DIY: Mass Effect's Genophage

Mass Effect’s genophage is one of the few fictions in gaming that is easiest to consolidate with real science. That’s probably because we can already manipulate and engineer viruses that manipulate genetics within biological systems. In Mass effect, the genophage was a Salarian-engineered virus capable of sterilizing the entire Krogan population. This reoccurring plot device was used to create friction between alien Krogan, Salarian and Turians as well as develop several of Mass Effect’s characters (particularly, Mordin Solus). It brought up the necessary moral dilemmas to challenge players outside of running and gunning and reminded them they can be accountable for their actions. While such a bioweaponized feat is difficult to create within model animals (let alone sapient life) let's have some fun speculating how close theory can be to practice.

So, how easy is it to grow a virus? Well we've got a pick from some of the most virulent strains out there as blueprints... Lab practices have effectively eliminated the pathogenicity of HIV, herpes, and hepatitis allowing them to manipulated as empty vehicles to carry genetic information of our choosing. In essence, a virus can be considered the sum of a protein “envelope”, capsid “core” and a viral genome. Their genome is often sufficient enough to carry the information to make the rest of the virus (capsid and envelope) and is the easiest to manipulate. When we decide to make a virus we often build each of these components separately with host cells and use assembly proteins to combine them to into functional viruses.

Lentiviruses are current gold standards in engineered viruses. Three plasmids code all the components of a virus, which uses “producer cells” as hosts

So now that you have a viral vehicle to carry information, how would this virus carry out reproductive genocide? By its own definition the genophage was a virus designed to "eat up" endogenous Krogan DNA and introduce mutations that cause sterility. Surprisingly we've relied on several proteins and enzymes that "eat up" DNA to carry out any type of genetic manipulation. Restriction endonucleases are nature's "molecular scissors" and recognize short specific sequences in DNA whereas enzymes called DNAses cut every piece of DNA they see. However, the most precise tool for the job would involve Zinc finger nucleases (ZFNs for short). ZFNs are artificially made proteins that can potentially bind long and specific sequences of DNA. They do this with one domain that specifically binds a 7-8 string of base pairs (for example: ACGTGG) and a second part that snips DNA. In practice you can actually give instructions to your virus to hijack cell machinery to synthesize 4-5 ZFNs proteins in a row to uniquely bind a 28-40 base pair piece of DNA. Think Christmas lights alternating colors to make a recognizable pattern... This pattern aligns with a DNA sequence effectively slicing and dicing DNA sequences of your choice.

(Left) Zinc Finger protein wrapped around DNA (Right) Restriction enzyme EcoRI cutting DNA

So now that you've got your virus and the right tool to "eat" Krogan DNA, how do you pick out a gene that can cause sterility? Assuming Salarians sequenced more than one species on Krogan homeworld, Tuchanka, the wizardry of bioinformatics could give you a decent understanding of their evolutionary origins. It's important to understand where you're coming from since the conservation of specific genes often indicates how important they are (hmmm, for let's say, reproduction). For example, pathways that dictate cell cycle and limb growth are largely conserved from humans to fruit flies. In humans you would consider folate metabolism since known mutations in these pathways result in stillbirths (i.e.: MTHFR mutations result in stillbirth in 1:1000 pregnancies). Other viable gene targets could affect sperm motility, uterine conditions, etc. Needless to say a great deal of fine tuning would get you exactly where you would need to go to make a working genophage. The science is out there but thankfully we use it to dissect a gene’s function for basic research and sometimes make night lights out of mice.

Green fluorescent protein is commonly used as a reporter when playing with these viruses to validate the efficacy of your infection.

In practice, you would have to overcome Krogan immunity and mediate the lethality of the virus itself. In fact it's been so difficult to engineer these viruses that currently only one has made it past trials, the oncolytic virus (designed to fight cancer). Ethically, the genophage served as an ugly reminder of human history in the early 20th century where several countries practiced forced sterilization, often as part of a eugenics program. While this piece by no means condones the creation of race-obliterating viruses or forced sterilization, it is worth noting that there are technologies that allow even the wildest fictions a little more plausible. But hopefully not...

Sebastian Alvarado is a postdoctoral fellow at Stanford and founder of Thwacke! For more science and video games follow him us Twitter and Facebook!

Protein structures courtesy of the Protein Data Bank