or introducing substitutions to improve specific properties) in order to increase its chance for extra clinical applications. While we have taken Dr. Chen’s advice here into consideration, we decided to focus more on optimizing our project for versatility and customizability than on modifying our initial chemical product, so that our consumers can easily produce a range of chemicals far beyond rosmarinic acid to satisfy their varied needs.

Do Chemical Companies Care About Their Chemical Sources (Synthetic vs. Plant-Derived)?

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Mr. Johnson explained that chemical companies are primarily concerned with the cost of manufacturing their chemicals. If they are able to make the chemical synthetically, they will do so unless there is a more cost-effective natural process to create it. Most of the products that Cayman sells are chemically synthesized, which can guarantee “cleaner” or more pure results. Cayman does occasionally source raw materials. Their cosmetics production team may have different needs for plant-based chemicals based on their customers’ demand for all-natural makeup and fragrances.

Chemical Sustainability

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Mr. Johnson reported that Cayman has no formal statement on sustainability, but practically their company cares about preserving the biological sources of their materials. For their natural products, their investment in maintaining a sustainable supply of their raw materials is specific to what they are harvesting. Switching over from a natural product to synthetically deriving chemicals is likely to occur if raw material shortages occur or prices fluctuate. However, current methods for chemical synthesis involving synthetic biology are too expensive, time consuming, or simply do not work for the chemicals that Cayman supplies. Therefore, Cayman is not looking to use synthetic biological techniques to solve their production issues.

Comparing Yields

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Mr. Johnson said that when Cayman purifies their chemical products, they run HPLC (high-performance liquid chromatography) that separates the enantiomers in a given product mixture. When comparing purification techniques involving either chemistry or synthetic biology, it is a volume issue. HPLC can purify higher volumes of product than a petri dish can. Overall, Mr. Johnson told us that Cayman Chemical Co. does not deal a lot with microbial processes mainly due to cost.

Issues in Current Chemical Production Processes

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If the purity of a given product is lower than what is anticipated, Cayman’s chemical manufacturers must add an additional step into the purification process. Cayman also works with proteins, both cultivating proteins synthetically and isolating them from raw source material. However, raw materials can vary in type and quality, and sources that reliably produce high-quality products can suddenly go out of business. Cayman can also evaluate and produce products from custom materials if the customer covers some of the additional cost.

What Cayman Liked About Our Project

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Mr. Johnson told us that he liked our project’s sustainable idea of producing clean botanical chemicals using synthetic biology in a laboratory setting to avoid the unregulated cultivation and overharvesting practices of medicinal and aromatic plants. Also, our project overcame the geographical limitations of cultivating valuable plants. Without the geographical limitations of traditional agriculture and with the local chemical source our manufacturing method provides, it may be possible for our commercial customers to save on transportation costs and to open new industry locations, generating more economic value.

What We Can Improve

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Mr. Johnson pointed out that Cayman Chemical and other large-scale chemical manufacturers will care primarily about the quantity of the chemicals that can be produced using our synthetic biology method when we transfer our product from a laboratory to an industrial setting, as well as the purity of the products that can be produced with our system.

To address this first concern, our Human Practices team worked with the Hardware and Wet lab teams as well as chemical engineering experts to develop an industrial scale-up plan for our product, and estimate the amounts of product that can be generated by our system within a certain time frame at different scales. To guarantee product quality and ease of purification for our potential customers, we will also need to assess the purity of the chemical product and intermediates produced by our hydrogel-encapsulated microbes, as well as develop cost-effective purification plans for both small and large-scale applications of our project that can be customized for the product molecule that our system is being used to produce.

Capra Biosciences' Development Process

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As Dr. Onderko explained the process of developing her company and finding its niche within the wider biomanufacturing market, she also gave us many important factors to consider about the ways in which we would categorize and advertise our own product to potential customers.

Dr. Onderko and her co-founder Dr. Magyar developed their biosynthesis system using biofilms while they were postdoctoral research fellows. They originally only had a working model on a laboratory bench scale, but developed the idea for their company and outsourced their industrial scale-up through a bioprocess scale-up company.

