Week 1 HW: Principles and Practices

Question 1 – Application & why

1. First, describe a biological engineering application or tool you want to develop and why.

Introduction

My proposition for a biological engineering application is a synthetic cell circuit for neuroprotection in neurodegenerative diseases that is non-invasively controlled by a physical sound/ultrasound signal to help modulate inflammation and support brain health.

Motivation During my junior year, I started learning about neurodegenerative diseases and current therapies. I came across lots of reading explaining non-pharmacological tools, such as music therapy, that are used as a complementary support rather than precise, controlled interventions. My interets was going beyond background music therapy and instead treating acoustic stimulation to its full potential as one possible non-invasive control channel for an engineered neuro-immune circuit. Synthetic biology has already shown that mammalian cells can be engineered with mechanogenetic and sonogenetic switches to trigger therapeutic gene expression via receptor or responsive promoters. Music and music-like acoustical interventions could be engineered to play the role of an external controller that does not require being injected or physically contact witha patient

Design A simple example would be an acoustic‑controlled promoter driving anti‑inflammatory cytokines such as IL‑10 or TGF‑β, neurotrophic factors like BDNF or GDNF, or enzymes that enhance clearance of toxic proteins such as Aβ. The core logic gate would be an AND gate that requires both an acoustic input and a local inflammatory signal (for example, NF‑κB activation) before turning on the therapeutic gene, so that the circuit activates only when the brain is inflamed and the specific sound signal is applied.

Question 2 – Governance goals

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.

Goal 1: Long-term biological safety of use

Ensure that sound-controllable synthetic immune circuits are designed and used in a way that is biologically safe and technically trustworthy.

• Sub goal 1.1. Manage biological and technical risks

Identification and termination of key risks. Targeted circuit development design.

• Sub goal 1.2. Robust testing and monitoring

Ensure there is detailed preclinical testing and long-term clinical monitoring before device deployment

Goal 2: Protection and respectful use in memory-impaired patients

Protect the rights and autonomy of neurodegenerative patients who receive this treatment and avoid health inequalities

• Sub goal 2.1. Control and consent

  Develop a consent and specialised process that would not violate rights of memory-impaired individuals patients

• Sub goal 2.2. Ability to withdraw

  Ensure patients can decline the intervention or request deactivation/removal of the circuit

• Sub goal 2.2. Promote equity in access

Allow public health systems and diverse patient groups to benefit from this technology

Question 3 – Governance actions

Next, describe at least three different potential governance “actions” by considering the four aspects below (Purpose, Design, Assumptions, Risks of Failure & “Success”). Try to outline a mix of actions …

Option 1: Establishing Regulation Rules and Technical Standards

• Purpose: Outline clear guidelines for such circuits to create standardized safety requirements before any medical implementation and fabrication.

• Design: The regulators for such action would include national FDA-like agencies, neurology societies, and expert committees. A specific category and preclinical studies would be defined to mitigate potential risks of off-target activation, long-term expression, response to repeated acoustic exposure, and biological safety. The “safety checklist” could be developed for synthetic switches and minimum acoustic parameter requirements.

• Assumptions: This assumes developers would agree to additional testing and expert review for approval.

• Risks: In case of standards being considered too weak for fabrication without consideration of unknown long-term risks. On the contrary, overly complicated standards might make the whole project too expensive and unachievable.

Option 2: Setting Advance Directives

• Purpose: Build a system that lets patients with neurodegenerative disease state their wishes in advance and appoint a trusted person to help control when and how the acoustic stimulation is used if their memory or decision‑making declines.

• Design: Use advance directive forms specific to this intervention, completed while the patient still has capacity, where they can (a) record preferences about starting, pausing, or stopping stimulation, and (b) designate a person/guardian who is allowed to initiate, schedule, or terminate acoustic stimulation.

• Assumptions: Assumes patients receive a diagnosis early enough, and with enough support, to complete advance directives; that legal systems recognize such documents and surrogate decision‑makers for neuromodulation or implantable synbio interventions; and that clinicians have time and training to revisit consent and preferences over time.

• Risks: Some patients may never complete directives, leaving families and clinicians uncertain; designated guardians might have conflicts of interest or interpret wishes differently from what the patient would want. Strict reliance on old directives could also override a patient’s current expressions if they still have partial capacity or have changed their mind, which could undermine respect for present‑time autonomy.

Option 3: Set a transparency and public access

Purpose: Ensure the proven safety and effectiveness to the public with an understanding of all risks, benefits, and intervention procedures.

• Design: Build a public interest campaign/communication platform with an explanation of the technology and treatment procedures, including uncertainty and possible side effects. Require recruiting diverse groups in clinical trials. Not limit the research to private research hospitals only.

