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.
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In addition to a thorough analysis of treatment safety, this process involves identifying precisely who might be affected by the changing landscape of menopause therapies and who is likely to be left behind. Explore our process below.
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<h2>Safety Concerns</h2>
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<p>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.</p>
<h4>Should hormones be replaced at all?</h4>
<p>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.</p>
<p>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.”</p>
<p>Despite this pushback and varied evidence on the cost-benefit analysis of HRT, the therapy still represents an important treatment option for many women.</p>
<h4>Breast Cancer Risk</h4>
<p>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.</p>
<p>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.</p>
<h2>Representation of Women in Medical Research</h2>
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<p>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.</p>
<p>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.”</p>
<p>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.</p>
<h2>The SWAN Study</h2>
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<p>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.</p>
<p>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.</p>
<h2>Our Model</h2>
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<p>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.</p>
<p>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.</p>
<h2>Design: Bioproduction vs. Live Biotherapeutic</h2>
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<p>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:</p>
<h4>Therapeutic Engineering</h4>
<p>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.</p>
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<li>Constrain bacterial survival spatiotemporally via genetic biocontainment strategies</li>
<li>Include biomarker for ease of tracking</li>
<li>“Kill-switch” to cease pathway production</li>
<li>Auxotrophy to limit non-gut proliferation</li>
<li>Payload optimization for chassis like <em>Lactococcus lactis</em>, which is currently being developed by Acto Bio Therapeutics.</li>
<li>Adherence to existing regulations for Live Biotherapeutic Products (LBPs).</li>
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<h2>Project Evolution</h2>
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<p>While our analysis of the existing literature suggested equol has promise as a therapeutic, part of our approach to human practices was understanding the full scope of daidzein’s potential. Our initial plan streamlined the project to maximize results on equol, but we ultimately decided to diversify our deliverables, recognizing that other daidzein-based chemicals may have better human health applications.</p>
<p>We also sought to bridge the gap between flavonoid research and its applications in human health, especially in the context of women's health. Most literature focuses on the benefits of "x" chemical without addressing the challenges to its application. This shift in perspective led us to focus on tackling those challenges, such as poor aqueous solubility, to make these chemicals more accessible for research and therapeutic use.</p>
<p>Our project evolved through several phases:</p>
<ol>
<li>Focus on improving the equol pathway, either downstream or directly on the pathway itself.</li>
<li>Shift to daidzein production due to its own health benefits and other applications.</li>
<li>Recognize the importance of intermediate chemicals in research and women's health, leading to a modular design.</li>
<li>Address economic viability issues by implementing genomic integration and modifying feeding and extraction protocols.</li>
<li>Include health application-based modifications to our methods, improving the potential impact of our deliverable.</li>
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<p>With this comprehensive approach, our next steps involve researching the connection between flavonoid research and human health, specifically in the context of women's health. We will also adjust our commercialization process to account for this gap and apply our findings to the development of our final daidzein/equol strain.</p>
<h2>Unknown Risks of Equol</h2>
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<p>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.</p>
<h2>Conclusion</h2>
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<p>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 to ensure that our wet-lab work aligns with both our personal and societal values to ensure we promote effective and ethical scientific practices. From considering safety concerns through product design to building machine learning models to help women understand how factors in their life may impact their access to HRT, we have attempted to build a project that blends pragmatism with a bold vision for the future of menopause treatment.</p>
<p>By consulting literature and experts in the field, we gained a better understanding of the broader societal context regarding women’s medicine, plus practical insight into how to deliver a safe, affordable product. Our hope is that by engaging with these important ideas, we can join and amplify the voices of the scientific and medical community dedicated to helping women navigate menopause happily and healthily.</p>
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<h2>Introduction</h2>
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<h2>The SWAN Study</h2>
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<p>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-age women.
</p><p>While this study may sound like a vast trove of information, our analysis revealed a more complicated story: of the thousands of women who participate in the study, only about ___% were actively receiving hormone-related treatments. When broken down by, for example, racial or ethnic group, the subgroup sample sizes dwindled into the ___, effectively eliminating our ability to make confident statistical observations.
</p><p>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.
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<h2>Equity</h2>
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<p>With a deeper sense of the historical context and current stakeholder interest in our work, iGEM will pursue the second pillar of its IHP approach: community engagement. By strengthening discourse between various communities with vested interest in menopause research, we hope to generate interest and critical thought about the future of synthetic biology and menopause research. Whether through discussion events or features written in the Yale Daily News, we hope to put people in contact with resources for understanding our work and the future of the field.
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<p>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-age women.
</p><p>While this study may sound like a vast trove of information, our analysis revealed a more complicated story: of the thousands of women who participate in the study, only about ___% were actively receiving hormone-related treatments. When broken down by, for example, racial or ethnic group, the subgroup sample sizes dwindled into the ___, effectively eliminating our ability to make confident statistical observations.
</p><p>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.
