Week 1 HW: Principles and Practices
- First, describe a biological engineering application or tool you want to develop and why. This could be inspired by an idea for your HTGAA class project and/or something for which you are already doing in your research, or something you are just curious about.
Response
I’m interested in developing synthetic biology and pharmaceutical based platforms that use engineered bacteria to address major environmental and health challenges, more specifically I want to to explore the effectiveness of bacteria as therapeutic agents to prevent or treat certain type of conditions such as malaria or cancer. These engineered bacteria can live in the human as part of the normal flora but is also cheaper and less harmful as normal pharmaceutical medications.
Another part of the engineering bacteria ambitions is related to climate change and carbon footprint, as it looks synthesising bacteria that could decrease human wastes then give us oxygen and decrease carbon dioxide seems as hopeful goal and contributing to the long lasting of human civilisations and human health.
This connects my pharmaceutical field of study with synthetic biology to create solutions that are global irrelevant, beneficial and scalable.
- Next, describe one or more governance/policy goals related to ensuring that this application or tool contributes to an “ethical” future, like ensuring non-malfeasance (preventing harm). Break big goals down into two or more specific sub-goals.
Response
- Main goal: One of the primary governance goals for this application is ensuring that the engineering bacteria are used in pharmaceutical production and environmental intervention remain control safe and aligned with their public health. Throughout the life-cycle from design to testing to implementation and disposal, these engineered bacteria should have two precautions:
Subgoal Their design should be reversible and enable to persist evolving or spread outside and intended context. This include preventing the gene transfer or the uncontrolled mutations or surviving beyond defined conditions.
Subgoal Preventing that misuse risk is also important to ensure the uses of vaccines and co2 metabolism cannot be repurposed into harmful applications.
- Main goal: The second governance goal is to ensure that the benefits of the engineer bacterial system are distributed fairly and not enhancing the already existing environmental and global health inequalities.
Subgoal This can achieve by ensuring global accessibility and affordability by giving engineered bacteria locally by a lot of effect, especially for populations that are more affected with the problems of malaria or air pollution.
Subgoal Also the public trust, and transparency should be very highly valued as communication, oversight and accountability are needed to understand how and why the engineering bacteria are used in a particular environmental context.
- Next, describe at least three different potential governance “actions” by considering the four aspects below (Purpose, Design, Assumptions, Risks of Failure & “Success”).
Governance actions:
Mandatory built bio-containment for engineered bacteria:
Proposal: currently, many engineeried bacteria rely on physically engineered containment such as like labs and bio reactors, but this action focuses on requiring genetic biocontainment mechanism such as killer switches or metabolic dependencies or genetic methods for the bacteria engineered in pharmaceutical production or environmental applications.
Design: Actors: Academic researchers, biotech companies, funding agencies, regulators.
Funding agencies are regulators required by a containment future plan as a condition of approval of funding. Researchers should design organisms that cannot survive without specific laboratory or industrial conditions. Companies must document containment strategies during review and production.
Assumptions: bio-containment strategies are reliable and may remain effective overtime, and researchers can implement these mechanisms without losing functionality or effectiveness.
Risks: the containment mechanisms may fail or mutate allowing the survival and unintended environments. Or it could overly strict the requirements to produce or research or design a new innovation in academic settings.
Tiered regulatory oversight based on use case.
Proposal: engineered microbs are often regulated similar regardless of whether they are only used in contained pharmaceutical manufacturer or environmental application. This action is tiered oversize system with increasing scrutiny as a potential exposure and scale exposure.
Design: Actors: federal regulators institutional, safety committees or IBCs and the public health agencies. to lower risk, fully contained bacterial systems should face streamlined approval, other high-risk applications must require additional review testing and monitoring, and IBCs should coordinate with nation regulators for high impact deployment.
Assumptions: the risk can be reasonably categorised by application type and scale of use; regulatory agencies also have expertise and resources in such fields.
Risks: misclassification could underestimate real world risks, while complex regulatory layers may delay the deployment of urgently needed vaccines or the therapeutics.
Equity-founded access requirements:
Purpose: when novel treatments are discovered currently, the overall productions and benefits may not reach the populations most needing that treatment, this action proposes linking innovation to equitable access outcomes
Design: Actors: government global health organisations and pharmaceutical companies.
Public funding is title to avoid ability or access commitments and partnerships should be established to support global distribution and manufacturing. Also the affected communities should be supported with knowledge in order to grow and contain the bacteria within the communities.
Assumptions: the access conditions can influence how the industry and research operations can improve. Also, global partnerships can overcome the current infrastructure barriers.
