Team:IISER-Tirupati India/Implementation
iGEM aims to solve real-world problems using synthetic biology and this is only complete with a proposed implementation plan along with the solution.We tried to address this by considering various aspects such as end-users, safety and engineering. Meeting with various stakeholders from fields such as translational research, contraceptive development and business management helped us understand the challenges and opportunities of implementing OviCloak in the real world. Overall, OviCloak can be implemented in the real world with consideration for the safety aspects and challenges associated with it.
END USERS
Uterus owners
The end-users of OviCloak are proposed to be sexually active uterus owners. OviCloak will be optimal for uterus owners as it is non-hormonal and mimics a natural process to block fertilization. It doesn’t act on their body, but only on the gamete and due to this specific targeting, there will be minimal side effects on the body of the uterus owner with the benefits of long term contraception and reversibility.
Gynecologists and IVF Specialists
The best place for implementation of OviCloak is going to be in a hospital or clinic. The chosen technique for delivery of the genetically modified organism is hysteroscopy, which is a standard procedure known to healthcare professionals working in the Gynecology and Obstetrics field and IVF.
Implementation In The Real World
While designing OviCloak, the biggest challenge we were facing was to find a way to introduce the bacteria to the fallopian tubes. As a part of our Human Practices, our interactions with various experts in the field introduced us to an existing and commonly used method in hospitals and clinics called hysteroscopy.
The hysteroscopy method is commonly used in gynecology and IVF Fields and is a safe, effective, and non-invasive method compared to conventional gynecological procedures. [1]
For implementing OviCloak in the real world, we decided to deliver the genetically modified bacteria with Hysteroscopy. Due to the various problems associated with devices that stay inside the uterus, we didn’t want to develop a new device that will be retained in the uterus of the user, and thus, the method of hysteroscopy is ideal for OviCloak.
Hysteroscopy is done with medical assistance and requires constant X-Ray monitoring to ensure that the catheter is inserted without any issues. This is due to the fact that the Ostia and the Fallopian tube are dynamic structures and that there is no chemical or significant physical difference between the ampulla and the other components of the Fallopian tube.
As advised and recommended by an IVF specialist, the diameter of the hysteroscope used will be about 2.9 mm and it further narrows for the part that enters the fallopian tube. The volume of the hysteroscope is about 2-3mL. We’ll use air as our pushing entity to inject 1.75 mL - 2 mL oil or a saline solution containing the genetically modified bacteria. Oil is USG opaque which helps in guidance for the injection of the droplet.
A solution of genetically modified bacteria of a specific concentration will be prepared. Then, the catheter will be inserted under medical guidance up to the ampulla. An injector is projected with narrow long incisions on both sides of it, which ensures that the genetically modified bacteria form a ring along the circumference of the fallopian tube.
Our team chose this procedure to bring OviCloak into reality as this allows the doctor to directly inject fluids in the fallopian tube compared to other procedures. As this standard procedure is in regular practice by healthcare professionals, it will aid in OviCloak’s implementation in the real world.
Some additional points on implementation from our human practices:-
(i) Talking with gynecologists, we realized that many uterus owners opt for long-term and reversible contraception after parturition. In such cases, the user will already be in a hospital setting during parturition. Thus, OviCloak can be administered easily.
(ii) While performing hysteroscopy on individuals belonging to the transmasculine spectrum, (especially those on hormone replacement therapy), a smaller size speculum [3] is suggested to be used by the gynecologist.
(iii) When administrating the contraceptive for individuals belonging to the intersex spectrum, special care should be taken so that the genetically modified bacteria does not go in the urinary bladder, instead of the uterus. Performing a procedure like a hysteroscopy on intersex individuals requires more precision on the healthcare professional’s part to make sure that the bacteria reach the fallopian tubes.
If and when, the user wants to reverse the contraception, using the same procedure, xylose can be transported to the fallopian tubes. Xylose is a sugar molecule that is generally not found in the fallopian tube environment. Through our model, we were able to calculate the amount of xylose that will be required to reverse the contraception. The concentration of Xylose required to reverse the contraception should be about 0.033 M. Xylose is readily available for purchase and is easy to handle.
