JOURNEY TO HORM-OWN

We support the rights of individuals to live their lives in a healthy body that reflects who they are inside. Whether that be an aging or infirm cisgender man or woman seeking the endocrine support they need to be vivacious, pain free, and hearty or a transgender or intersex person seeking gender affirming care. In the scope of Human Practices in our process, we aim to address 1), drug shortages, 2), increase the access and decrease cost, 3), the need of our potential users and the means to deliver our values to them, and 4), misuse of testosterone, adverse effect and how to protect the susceptible population.

Drug Shortages, access, cost and our approach

Steroids are highly diverse biomolecules that are useful, difficult to synthesize chemically, and valuable enough to justify the costs of developing a fermentation process. Statistically, they are the second largest class of drugs after antibiotics. Testosterone is a generic drug and is listed in Essential Medicine by WHO[1]. Testosterone and Estradiol have experienced repeated, current, and longest lasting shortage durations[2], [3] for a variety of reasons, including manufacturing issues, supply chain complexity and disruptions[3]. A de novo process for their fermentation could provide real and lasting relief for this repeated issue, as it would provide the opportunity to dramatically open the market and supply these critically undersupplied generic drugs[2]. Thus, for us, de novo synthesis is a “green”, attractive alternative in opposition to extraction procedures using animal product and/or extensive organic synthesis steps. We hoped our process could both reduce environmental burden and the cost due to drug shortages. Successful cholesterol and human steroid hormone de novo synthesis attempts such as Duport et al 1997[4], Souza et al. 2011[5], Sczcebara et al. 2003[6], and Hirz et al. 2013[7] have further encouraged and motivated us to go further with our pitch (de novo testosterone biosynthesis) due to its originality, novelty, future potentials in transforming into a larger, independent project, and in contributing to opensource production to increase access and reduce cost.

Understanding and addressing our potential users, delivering our values

As one of our first inspiration sources, UC Santa Cruz 2018 team created “PoPPY”. “PoPPY” is an acronym for “Portable Progesterone Production in Yeast”. We resonated with their initiatives and are highly motivated by their primary focus on the application of progesterone as birth control for the developing world and for family planning in places that lacked steady access to pharmaceuticals. However, we were concerned by fact that they didn’t have any medals listed on the 2018 Jamboree page. Especially, we were concern that this framing was considered unethical, or unsafe by the iGEM community. In addressing our concerns, we reviewed researches in gender medicine, testosterone safety in different hormonal therapies such as HRT (Hormone Replacement Therapy) and GAHT (Gender Affirming Hormone Therapy); we reached out to and approached other communities, experts and organisations for help to target our audiences and to deliver our values to our potential users and the general public.

Finally, we conducted a survey to attempt to assess the need for testosterone, its current state of accessibility, and safety. Based on our survey, we concluded that 1), the general public lacked knowledge in sexual hormone and the hormonal therapy. Consequently, participants’ responses strongly urge for accessible educational regarding hormone therapy in general. 2), there is a clear preference in opensource production and non-profit pharmaceutical manufacture. 3), participants’ responses showed that while hormone therapy is rather well understood and accepted in the society, a person undergoing gender affirming hormone therapy may face high likelihood of discrimination. Finally, 4), a significant amount of participants claimed that they or someone they know used testosterone without medical oversight. Interestingly, there are strong disagreement among participants in whether a person is eligible to decide for their own gender and sex, however participants respond in “whether use of testosterone for increasing perceived masculinity should be restricted” are overall conservative.

INTERVIEWS AND INTERACTIONS

Interview with Professor Christian Kögl (he, him).

Interview: Thomas and Carlo

Professor of Patent Law - Austrian Patent Office - BOKU

“If a patent application is older than 20 years it’s not relevant anymore.”

In our pursuit of understanding patent documents and extracting valuable insights, we recognized the critical importance of conducting thorough patent searches and seeking professional guidance to avoid misinterpretation.
To gain insights into these aspects, we sought guidance on how to effectively perform a patent search and had specific questions related to our patents. Our goal was also to delve into the realm of Technology Transfer. Recognizing the expertise of Prof. Kögl, we believed he was the ideal person to consult.
Prof. Kögl proved to be an invaluable resource. He provided us with valuable background information on patents and shed light on the Material Transfer Agreement (MTA) process, which is vital in technology transfer. His guidance emphasized the need to understand all the contents of a patent document, even though only the claims are legally binding.
With Prof. Kögl's assistance, we were able to establish a connection with the Technology Transfer office. Regrettably, despite our efforts, we encountered challenges in scheduling a meeting with them.