Dr. Onderko explained that biomanufacturing companies can either sell their products “B2C,” business-to-consumer, or “B2B,” business-to-business. Because a B2C sales strategy involves more marketing to the general public, Capra Biosciences chose to sell to other businesses–specifically those within the cosmetics industry. Retinol, the first commercial chemical product of Capra Biosciences, is a fat-soluble form of vitamin A that is commonly used as an ingredient in skincare products to reduce effects of skin aging [28]. Because it sells for $3000/kg [29], it was a lucrative molecule for the company to create. Dr. Onderko told us that several different components of the personal care/cosmetic market which could contain potential purchasers of chemicals:

• Brand name cosmetic companies manufacturing their own products
• 3rd party manufacturers that create generic cosmetic products and sell to brand names
• Chemical distributors that supply cosmetic brands and manufacturers

Capra Biosciences has targeted diverse customers across this range, as they are trying to obtain as many potential buyers as possible.

During our interview with Mr. Ferrer, the founder of RebX, he told us about some of the difficulties that biosynthesis companies such as his face when competing with traditional chemical manufacturers for customers, including higher costs, longer production time, and limited product volumes that can be produced using biosynthetic techniques. We asked Dr. Onderko how Capra Biosciences is addressing these concerns in their system design and marketing.

She responded that yes, “green premium” synthetic chemicals which cost more due to their sustainable manufacturing methods are a hard sell. While it is difficult to be cost-competitive with petrochemical manufacturers, it is also necessary, as any customer’s primary concern when purchasing chemicals is going to be price. She did tell us that sustainability paired with price-competitiveness can be a useful marketing tool for biosynthetically produced chemicals. In the personal care market especially, there is a lot of focus on the branding of products. Companies want to be able to market their products as “all-natural,” and biosynthetically derived chemicals can offer corporate customers this natural or petroleum-free label for their beauty products.

In terms of production quantity, Dr. Onderko told us that the quantity of product that can be produced using biosynthetic techniques depends on the exact production strategy used, but that biosynthesis companies must market themselves to customers who require product amounts that they can feasibly create. Dr. Onderko and her business partner encountered this issue with Capra Biosciences. When first devising their business plan, they were initially interested in creating lubricants for the aerospace industry using their system due to the high value and demand for these types of chemicals, however limitations on the volume of product that their biosynthesis system could create led them to instead market themselves as a business-to-business cosmetic chemical supplier.

In addition to sales and marketing, Dr. Onderko also pointed out many other factors that must be considered when founding a biosynthesis company, such as chemical analysis, purification, and logistics, the downstream costs associated with these processes which can comprise up to 50% of total production costs and the fulfillment of legal product purity standards. Dr. Onderko advised that we begin to think about these production and marketing details now in our entrepreneurship plans, as many startups neglect to plan ahead in these areas and suffer down the line because of it.

Industrial Scale-Up

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We asked Dr. Onderko what the typical industrial scale-up process looks like for biosynthesis systems like the one developed by Capra Biosciences. She told us that conventional fermentation bioreactor scale-up is often done using CMOs (contract manufacturing organizations), large-scale facilities with huge fermenters that biosynthesis companies can essentially rent out for their individual use and modification. While this scale-up strategy is fairly accessible, Dr. Onderko also told us that CMOs are in short supply and that their demand is increasing as biosynthesis becomes a more established form of chemical manufacturing. There are often long wait times involved in contracting these facilities, and they can be costly to build out to an individual company’s specifications. A company with its own biosynthesis platform can avoid this CMO bottleneck, however it must take on the additional cost and effort of building and scaling its unique technology.

In Capra Bioscience’s own scale-up process, Dr. Onderko told us that her company faced challenges when determining how to sterilize their system and media without the use of an autoclave, and that it is difficult to find experts in such a niche field as bioreactor scale-up. She suggested that we consult with bioprocess scale-up contractors or synthetic biology experts directly, as the chemical engineers at the University of Rochester whom we mentioned we had an interest in contacting likely would not have biology experience and work mostly with petrochemicals.

