Week 1 HW: Principles and Practices

Week 1 homeowrk

Snail population suppression for schistosomiasis

The intervention

Schistosomiasis is a neglected tropical disease caused by parasitic worms which infected ~220 million people in 2025. Schistosomes use aquatic snails as an intermediate host to grow from the miricidia stage to the circaria stage, which is the stage at which they are able to penetrate human skin and infect the blood. By reducing the population of intermediate host species through a gene drive, the life cycle of the schistosomes can be interrupted.

Governance - ensuring non-maleficence

The principle of non-malificence requires us to prevent unnecessary harms being caused to others. Communities who live and depend on the local ecosystem should be empowered in decision-making, and maintaining open communication with the community is essential for harm reduction. All moral patients involved should be considered, including those unable to advocate for themselves, such as wildlife and future generations.

Subgoals

Preventing harm to local communities

responses of the local community should be monitored after the release of the gene drive in the field.

Preventing harm to other communities

Rigorous testing is required to ensure that the impacts of the gene drive will be localised to the intended area, and not to external communities who did not have decision-making power.

Preventing harms to wildlife

Ecological applications of genetic engineering technologies require a special degree of caution due to the risk of unintended, potentially irreversible impacts on interdependent species.

Preventing harms to future generations

The potential for long term impacts should be considered, including the development of resistance in the schistosome parasite.

Governance actions

Rigorous testing

Researchers should follow a structured, phased approach to the development of the gene drive such as the traffic light model to ensure safety before field release.

Stage 1: Secure lab research Stage 2: Contained field trials and ecological modelling Stage 3: Regional field trials, perhaps using a daisy-chain gene drive designed to disappear after a few generations

Localised community impact monitoring

Funding bodies could directly fund the community to monitor ecological impacts after the release of the gene drive, which also serves to fulfil a secondary goal of community empowerment and engagement.

Mandatory “fail-safe” reversal drives as a molecular containment strategy

Regulators could require tested “reversal drives” before releasing gene drives in the field prepare for the possibility of unintended harms being caused to the ecosystem.

Governance action evaluation

A variety of governance approaches will be required to use a gene drive to suppress the population of aqautic snails in a way that aligns with principles of ethics. While I have focussed on actions related to harm mitigation specifically, the principles of beneficence, autonomy and justice should also be considered and form part of the governance approach. While some approaches (eg. rigorous testing) reduce the risk of harm, others enable a quick response to prospective harms. There is not silver bullet solution to ensuring that biotechnology is used ethically and effectively, however I think each of the 3 policy options I have looked at are effective at achieving different specific goals. Of these 3 approaches, I think the most essential for maintaining biosecurity are phased testing and reversal drives.

Assumptions One assumption I have made here is that it’s possible to ensure that gene drives are localised to a high (~85+%) degree of certainty. If risk of release in unintended environemtns were larger, I would stress the need for international coordination more, and imagine that this could be one of the most significant barriers to the successful completion of this project.

Week 2 Preparation

Q: 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? DNA polymerase has an error rate of about 1 error per 10^{7 nucleotides, and the human genome has 3x10}9 base pairs, meaning there would be 300 errors per replication which is significant and requires error correction mechanisms.

Q: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? For a single protein roughly 3^400 nucelotide sequences poissble given average protein ~400 amino acids 64 codons code for 20 amino acids.

Q: What’s the most commonly used method for oligo synthesis currently? The current industry standard for oligo synthesis is phosphoramidite chemistry, whihc has ~99% coupling efficiency per step

Q: Why is it difficult to make oligos longer than 200nt via direct synthesis? ~1% arror rate accumulates so yield drops exponentially with length

Q: Why can’t you make a 2000bp gene via direct oligo synthesis? at 2000 base pairs with 99% efficiency (0.99)^2000=0.0000002% full length, yield would be extremely low

Q: What are the 10 essential amino acids in all animals and how does this affect your view of the “Lysine Contingency”? Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Arginine, Leucine, and Lysine are the 10 essential amino acids. The human body cannot produce them, meaning they have to be consumed through our diets. The lysine contingency involves dinosaurs being genetically engineered to depend on lysine from their food to prevent them from surviving in nature once escaped. However, the fact that all living organisms require lysine means that (provided the dinosaurs can metabolise proteins) its abundance in nature means this is not a useful restriction, and the dinsosaurs are not actually dependent on the Jurassic Park staff for lysine. A good alternative could be engineering the dinosaurs to depend on a synthetic amino acid not present in nature from their diet, such as 3-Fluoro-D-phenylalanine.