In the Marvel Cinematic Universe, where the Avengers battle on the big screen, the math seems pretty simple. Captain America equals good, Thanos equals bad. Captain America equals right, Thanos equals wrong. Cap was designed by science, the Mad Titan uses magic to redesign the galaxy.
Or does he? If we look at these two characters, the choices they make, how they came to be and what they do, who's really on the side of science?
To answer this question, we must enter the realm of gene editing where we meet something that sounds like something out of 1950s B movie: CRISPR! A Nature News article published in 2015 even carried the B-movie title “CRISPR, The Disruptor.” But while CRISPR has a sci-fi, cosmic-sounding ring to it, it is actually derived from the inner workings of the most ancient life here on earth: bacteria.
A puzzle about sequencing patterns in the genome of bacterium Escherichia coli that began in 1987, deepened further in 1995 when it was discovered that other microbes showed the same pattern of “clustered regularly interspaced short palindromic repeats.” That long stretch of words birthed the acronym “CRISPR.”
So, the puzzling sequence had a name, but what did it do and why was it there? In 2007, food scientists at Danisco noticed that CRISPR represented DNA from viruses that attack bacteria. In a similar fashion to your immune system maintaining a “hit list” of pathogens to attack, CRISPR represents an ancient part of the bacterial immune response that allows instant recognition and targeting during a viral invasion. All of this would be neat and useful but CRISPR wouldn’t be so “avenging” if all it could do was help recognize an invader. It needs to be able to attack invaders too.
This is where CRISPR-associated (Cas) proteins, always found near the CRISPR sequences in the DNA, make a grand entrance. Scientists realized in 2012 that CRISPR could be used in the greatest biological attack mission ever: gene editing. Cas proteins go in and chop up the DNA of viral attackers, thus destroying the virus and preventing it from replicating. Cas9 is the most commonly used enzyme and comes from Streptococcus pyogenes—the bacterium infamous for giving you strep throat.
DNA strands are then repaired if it’s a gene deletion, or a new sequence (that can be either beneficial or damaging to the organism) can be inserted to alter the host genome. More recent discoveries like CRISPR-Cas3 are even more powerful. Cas3 doesn’t chop up the DNA but rather erases huge stretches of it. If precise control of the erasure boundaries can be enabled, this holds even more power and promise for gene editing.
Using these procedures in an embryonic (egg or sperm) cell enables the “edits” to be part of the genetic code that goes to the next generation as “inherited characteristics”. As long as you know the right sequence—a guide RNA—to give the Cas9, you can do a cut-and-paste job into any genome.
This is both thrilling and terrifying. In 2019 a mind-boggling record 13,200 changes has been made to DNA of a single human cell using CRISPR.
This potential power of CRISPR stimulated one of the mostly hotly debated biomedical ethics issues of all time. There were calls for a moratorium on the use of CRISPR for editing the human germ line—those cells like sperm and egg cells that pass genetic information to the next generation. Several groups ignored the calls, pressed ahead, and used human embryos as test beds to determine how well the technique might work.
It did work, but there were some issues. Targeting errors associated with the guide RNA gave “off-target repeats”. Meaning, it wasn’t nearly as precise as needed for routine use in humans and suggesting that it might be premature to give the technique a clinical application. Despite that, on November 28, 2018 researcher He Jiankui, from the Southern University of Science and Technology in Guangdong, China, revealed that, in contravention of global ethical protocols and regulatory oversight, he had performed ex-vivo gene editing on two human embryos.
The controversy rages on in our reality, but in the fictional world of the Marvel Universe there is no controversy about using gene editing to transform the frail Steve Rogers into the superhuman super-soldier Captain America. Myostatin gene deletion for super strength? Check. APOE for protection against dementia? Check. BDNF enhancement for memory? Check. IGF2R for calculating critical conundrums during combat? Check and check. Most folks don’t have a problem with such biological tinkering if it helps with disease or enhances humans to fight for what’s right alongside the Avengers.
CRISPR, though, is a technique that cuts both ways and can be both good and bad. Here the bad is how Thanos might use gene editing to achieve his end goal of deleting half the life of the universe. CRISPR methodology can be used to create and activate a “gene drive” mechanism that can have influence over an entire species within a given population. In the case of a gene drive, changes could include deliberately “infecting” a population with faulty genes mutated to be dysfunctional and pathological. Definitely sounds like part of Thanos’ job description!
Spreading a genetic mutation in a whole population of organisms usually takes a long time because a mutation on one of a pair of chromosomes is inherited by only half of the offspring. But a gene drive using CRISPR produces a targeted mutation that is then copied to every partner chromosome in every generation. The mutation spreads extremely rapidly through a whole population. While it’s not as fast as “the snap” Thanos used with the Infinity Gauntlet in Avengers: Infinity War to immediately kill half the life in the galaxy, it’s still incredibly fast in biological terms.
In our reality, within a single season a gene drive could be used to sweep through and destroy an entire mosquito population carrying malaria or West Nile virus. This would constitute a tremendous advance for infectious disease control. Molecular biologists are concerned with off-target propensities of the guide RNA. The danger is that the guide RNA itself will probably mutate while passing through successive generations. This will lead to targeting other areas of the genome, which would then subsequently race through the population with unforeseen consequences. But it would also disrupt predator-prey interactions that would be compromised by wiping out an entire population and could lead to widespread collapse of whole ecosystems.
Which brings us to the nature of science. Scientific discoveries aren’t good or bad in the way we can think of characters in the Marvel Cinematic Universe. Discoveries don't care about your intentions. Once knowledge is acquired it can be used in many ways that were never intended or even imagined by the discoverer. Wisdom to go along with knowledge takes time to acquire and we are often too impatient to wait.
Evolved ecosystems live in an organic balance. This balance is sustained by interactions across all species and all life within the ecosystem. If we consider the universe depicted by Marvel as a macro ecosystem, Thanos's attempts to wipe out half of all life would result not in better living for the survivors (as he seems to think) but in a complete collapse of the living world. Getting rid of half of all organisms would destroy the web of relationships that connects all species.
Similarly, there are things in our current reality we may not know about as implications of our decisions, yet we take them anyway and so can unwittingly bring on the downfall of our own and related ecosystems when we start using things like gene drives.
The late, great Stan Lee said “With great power must also come great responsibility.” He was talking about Spider-Man’s origin story, but this phrase should resonate with us all every day with every decision we take. Scientific advances support both the genetic engineering needed to produce Captain America and the means to enable the cataclysmic and nefarious plan of Thanos.
It might be okay to plunge ahead with a risky galaxy-saving plan in the just-released movie Avengers: Endgame, but in real life gene editing we are not playing games. Instead of just doing what can be done because we think it’s right, we need to pause, reflect and exercise the responsibility that is commensurate with our ever-increasing power.