Week 1 HW: Principles and Practices

Class Assignment

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

I want to develop a membraneless organelle within plant cells that is able to detect breakage of the cell membrane by a foreign organism. This organelle, which is comprised of intrinsically disordered proteins (IDPs), would trigger immune system responses upon detection. The purpose of this organelle is to detect and shut down fungal plant pathogens that infect through breaching cell membranes. This novel application would lower yield loss in rice plants (primarily Oriza Sativa) from fungal diseases like Rice Blast (Magnaporthe grisea) which is responsible for 10%-30% yield losses every year for rice, preventing the possibility of feeding about 60 million people.

2. 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.

To ensure an ethical future, it is imperative to use preventative measures against ecological harm or unintended spread of this tool. One sub-goal to support this goal is to pursue the genetic containment of any engineered constructs within the plant cells. This could be done through designing constructs that can only function within plant cells. Another sub-goal is ensuring reversibility of the tool and monitoring altered organsism over time. Molecular constructs that are able to disable the tool along with monitoring programs can secure reversibility in case of adverse effects to the environment. Another policy goal to pursue is promoting equitable and responsible agricultural use. Promoting equitable use can be done through confirming affordable implementation for small farmers. Practicing transparency on the mechanics of the engineered system with farmers and consumers along with informed consent are vital for responsible agricultural uses.

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

Option 1. Currently, engineered crops are evaluated for environmental risk without any requirement for active containment mechanisms beyond general biosafety assessment. Federal regulators like the USDA-APHIS should create a requirement where engineered disease-responsive crops must have genetic containment features within its design to reduce unintended spread. This requirement should be a condition for any field trials/commercialization of genetically modified plants. The developers of the engineered crops will document containment logic and submit documentation to regulators within the federal agency for approval. This design assumes that genetic containment strategies will effectively reduce ecological risk and that regulators can consistently evaluate various containment designs across differing technologies. This option carries the risk of mutations or environmental variability bypassing containment procedures in practice. In addition, this option could slow innovation and burden smaller developers.

Option 2. Novel pathogen resistance strategies often only evaluated for efficacy and not for how they can shape pathogen evolution. Research institutions and academic funders (e.g., NSF, USDA-NIFA) can create new incentives for researchers to create new design strategies for pathogen resistance that take evolution and ecological pressure into consideration. Academic funders can reward researchers for designing damage-based or multi-signal immune systems over single effector type targets. This can be enforced through giving priority funding or recognition to projects that demonstrate reduced selective pressure. This option assumes that researchers can accurately anticipate evolutionary dynamics upon design. There is still a risk of pathogens adapting in an unforeseen way. It is also important to note that pathogen resistance strategies can lead to overly sensitive immune responses in crops which could hinder crop yield.

Option 3. Many engineered crops today are owned and controlled by companies which makes it more difficult for farmers to use these technologies. By using regulatory or financial incentives, we can encourage developers to commit to equitable licensing and deployment models to ensure more accessibility for small farmers. Government agencies can offer incentives such as faster regulatory review or public grant eligibility so that developers will agree to low-cost licensing and clear communication to farmers on benefits and limitations. This policy assumes that broader access to engineered crops will improve food security and the incentives are enough to influence company behavior. A possible issue with this policy is that smaller crop developers may struggle to meet equity requirements, unintentionally favoring bigger companies.

4. 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.

The scoring demonstrates that the best course of action would be to combine Option 2 (incentives for evolution-resilient design) and Option 3 (accessible deployment and licensing). Option 2 would be prioritized as it performs the strongest in prevention-focused categories (biosecurity and environmental protection) while also minimizing burdens on researchers and scientific discovery. This option is vital in preventing detrimental harm to the environment.

Option 3 complements Option 2 by strengthening its gaps found outside of prevention-based categories. Option 3 allows for accessibility while also minimizing costs to stakeholders. By combining these two options, my bioengineering tool maximizes accessibility and impact while minimizing risks to the environment.

While Option 1 is strong in response to risks, it scored poorly on cost, accessibility, and research freedom. Prioritizing this option would ultimately slow innovation and burden smaller research teams. With our chosen options, we assume that developers would prioritize equitable deployment incentives and that early design decisions are effective at preventing ecological/evolutionary risk. However, we are uncertain as to whether incentives may be enough to convince profit-driven companies and if preventative design measures are able to prevent pathogens from evolving in unforeseen ways.

Week 2 Lecture Preparation

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?

The error rate of polymerase is 1:10⁶. Since the human genome is 3.2 billion base pairs long, this error rate would create about 32,000 errors per replication cycle. This would be catastrophic for genetic stability. Biology deals with this discrepancy by using error correcting polymerase, which actively corrects mistakes before they become permanent mutations in the DNA.

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?

The average human protein has about 1036 base pairs. With about 345 codons, there can easily be 10¹⁰⁰ or more ways to code the average human protein. A possible reason for why all these different codes do not work to code for the protein of interest is that mRNA could have an altered structure which could affect translation initiation, elongation, or stability. Another possible reason is that some sequences can create splice sites, promoter elements, or miRNA binding sites.

Homework Questions from Dr. LeProust

1. What’s the most commonly used method for oligo synthesis currently?

The most commonly used method for oligo synthesis currently is phosphoramidite-based solid-phase synthesis.

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

The main reasons for why it is so difficult to make oligos longer than 200 nt via direct synthesis is because of various reasons. To start, each cycle has a small failure rate which dramatically drops yield after 200 cycles. Long synthesis also increases the risk of base damage and full-length product is difficult to separate from failure sequences of a similar length.

3. Why can’t you make a 2000bp gene via direct oligo synthesis?

You can’t make a 2000bp gene via direct oligo synthesis as the small failure rate for each cycle would make the yield essentially zero. Too many errors would accumulate for a 2000-mer sequence.

Homework Questions from George Church

1. 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 acid in all animals are histidine, isoleucine, lysine, methionine, phenylalanine, threonine, typtophan, valine, and arginine. This makes me feel as if the Lysine Contingency is a very flawed method. While the dinosaurs did require lysine to survive, they could have eaten lysine from any animal in their diet. A more robust contingency would’ve involved multiple essential nutrients or synthetic auxotrophy.

2. What code would you suggest for AA:AA interactions?

For AA:AA interactions, I would suggest a “Lock-and-Key” chemical match based on the charge, hydrophobicity, size, shape, and special pairs (like Cysteine forming strong bonds).

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

If our most advanced biological medicines were as easy to store and ship as aspirin, this would mean that more people could receieve life-saving gene and cell therapies. We would not have to worry about ultra-cold freezers which saves hundreds of thousands of dollars. We would be able to reach people in remote areas who would not have the resources to have frigid freezers to store medicines. This would revolutionize medicine and allow for cheap distribution to every corner of the world.