Interview with Danny Chan (they, them)

Interviewer: Thomas

Cofounder of the community biotech lab - Biotech without Borders

Thomas had an important interview to discuss the future of our project post-iGEM. This discussion encompassed our eligibility to become a part of the lab, the concept of fiscal hosting, and the pursuit of 501(c)3 non-profit status in the United States. Additionally, it involved the establishment of a separate bank account capable of collecting tax-deductible donations.
This interaction had a significant impact on our project by prompting us to consider how we could integrate with the BwoB community more effectively and leverage each other's resources. As a result, we gained access to their internal communication forum, and Thomas was empowered to create a post outlining our objectives and seeking feedback on how the community could assist us. In the process, we received valuable feedback from Ellen Jorgenson, a highly respected community biotechnologist.
This conversation emphasized the potential to network within the NYC community and utilize the 501(c)3 non-profit status to fundraise with tax-deductible donations. This revelation opened up opportunities for fundraising and ongoing research beyond the scope of the iGEM competition.

Interview with Deborah Davies (She, her)

Interview: Thomas

Business Development Director - CDMO Biotech – Olon

“Always need an expert organization in the loop to manage risk. Otherwise the legal responsibility is too great and someone could get hurt.”
Thomas established a connection with her during the ABPDU Conference, and subsequently, he initiated contact to explore the intricacies of calculating the cost of a large-scale process. During their conversation, she also provided valuable insights into the scaling steps for Pichia pastoris.
Moreover, she extended a standing invitation for us to seek her expertise in reviewing our process design, with a particular focus on identifying potential red flags. This generous offer represents a valuable resource for our ongoing endeavors.

Interview with Sara Holland (She, her)

Interviewer: Thomas and Paola

Top Biotech Patent Attorney in the UK - Potter Clarkson

“Open source can increase legal risk, because people can sue you for any reason and all of your weaknesses are visible.”

The discussion revolved around patent analysis and the crucial concept of Freedom to Operate (FTO). Initially, we possessed a collection of patents but were puzzled by how to interpret them and evaluate the associated legal risks. It was clarified that merely holding a patent doesn't guarantee FTO; patents can cover various aspects of technology, both upstream and downstream.
Different countries may have distinct interpretations of patent claims, and courts play a significant role in determining enforceability, making it a complex task. To address this complexity, the suggestion of utilizing patent clerks for thorough searches was emphasized, especially if we were considering commercialization. This was viewed as an essential initial investment to navigate the intricate patent landscape effectively.
Furthermore, the importance of seeking Intellectual Property (IP) protection was underscored. It not only provides more control over the licensing process but also instills confidence in potential business partners. However, it was made clear that even with a patent, FTO is not guaranteed.
In this conversation, an analogy was drawn - FTO is akin to building a house. If you have a patent for a house and someone invents a house with a window, you can still pursue legal action against them, even if their invention is novel and inventive. In summary, the discussion highlighted the complexities of patent analysis and FTO determination, the role of patent clerks, and the significance of IP protection in a world where patents don't automatically secure freedom to operate.

Interview with Gabriel Licina (he, him)

Interviewer: Thomas

Biohacker, Independent Researcher

“The most important thing you need is infrastructure, you can’t do anything with just good will, except maybe raise money for things you never intend to deliver. Start a company.”

In our discussions about Open Source Models for Steroid Production, we sought insights from an expert who specializes in frugal science and subverting patents for the benefit of the public in the biotech landscape.
One of the specific topics we were curious about was Open Insulin and whether their resources or organizational model could be advantageous to our goals. It was clarified that Open Insulin primarily operates as an advocacy group and is unlikely to engage in the shipment of physical components or products.
During our conversations, we received valuable advice regarding the importance of seeking diverse perspectives early in the process. Additionally, our contact shared information about a laboratory specializing in scaling therapeutics independently, bypassing the traditional pharmaceutical company route. This guidance provided us with valuable options for pursuing our objectives in steroid production within the open-source framework.

