Our homebase city, Boston, is well-known for harboring a substantial number of medical institutions: 25 hospitals and 20 community health centers [1]. These hospitals include Mass General Hospital, Boston’s Children’s Hospital, and Brigham and Women's Hospital (BWH). In other words, the medical centers here in Boston are notable both in abundance and in size. More than 70% of heparin in the US is sourced from China [2]. For this reason, the use of porcine-derived heparin from foreign countries is a local, attention-grabbing issue to our team.
Fig. 1. An image of Massachusetts General Hospital [ 3]
In addition, there is a rising demand for heparin around the globe. The global heparin pharmaceutical market is projected to grow from US$9.38 billion in 2021 to US$12.06 billion in 2028. Not only is this due to the increase in cardiovascular disease and thrombosis cases in older populations, but COVID-19 associated thromboprophylaxis and thromboembolic disease have substantially increased its usage in hospitals [4].
Moreover, a number of individuals in society today are prohibited from or refuse to consume pork products for various reasons. Those who follow Islam or Judaism are religiously forbidden from consuming porcine products. Muslims have 1.8 billion adherents, roughly 24% of the world’s population. Jews are numbered at roughly 15 million and this adds 0.2%. If we add in Hindus who generally also don’t eat pork, that’s another 1+ billion people, or about 15% of the world’s population [5]. Also, 1-3% of individuals worldwide and 1% within the US identify as being vegan, meaning they vow to avoid consuming any animal-derived products [6]. So in total, around 40% of the world’s population does not eat pork products due to religious or moral reasons. Almost all of these individuals will, at least once in their lifetime, require heparin as part of their medical treatment, and this is a substantial number of people who would face moral and ethical conflict.
Fig. 2. SDG #3 [ 7]
1. Side Effect (HIT) Prevalence Reduction
By using the E. Coli strain Nissl 1917 to biosynthesize the anticoagulant heparin, our project effectively achieves this goal. To start, the most adverse side effect of being administered heparin is Heparin Induced Thrombocytopenia Type 2, or HIT Type 2. HIT development first begins with the binding of heparin molecules to PF4 molecules located on the surface of platelets. Patients may then develop antibodies to the heparin-PF4 complex, which in turn activates platelets and leads to major clotting. HIT is much more likely to develop (around 13 times more likely) in patients who receive UFH rather than LMWH [8]. This is mainly attributed to the bigger molecule size of the UFH, which has been shown to increase heparin molecules’ affinity to PF4 and thus elevate the chance of HIT development.
Fig. 3. Infographic on Heparin-induced Thrombocytopenia (HIT) [ 11]
Despite this being widely circulated knowledge, the drug cost barrier is still an obstacle for many hospitals when deciding between which heparin type to purchase. However, with the biosynthesis of heparin through E. coli, the molecular size variability is diminished as mentioned before, meaning that the risk of HIT is further minimized. In addition, other side effects caused by heparin overdoses (urine bleeding, internal bleeding, etc) are also mitigated through Ecorin’s consistent molecular size. Thus, Ecorin meets the subgoal 3.9, which states that society needs to work towards “substantially reducing the number of deaths and illnesses from hazardous chemicals and contamination” [12].
2. Stable Availability
Another major issue with the current heparin production system is its rather unreliable nature in terms of quality and availability. This is because of its vulnerability to epidemics and its dependence on the health of the swine from which the heparin is sourced. The epidemic of 2008 and 2019, caused by the porcine reproductive and respiratory syndrome (PRRS) and the African Swine Flu (both virally spread), resulted in chaos for heparin consumers and the heparin market. The 2019 crisis led the US House Committee on Energy and Commerce to issue a letter to the FDA warning of the outbreak's potential threat to the heparin supply to the USA [4]. The drastic inflation in prices of pork-related products led manufacturers to add over‐sulfated chondroitin sulfate (OSCS), a type of chondroitin sulfate sourced from mammal or shark cartilages, to mimic the anticoagulant properties of heparin. Not only did this result in a substantial number of deaths and injuries in patients, but it also substantially raised the prices of heparin on the market [13].
Fig. 4. Fluctuating pig prices across the decade 2011-2021 [ 14]
For this reason, producing heparin through bacteria eliminates the unstable accessibility of this anticoagulant to patients, since epidemics and overall health condition is a negligible quality factor for Ecorin.