Advice for Our Project

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Dr. Onderko also gave us advice related to the potential commercialization of our project. Firstly, she pointed out that if we are planning to start a business, we need to determine what exactly we are selling. For us, this could be chemicals produced with our hydrogel co-culture system, products produced from those chemicals, or our modified 3D bioprinter technology itself. The market for our product and our business plan itself will obviously differ greatly depending on what facet of our project we plan to sell. If we are selling a chemical production platform, Dr. Onderko pointed out that we will also need to develop corresponding software, user interface, and tech support services in order to attract and maintain customers. Regardless of the product we are selling, we will need to establish the competitive advantage of our technology over existing products, which involves both identifying and analyzing the strengths and weaknesses of our product’s would-be competitors. For more assistance on our entrepreneurship journey, Dr. Onderko recommended that we look into the Innovation Corps (I-Corp) program run through the National Science Foundation, a seven-week long intensive entrepreneurial training program that guides scientists and engineers through the process of commercializing their inventions [31].

Our interview with Dr. Onderko gave us many considerations to take into account as we create a business plan and begin to envision our project as a commercial endeavor. While creating a cosmetic product using the rosmarinic acid purified from our biosynthesis system would likely require more time and expense than we have available to us, marketing either our rosmarinic acid or our printer itself as a product is highly feasible. Based on which one of these potential items we select as the basis for a business, our market analysis, sales plan, advertising strategies, and existing competitors will change dramatically. If we orient our entrepreneurship plan around selling our modified 3D printer or individual printer parts, we must make our hardware design as intuitive as possible via user testing, and design official guides, software, and help tools to assist customers with their use. These are luckily already important facets of our 3D bioprinter, however we would need to expedite their creation if we wish to show this product to potential investors and obtain their feedback.

If we instead choose to create a chemical manufacturing business plan, we must devote a great deal of thought and research to our post-production processes, and our Human Practices team should coordinate with our Wet Lab team to determine the most efficient and cost-effective ways to purify rosmarinic acid from the media in which our hydrogels are submersed. Most importantly, we must extensively research commercial-scale biosynthesis techniques to devise an industrial scale-up plan, and consult with experts working with industrial bioreactors in this plan’s refinement. Could we design a hydrogel co-culture system that is compatible with existing contract manufacturing organization facilities? Should we instead design an entirely new platform for these large-scale hydrogels to avoid the CMO bottleneck that Dr. Onderko mentioned? Our interview with Dr. Onderko has allowed us to identify several next steps to pursue as we begin to develop an entrepreneurship plan.

Bioinks

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• Dr. Nelson suggested using rheology to find the shear modulus of the bioink.
• He warned us to watch out for early crosslinking of the cell-laden gels; there might be oxidative stress between the printing cells as they are not in their native conditions.

G-code

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• We must test multiple times to adjust the structure we wish to print.
• We must individually name the extrusion heads and syringe tips in our G-code.
• Extruder functionality is the priority when writing our code.
• Dr. Nelson mentioned that his lab uses a Hyrel printer, and the ability of our Ender printer to remain stable and print the bioinks smoothly is a concern.
• He advised us to keep the printer design as simple as possible so that it is easy to fix when debugging.

Issues to Tackle

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• Dr. Nelson told us that current issues around 3D bioprinting involve accessibility due to high costs, and a lack of innovation into multi-material continuous printing. He advised that making our printer low-cost (around $500) would be ideal as it would make our project accessible for average labs.
• He also told us that we must control the viscosity of the bioink and make sure that our flow rate is not interrupted and chunky.

Through this interview, we obtained valuable advice on refining many of our 3D bioprinting techniques. For example, when developing G-code, we need to ensure precision, accuracy, and biocompatibility, which are essential for controlling the motion of the printer and the deposition of high spatial resolution bioinks, minimizing errors, and ensuring smooth printing. Biocompatibility is critical to ensure that the chosen materials and printing process do not compromise the viability and functionality of the bacteria and yeast being printed. Furthermore, optimizing the printed structure is crucial to achieve the desired bioprinting results while minimizing the risk of cell damage or material deformation.

