The Odyssey, Trojan Horses, and the Future of Genetic Medicine.

An optimistic, yet cautionary tale.

By Joshua Greenlee, Ph.D.

B.S. in Chemical and Biomolecular Engineering | Ohio University | Class of 2017

Ph.D. in Biomedical Engineering | Vanderbilt University | Class of 2022

Interest in The Odyssey has skyrocketed in

recent months, with Christopher Nolan’s

adaptation making it to the big screen—okay but

did you see it in 70 mm IMAX? One of the

legends depicted in this film is the final siege of

Troy, which ended the Trojan War and was made

possible only through an insidious act of

deception. After 10 years of struggle, Odysseus

and his soldiers enter through the walls of Troy

not through force, but through wit. The Trojans

came upon a huge, hollow wooden horse, and

the Greeks explained that it was an offering to

the gods that would make the city impenetrable.

The Trojans eagerly dragged the horse within the

city walls, but, to their own peril, they were

unaware that Odysseus and his men were hiding

within the offering. You know the rest of the

story: by the next day, Odysseus and his men

had taken the city from the inside out. Instead of

fighting to breach the city walls, they disguised

themselves in a form that the city of Troy would

gladly accept.

While this is a legendary story made for cinema

—and for Matt Damon; love that guy—you may

be wondering, “What does this have to do with

human biology and the future of medicine?” I’ve

dedicated the past twelve years of my career to

working as a biomedical engineer in both

academic and biopharmaceutical research

laboratories. The majority of my research has

focused on how we can effectively deliver

therapeutic payloads to targets within the

human body, a task that is much more difficult

than it sounds. For starters, the human body has

evolved to recognize “self” versus “foreign

entities” through a variety of mechanisms,

harnessing both the innate and adaptive arms of

our immune system. Additionally, the liver plays

a central role in metabolizing, processing, and

clearing medications from the body, often

preventing them from getting to where they’re

supposed to go. Finally, genetic material needs

to be delivered inside the cell to become

effective. This requires passing through the cell

membrane, avoiding the lysosome, escaping the

endosome, accessing the cytosol, and,

depending on the therapy, entering the nucleus.

Genetic diseases are caused by heritable

mutations within our genetic code (DNA) that

result in improper transcription into messenger

RNA (mRNA). This can produce an improperly

translated protein encoded by the DNA, often

resulting in a loss or gain of function in the

mutant protein. Genetic medicine delivers

endogenous-like nucleic acids in the form of

DNA or RNA, which act as a set of instructions

for cells to carry out a specific task. These

instructions might direct cells to make a protein

(mRNA), silence a gene (siRNA), or prevent or

correct the translation of mutated mRNA

strands (antisense oligonucleotides, PMOs,

etc.). Our capabilities have been further

advanced through the discovery of CRISPRCas9, allowing us to target a specific sequence

of mutated DNA within the human body, delete it,

and replace it with the proper sequence

encoding a functional, healthy protein. For the

first time, genetic medicine has given us the

capability not only to treat diseases, but to

instead cure them entirely.

As gene therapy scientists and engineers, we

utilize tactics similar to those of Odysseus to

deceive the body’s machinery into delivering our

therapy of interest. This usually involves hiding

the genetic material inside a “vector”—a Trojan

horse, if you will. This delivery vehicle will often

mimic signaling mechanisms found under

normal conditions within the cell. For example,

mRNA can be encapsulated within lipid

nanoparticles, which have a composition very

similar to that of the cell membrane’s lipid

bilayer; this is the platform used by the Moderna

and Pfizer mRNA COVID-19 vaccines.

Alternatively, we can hijack a viral vector that

avoids immune detection—a nonpathogenic

adeno-associated virus, or AAV—and equip it

with DNA instructions to replace a loss-offunction protein. Once inside the cell, the vector

drops its genetic payload and utilizes the cell’s

machinery to make the therapeutic protein of

interest. What's even crazier is that this AAV

genetic code can exist inside of the cell

indefinitely within an episome without actually

integrating into the host genome. This gene

therapy makes it possible to deliver lifelong

treatments to patients from just one dose.

Hopefully, you are starting to see the similarities

to Homer’s epic. The horse is the vector, and the

soldiers inside it are the genetic payload. The

way we deliver therapies to cells is not through

force, but wit. It’s brilliant.

While this analogy may seem trite at face value

to those within the field, I believe that, if we look

a little deeper, we can find a valuable and rather

profound lesson. One of my favorite moments

from Nolan’s interpretation of The Odyssey is

when Odysseus, disguised as a beggar, returns

to Ithaca and speaks with Penelope. He warns

Penelope about the precedent set by their

deception at Troy. He explains that perhaps they

have become the evil they once feared: the

recurring threat of “the people of the sea” was

really themselves all along. Gene therapy and

gene editing have started a biotech revolution

that has completely changed how we approach

medicine. Hundreds of diseases, from rare to

common, that were once thought to be

untreatable now have therapies in clinical trials

or received FDA approval. This is all made

possible by harnessing the aforementioned

deceptive biological tactics involved in viral and

nonviral gene delivery. As this technology

becomes further developed and more

mainstream, we have our own ethical

considerations to ponder. Under what

circumstances should genetic alteration be

employed? Purely for therapeutic benefit to

reverse a particular disease phenotype? What

about optimizing performance? Aesthetics? The

hair and eye color of offspring? These questions

are particularly provocative for gene editing.

While current gene-editing therapies target

somatic cells that are incapable of passing the

edited genome to offspring, such technology

could also be used to edit the germline,

modifying DNA that would be passed to

offspring and persist indefinitely for generations.

Genetic engineering is being widely employed in

animals, largely to suppress, alter, or reduce wild

populations of invasive species and disease

vectors. A Chinese scientist has even completed

similar work in humans, using CRISPR-Cas9 to

genetically edit human embryos, resulting in twin

girls with genetic alterations intended to make

them resistant to HIV infection. This has raised

serious ethical concerns, especially because

these alterations will be passed on to future

offspring. We are living in an age when

biological concepts once thought to be science

fiction are now routinely being developed in

research laboratories all over the world. While I

believe that these breakthroughs in biological

research will have an incalculably positive

impact on the lives of patients and their families,

we must remain cognizant of the precedent they

create. With great power comes great

responsibility.

Something Christopher Nolan does so well in his

movies is appeal to our humanity and our

deepest existential fears through his depictions

and storytelling. In the final scene of his movie

Oppenheimer, the physicist Robert Oppenheimer

asks Albert Einstein, “When I came to you with

those [nuclear fission] calculations, we thought

we might start a chain reaction that would

destroy the world.” “What of it?” Einstein replies.

With the camera zooming in on Oppenheimer’s

face, he says, “I believe we did.” While the

original discussion revolved around the fear that

nuclear fission would create an uncontrollable

chain reaction, the final realization was that the

precedent set by dropping the bomb was the

true danger: the world ending from nuclear war.

Now, in no way am I comparing genetic

engineering to the atomic bomb, but policy and

ethics always lag behind scientific discovery and

technological advancement—just look at what’s

happening with AI. We must remain good

stewards, continuing to create for good. We

must continue our relentless pursuit of genetic

therapies for those plagued by debilitating

diseases while also ensuring that these

platforms are not misused.