3. No Viable Alternative
Heparin is not the only anticoagulant currently on the market. In fact, there are around 8 different other well-known blood thinners on the market (apixaban, dabigatran, dalteparin, edoxaban, enoxaparin, fondaparinux, rivaroxaban, and warfarin) [15]. Why can’t we just use these blood thinners instead of heparin if it’s unstable? Firstly, the majority of these anticoagulants are orally ingested, meaning they can’t be used in live surgery to maintain a certain level of blood clotting. Aside from heparin, fondaparinux and warfarin are the two other major anticoagulants used in patients. Unfortunately, both are less suitable for widespread use compared to heparin. To start, fondaparinux is more expensive than heparin, costing around $34/mL [16] while for heparin it’s closer to $5.04/mL [17]. In addition, the half-lives of both fondaparinux and warfarin are longer than heparin. The half-life of fondaparinux and warfarin are 17 hours [18] and 40 hours [19], respectively, while it’s 60 to 90 minutes for heparin [20]. A short half-life is essential for anticoagulants used in emergency surgeries because of their relatively quick time to take effect as well as wear off. Also, warfarin has been shown to cross the placenta of pregnant women and affect the fetus inside, meaning that adopting warfarin as the main anticoagulant would restrict pregnant women from access to anticoagulants. For these reasons, our team determined that working to make heparin better instead of looking for alternatives would be the most effective and beneficial choice for the medical field.
4. Cheaper Costs
There are currently two main types of heparin, low molecular weight heparin (LMWH) and unfractionated heparin (UFH). LMWH is a filtered, enzymatically cleaved version of UFH, and has a relatively shorter, consistent length for the heparin molecules [8]. LMWH is preferred by hospitals because of its relatively lower variability in molecular size. Heavy molecule size variability present in UFH makes it difficult to predict the anticoagulation levels, as larger sizes lead to greater spikes in anticoagulation and require heavy monitoring to prevent unnecessary bleeding in the patient. However, LMWH remains difficult to choose over the UFH option in more rural hospitals due to its higher cost [9], thus forcing them to treat patients with an unfavorable anticoagulant of lower quality than is available.
Our final vision is to mass-produce heparin through a population of genetically modified E. coli in a bioreactor. With this method, the total quantity of heparin available on the market will increase, which will in turn decrease the overall price of heparin. What makes Ecorin (our heparin product) better than LMWH is that the variability in size between the heparin molecules is substantially reduced (since it’s no longer crudely sourced from pig intestines or relying on enzymatic cleavage, just produced by E. coli systems), while still offering a more affordable price. With this, more rural and less fortunate communities will be able to access a higher quality anticoagulant while sustaining their budget.
Fig. 5. SDG #5 [ 21]
According to the 2030 Agenda for Sustainable Development, “Governments, international organizations, the business sector and other non-state actors and individuals must contribute to changing unsustainable consumption and production patterns, including through the mobilization, from all sources, of financial and technical assistance to strengthen developing countries’ scientific, technological and innovative capacities to move towards more sustainable patterns of consumption and production” [12].
A major issue with sourcing heparin from pigs is the environmental emissions that result from the production process. Not only does the extraction of heparin from the pigs’ intestinal mucosa release GHGs, but the transportation of heparin from China to the USA (as well as to other countries) also contributes a substantial amount of emissions.
Unsurprisingly, the full extraction process of heparin from pigs is a highly guarded industrial secret. However, from the available information, we determined that the solvents and detergents used during the production process cause air and water pollution. These include Folch solution (a mixture of chloroform and methanol) and sulfuric acid [22]. One pig produces 650 mg of crude heparin, and the carbon footprint of raising 1 pig produces around 670 kg of CO2, which poses a serious threat to the environment.
Fig. 6. Extraction process of heparin from pigs [ 22]
Fig. 7. Separating mucosa from pig intestines [ 23]
To meet the rising global heparin demand, around 1.1 billion pigs are required annually. Almost all pigs, around 95% of them, are raised in east Asian countries, and China alone produces around 50% of the global requirements of heparin. At the end of March of 2021, there were a reported 415.95 million pigs used by China to make heparin [4].
Fig. 8. SDG #13 [ 21]
Deriving an essential anticoagulant from pigs further complicates the step we need to take away from raising farm animals, which is a crucial part on our way to reducing greenhouse gas emissions and reaching net-zero goals. As mentioned, raising pig livestock emits a significant amount of harmful gasses. On the other hand, Ecorin not only minimizes these emissions by producing heparin through E. coli, but there’s no extra emissions that would normally be produced by the purification and transportation processes of porcine-derived heparin since the heparin molecules produced by E. coli are consistent in size and are produced locally (produced within the US, not sourced from foreign countries like China).
Ecorin aligns with Sustainable Development subgoal 13.1, which is to “strengthen resilience and adaptive capacity to climate-related hazards and natural disasters in all countries” [12]. As global temperatures rise with climate change, the pork industry faces a number of new setbacks. For instance, the higher temperatures lead to heat stress in the pigs. This not only lowers their health and makes them more susceptible to disease, but it also decreases their food intake, increasing prices for veterinary services and medication.