Dr. Nelson was impressed by our customizable dual-channel 3D bioprinter idea. He highlighted the challenges and considerations related to G code programming for 3D printing, emphasizing the importance of testing to ensure the desired structure. He mentioned the need for extrusions heads to have different names from syringe tips in the G code for dual-channel printers. He emphasized that we should focus on simplicity and the effectiveness of the bioink we planned to print. Based on this interview, we decided to focus on making our technology low-cost, address the accessibility issues of multi material printing, and emphasize sustainability. Based on his feedback, we engaged in literature research, modeling and experimental testing for the optimal shape of the bioinks, and experimented with different shapes for printing. We realized that research labs could also be one of our project’s potential customers even on its current scale, as the ability to easily and cheaply modify a standard 3D-printer into a dual-channel bioprinter could be useful for laboratories looking to shape and refine the material properties of all manner of biomaterials (tissue, collagen, etc), as well as for laboratories looking to produce rare or expensive chemicals for research purposes, or to examine the biosynthetic capabilities of their own engineered organisms in many environments and relative concentrations. We have attempted to use minimal and inexpensive materials in our printer development to ensure the price of our overall design is accessible for average laboratories who wish to purchase our 3D bioprinting system for use in their own research.

Dr. Buckley is experienced in the mechanical testing of biomaterials. He suggested that we determine the swelling ratio of the hydrogels we are considering and use this data to calculate the mesh size of each gel. He illustrated the importance of using these tests to determine the Young’s modulus and permeability of the hydrogels. After finding each gel’s modulus and permeability, he explained that we can then calculate the pore size and examine which hydrogel will be the best fit for our customized 3D bioprinting material. Dr. Buckley predicted that it would be very useful for us to use a rheometer to monitor gel formation and measure gel strength, as well as to learn and compile polymerization methods for each gel we are testing and further characterize them in order to find the gel which best suits our bioprinter by doing cell viability tests.

After listening to Dr. Buckley’s advice, the team decided to add additional testing cycles to our hardware module and to do rheometric analysis as one of our material properties tests, which led us to arrange subsequent meetings with biomaterial testing experts Kevin Ling and Ming Yang in the Department of Biomedical Engineering at the University of Rochester Medical Center.

The meeting with Dr. Buckley and Kevin provided us with a substantial amount of background information, enabling us to better understand and contextualize the issues we aim to tackle in our project. Finally, an entire new problem came into our minds as a result of this consultation: what kind of tests should we use to better understand the fidelity and printability of our bioinks? At this stage, we were unsure about how to address this problem. We decided to reach out to Ming Yang, a Ph. D. student in Dr. Awad’s lab, for more suggestions and advice, as his research focuses on using rheometry to investigate the properties of 3D biomaterials.

Mr. Yan described the different properties of the five bioinks we chose. He mentioned that alginate is not shear thinning. For collagen, he suggested that we could place a luer lock into our syringe and mix the hydrogel between syringes. He told us that alginate is very soft and will gel at 37 °C, and liquifies at 4 °C. Chitosan must be made in low-pH conditions. GelMA gels at 4 °C and liquefies at 37 °C. Mr. Yan also mentioned that we do not need to test the pore size of the bioink, as most microbes are not small enough to escape the bioink pores.

Mr. Yan mentored us on improving our gel printability and fidelity, making sure we could print the bioinks smoothly and that our yeast and E. coli cells would not die during printing. He stated that the needles of 3D printers can only print very soft materials and are easy to clog. He said that needles should work for our printing system, but that we must ensure our bioink stays in liquid form as it is being printed. He mentioned that GelMA solidifies at a different temperature than other bioinks, and this will affect its rheology results. Furthermore, he suggested that it is not necessary to investigate the pore size of the hydrogel, as this property does not generally affect microbe growth as the pore size was already large enough for the microbes to get through. Forgoing this aspect of gel characterization will allow us to focus on other important tests as we develop our final 3D printer design.

Mr. Yan introduced us to the many variables involved in 3D bioprinting technology. Our printer design and bioink protocols have been heavily influenced by our conversation in-person with him, and we stayed connected with him and sought his guidance for our 3D printer. He also supplied us with some of his synthesized GelMA to test for compatibility with our printer.