Interview with Kristy Hawkins (she, her)

Interviewer: Thomas

CSO of Antheia Bio - Yeast Pharmaceutical Company

Thomas had the opportunity to connect with this individual at the SynbioBeta event due to their expertise in yeast metabolic engineering. Their background included successfully commercializing the first yeast-based pharmaceutical production at a substantial scale of 126,000 liters. Furthermore, they had been actively involved in addressing drug shortages.
Our primary inquiry during our conversation was related to the process of scaling up a fermentation operation to a large, commercial scale. In response, they provided us with validated data and engaged in discussions regarding the legal intricacies associated with manufacturing-controlled substances. They also shared insights on how certain companies in this field were established. Their real-world perspective shed light on the challenges of scaling up a fermentation process, including the legal documentation required in both Europe and the United States. They offered valuable insights into what to expect when collaborating with Contract Manufacturing Organizations (CMOs) in the generic pharmaceutical space and shared their experiences with nonprofit technology development.

It became apparent that in the world of generic pharmaceuticals, pricing is driven to be as low as possible to enhance accessibility, necessitating the development of innovative technologies. They emphasized that nonprofit entities engaged in process development couldn't solely rely on grants; they needed wetlab facilities and downstream processes. When it came to scaling up, they cautioned that it typically requires investments in the tens of millions, covering technology transfer, capital expenditures (CapX), and operational expenses (OpX). The message was clear: “Even in the non-profit and pharmaceutical fields, someone always needs to find a way to sustainably fund the endeavor, given the substantial expenses associated with large-scale operations.”

Survey

Introduction

Androgen abuse is obtaining androgen from illegal or local supplier sources and using androgen without medical oversight[8], [9]. Androgen abuse is associated with sport performance, among ageing males, or young body dysmorphic disorder[9]. Though the transient side-effect of androgen abuse is well characterized, Randomized studies have shown that androgen abuse may cause heart failure, liver toxicity and subfertility[9].
In addition, in response to Ellen Jorgenson’s feedback to our process:
“This project is better suited for a university or company that has all the necessary permits and safeguards to handle steroid manufacture. Having been a mentor and judge for over 12 years at iGEM, I am particularly disturbed by the idea of people trying to replicate your process in order to self-treat.”,
We would like to investigate how our process might be influencing public, medical professionals and our potential user. We were grateful to be warned that our process might be likely subjected to be replicated and used for self-treat process without medical professional oversight. To understand what the potential effect of our goal and value – opensource sex hormone de novo production are to the public, we designed a multi-sectional and multi-lingual (English, Chinese and German) survey. With this survey, we are able to answer the following questions:

1. how are the public informed about hormone and hormone therapy (and how is their background correlate with their knowledge in hormone in general);
2. If they and/or people in their circle are undergoing hormone therapy in various forms; If they have faced barriers in seeking the desired medication
3. If hormone therapies considered safe, and if the patients experiences side effects
4. we are concerned if hormone therapy in general are recognized differently as gender affirming therapy, thus, if people undergoing hormonal therapy or gender affirming therapy are subjected to (any forms of) discrimination
5. how can we address testosterone abuse (use of testosterone without medical oversight), what is the public’s awareness of the testosterone mis- and abuse and how we can protect susceptible groups

Methods and materials

Participants information: Participants: because this is an opinion-based survey, we would like to be as inclusive as possible, thus, we included all participants who has agreed with our terms (participation information sheet and filled out the consent form) and whose age is over 18.

Survey design: : the survey comprises of 7 parts: 1), participants information, 2), consent form. Participants must agree to the terms before continuing. 3), participants (demographic) information, including age, gender, background, etc. 4), assessment of general knowledge of hormone. 5), participants opinion on hormone therapy in general, 6), participants opinion on gender affirming therapy, and 7), their opinion on testosterone mis-/abuse.

Survey platform: the survey platform is provided by Sosci survey (https://www.soscisurvey.de), and accessed via university of Vienna (https://sosci.univie.ac.at). This is because it allows compatible data analysis. furthermore, it ensures data anonymity.

Survey delievery: our survey is firstly developed and accessed in English. We further translated into Chinese (due to collaboration) and German version (local language). Each question is then assigned with a code and grouped in to either section 0 (participants information), 1 (basic knowledge about hormone), 2 (hormone therapy), 3 (gender affirming therapy), and 4 (testosterone misuse), and transferred into the Socie system. A questionnaire can then be generated from these question pools. The surveys are then published (activated) with a link and a QR code. The Links and QR codes are share via social media (subreddit), University WhatApp (study) groups, posting (at info counters at different faculties), via connections, leisure groups, local communities, iGEM communities, and Expo-events of university of Macau, ShanghaiTech iGEM teams and the Gut Alliance (iGEM teams of many Chinese universities).

