Week 1 HW: Principles and Practices

1. “An application of synthetic biology that I recently found out about, and I’m really excited for, is partial cellular reprogramming.”

It’s achieved by inducing the expression of factors called “Yamanaka factors”, which enable a cell to regain a pluripotent state in which DNA methylation patterns and chromatin architecture are reset to a younger state in a “rejuvenation” process that enhances health and lifespan for individuals. (1, 2) Recently, a treatment intended to treat optic neuropathies based on this mechanism was approved by the FDA for its first clinical trials; this treatment consists of an AAV2 vector that carries the Oct4, Sox2, and Klf4 factors. Systemic doxycycline administration is needed for almost two months to activate OSK expression. (3) What if we could engineer a self-regulated genetic circuit that, by utilizing biosensors, detects aging or disease markers like transcription factors that enhance senescence-associated secretory phenotypes (SASPs), and thus activates itself and begins rewiring? To ensure non-malfeasance, the system incorporates a failsafe kill switch as a safety module that induces apoptosis if the cell loses its differentiated identity or if markers of full pluripotency, such as Nanog, are detected, to reduce the risk of cancer. By the time a “safe-by-design” technology like this becomes approved and available to the general public, there must be some important regulations upheld.

2. The policy goals

Biosafety:

• Genetic safety and vectors: Ensure that the reprogramming does not result in oncogenesis and that the use of vectors (such as AAV2s) does not cause insertional mutagenesis or unforeseen infections (due to its viral nature).
• Responsible usage: Restrict access to reprogramming vectors to authorized hospitals to prevent self-administration and prevent the genetic circuit from being altered or replicated at home without adequate security controls. There shouldn’t be people modifying or hacking the genetic circuit nor the vectors.

Public accessibility and equity:

• Universal access: Everyone should be able to access such treatment if required, so there should be financing or insurance programs that guarantee it.
• Inclusive standards: Treatment must work on a global genetics level, being effective regardless of ethnic diversity
• Transparency: People should be taught the nature of things we apply on them and informed of possible risks

3. The potential actions and the actors:

Actors: Researchers, Medics, Industry, Government and Patients

1. Enhance safety by standard design:

Main cast: Researchers, Industry

• The researchers must develop a genetic circuit design that must induce apoptosis whenever there is a risk of oncogenesis or a full dedifferentiation process; industry must standardize that design to diminish risk.
• We are assuming that the pluripotency (nanong) indicators are completely accurate.
• Failure here results in the formation of teratomas or tumors.

2. Funding to ensure equity and access:

Main cast: Government, Medics, Patients

• The government must finance treatment for patients that need it but can’t afford it (through funding the program through taxes on purely cosmetic longevity treatments, for example) and incentivize the creation of genomics databases of different ethnic groups. Medics must contribute to the genomic database by taking samples while doing service in the mentioned groups.
• We assume that the cost of such treatment decreases as time passes and advances are made in the field.
• Failure here results in discrimination (economic and/or ethnic) and leaves people without support.

3. Development of transgene control systems

Main cast: Medics, Researchers

• Researchers should develop sophisticated control systems, not only in the form of a synthetic chemical compound (drug) that inhibits the circuit by marking its proteins for degradation, but also in an inhalation-mediated inhibition mechanism with a volatile compound that triggers an inducible promoter that codes for a regulatory protein that instantly degrades the Yamanaka factors. Physicians should prescribe this drug to stop any unwanted side effects that some patients might experience (oncogenesis).
• We assume that the transgene control systems are effective and fast enough to reverse a dedifferentiation process before it becomes irreversible or tumorous.
• Failure here results in possible untreatable disregulations of the system.

4. Scoring the options

5. What to prioritize

I believe that options 1 and 3 are the most important in this case, so I would recommend developing a standard circuit design that is self-regulating and has an external regulation mechanism in case, in a physician’s judgment, it is considered necessary to stop the process in any patient. I would suggest this kind of approach as a prerequisite for any autonomous reprogramming system intended for human use in the FDA.

6. Bibliography

1. Takahashi & Yamanaka (2006) Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 126, 663–676. http://dx.doi.org/10.1016/j.cell.2006.07.024
2. Schmidt & Plath (2012) The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. http://genomebiology.com/2012/13/10/251
3. Ocampo et al. (2016) In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 167, 1719–1733. http://dx.doi.org/10.1016/j.cell.2016.11.052
4. Macip et al. (2024) Gene Therapy-Mediated Partial ReprogrammingExtends Lifespan and Reverses Age-RelatedChanges in Aged Mice. http://dx.doi.org/10.1089/cell.2023.0072
5. Biosciences, L. (2026). Evaluating ER-100 for Safety in People With Glaucoma or Non-Arteritic Anterior Ischemic Optic Neuropathy (Optic Nerve Conditions). https://clinicaltrials.gov/study/NCT07290244

7. Searches:

• Google: “Life Biosciences”
• Gemini:

1. “Me gustaría que clarifiques la redacción de la introducción a la aplicación de la biología sintética de la que voy a hablar en mi tarea.”
2. “Leí estos dos papers Takahashi & Yamanaka (2006) y Schmidt & Plath (2012). Estos hablan de los factores OSK ¿Ya han habido avances de terapias desarrolladas con estos? ¿Cuáles son los avances más recientes?”