• Assumptions: Health systems are willing to invest in high-quality communication and marketing to reach diverse communities.

• Risks: With too succesfull communication campaign, the public may overestimate benefits or underestimate uncertainty and risks. Policies to ensure inclusive trials and access may increase costs and administrative complexity for hospitals.

Question 4 – Scoring the options

Next, score (from 1–3 with 1 as the best, or n/a) each of your governance actions against your rubric of policy goals.

Question 5 – Recommendation & reflection

Last, drawing upon this scoring, describe which governance option, or combination of options, you would prioritize, and why …

According to the scoring table, I prioritize both Option 1 and 2, which balances the hospital ethics and regulatory rules approved by national regulatory actors. This combination ensures that the biological tool is governed by both human-centric ethics and rigorous technical safety. The target for this choice would be the FDA and NIS communities, with international groups working in neurology and the clinical trial approval committee.

Option 2 scores well (1) on feasibility, low costs, and patient autonomy—it uses existing hospital systems for quick consent processes and monitoring. Option 1 scores best (1) on biosecurity and lab safety prevention, adding uniform rules like safety checklists for acoustic frequencies. Together, they cover biological safety (Goal 1), patient rights (Goal 2), and fair access through trials (Goal 2) without major delays to research.

Considered Trade-Offs & Assumptions This combination may have risks in uneven standards across hospitals, since each hospital may have its own patient consent, as well as higher costs and longer approval times.

Reflecting on what you learned and did in class this week, outline any ethical concerns that arose … then propose any governance actions you think might be appropriate to address those issues.

From the first week’s lesson and recitation, the topic that caught my attention was genetic engineering and pathogen research/studying viruses in bats or building synthetic genetic circuits in these organisms. Even simple work, such as modulating pathogens or implementing circuits in cells, carries big biosecurity risks. If not handled carefully, a dangerous pathogen could escape the lab, spread to people, or be misused. This led to long thought for me on how this issue is being regulated now and how these experiments are conducted safely without stopping important science.

Governance solutions

• Mandatory additional training: Require specialized training for all lab workers on incident reporting, strict entry/exit protocols, and emergency response. This builds skills to prevent accidents, like pathogen leaks during bat virus studies.

• Screening panels with oversight: Create independent review panels of scientists and safety experts to screen high-risk experiments (e.g., pathogen modulation or synthetic circuits). These panels would approve protocols, monitor ongoing work, and ensure regular audits—similar to dual-use research reviews.

Another frequently mentioned topic from class was “core libraries” in synthetic biology. Biobanks, genetic databases, and DNA sequence archives are presented like reusable IP blocks. In many cases, patient data or cells are taken without permission and used for science or profit.

Governance solutions

• Broader consent involvement with time-limited withdrawal rights. When patients enter treatment, get broad consent for future unknown uses. Allow donors or families to withdraw from data access within a clear time period (e.g., 6-12 months). This protects privacy early on while preventing disruptions after data is already shared and in open research use.
• Rules for sharing and minor benefits to track the contribution by group.

Pre-lecture Questions

Homework Questions from Professor Jacobson:

Answer

DNA polymerases have an error rate of about 10*-2 errors per base. The human genome is ~3.2 × 10*9 bp in lenght, so this creates a significant disperancy which results in thousands of errors percopy.​ Biology fixes this with proofreading by polymerase and post‑replication mismatch repair (MutS/MutL/MutH etc.), which together reduce the error rate.

Answer

An average human protein is ~330–350 amino acids, giving the possibility of a massive number of DNA sequences (around 10*150), because of the portein redundancy of the genetic code. Many possible codes “don’t work” because sseries of resons: secondary structure of mRNA; poor codon usage/tRNA availability; splicing or binding sites.

Homework Questions from Dr. LeProust:

Answer

The standard, most widely used method is solid‑phase phosphoramidite chemistry.

Answer

It is difficult to make long oligos via direct synthesis due to comulative yiel loss. By ~200 bases there are many truncated and error‑containing products and it is hard to purify the correct full‑length oligo.

Answer

A 2 000‑step phosphoramidite synthesis would give zero yield.

Instead, synthesizing many shorter oligos, then assembling them enzymatically (PCR assembly, Gibson, etc.) into longer gene fragments is used.

Homework Question from George Church:

Answer

Essential for humans/animals: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and arginine.​

Animals already depend on the diet for multiple essential amino acids, including lysine, so making organisms “lysine‑dependent” is not a safe way to contain a synthetic organism. Though for movie purposes it is a fun scientific explanation.