The presence of xylose will kill the genetically modified bacteria due to the kill switch it is engineered with. Thus, effectively reversing contraception.
Storage and packaging
The Lactobacillus species have been shown to be stably maintained at 4°C for 24 months. The bacteria can even stay stable at 22°C (room temperature) for up to 4 weeks. [2]
Most of the hospitals or clinics have a 4°C refrigerator available and thus, they will be able to store the Genetically modified organism and administer doses to several uterus owners for a long time. Thus, there is no additional cost of storage of the genetically modified organism on part of the hospitals.
Through our Model, we were able to calculate a rough estimate of the initial inoculum of the genetically modified bacteria that will be required. The minimum concentration of bacteria required for transfer should be about 600-900 CFU/mL. Accounting for all unknown losses, the value administered should be around 1000 CFU/ml. As the volume of the hysteroscope is about 2-3 ml, each transfer will contain about 1.75 ml - 2 ml solution. To deliver the desired amount, 4-6 such transfers are required.
The vials for packaging of the genetically modified bacteria should be amber-colored or black. This is due to the fact that our genetically modified bacteria have a light-inducible kill switch for biosafety and thus, they should not be exposed to visible light conditions. Each vial can hold up to 12 ml of bacterial culture solution. Each administration of OviCloak will use up to two vials. These vials would need to be sealed off properly,only to be opened inside the hospital or clinic under the supervision of a healthcare professional.
These guidelines for packaging will also take care of the fact that our product is not communicated in a way that makes it implied for any particular gender. This non-hormonal method can cater to the needs of all people with a uterus and this should be maintained.
Specific protocols for delivery of OviCloak using hysteroscopy can be developed once the safety of OviCloak has been established and when it goes into the clinical trials stage.
Implementation in Public Sector
During our discussion with the Contraceptive Technology Innovation (CTI) Exchange, a global contraceptive research platform funded by Bill and Melinda Gates Foundation, we came to know about the different procurement agencies that interact with the manufacturers of contraceptives and procure contraceptives for NGOs and National governments.
Once these procurement agencies are convinced about the viability and importance of the product, they recommend the governments go forward with it and implement it on a large scale. The national governments and NGOs go ahead and distribute contraceptive products with the help of a third party.
With respect to OviCloak, a similar strategy will be applied for accessibility of the contraceptive around the world.
Our country India was one of the first countries to initiate nationwide family planning programs around the 1950s. Now, India has an extensive network of family planning through various schemes. Most contraceptives in remote corners of India are available in local clinics and hospitals at subsidized rates and can be availed with the help of national schemes. Procedures like hysteroscopy are performed on a regular basis for free or with minimal costs in government hospitals across the nation.
Implementation in Private Sector
It is quite expensive to perform hysteroscopy in a private hospital. In India, due to the lack of healthcare facilities in the public sector, many individuals from metropolitan cities prefer private healthcare facilities. With good health care insurance on the user’s part that covers contraception, the implementation of OviCloak in the private sector can also happen smoothly.
SAFETY ASPECTS
While implementing OviCloak, the following safety aspects need to be considered:-
- Biosafety: While developing any genetically modified organism, the most important factor is the safety of the environment. As the uterine and fallopian tube environment is a dynamic one, there are chances of the bacteria flushing out of the system. For such a scenario, we have engineered the bacteria with visible light ( 450-500 nm) inducible kill switch, which will kill the genetically modified bacteria in the outside environment.
- The modified bacteria will be commensal, so ideally the risk should be minimal. However, as it is a novel technique to introduce the bacteria to the fallopian tubes, there can be unknown complications that can arise due to a genetically modified organism being introduced into that environment. Hence, in order to investigate the effect of the GMO on the microbiome of the fallopian tube, comprehensive in vivo studies will be required.
- It has been shown that the microbiome of the human population can also be affected by age, ethnicity, and demographics. As mapping out the human microbiome is a relatively new field of research, the comparative data of different demographics and ethnicities is still incomplete. Thus, the different native microbiomes are another safety factor to be considered while implementing OviCloak around the world.