We learned that there is a larger tolerance needed on the CAD models, instead of the models being line to line because the parts need clearance. Additionally, we learned that some of the parts we wanted required too much filament to 3D print, and machining these parts would be an equally accurate, but more cost-effective solution if their designs were slightly changed. Based on Mr. Alkins’ feedback, the base design of the printer was redesigned to incorporate aluminum channels, a plastic block as the syringe height offset, and a CNC polycarbonate base in order to secure all parts in the correct dimensions. Additionally, the offset tool in Onshape, a computer-aided design software system that helps CADing parts from the software for 3D printing [35], was used to create larger spaces between parts that need to come in contact, so they can interact correctly. Other parts, like holes, were also changed to give clearance.

In Context

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Meeting with the Ain Center was part of our initial planning process for the launching of our product into the biosynthesis market. In a series of entrepreneurial workshops, the Ain Center staff taught us how to ask open-ended questions during interviews with potential beneficiaries or investors of our project in order to receive the most information from them, as well as how to identify potential customers for our biosynthesis system using a customer discovery session. We then focused on developing a value chain for medical and aromatic plant compounds to identify pains and shortcomings which our product could address, and transitioned to conducting customer discovery interviews with representatives from industries who would be utilizing our product, and to conducting end-user testing. We created customized marketing and business plans for our project based on iGEM’s entrepreneurship framework with the guidance of the Ain Center team.

What is a Value Proposition?

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A value proposition is a specially crafted statement which conveys the value and uniqueness of a product or service by succinctly describing what the product or service does, who it is for, and what specific pain points it is fixing for this audience. A strong value proposition can help with customer acquisition and retention [52].

During our first workshop, we studied value propositions from companies like Airbnb and Vimeo and brainstormed a simple and precise value proposition for our product based on these inspirations. During our second workshop, we refined our previous wording: we decided to change “parallel culture biosynthesis system” to “optimized 3D bioprinter” to further reduce the use of scientific jargon in our statement, which might cause confusion for people without a science background. We added a better description of our project and its uniqueness into our value proposition to make it more appealing to the public.

What is a Business Model Canvas?

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The business model canvas is widely used in the entrepreneurial field and it helps organize the the key components of the business model including customer segments, distribution channels, resources required to develop the business, the key processes and activities required to deliver the value propostion, external organzations that the company engages with to enhance the development process, different revenue steams of the project, and pricing of the entire research and development process including variable costs and fixed costs [36].

What is Customer Discovery?

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Customer discovery is the process of discovering potential customers for our product, networking with them via different social media outlets and email, and arranging structured conversations with them to obtain their feedback on our project and refine our ideas to better address their specific pains. This process is important because the problems that customers are actually experiencing and seeking fixes for may be different from those that we hypothesize before building the actual product, therefore listening to and acting based on their viewpoints rather than simply making assumptions about their needs can help us reshape our project to be more appealing to them, leading our team’s research in the correct direction and saving us both money and effort. As we worked with the Ain Center on this process, we devised open-ended questions to use when talking to industrial representatives from Cayman Chemical and in order to get a better idea of the prevailing trends in the chemical manufacturing industry and uncover other important information, such as more possible applications for our project.

Do Chemical Companies Care about the Origins of their Chemicals?

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“Chemicals” is a very large category, but the chemical products that RebX is creating will target the personal care market, which includes fragrance and cosmetic manufacturers, cosmetic chemical distributors, and brand-name cosmetic companies. Mr. Ferrer told us that, in researching the needs of companies within these industries, they tend to care about two things with regards to the chemicals they source: replacing petrochemicals in the chemical manufacturing process for sustainability and consumer preference reasons, and finding a reliable and cheap supply of chemicals with which to create their products.

What is the Federal Approval Process for Selling Biomanufactured Chemicals?

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Fragrances have some government regulation, but their ingredients do not require FDA approval, which is why RebX is targeting this market. Mr. Ferrer told us that food production and agriculture are highly regulated processes, however, and that obtaining legal approval to sell synthesized chemicals for specific purposes is a major hurdle that biosynthesis companies face. He also said that if our system is being used to make a product that has already been produced with traditional chemical manufacturing or extraction techniques, it would be an easier approval process for us as we can validate our product’s quality with standard chemical analysis techniques. Pharmaceutical compounds still require approval, but not from the FDA. The approval process becomes more rigorous if our system is being used to produce a novel drug.