Data collection: the survey is stopped, and subsequently, data were called on 9th of October. All data are collected and encoded in form of Excel sheet.

Selection, trimming, curation and analysis firstly, all participants (2160), who hasn’t completed the consent form, are censored at the very first step (crosRef consent form). Each participant is assigned with a number (autogenerated by Sosci) and assigned with either CN (99), DE(18), or EN(149) to indicate the language in which the participant has answered the survey. Subsequently, participants age fraction was analyses. All participants who have agreed the consent form (that participants must be over 18) and selected “under 18” in the age question are censored. All participants, regardless of the survey language, are pooled together for further analysis (n=190). Due to time issues, we were only able to conduct descriptive analysis. Single-choice-answer questions are given in pie charts; scale (1-5) rating questions were presented by bar charts; and opinion selection (multiple choices) are presented by bar graphs (see illustration 1).

Compounding factors for association/correlation: “quiz-score/info-source factors”: Participants were asked to consent not to google or ask for help during this section before the start of the first question. Three multiple choice questions were asked to assess their background knowledge. Choosing a correct answer will earn participants 1 point and choosing a wrong answer will take 0.5 point from each participant in the corresponding questions. A maximum of 17 points can be achieved in all three questions, and the minimal possible score is -8.5. In addition, one question asks where they have encountered the term hormone the most frequently. We assigned a modification point to each of the choices by the academic credibility of those resources, such as 0.25 for social media, like Instagram, Facebook, Twitter and Ticktock, 0.75 for online health articles (including credible researches, but we also consider misleading information and frauds) 1 for TV and newspapers, 1.5 for “from medical professionals”, 1.75 for “at place of work”, and 2 for research and review articles, as well as school and text books. “Background/research factors”: The participants background information are binned into 10 categories. Each category is assigned with a number which describes how likely a person from that category shows expertise in hormone biology (from 7-1). Our participants may show multiple background that are not necessarily related to the topic hormone, thus, a “deflation” modifier (X1 for selecting 1 background, X0.75 for selecting 2 fields, X0.625 for having 3 and X0.5 for having 4).

RESULTS, CONCLUSIONS ARE DISCUSSIONS

Due to time issues, we were not able to present the entire analysis. However, the entire figure set can be (found here), and the pooled data will be published after iGEM and made open. Here, readily interpretable data are discussed

Age, geography, gender, professional background, and research activity composition of participants

Majority (39%) of our participants are between 18-25. This is consistent with the fact that we posted our survey mostly at university buildings and online communities. The second major participant population aged between 26-35 (27%). Interestingly, under-age participants made up 21% of all participants before removal (Fig.1a). Majority of our participants are Asian, by geographic locations; 26% and 24% of all participants are European and North/Central American, respective, and 10% have not specified (Fig.1b). About half of our participants identify themselves as female, 35% as male, and 13% as neutral or non-binary (Fig.1c). More than 50 participants in our survey (1/4) claimed that they have background in medical, health, biological or psychological sciences (Fig.1d main), and 53% of all participants claimed that they are active in research (Fig.1d inset). This may well reflect biases in our sampling (means by which we spread our survey). We binned participants background and assigned a number according to relevance and research activity (see methods and materials) to create a factor for inferential analysis. However, this is not shown in our iGEM Wiki because of limited times.

Performance on general knowledge of hormone (section 1).

In section 1, we asked our participants a set of questions to assess their basic knowledge about hormone, and where do they encounter the term “hormone” most frequently. Their resulting quiz-score (see Fig.2a, left/green) is compounded with a modifying score assigned according to their information source (see method and materials section, so called “quiz-score/info-source factor”). Notably, the modified quiz-score/info-source factors (Fig.2a, right/blue) are bimodally distributed: the upper peak with larger mean and variance, and a lower peak with lower mean and smaller variance. We thought this (both scores modified and unmodified with their most frequent source) might be an interesting factor to correlate with their responses to section 2, 3 and 4. We managed to show that our methods might explain some variances when we associated background (“background/research factor”) and research status to their performance in the quiz (“quiz-score/info-source factor”). When only the background score (assigned number) is correlated with either quiz score or quiz-score/info-source factor, the correlation coefficient is negative(Fig.2b). When both factors are modified, the correlation co-efficient is positive and 7% of variance can be explained by this model (Fig.2c). This suggests that our data is very noisy and further curation, analysis showed performed accordingly.

