Week 1 HW: Principles and Practices

The Prometheus Symbiont


🎅1.“The Prometheus Symbiont” is a conceptual, living medical system designed to symbiotically integrate with the human body. It merges biomimetic photosynthesis, synthetic biology, and flexible electronics, aiming to shift medicine from “passive treatment” to active, sustained life maintenance and enhancement. You can think of it as a sunlight-powered, wearable or implantable “second life-support system.”

🎅The Prometheus Symbiont is not merely a technological concept; it is more akin to a philosophical proposition about the future form of life. It blurs the boundaries between therapy and enhancement, between human and machine. Its ultimate significance may lie in compelling us to re-examine: “what constitutes health, and indeed, what it means to be human.”

Technical Integration How can living cells, electronic components, and polymer materials work together stably and safely within the human body over the long term?

Biosafety How can we prevent the leakage or mutation of genetically engineered microorganisms? How do we ensure the system can be safely degraded or cleared upon failure?

Ethical & Social Where is the boundary between the human body and machine? How is data privacy guaranteed? How can technological fairness be achieved?

Regulatory & Approval Does it belong to the category of medical devices, pharmaceuticals, or a new biological product? How can a completely new regulatory framework be established?

🎅Purpose: Current State vs. Proposed Change

What is done now (Current Paradigm): Medicine primarily operates in a reactive and episodic manner. Patients seek help after symptoms appear. Treatments involve separate devices (monitors), pharmaceuticals (drugs), and procedures, often with significant side effects and limited personalization. Sustainable energy and materials for medical devices are external concerns.

What we propose (Paradigm Shift): We propose a shift to a proactive, continuous, and integrated symbiosis. The Prometheus Symbiont is a single, autonomous system that continuously monitors, analyzes, and responds to the body’s state in real-time. It moves beyond treating illness to sustaining and enhancing baseline health. Crucially, it aims for energy and material autarky within the body by using biomimetic photosynthesis, fundamentally changing the relationship between medical technology and the patient’s own biological processes.

🎅Design: Requirements for Functionality & Key Actors Technical Core: Research Scientists (Synthetic Biology, Materials Science, Biomedical Engineering), Bioethicists, University Tech Transfer Offices 1.Stable Hybrid Bio-Machine Interface: Materials and protocols to seamlessly integrate living cells (engineered cyanobacteria/yeast), flexible electronics, and polymers. 2.Advanced Synthetic Biology: Engineered microbes for photosynthesis, sensing, and drug production with robust safety “kill-switches.” 3.Efficient Energy & Data Transfer: Systems for light capture, intracellular energy (ATP/NADPH) transfer to synthetic pathways, and secure bio-electrical data communication.

🎅Clinical & Regulatory Pathway: Government Regulators (FDA, EMA), Clinical Researchers, Ethics Boards, Patient Advocacy Groups 1.New Regulatory Framework: Classification as a novel “Symbiotic Biotherapeutic Device” requiring new FDA/EMA pathways. 2.Phased Clinical Trials: Long-term studies focusing on safety, stability, and efficacy for chronic conditions (e.g., diabetes, wound healing).

🎅Commercialization & Society: Venture Capitalists, Pharma/MedTech Companies, Government Funders (e.g., ARPA-H), Sociologists, The Public (as end-users and citizens) 1.Public-Private Funding Consortium: To fund high-risk R&D and scale-up. 2.Public Dialogue & Education: To build understanding and address ethical concerns before deployment. 3.New Manufacturing & Service Models: For growing, implanting, and maintaining living medical systems.

🎅Assumptions: Potential Uncertainties Technical Feasibility: We assume the extraordinary challenge of long-term, stable integration of diverse biological and electronic components within the dynamic human body can be solved. This is a fundamental uncertainty.

Biological Stability: We assume engineered genetic circuits will function predictably and reliably for decades without mutation or interference from the host’s immune system and microbiome.

Societal Acceptance: We assume that a significant portion of society will accept a permanent, living machine symbiont as a therapeutic or enhancement, overcoming the “yuck factor” and philosophical objections.

Regulatory Adaptability: We assume regulatory bodies can and will adapt at the pace of the technology to create prudent, effective pathways for such a disruptive product.

🎅Risks of Failure & “Success” Risks of Failure: Catastrophic Biofailure: Engineered microbes could mutate, cause infections, or disrupt vital physiological pathways, leading to patient harm. Rejection & Waste: The body’s immune system could reject the symbiont, or components could degrade into toxic byproducts. Technical Obsolescence: The embedded electronics or software could become outdated or hacked, rendering the system useless or dangerous.

