Week 1 HW: Principles and Practices

–

1. Biological Engineering Application

Proposed application: Engineered microbial biofactories for small-molecule drug production.

Having a background in Biomedical Science and current training in translational physiology and pharmacology, I am particularly interested in small-molecule drug development. This project proposes engineering commercially viable cells capable of producing small-molecule drugs that are difficult or costly to synthesize using traditional chemical methods.

Inspired by microbial production of compounds such as penicillin, this approach would use bacterial or alternative host cells to generate either full drug molecules or high-value intermediates, depending on chemical feasibility. Using CRISPR or prime editing, metabolic pathways would be modified to enhance yield and specificity, similar in concept to the work by Paddon et al. (Nature, 2013).

As a proof of concept, the kappa opioid receptor (KOR) is selected as the biological target, with Salvinorin A as the compound of interest. Chemical synthesis of Salvinorin A suffers from extremely low yields (~0.15–5%), making it expensive and impractical for large-scale research. Improving yield through microbial biosynthesis would reduce costs, accelerate KOR research, and support the development of novel analgesics.

2. Governance & Policy Goals

Goal 1: Safety

• 1a. Prevent misuse of engineered microbes to produce psychoactive or harmful substances
• 1b. Prevent harmful exposure to laboratory personnel

Goal 2: Equal Opportunity

• 2a. Maintain low production costs to ensure global accessibility
• 2b. Avoid monopolization of the technology and promote open access

Goal 3: Ethical Innovation

• 3a. Encourage transparent reporting of methods, yields, and failures
• 3b. Align research incentives with public health goals, particularly analgesic development

3. Governance Actions

Action 1: Biosafety Review (DURC)

• Purpose: Identify misuse and safety risks in engineered microbes producing bioactive compounds
• Design: Mandatory dual-use and toxicity assessments by IBCs; compliance tied to funding and regulatory approval
• Assumptions: Honest reporting; predictable risks
• Risks & Success:
  • Failure: Bureaucratic burden slows research
  • Success: Improved biosecurity and public trust

Action 2: Genetic Kill Switches

• Purpose: Prevent environmental escape or uncontrolled proliferation
• Design: Engineered auxotrophy and kill-switch mechanisms; incentives via funding and approvals
• Assumptions: Stability and affordability of safeguards
• Risks & Success:
  • Failure: Mutation or safeguard failure
  • Success: Reduced environmental risk

Action 3: Pharmacovigilance

• Purpose: Monitor production and use of KOR-targeted molecules
• Design: Controlled distribution; adverse-event reporting by clinicians
• Assumptions: Reliable detection and reporting
• Risks & Success:
  • Failure: Under-reporting or diversion
  • Success: Safe translation without blocking research

4. Governance Scoring Matrix

5. Prioritization & Ethical Reflection

Based on the scoring, Options 1 (DURC biosafety review) and 2 (genetic kill switches) are the highest priorities. These address the most immediate ethical risks associated with misuse, environmental contamination, and accidental exposure.

While pharmacovigilance is important, it becomes more relevant at later translational stages. Trade-offs include increased upfront costs and longer development timelines; however, these are justified by improved safety, transparency, and public trust.

The primary ethical concern identified during this week’s coursework is dual-use misuse of engineered microbes, including unauthorized production or environmental release. Strong oversight, transparency, and adherence to biosafety protocols should sufficiently mitigate these risks.

Homework – Lecture 2 Questions

George Church Question

Question: What are the 10 essential amino acids in all animals, and how does this affect the “Lysine Contingency”?

Answer:
The 10 essential amino acids in animals are:

• Histidine
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenylalanine
• Threonine
• Tryptophan
• Valine
• Arginine

Animals cannot synthesize lysine endogenously and must obtain it from their environment. This weakens the concept of the lysine contingency as a biosafety mechanism for engineered organisms. Many natural environments already contain lysine, meaning deprivation is unreliable. Additionally, organisms can evolve around this dependency, making lysine-based containment a fragile and insufficient safety strategy on its own.