- Different comorbidity factors like diabetes, obesity, previous drug abuse, and future plans of pregnancy have to be kept in mind while administering this contraceptive. There will be designing of experiments where each of the factors are tested independently and then correlated with other factors. Theoretically, the above-mentioned external factors will NOT be weighing too heavily on the real-life implementation, but these factors play a crucial role in the safety of the user.
- Another safety factor to be kept in mind while implementing OviCloak is Horizontal Gene Transfer with other commensal bacteria residing in the system. To tackle this, we have preferred genome integration for genetically modifying the organism. This reduces the chance of HGT .
- Due to specific targeting of the contraceptive, there will be almost NO hormonal disbalance. This will reduce the secondary side effects that we usually see in normal birth control pills, IUDs, and other synthetically made contraceptives.
To know more, see Safety
Challenges
There are numerous challenges that can be faced while implementing a solution like OviCloak. Some of them are:-
- In many cultures, contraception is still viewed as taboo. This can hinder sexually active uterus owners in need of non-hormonal, long-term, and reversible contraception to access OviCloak. Another challenge is the lack of awareness that is rampant in many areas across the globe.
- After the COVID-19 pandemic, there is a general fear of microorganisms in people’s minds and thus, OviCloak being a genetically modified microorganism might make it difficult for people to accept this solution to contraceptives
- The hysteroscopic method, though being a common gynecological procedure, might not be available in the remote corners of India. This may hinder people from rural backgrounds from having access to OviCloak.
- The distribution of OviCloak can be difficult as a cold chain needs to be maintained while transporting the bacteria. Any breaks in the cold chains can lead to decreased viability of the genetically engineered bacteria. Thus, the distribution of OviCloak, especially over long distances can be challenging.
- Due to the factors stated above, human clinical trials and follow-up might be difficult to carry out properly and thus, a credible proof of concept for humans can be challenging to show.
- Due to the stigma around intersex individuals and transphobia, finding queer affirmative healthcare professionals who are trained to perform surgeries on the transmasculine and intersex community can be challenging for individuals around the world.
- As OviCloak is a novel approach to contraception as well as the introduction of Genetically modified organisms to the fallopian tube of uterus owners. There is a lack of studies on how a genetically modified organism interacts with the human body, which can make the implementation of OviCloak challenging.
Conclusion
OviCloak is a modern-era contraceptive with the least side effects and large-scale availability. It is a novel technique and thus, its implementation in the world will be unique as well as challenging. By merging our contraception with an already existing and commonly practiced procedure in hospitals, we have taken the first step in implementing this contraceptive in the real world in a best-suited way. When it comes to packaging and storage, due to the stability of Lactobacillus at 4°C for a long time, there will be no additional cost of storage of OviCloak in hospitals. Due to the well-established systems of large-scale contraception procurements and distribution, OviCloak can reach the public and be accessible to uterus owners all around.
Several safety aspects are associated with the implementation of OviCloak in the real world ranging from environmental contamination to the physical health and priorities of the user. Along with them, many challenges such as availability of equipment, social stigma, distribution, and non-availability of healthcare professionals have to be addressed and overcome to implement OviCloak successfully.
Summing up, OviCloak which is a novel contraceptive for uterus owners has a great potential to be implemented in the real world and bring about a positive change for the health and well-being of uterus owners.
References:-
- Fard, S. A., Gharabaghi, P. M., Montazeri, F., & Mashrabi, O. (2012). Hysteroscopy as a minimally invasive surgery, a good substitute for invasive gynecological procedures. Iranian journal of reproductive medicine, 10(4), 377.
- Rerksuppaphol, S., & Rerksuppaphol, L. (2010). Lactobacillus acidophilus and Bifidobacterium bifidum stored at ambient temperature are effective in the treatment of acute diarrhoea. Annals of tropical paediatrics, 30(4), 299-304
- Krempasky, C., Harris, M., Abern, L., & Grimstad, F. (2020). Contraception across the transmasculine spectrum. American journal of obstetrics and gynecology,222(2), 134-143.
- Moore, J. F., & Carugno, J. (2020). Hysteroscopy. StatPearls [Internet].
Our Sponsors