Could Our Project Displace Farmers?

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In terms of marketing to fragrance and cosmetics companies, Mr. Ferrer said that these companies would not generally care about any negative impacts of our project on agriculture or farmers unless they are also sourcing raw materials from them. Mr. Ferrer’s opinion on the general ethical implications of our project was that technology always disrupts existing systems, but there are still many kinds of work for farmers even if they are no longer growing medicinal and aromatic plants. They can always make a profit growing essential food crops and spices, for instance. Our project would allow for less land to be used for agriculture, which could be beneficial if that land instead went towards housing or preserving ecosystems. Mr. Ferrer also pointed out that prices of land used for housing developments are much higher than land sold for farming, so farmers can sell uncultivated land for housing and make a profit.

The Human Practices team noted that his opinion is somewhat controversial, as poor rural farmers often rely on their land to produce vital crops for themselves and their communities, and cannot simply sell their land for profit like Mr. Ferrer is suggesting. Nevertheless, his general sentiment–that the business of MAP farmers would not be significantly affected by biosynthesis systems such as ours–is one that was echoed both by the farmers that we spoke to and by biotrade experts.

Is There Business Potential in the Chemical Manufacturing Industry?

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Mr. Ferrer told us that utilizing synthetic biology for chemical manufacturing is expensive, which is why SynBio manufacturers such as his company tend to target the fragrance and cosmetic industry or produce rare and in-demand pharmaceuticals that these markets have higher markups on the price of the products than does food or fuel. He does believe that commercial demand exists for biosynthetically produced chemicals, however. Even for large-scale chemical distributors, the price fluctuations of raw materials and the chemicals produced from them can pose an important problem to their business, and can be as critical of an issue as ingredient scarcity and supply chain issues. Biosynthetic techniques can solve this cost fluctuation issue where extraction and chemical synthesis cannot, as biosynthesis is neither reliant on unstable medicinal and aromatic plant markets, nor on the constantly shifting petroleum market. Generally, Mr. Ferrer advised that there is business potential for our product in the chemical manufacturing and supply industry so long as our product addresses a pain that companies in this sphere experience and is priced competitively when compared to existing manufacturing techniques.

What Did You Wish You Knew Before Starting a Business?

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Mr. Ferrer offered two pieces of advice for us. Firstly, he told us that we should plan simple and cheap “short loop” experiments to demonstrate to investors that our microbes can make our desired compound, such as cytotoxicity tests. Secondly, he told us to talk to many people throughout our project development and improve our product before it is even introduced to the world.

What Market Research Did You Conduct During Business Development?

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Mr. Ferrer told us that the RebX staff never conducted market research themselves, but instead examined existing market reports to understand the current market for biosynthetically sourced chemicals and its growth trends. He suggested that we do the same, and added that we can write to large associations of biomanufacturing companies to ask for statistics if data is not readily available online. He also said we should keep in mind that, in terms of current chemical manufacturing prices, many manufacturers list much higher small-scale prices than those they actually sell for on a long-term, constant supply basis to corporate buyers.

How Did RebX Market Itself?

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According to Mr. Ferrer, the RebX team marketed their products to investors based on competitive pricing, as their biosynthesis system allowed for their products to be sold for less than petrochemical derived alternatives. As they consulted with investors, they simply asked what these cosmetic manufacturing companies paid for their chemical ingredients, how much they wanted to pay for their chemicals, and whether they experienced issues with cost fluctuation of their ingredients as purchased from their current suppliers. Our team observed that, on their website, RebX also markets their ingredients based on their natural, non-petrochemical sourcing.

Did RebX Have a Full Business Plan When They Won the iGEM Startup Competition?

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Mr. Ferrer explained that his startup won first place in the startup showcase at the 2022 iGEM Grand Jamboree, and that this contest mainly involved pitching their company to potential investors. He said that his team had a “roadmap,” for their business development when initially advertising themselves to potential customers during this competition, but not a highly developed plan for large-scale implementation.