Fig. 9. Infographic on how heat stress impacts pig health [ 24]
In addition, the high temperatures facilitate more efficient spread of both viral and bacterial diseases due to the widened range of fleas and other pests that spread these diseases. This may lead to a number of pig epidemics in the future (much like the crises in 2008 and 2019). Furthermore, climate change will continue to exacerbate the rate and severity of droughts throughout the world, affecting both the pigs and the crops raised to feed the pigs. Overall, these changes will increase the cost of raising pigs since new cooling technology will need to be installed and the pigs will need to be fed a higher-protein diet to compensate for the reduced amount of crop yield on the farm [4].
Fig. 10. Predicted number of pigs that will be contaminated with African Swine Flu (ASF) [ 25]
All of these changes in price and resource availability will make the porcine-derived heparin market extremely unstable, a dangerous situation considering the cruciality of heparin in modern medicine. So, by removing humanity’s dependence on pigs and instead utilizing transformed Escherichia coli populations, Ecorin strengthens the healthcare industry’s resilience against climate change and wavering heparin availability, thus meeting Sustainable Development subgoal 13.1.
In addition, Ecorin meets subgoal 13.3, which is to “improve education, awareness-raising and human and institutional capacity on climate change mitigation, adaptation, impact reduction and early warning” [12]. Over the year, we ran an Instagram account through which we reached a wider audience by raising awareness online. We have posted detailed information about our project and its purpose, using “Help Arin the Pig” as our personalized story to further promote our ideas. The account accrued a total of 80 followers.
Fig. 14. Series of posts made on our Instagram account detailing our project
This section briefly summarizes the long-term impacts of our projects in different areas, providing a clear vision of the kind of future we envision our project to create.
We hope to continue outreach and increase awareness amongst the population about the source of heparin to minimize moral and religious conflict within individuals. By uniting animal-rights advocates, religious followers, and vegans, our project can uncover the unknown source of this medical essentiality, building a base of supporters to help us turn away from our dependence on pigs. In addition, the project aims to encourage individuals to learn more about the real sources of their medicine and take initiative to become informed of their general medical experience.
To restate the critical facts mentioned above,
With the skyrocketing of global engagement towards a greener future, the project will aid in transforming the medical industry, one of the biggest sources of pollution and emissions, to become more sustainable and environmentally friendly. Clearly, depending on pigs to produce heparin is both environmentally unhealthy and unstable in the long run, which can create a positive-feedback loop of a sort that will only continue to exacerbate the environmental damage we bring about. By reducing emissions, harmful substances, and avoiding the detrimental impacts of rising temperatures on the stability of the medical industry, our project successfully envisions a greener future.
With the impending impacts of climate change on global temperatures, there is an increased global prevalence of disease and droughts, which, in turn, will dramatically escalate the cost of raising pigs due to crop shortages, cooling technologies, health check-ups, and a generally smaller pig size (which decreases the total amount of pig meat made). As seen with the 2008 and 2019 epidemic, unstable pig prices and availability will in turn cause substantial ups and downs in the cost and quality of heparin as manufacturers attempt to “cheat the system” to continue their source of profit. Our project will minimize these fluctuations in the heparin market as well as the price of pigs by shifting our dependence away from animals. By using E. coli, heparin becomes minimally affected by the rising global temperatures and other impacts of climate change, providing a much more economically viable option for the future.
Our team conducted a public survey to spread awareness about the sourcing of heparin and to collect information on our stakeholders’ opinions. We sent out a form that targeted individuals who specifically could not consume pork products due to moral or religious obligations (Muslim community, vegans, vegetarians, animal rights advocates, etc). We received 34 responses across a wide age range and geographic spread, having participants from Massachusetts, North Carolina, Michigan, Ecuador, India, and California.
Fig. 11. Demographics of survey respondents
Fig. 12. Pie chart showing awareness on the source of heparin
Fig. 13. Opinions on consenting to receiving heparin
Fig. 14. Opinion on the practicality of our project to the broader community
Additional comments added to the form by anonymous respondents:
“From what I'm aware, if the product is life saving then it wouldn't be an issue, but if there are alternatives then the alternative would be used.”
“According to Islamic law, substances that are typically prohibited to ingest are exempted for medical reasons. I.e. saving a human life is more important than the prohibition. However, if there is an alternative that does not use these substances, I think that would be preferred. Additionally the ethical treatment of animals is a serious responsibility, so that has to be taken into consideration.”
“This is a great step forward in advancing medical intervention and has the potential to save many lives. For those who refuse to take heparin for religious reasons, this opens the door for equitable health outcomes.”