🎅Risks of “Success” (Unintended Consequences): Exacerbating Inequality: The technology could create a biological divide between the “enhanced” wealthy and the “natural” poor, leading to unprecedented social stratification. Loss of Human Agency & Identity: If the system makes too many autonomous health decisions, it could erode personal bodily autonomy and challenge the very definition of being human. New Forms of Dependency & Vulnerability: Society could become dependent on a fragile technological ecosystem. Personal health data streams could be exploited for surveillance, discrimination, or coercion.

Ecological Impact: Widespread use and eventual disposal of genetically modified living devices could have unforeseen consequences on ecosystems if not perfectly contained.

In conclusion, the Prometheus Symbiont proposes a radical leap from repairing humans to architecting a hybrid human-machine biology. Its path is fraught with towering scientific hurdles and profound ethical questions, meaning its development must be accompanied by societal dialogue as intense as the engineering effort itself.

Based on the risk assessment of the disruptive technology “Prometheus Symbiont,” I recommend prioritizing the establishment of an “adaptive, multi-layered global governance framework” as the core focus of the governance strategy. My primary recommendation is directed at the Office of the United Nations Secretary-General, because the impact of this technology is inherently transboundary. Its ethical, safety, and equity issues require global coordination and consensus on principles; the potential risks cannot be effectively mitigated by the actions of any single nation.

My recommended priority solution is “Layered Adaptive Governance under Global Coordination.” This is not a single option, but a combination of international coordination, national/regional regulation, industry self-discipline, and public participation.

1. Top Layer: Establish Global Principles and Coordination Mechanisms (Led by the United Nations)

• Action: Promote the adoption of the “Global Declaration on Ethical and Governance Principles for Human-Technology Symbionts” and establish a standing, interdisciplinary Global Advisory Committee on Emerging Bio-Hybrid Technologies (GACEBT).
• Rationale: This provides the legitimacy foundation and “safety guardrails” for all subsequent governance. The committee, comprising scientists, ethicists, legal scholars, social activists, and government representatives, would be responsible for ongoing technology impact assessments, identifying transboundary risks (e.g., biosafety breaches, exacerbation of global inequality), and issuing non-binding guidelines. This avoids premature, rigid international legal constraints (which could stifle innovation) while establishing inviolable red lines.

2. Middle Layer: Develop National/Regional Specialized Regulatory Pathways (Led by Major Economies like the US, EU, and China)

• Action: Under the guidance of GACEBT principles, national regulatory agencies (e.g., US FDA, EU EMA, China NMPA) should jointly design new product categories (e.g., “Class I Symbiotic Therapeutic Device”) and approval pathways for “active symbiotic medical systems.” This should include mandatory phased clinical trial protocols and a post-market supervision model of “pre-certification, monitoring, and re-evaluation.”
• Rationale: This translates governance into actionable frameworks by entities with enforcement power. Coordination among major economies prevents regulatory arbitrage and provides a template for global standards. The pre-certification system allows for limited application under strict monitoring (e.g., for patients with terminal illnesses and no alternative therapies) while continuously collecting real-world data to refine the rules.

3. Grassroots Layer: Strengthen Industry Self-Regulation and Transparent Public Participation

• Action: Encourage leading research institutions (e.g., MIT, Chinese Academy of Sciences) and industry consortia to develop open-source safety standard protocols (e.g., engineering design standards for biocontainment modules). Simultaneously, legislation should require R&D projects to conduct transparent social impact assessments from an early stage and incorporate public input through mechanisms like citizens’ juries.
• Rationale: Governing technical details requires industry expertise, while public trust is foundational for societal acceptance. Open-source standards can accelerate the adoption of safe practices. Early public engagement helps identify social acceptance issues promptly, helping to avoid the public relations pitfalls experienced with technologies like GMOs.

🐱‍🐉Homework Questions from Professor Jacobson:

1.Nature’s machinery for copying DNA is called polymerase. 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?