Advice for Our Project

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Mr. Ferrer said that, when he competed in the startup showcase last year, he noticed that many startup teams lost points with the judges because they did not propose a detailed implementation strategy for their product. If we want to be judged favorably in entrepreneurship, he suggested that we have a long-term implementation plan for our product ready before the competition.

Mr. Ferrer stated that, because rosmarinic acid has no clinically proven therapeutic benefits, we should not attempt to market our current product to pharmaceutical companies. If we want to enter the pharmaceutical market or prove to investors that our biomanufacturing system can be used to make drugs and drug precursors, we should first identify pharmaceutical compounds that share a similar chemical pathway with rosmarinic acid and that our current system can easily be modified to produce.

Mr. Ferrer said that it is okay if our project itself focuses on a small-scale system and a specific product molecule, as many iGEM teams adopt a narrow focus for their projects due to the short time frame of the competition. For our final presentation, however, we should provide ideas for an industrial scale-up of our system and what resources and facilities would be required to scale our project. He suggested that we consult with chemical engineers to aid us in developing this plan, as he himself is attempting to recruit chemical engineers to his own company in order to refine his system design.

From this interview, we learned that we should avoid positioning rosmarinic acid as a drug in our marketing due to its lack of proven efficacy in a pharmaceutical context, and instead explore more commercially promising opportunities for marketing rosmarinic acid, such as its uses in fragrances and hair/skin-care products. If we decide to attempt to sell our product to pharmaceutical companies, we should emphasize the exploration of high-value molecules that can be created using our biosynthesis system, and present our molecule as a proof of concept. We should use some of the resources that Dr. Ferrer suggested to identify molecules with similar synthesis pathways to rosmarinic acid that can generate more revenue. Our Human Practices team must prepare a strong proposed implementation for our product and format our product pitch based on Mr. Ferrer’s feedback. The team will stay connected with Mr. Ferrer and possibly prepare a mock presentation for him before traveling to Paris.

Focusing on a Proof-of-Concept

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During our previous interviews, we realized that chemical suppliers and cosmetic companies mainly value large quantities and low prices in their chemicals, whereas that chemicals for pharma need to have clinically proven efficacy, which can be a hurdle for some chemicals like rosmarinic acid. Our rosmarinic acid product is better suited for cosmetic and nutraceutical companies than for use in pharmaceuticals. We have considered marketing our biosynthesis system based on its potential to produce compounds with greater medicinal value than our proof-of-concept molecule, however Mr. Saltzstein advised that, though different companies have different value equations, we should focus on one path to prove that our system is viable. We should show higher regulatory firms the right vision first by proofing our concept as an early stage project.

Combining Sustainability with Cost-Effectiveness

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Mr. Salzstein told the team that, from his previous experience, our extensive consideration of the environmental and social impacts of our project is strong as our method does not require a lot of transportation and does not have issues with worker rights for traditional agriculture practices for chemical extraction, but economic value is still of tantamount importance for customers when making their purchasing decisions. Customers always prefer economical products. An economical product with sustainable values is definitely better, but not the reverse. This meeting has inspired the team to brainstorming our project implementation and specifically our scale-up plan, since our 3D printing method is useful on a small scale as it is highly customizable and it does not satisfy these potential customers' needs.

3D-Printer Home User Feedback

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As a home 3D printer user, Mr. Saltzstein suggested that we make our printing material more affordable to increase its accessibility to the average user. Whenever there is an issue with his printer, Mr. Saltzstein will find the solution online, print the parts he needs, and add them to his printer to fix the problem. He suggested that we create a teleservice (B2C model) for our printer so that whenever our users experience an issue, we have a customer service team available to find solutions remotely for them.

Business Plan Feedback

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Mr. Saltzstein has created many business plans throughout the course of his career, and he has also helped to review many external business plans. After looking at our proposed plan, he recommended that we should include our interdisciplinary team backgrounds on the business plan. We should also address our intellectual property ownership and any commitments that company has to the University, and we should check the standard University of Rochester’s Technology Transfer Agreement. He suggested that some portions of the administration work should initially be outsourced because in its beginning phase, our company will not have the full-time employees necessary for a startup. He suggested that we should consult with regulatory agencies like the FDA when necessary and think internationally, not just about business opportunities in the US.