How do we ensure responsible innovation?
While Yale iGEM is primarily a laboratory and synthetic biology group, we recognize the centrality of context in ethical science. Given the complex social and political implications of menopause and its treatment, we have worked hard to ensure that our wet-lab work aligns with both our personal and societal values to ensure we promote safe, effective scientific practices.
Safety Concerns
Despite the lack of long-term evidence and recent disputes over the safety of treatments like traditional hormone replacement therapy, we have attempted to anticipate safety concerns at each point in the development of equol-based therapeutics.
Should hormones be replaced at all?
Other researchers suggest that, in a combination of pharmaceutical lobbying and misguided medical practice, HRT has long been overprescribed. Dr. Cynthia A. Stuenkel, for example, cites a warped conception of “natural” bodily transitions as “deficiencies” as a product of society, not medical fact.
In the same discussion, Dr. Mary Devreaux suggests that HRT treatment shifted from treating symptoms to preventing them — “It is this shift that got us into trouble.”
Despite this pushback and varied evidence on the cost-benefit analysis of HRT, the therapy still represents an important treatment option for many women.
Breast Cancer Risk
The potential linkage of equol to conditions like breast cancer must be weighed against the symptoms of menopause, which can include serious cardiovascular issues and osteoporosis. Studies have produced widely varied results, and consensus has been difficult to reach. Generally, it has been accepted that, while the impact on breast cancer risk is small, estrogen and especially combined estrogen-progestin treatment plans increase risk the longer a patient is taking HRT. Considering women above the age of 50 are already at higher risk for diagnosis of breast cancer, even small increases in the likelihood of disease should warrant concern.
Equally important to consider are the other health risks potentially associated with HRT, which include heart disease, stroke, and blood clots. Because the risk of each individual condition depends on factors like age, medical history, and the method of hormone therapy used, women starting treatment must weigh a variety of complex factors before beginning treatment.
Representation of Women in Medical Research
Yale iGEM is committed to understanding the historical marginalization that underpins gender-specific medicine. In addition to concerns surrounding gender parity, we are seeking to understand the potential implications of our work for low-income, queer, and BIPOC communities through engagement with activists and researchers.
In conversations with experts like Dr. Carolyn Mazure, we learned about the historical lack of representation of women in medical research. As Mazure and her colleague, Dr. Daniel Jones, observe in a 2015 paper, “it has been 20 years since the first requirements to include women as well as men in clinical trials and analyze results by sex were mandated by a U.S. federal law, yet not nearly enough progress has been made.”
As our team explores pathways with the goal of creating new therapeutics for women experiencing menopause, this fundamental lack of research must be taken into account for the wellbeing of female-identifying patients. After talking with Dr. Mazure, our team reinforced its efforts to understand not only the women’s health data available to us but also to recognize the important data points that remain either unfound or unpublished.
The SWAN Study
The SWAN (Study of Women's Health Across the Nation) initiative represents one of the most promising efforts towards amending the lack of research in women’s health. Supported by multiple government agencies, this longitudinal study takes regular, detailed epidemiological surveys and samples from about 3,000 middle-aged women.
While the study has produced a vast network of valuable research, its temporal and sample size limitations suggest a broader trend in a weak body of research on the health of women — particularly those from other historically underrepresented groups. Ultimately, we were able to extract meaningful conclusions through machine learning models and drew statistics from a wide variety of studies to corroborate our findings, but from a human practices perspective, safe distribution of new therapeutics is unavoidably hindered by this societal shortcoming.
Our Model
Using data from the SWAN study, we built machine learning models to predict healthcare outcomes for women based on socioeconomic, demographic, and health factors. Learn more about our modeling process and even try an interactive demo at our modeling page.
Our goal in the modeling process was to elucidate patterns in HRT access that may normally go unnoticed in data. Because societal biases are often reflected in medicine and by extension research, we used our model to gain a clearer understanding of the factors that influence whether or not women are treated for menopause-related symptoms.
Design: Bioproduction vs. Live Biotherapeutic
While our pathway could be used to produce equol in a laboratory setting, our goal is to create a product that augments an existing human pathway. While the bioproduction of equol would curb costs and provide more precise dosing, it could also require more regular pills (depending on the bacterial management approach). After previous conversations with our mentor, Dr. Farren Isaacs, we decided that the bioproduction method would be cheaper and thus reach more patients more quickly, plus pose fewer regulatory challenges. Despite this decision, we consider the potential risks associated with a probiotic therapy below:
Therapeutic Engineering
As our therapeutic is developed, we must be sure that our pathway remains compatible with an in vivo therapeutic. To ensure the scalability of our work, we consulted papers like the recently published “Developing a new class of engineered live bacterial therapeutics to treat human diseases.” In addition to limiting payload size for efficiency and eliminating mutations for safety, we would plan to implement the following steps as a part of future therapeutic development.
- Constrain bacterial survival spatiotemporally via genetic biocontainment strategies
- Include biomarker for ease of tracking
- “Kill-switch” to cease pathway production
- Auxotrophy to limit non-gut proliferation
- Payload optimization for chassis like Lactococcus lactis, which is currently being developed by Acto Bio Therapeutics.
- Adherence to existing regulations for Live Biotherapeutic Products (LBPs).
Project Evolution
The evolution of the project underwent several distinct phases, each driven by a combination of scientific, economic, and health-oriented considerations. Initially, the research focused on enhancing the equol pathway, either by intervening downstream or directly within the pathway. However, we worried about the short-term applicability of this approach given the scarcity of research on the long-term effects of equol and its implications for women's health. In response, we transitioned to a new focus, namely the production of daidzein, which we hoped would provide a wider range of applications as both a therapeutic and precursor. Despite daidzein’s flexibility as a precursor, it quickly became clear that the intermediates required for daidzein production would be prohibitively expensive at scale. Our final pivot involved orienting our project to the economization of daidzein production through a modular approach designed to be adapted by other groups interested in creating equol therapeutics.
Our focus on driving down costs of production involved implementing genomic integration techniques, modifying feeding and extraction protocols, and redirecting the project's final goals towards the creation of an endogenously producing daidzein/equol strain. To enhance the health applications of the project's deliverable, (5) health-based modifications were introduced to the research methods, including changes and additions to various reagents.
In light of these advancements, we plan to extend our research by further exploring the applications of flavonoid research in human health, with a specific emphasis on equol and menopause treatment. Simultaneously, we plan to continue honing both our daidzein/equol strain and commercialization process, with the ultimate goal of making meaningful progress against disparities in women’s healthcare.
Unknown Risks of Equol
Finally, it is crucial that we recognize the lack of robust research on the safety of equol. While the therapy has been shown to reverse vasomotor symptoms (VMS) like hot flashes, the therapy has not existed for a long enough period of time to be buttressed by years of longitudinal data. Considering equol is known to have estrogenic behavior, there is a chance that the molecule could create similar or unique risks. While these concerns are ultimately outside of the scope of our project and will require extensive clinical trials, we have worked to project the most honest perspective possible on the state of equol regarding both its promise and potential risk.