Week 1 HW: Principles and Practices

Governance Assignment

Biological Engineering Application

Immunotherapies are a promising avenue in cancer treatment as they leverage the immune system’s innate ability to recognize and target non-self structures. However, traditional immunotherapies often result in on-target off-tumor effects, particularly in solid tumors. Synthetic biology has enabled new avenues of discovery to minimize this immunotherapy-related toxicity: engineering immune cells to target tumor-associated antigens (TAAs) or engineering genetic circuits to detect cancer disease signatures (Zhu et al., 2024). For example, modifying the traditional Chimeric Antigen Receptor (CAR) T-cell immunotherapy approach with a synthetic Notch (synNotch) receptor has demonstrated the ability to suppress off-target cytotoxicity related to organ rejection (Reddy et al., 2024) and selectively target cancerous cells in the central nervous system of mice rather than elsewhere in the body (Simic et al., 2024). Yet, while synNotch-modified CAR-T therapies show promise in their ability to reduce immunotherapy-related toxicity, additional research is needed to effectively administer these bioengineered cell systems in patients beyond pre-clinical experimentation.

Governance Goals

Goal 1: Perform rigorous pre-clinical testing to ensure new immunotherapies meet safety and efficacy standards before introducing into human patients.

Goal 2: Design ethical clinical trials with standardized eligibility, safety, and efficacy protocols with consideration for unique patterns of patient progression or response to treatment.

Goal 3: Create policies and organizations to promote equitable access to cancer prevention, screening, diagnosis, and immunotherapy resources to patients from diverse backgrounds and socioeconomic statuses across the globe.

Governance Actions

Option 1: Create an international organization to create global standards for immunotherapy clinical trial design and safety measures

1. Purpose: Immunotherapy safety regulations are regulated at the national level, so efforts to promote global administration of novel cancer immunotherapies may experience roadblocks if national standards do not align. Establishing international safety and efficacy standards for immmunotherapy clinical trials will promote efficient administration of immunotherapy treatments across global lines.
2. Design: An international healthcare organization, such as the WHO, must establish and agree upon an international standard for efficacy and safety in immunotherapy clinical trials. Then, all countries that participate in this organization must agree to the international standards to ensure ease of treatment deployment across global lines.
3. Assumptions: This option assumes that international clinical trial standards will supercede any national guidelines, and that countries will be willing to adopt the international standard and/or deploy their immunotherapies in other countries.
4. Risks of Failure and “Successes”: Establishing international immunotherapy clinical trial safety and efficacy guidelines may “fail” if the organization lacks the power to enforce the adoption of these guidelines across its participating countries. However, “success” of this option may delay the time it takes to put immunotherapies into clinical trials if international standards are incredibly restrictive and difficult to meet.

Option 2: Establish an international database to upload immunotherapy pre-clinical and clinical trial data

1. Purpose: To create a centralized, accurate database with the safety and efficacy data for immunotherapies in pre-clinical and clinical trials adminsitered to diverse patient populations. This database will ultimately promote safer and more effective administration of immunotherapies as a large dataset is available for review.
2. Design: Either an international healthcare organization (ex. WHO) or an independent organization would oversee the funding for the database and ensure the uploaded data is both reliable and accurate.
3. Assumptions: This option would assume that immunotherapy administration can be standardized across diverse healthcare settings, particularly on the global scale. Additionally, creating a comprehensive and accessible database assumes that uploaded data is not subject to reportability bias.
4. Risks of Failure and “Successes”: This measure would fail if the uploaded data is skewed toward well-funded research programs and not local healthcare systems with patients who experience barriers to immunotherapy access because this would not be a comprehensive dataset. However, if this measure is “successful”, immunotherapies with lower overall efficacy according to database metrics but high efficacy in a small patient population may be deprioritized or defunded.

Option 3: Establish an independent organization to increase access to preventative cancer screenings, diagnostic tools, and long-term care

1. Purpose: Inadequate access to preventative cancer screenings (i.e. mammograms, pap smears, colonoscopies, etc.) as a result of financial, geographic, or other barriers leads to later diagnosis and poorer progonosis. As immunotherapies are most effective when treatment is begun at earlier stages of cancer progression, inadequate preventative measures undermine the innovative bioengineering design of novel immunotherapies. Establishing an organization to ensure equitable access to cancer screenings and diagnostic tools without financial barriers, both within the United States and abroad, will allow the advances of innovative immunotherapies to benefit more patients than just those with easy access to preventative measures.
2. Design: As this organization would be independent of government funding, it would require public or philanthropic funding to decrease the cost barriers to preventative cancer screenings for patients with financial concerns. Additionally, the efforts of this organization would need to be integrated with healthcare systems on both the local and international scales to establish sites to receive preventative screenings and the capability to receive long-term follow-up care.
3. Assumptions: This option relies on the assumption that patients whose cancer is detected by increased preventative measures will then be able to access the immunotherapy treatments that target their cancer.
4. Risks of Failure and “Successes”: Without sufficient funding, this independent organization could ultimately shut down and fail in its mission to increase equiable access to preventative cancer screenings. Additionally, if the organization does not have reliable connections to local healthcare systems, its efforts to reduce cost barriers for patients seeking cancer screenings will not be realized. If this organization were to be “successful”, the influx of patients who are identified by screening measures may cause strain on the healthcare system.

Scoring Governance Actions

Prioritization

I believe Option 3 should be prioritized. While innovative bioengineering applications to cancer immunotherapies are a promising avenue for decreasing cancer mortality both nationally and internationally, these efforts are in vain if they cannot be administered effectively in a large patient population. Increasing early detection of cancer by promoting equitable access to cancer screenings and diagnostic testing will ultimately increase the use of bioengineered immunotherapies as cancers detected at earlier stages are better candidates to be treated by immunotherapy approaches.

Week 2 Preparation

Professor Jacobson

1. The error rate for a polymerase is 1 in 10⁶ (1,000,000) bases. The human genome is 3x10⁹ (3,000,000,000) base pairs in length, leading to an estimated 3,000 errors per replication of a human cell. Biology has processes in place, such as mismatch repair, capable of recognizing and excising these errors, then synthesizing the correct nucleotide.
2. The genetic code is comprised of 64 distinct codons that encode 20 naturally-occuring amino acids. However, not all codons are used equally because each tRNA with an anticodon specified for a particular amino acid are not equally expressed in every organism.

Dr. LeProust

1. Currently, the most commonly used method for oligo synthesis is phosphoramidite chemistry.
2. Oligos longer than 200 bp have high error rates and high rates of decay.
3. As a result of the high error rate and rates of decay, a 2000 bp gene synthesized via direct oligo synthesis would no longer resemble the desired sequence and would not encode the desired protein.

George Church

1. The 10 essential amino acides are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These amino acids are not naturally synthesized in the human body and therefore must be consumed through the diet. The “Lysine Contingency” from Jurassic Park describes a genetic mutation introduced into the dinosaur enzyme for lysine synthesis as a means of protection from dinosaurs getting off the island (if the dinosaurs cannot synthesize an essential amino acid like lysine, they will not survive long). However, considering lysine is one of the amino acids that is solely ingested through the diet, the “Lysine Contingency” would not have any affect on dinosaurs because they should not have an enzyme responsible for lysine synthesis.

Website Preparation

I completed the setup of my personal HTGAA website, including adding my biography, contact information, and cover photo to my homepage.