A Small Rampage Over STAT's Movie Piece

A movie opened this weekend which, by all prior evidence and new reviews, is unbelievably silly but destined to rake in the bucks. Rampage is very loosely - as if it could be another way - based on a video arcade game. The original game’s backstory had a mysterious ray transforming people into monsters, but the movie has changed that to CRISPR. So STAT had a piece which, to my great disappointment, gave the movie’s science a near pass in a piece featuring two writers chatting . . (Note: this post has mild spoilers, though if you've seen the trailers they give almost all of this away).

Rampage was actually one of my favorite arcade games, purely due to the absurd setup. Once transformed into a monster, you climbed buildings to punch and smash them, gaining points by eating occupants and doing damage. But eating the wrong things, falling off a building or being attacked by soldiers would damage your health, eventually causing the avatar to revert to human form and scurry off-screen while comically covering their nakedness. I was never good at video games, so the silly setup was a key aspect for me.

Believe it or not, I can suspend disbelief at the movie - but I tend to have a lesser threshold for biology absurdity than physics. Faster than light travel in Star Trek? No sweat. Alien races in same franchise evolving on different planets being interfertile? Horrors!

But the problem with CRISPR as a plot point is that many people will see this movie and it will color their perception of the technology. It’s totally appropriate for a niche publication like STAT to try to ride the hype a bit around the movie. But they had a choice, and cheerfully ripping the premise to shreds is a time-honored path they failed to take. Co-author says, in regard to one bit of the movie, "And, yes, that’s not exactly how CRISPR works, but it’s not completely off base either!"

Sorry, but that’s not remotely how CRISPR works. The movie is one more awful form of “CRISPR is an all powerful magic wand” hype bundled with with “genes are magic beans” nonsense.

First is the problem of delivery. Real CRISPR must be delivered to the correct cells. That generally means viral vectors - which have species and tissue specificity. A vector capable of infecting both a primate, carnivore and a rodent is slightly plausible - but a lizard too? And this isn’t trivial - given the depressing level of public worry that diseases such as cancer are transmissible, seeding the idea that gene therapy might be is awful.

But let’s get to CRISPR itself, which works via guide RNAs targeting cleavage or edits to a specific DNA sequence. This is where the “science” is completely wrong. The odds of an appropriate guide RNA sequence being conserved in three mammals is slim - and we still have the freaking lizard!

And about that brings up the problem of the gigantic growth. Of course, there’s the mass conservation issue - or put another way, if your lab rat is rapidly growing out-of-control stop feeding it! But for more esoteric biology, scaling up isn’t trivial. But more importantly, a big part of growth is elongating the long bones of the limbs - and once your past adolescence it just can’t  happen again. Those bones have growth plates, which disappear - and once gone are gone. This was a real concern in Infinity’s hedgehog inhibitor program, as it raised a stark ethical issue for pediatric cancer usage. Hedgehog signaling is key to keeping the growth plate open, so the very real concern was that saving a child’s life would also freeze their stature, perhaps at infant size. .IPI-926 failed in adult trials and the program halted, so the issue didn’t become more than theoretical

Okay, one last poke at STAT. In the movie, the wolf not only becomes gigantic but grows wings. And all STAT’s Andrew throws in is "One question I have is whether these animal features are polygenic as opposed to tied to one gene."

Well, where to start? Of course functional wings would require a lot of genetic changes! That’s important since CRISPR is hard for one gene, and much harder for many. Depending on which flavor of CRISPR is used - and an under-reported aspect of CRISPR is that it is a huge suite of technologies far beyond editing - you need to pack other stuff into your viral vector to get something done. These could include guide RNAs, repair templates, activator or repressor constructs. But gene therapy vectors don’t have much space, so even getting one gene edited is a problem.

But again there’s an important lesson in developmental evolution (aka evo-devo) that could have been delivered. Look at all your land vertebrates and count limbs. We ain’t called tetrapods for nothing - four is the number of limbs. Our body plans arise from the interactions of myriad genes, which lay out the complex arrangement of muscles, tendons, ligaments, vasculature, nerves and the like in the embryo. That happens through progressive layering of patterns.

But that winged wolf has six limbs. There just ain’t no small number of edits that could make that happen in an embryo, let alone an adult. Mammals just aren't built that way. If you want wings, you gotta give up forelimbs -- that's the trade!

So Rampage’s directors should have stuck to an alien transform-o-ray. Hack may it be, but deus ex machina can explain away any phenomenon. Stick to something that really exists and gadflies like me will go after you.

Enough. Time to go relax - where’s a building I can stomp on?