Answer： 1.Error Rate of DNA Polymerase: 1:106；Beese et al., (1993), Science, 260, 352-355. 2.The haploid human genome contains roughly 3.16 billion base pairs (≈ 3.16 × 10⁹ bp)；Without proofreading (at ~10^{-6 errors/bp), copying the entire genome once would introduce roughly: (3.16×10⁹)×10}−6≈31,60 mutations；With proofreading (at ~10-¹⁰ errors/bp), the expected number of errors per genome replication is: (3.16×10⁹)×10^-¹⁰≈0.316 mutations. This means, on average, less than one error per replication cycle—a biologically tolerable rate. 3.To ensure stable genome expression, biological systems employ multiple layers of regulation that calibrate differences arising from genetic variation, environmental influences, and stochastic molecular events：

Transcriptional Fidelity & Regulation 1.Proofreading in transcription: Although RNA polymerases lack the extensive proofreading seen in DNA replication, some backtracking and cleavage mechanisms exist (e.g., in eukaryotic Pol II) to correct misincorporated nucleotides. 2.Promoter specificity & transcription factors (TFs): TFs and enhancer/repressor elements precisely control when and where genes are expressed, minimizing off-target or noisy transcription. 3.Chromatin remodeling & epigenetic marks: Histone modifications, DNA methylation, and nucleosome positioning ensure that genes are expressed in the correct cell type and developmental stage, buffering against improper activation or silencing.

Post-transcriptional Control 1.RNA processing: Splicing, capping, and polyadenylation are highly regulated to produce consistent mature mRNA isoforms. 2.RNA surveillance pathways: Nonsense-mediated decay (NMD) degrades mRNAs with premature stop codons. No-go decay (NGD) and non-stop decay (NSD) clear stalled or faulty transcripts. RNA editing (e.g., A-to-I editing) can correct or diversify transcripts in a regulated manner. 3.MicroRNAs & other small RNAs: Fine-tune mRNA stability and translation, reducing expression variability and silencing aberrant transcripts.

Translational Accuracy & Control 1.Ribosome proofreading: During tRNA selection, ribosomes favor accurate codon–anticodon pairing; elongation factors (e.g., EF-Tu) and ribosomal RNA help discriminate correct vs. incorrect tRNAs. 2.Regulation of initiation: Initiation factors (eIFs) and upstream open reading frames (uORFs) modulate translation rates to match cellular needs and stress conditions. 3.Ribosome quality control (RQC): Recognizes stalled ribosomes and triggers degradation of incomplete polypeptides and potentially faulty mRNAs.

Protein Homeostasis (Proteostasis) 1.Chaperones & folding catalysts: Assist proper protein folding, preventing aggregation of misfolded proteins. 2.Ubiquitin-proteasome system & autophagy: Degrade damaged, misfolded, or excess proteins. 3.Feedback regulation: Many metabolic and signaling pathways use allosteric feedback or post-translational modifications to maintain stable protein activity levels.

DNA Repair & Genome Integrity Maintenance 1.Continuous operation of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), and double-strand break repair pathways prevents mutations from accumulating and altering gene expression programs. 2.Cell-cycle checkpoints halt division if DNA damage is detected, allowing time for repair or triggering apoptosis if damage is irreparable.

Systems-Level Buffering 1.Genetic redundancy: Duplicate genes or paralogs can compensate for loss or reduced function of one copy. 2.Robust network architectures: Many regulatory networks (e.g., transcription factor networks, signaling cascades) are built with feedback loops, redundancy, and modularity to maintain stable outputs despite perturbations. 3.Noise filtering: Stochastic fluctuations in molecule numbers are dampened through negative feedback, time-averaging mechanisms, or threshold-based activation.

2.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?

Answer： 1.For a 375-amino-acid protein, the total number of DNA sequences is the product of the number of codon possibilities for each position. 2.In essence, natural selection has chosen the specific DNA sequence for each human gene not just to encode the correct amino acids, but to also contain the precise regulatory, structural, and kinetic instructions needed for its proper expression, regulation, and function. The vast majority of theoretically possible sequences lack this full suite of integrated instructions. So it’s difficult to achieve under artificial conditions.

🤳Homework Questions from Dr. LeProust: 1.What’s the most commonly used method for oligo synthesis currently? The most widely used and established method for oligo synthesis is solid-phase synthesis using the phosphoramidite method. This technology is the industry standard for producing both DNA and RNA oligonucleotides in research and commercial settings. High Efficiency & Automation: Each coupling step has an efficiency exceeding 99%, enabling fully automated, high-throughput synthesis on machines. Versatile Chemistry: It provides a robust platform to introduce a vast array of chemical modifications (to the phosphate backbone, sugar, or base), which is crucial for creating therapeutic oligonucleotides like antisense drugs or siRNAs. Proven Reliability: As a mature technology refined over decades, it is the universal platform for commercial vendors and core facilities.

2.Why is it difficult to make oligos longer than 200nt via direct synthesis?

The ~200 nucleotide (nt) barrier for direct chemical synthesis is a fundamental limitation of the dominant phosphoramidite solid-phase method. The difficulty isn’t a single issue but a cascade of compounding chemical and practical problems.