Hormone therapy

When participants were asked if they are well informed about hormone therapy, their response showed they are intermediate well informed (Fig.3a). In contrast, when they were ask if the public is well informed, the responses clearly showed that great majority of our participants believed that the public is poorly informed about hormone therapy(Fig.3b). This is consistent with Fig,3c, where there is an agreement among participants on that there should be more accessible educational resources about hormone therapy. When participants were asked which aspect of hormone therapy they would like to know more about, the top one hit is risk and safety (Fig.3d). In contrary, majority participants believed that the public should be better informed about the purpose of hormone therapy(Fig.3e). Essentially, 63% of our participants know one or more people undergoing any sort of hormone therapy personally (Fig.3f), and more than 70 participants registered that the person (people) they know of are receiving gender affirming hormone therapy (Fig.3g).

Gender affirming therapy

One of our primary interests in this section is assessing factors such as costs, health provider availability, knowledgeability and supportiveness of the health providers. For when asked if the cost, accessibility, knowledgeability, and supportiveness of their (and of their circle) were asked, majority of participants have given “I don’t know” as answer (Fig.4a and b). The second major (compound) response for cost and accessibility are yes to both questions (“yes, unaffordable”, “yes manageable” for cost; “yes, unable to find” and “yes, difficult but possible” for access). However, the fraction of both answers are similar. 23% reported that the cost of therapy was not a barrier, which is equivalent to the number of participants who reported the cost of therapy was burden but manageable. In contrary, 11% reported that I was easy for them to find a clinic/health provider, reflecting that access and availability barriers might override cost burden. Notably, 33% of participants reported that they are not satisfied with their health provide due to lack of knowledge and support(Fig.4c). This might be a plausible consequence of lack of gender medicine specialties.

When asked about safety concerns, more than half of all participants believed that gender affirming therapy is safe only under appropriate medical oversight. However, 13% of participants believed that gender affirming therapy is very safe.

Participants’ responses have clearly shown that people receiving gender affirming therapy are very likely to be subjected to discrimination. Most participants believed that educating the general public about sex and gender could provide means to alleviate potential discrimination.

Testosterone abuse

Finally, we asked if hormone abuse and misuse were common, at least in the scope of this survey. 51 participants responded that they or someone in their circle used testosterone without medical oversight for various purposes (Fig.5a), and a large fraction of those who either considered or actually used testosterone without medical oversights are not motivated by winning a competition (Fig.5a, inset). 30 participants reported that their (or their acquaintances’) consideration to use or use of testosterone without medical oversight are driven by aligning sex characteristics to their gender identity (Fig.5c). A slightly small fraction of participants have given the confirmed that their psychological discomfort was related to desired muscle mass and hyper-masculinity. When our participants were asked if the use of testosterone for increasing perceived masculinity should be restricted, participants’ responses showed rather conservative opinion (Fig.5d)

Concluding remarks

In this survey we try to address public awareness of hormone biology, hormone therapy in general, gender affirming therapy, risks for discrimination and testosterone abuse. During the survey, we assessed public’s knowledge about hormone by asking participants to answer a quiz. However, because the majority of our participants have professional background in medicine/health/biological/psychological science, and more than half of our participants are active in research, we highly suspect that we have overestimated the public’s knowledge due to selection bias (i.e., by distributing the survey in an academic environment). We have shown that there is an agreement in that our society is generally poorly informed about hormone therapy, and more educational resources about hormone therap should be make availble.

In surveying gender affirming therapy specifically, we observed potential inaccessibility of gender affirming therapy du to high cost, unmet availability of medical professionals and low satisfaction with health providers. These could all possibly be consequences of limited gender medicine specialists. Importantly, our data clearly showed that gender affirming therapy patients are much more likely to be subjected to general hormone therapy. Finaly, we show that testosterone abuse without medical oversight can result from poor accessibility. Motivation of testosterone abuse may include desire to align sex characteristic to gender identity and body dismorphic disorders.

REFERENCES

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