Risks: access may still not be enforced overly in a fair way. or we can have lost of profits that could limit private sector participation.
| Does the option: | Mandatory built bio-containment | Tiered regulatory oversight | Equity-foundation |
|---|
| Enhance Biosecurity | 1 | 2 | 3 |
| • By preventing incidents | 1 | 2 | na |
| • By helping respond | 2 | 1 | 3 |
| Foster Lab Safety | 1 | 2 | 3 |
| • By preventing incident | 1 | 2 | na |
| • By helping respond | 2 | 1 | na |
| Protect the environment | 1 | 2 | 3 |
| • By preventing incidents | 1 | 2 | 3 |
| • By helping respond | 2 | 3 | 1 |
| Other considerations | | | |
| • Minimizing costs and burdens to stakeholders | 3 | 2 | 1 |
| • Feasibility? | 1 | 2 | 3 |
| • Not impede research | 3 | 2 | 1 |
| • Promote constructive applications | 3 | 2 | 1 |
Last, drawing upon this scoring, describe which governance option, or combination of options, you would prioritize, and why. Outline any trade-offs you considered as well as assumptions and uncertainties.
Response
Based on the scoring in the question four, I would prioritise mandatory built-in bio containment and regulatory oversight as a supporting governance mechanisms for my platform.
The bio-contanment consistently scores highest for preventing incidents across bio security, lab safety and environmental protection. This will show it as the preventative measure embedding safety directly into the engineered bacteria to reduce reliance on monitoring or human compliance. This also lowers the likelihood of irreversible harm before it occurs.
The regulatory oversight compliments this approach by scoring strongest in helping to respond to accidents while it’s less effective to prevention. It provides a good responsibility and adaptive oversight especially in higher risk contexts.
Together, these two approaches balances the front-end prevention and the backend response capacity.
However, the equity focused approach scored the lowest in safety and prevention, but I view it’s importance comes later after all the safety and security measures are already in a place that’s it’s a secondary action in promoting constructive applications.
My prioritisation assumes that genetic bio-containment is a very possible measure and that is robust and the regulators have an idea of risk tiers. The the trade-offs come in increased cost and potential friction for researchers however giving the potential consequences of failure these costs are justifiable.
These recommendations are direct toward the national funding agencies and the federal biotechnology regulators, and also the high universities who are inspiring to work in both policy making and research, especially in my country Iraq. This requires safety by design while coordination to enable creative ideas..
Week 2 pre-Lecture HW: DNA Read, Write and Edit
Questions from Professor Jacobson:
- What is the error rate of polymerase? How does this compare to the length of the human genome. How does biology deal with that discrepancy?
Response
DNA polymerases make about 1 error per 10⁶ bases during DNA synthesis when proofreading is included (≈10⁻⁶ per base). Given that the human genome is ~3.2 × 10⁹ base pairs (haploid), If replication relied only on a 10⁻⁶ error rate, each cell division would cause thousands of mutations (≈3,200 errors per replication), which would be biologically dangerous.
However, cells have multiple error reduction mechanisms: such as Polymerase proofreading (3′→5′ exonuclease activity) that removes most misincorporated bases during synthesis. And post-replicative mismatch repair (MMR) detects and fixes remaining mismatches after replication.
Also, it’s important to remember that DNA have intersting properties such diploidy, noncoding DNA and kill switches
- How many different ways are there to code (DNA nucleotide code) for an average human protein? In practice what are some of the reasons that all of these different codes don’t work to code for the protein of interest?
Response
An average human protein has about 350 amino acids, can be encoded in roughly ~10¹⁸⁰–10¹⁹⁰ different sequences of DNA, due to codon degeneracy.
Why don’t most work in practice? Mainly due to: Codon bias or tRNA availability causing inefficient translation. Could also be mRNA structure because of poor ribosome loading or elongation. Can also be GC content extremes leading to instability, synthesis and amplification problems
Questions from Dr. LeProust:
- Most commonly used oligo synthesis method?
Solid phase phosphoramidite chemical synthesis
- Why it’s hard to make oligos >200 nt directly?
Chemical synthesis is open-loop with an error rate of 1 per 10² bases. Each coupling step is less than 100% efficient, by the time we cross 200nt the yield and accuracy drop dramatically.
- Why you can’t make a 2000 bp gene by direct oligo synthesis?
Over thousands of cycles, cumulative coupling failures and errors reduce the full-length product to almost zero. Long base genes must be made by assembling many short oligos with enzymatic error correction like Gibson assembly.
Question from George Church:
- What are the 10 essential amino acids in all animals and how does this affect your view of the “Lysine Contingency”?
The 10 essential amino acids in animals that can not be synthesized by their cells and must come from diet are: Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine, and Arginine all universally essential during growth and functionally essential across animals. Humans included!
Lysine is both essential and commonly limiting, especially in cereal-based and plant-heavy diets. This means that protein synthesis, growth, and health can be constrained by lysine availability even when total calories or protein intake is adequate. As a result, lysine availability disproportionately shapes nutrition, agriculture, and evolution, supporting the idea of a “lysine contingency” in which access to lysine strongly influences biological and societal outcomes.
Sources / prompts used:
Google search: “essential amino acids animals”; Lehninger Principles of Biochemistry 6th edition, introduction; Prof. George Church, HTGAA slides (#4).