The primary bottleneck is that synthesis is a stepwise process, and no chemical coupling is 100% efficient. This means for a 200-mer synthesis, over 60% of the product is shorter, failure sequences.

3.Why can’t you make a 2000bp gene via direct oligo synthesis? The challenges aren’t just linear; they become exponentially and prohibitively severe beyond ~200 nucleotides (nt). Synthesizing a 2000bp double-stranded gene would require creating a single-stranded oligo of at least 2000nt, which is scientifically and practically impossible with current direct chemical methods.

No existing purification technology (HPLC, PAGE, etc.) can separate a 2000nt strand from a 1999nt strand (a 0.05% difference in mass/length). The desired product is physically indistinguishable from the “near-miss” failures.

Gene assembly is the practical solution: it builds the skyscraper in prefabricated, high-quality sections (short oligos) and then welds them together with enzymatic precision.

😎Homework Question from George Church: 1.Choose ONE of the following three questions to answer; and please cite AI prompts or paper citations used, if any.

AI prompts:[Using Google & Prof. Church’s slide #4] What are the 10 essential amino acids in all animals and how does this affect your view of the “Lysine Contingency”?

Leucine\Isoleucine\Valine\Lysine\Methionine\Threonine\Tryptophan\Phenylalanine esp. for infants/young:Histidine Conditionally essential(esp. for young):Arginine

The “Lysine Contingency” is a clever plot device but is fundamentally flawed as a biological containment strategy for several key reasons:

the lysine contingency in Jurassic Park（Maynard, 2018; Rubini & Mayer, 2020） Lysine is already an essential amino acid for all vertebrate animals, including humans. This means animals like dinosaurs naturally cannot synthesize it and must obtain it from their diet. Therefore, the idea of “removing” a lysine-synthesizing ability they never possessed doesn’t work.

In summary, while the “Lysine Contingency” is an imaginative concept, it misunderstands basic animal biochemistry and fails as a practical fail-safe.

Rubini, R., & Mayer, C. (2020). Addicting Escherichia coli to new-to-nature reactions. ACS chemical biology, 15(12), 3093-3098. Maynard, A. (2018). Films from the future: the technology and morality of Sci-Fi movies. Mango Media Inc.

2.[Given slides #2 & 4 (AA:NA and NA:NA codes)] What code would you suggest for AA:AA interactions?

Energy-Based Interactions (More Accurate)

Using PyRosetta or BioPython with energy functions

import pyrosetta pyrosetta.init()

def calculate_interaction_energy(pose, res1, res2): """ Calculate interaction energy between two residues using PyRosetta. """ # Create a two-body energy calculator sfxn = pyrosetta.get_fa_scorefxn()

# Calculate energy between residues
emap = pyrosetta.EnergyMap()
pose.energies().residue_pair_energy(res1, res2, sfxn, emap)

return emap.total()

3.[(Advanced students)] Given the one paragraph abstracts for these real 2026 grant programs sketch a response to one of them or devise one of your own:

What if our most advanced biological medicines were as easy to ship and store as aspirin?

To break biologics’ extreme reliance on ultra-cold chains, a systemic transformation across science, logistics, and policy is required.

The immediate focus must be on re-engineering the molecules themselves. Massive investment in formulation science—utilizing advanced lyophilization, stabilizing sugars and polymers, and novel drying techniques—can shift storage from -70°C to 2-8°C or even room temperature. Parallel development of subcutaneous auto-injectors or oral delivery systems reduces dependency on clinic-based intravenous infusion.

Simultaneously, we must redesign the supply chain with intelligence and resilience. Deploying IoT-enabled smart containers with real-time tracking and blockchain ledgering ensures integrity and accountability. Creating distributed networks of certified storage points at regional centers expands access geographically. AI-driven predictive logistics can preempt shipping failures.

Long-term disruption will come from decentralizing production. Adopting modular, continuous biomanufacturing platforms enables regional or even hospital-based production, slashing distribution miles and cold-chain complexity. Next-generation platforms like thermostable lipid nanoparticles for nucleic acid therapies are equally crucial.

Finally, policy must incentivize accessibility. Regulators should create expedited pathways for thermostable products. Payers must align reimbursement with value metrics that include reduced logistical burden and improved patient access. A national strategy, treating biologic supply as critical infrastructure, can coordinate public-private R&D and strategic stockpiling.

The ultimate goal is a transition from a fragile, centralized, cold-dependent model to a resilient, distributed system where life-changing therapies are defined by their efficacy, not by the freezer they inhabit. This convergence of science, smart engineering, and supportive policy will democratize access to advanced medicines.