It was surprising to us that out of all of the broad regions we reached, a whopping 94.1% of respondents were not aware that heparin was sourced from pigs. This emphasized the clear lack of awareness around the source of heparin, demonstrating the blind trust that most people place in the medical industry when receiving treatment. We were also shocked by how many people would not consent to being treated with heparin with this new knowledge (64.7% of respondents), and this brings light to the validity of ethical concerns that surround sourcing heparin from pigs.
Dr. Figueiredo is a pharmacist, microbiologist, physiologist, and neuroscientist residing in Zurich, Switzerland. The following are a select few quotations that we deemed to be the most impactful in determining the direction of our project:
“So the trend is that you try to fix the problems with the supply chain and they will adapt. There will be initial complaints from producers but then they will adapt and they won’t be a huge disruption in the market.”
“Hospitals try to look for cheaper options, especially in America since you guys have medicines that are quite expensive. For a drug to be approved by the FDA, it needs to be ample and not have any toxicity. Once it is approved, hospitals only care about its price. They will go for the cheaper option. I don't think the patients will have the option to choose between different heparins because hospitals will only offer the cheaper version.”
“People will be receptive to this type of synthetic heparin but there is a problem with the cost. Currently, I check that there are some synthetic heparin in the US market but the reason why they are not widely used is their price. If you get to produce it in a cheaper way people go with your synthetic option. It all comes to cost.”
From this interview, we gathered that our solution must maintain an economically viable cost of production and must be sold at a reasonably cheap price, preferably cheaper than the porcine-derived heparin available on the market today. With this feedback, our team initially envisioned an in vitro system where the E. coli would secrete the heparin product, but we found this to be too complex and simplified it to lysing the bacteria after cultivating them in a large bioreactor. Since we are directly modifying the genome of the E. coli, once we are able to harvest a surviving population of E. coli bacteria that has successfully integrated the additional enzymes we transformed them with, this population can be forever grown and maintained, ensuring minimal costs and hassle.
Dr. Galletti is an accomplished pharmacist from Montana with extensive experience across various clinical settings. The following are the most informative quotations we took away from her interview:
“We use heparin daily for DVT prophylaxis and occasionally for acute situations. It is more commonly used in emergency surgeries at large cardiac centers.”
“As a critical access hospital, we generally don't face severe restrictions on medications. However, during drug shortages, we may experience allocation limits from distributors, restricting how much we can order.”
Thanks to Dr. Galletti, we were able to gain a general perspective from someone who works with heparin firsthand. One thing we were not aware of was that even critical access hospitals are not exempt from the effects of drug shortages. This further motivated our team to pursue this project because Ecorin would provide a consistent, reliable source of heparin (just requires harvesting from a bioreactor, which goes through various quality checks and lasts 15-20 years on average). In addition, she clearly emphasized the fact that heparin is used on a daily basis and is thus exposed to numerous patients during non-life-threatening situations. With this in mind, we believe the religious obligations become even more conflicting since the medical situation they may be in may not be life-threatening when they receive porcine-derived heparin, a usual requirement when consuming animal products in some religions.
At Tufts University, Professor Blanchette teaches about environmentalism, capitalism, labor politics, value beyond work, interspecies relations, food production, political economy, ethnography, and the rural US. We determined the following to be the most relevant quotations to shaping our project:
“But, as a general principle, it certainly seems problematic to have the production of a medically-vital ingredient made in any one global location given the fragility of industrial animal agriculture, including the US.”
“I also imagine you’d have to think about the global political economy. What will your product cost versus porcine-derived heparin? Is it possible that we’d get a situation where your product circulates in higher income countries, while the porcine-derived drug begins circulating more, for cheaper, in lower-income countries? So would your product actually ‘end’ animal derived heparin, or instead change its circulation. Are there heparin shortages in the broader world that might be alleviated by this split in the market? I don’t know, but that seems like one way to think about impact – for better, or worse.”
Dr. Blanchette brought up a crucial point about how porcine-derived heparin could still subsist and circulate in the market even after our product becomes available on the market. In response, we determined that the only way for our product to dominate the current version of heparin was to minimize the production price and market value of Ecorin. This way, since hospitals will be inclined to choose the cheaper option, Ecorin is more likely to dominate over the current heparin.
We collaborated with the Thailand-RIS team on September 21st to present our projects to each other and get feedback. Through this collaboration event, we gained a lot of insight about how other teams are approaching their projects, especially in the human practices area.
In addition, we attended the iGEM Boston Meet-up hosted at Boston University. Here, we were able to engage with the Northeastern iGEM team as well as the Boston Univeristy iGEM team by presenting our project and also listen to their projects to learn more about the approaches they took with synthetic biology. We received valuable feedback about our presentation and we were glad to have been able to connect with iGEM teams outside of the high school league.
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