“Upgrade” Chillingly Conjures a Genetically-Enhanced World

It was inevitable that sci-fi would take on genetic enhancement, but I somehow missed Blake Crouch’s brilliant 2022 dystopian novel Upgrade. He’s one of my favorite authors, the brains behind Wayward Pines and five other novels, as well as 2024’s Dark Matter on Apple TV+.

Because I’m working on the zillionth edition of my human genetics textbook, I’m ultra-sensitive to accuracy, and Upgrade doesn’t disappoint. The tale’s compelling view of what could be is far more detailed, and entertaining, than the gloom of GATTACA.

A Gene Drive with Unforeseen Consequences
I admit I’ve never thought much about genetic enhancement; my books and articles have always been about preventing or combating disease. But the invention of CRISPR gene editing in 2012, its ease and versatility, quickly changed what was possible.

In Upgrade, protagonist Logan Ramsay is an agent for the Gene Protection Agency. His notorious mother, geneticist Miriam, was responsible for a gene drive (which eliminates a specific genotype) that unintentionally killed millions. Gene editing is now banned, parents who edit their sick kids’ DNA imprisoned, but novel DNA tweaks still happen in “dark gene labs.” Billboards announce “GENE EDITING IS A FEDERAL CRIME.”

Mom Miriam also ran a company called “The Story of You,” which held millions of peoples’ genome sequences in its databases. It’s mentioned briefly, overshadowed by her major contribution of Scythe, “the most powerful genome-modifying system ever created” that spawned “the largest accidental mass killing in human history.”

Scythe was used to engineer locusts to deliver viruses genetically modified to protect indica rice plants growing in Zhaoqing, China, from a bacterial leaf blight. But Scythe veered off-target, as gene editors can do, knocking out genes for seed production. Oops! “Within a year, the vector locusts began propagating exponentially.”

When the modified viruses spread to other crops, the resulting “Great Starvation” radiated out along the food webs that interconnect all life on Earth. The cascade of environmental changes eventually plunged coastal cities under water as an island of glomming microplastics emerged in the Indian Ocean.

“My mother had tried to edit a few rice paddies and ending up killing two hundred million people,” explains protagonist Logan. He’d worked in her lab, helped the gene editing take root in China, and ended up in prison for the crime of germline modification.

Skewing Mendelian Ratios
Gene drives were envisioned to knock out populations of insects that carry pathogens, like the mosquitoes behind malaria. The technology erases the contribution of one parent of a sexually-reproducing organism, altering Mendel’s first law of gene segregation.

Crouch explains it well:

“Say the mother has brown eyes, the father blue. With a gene drive, you can overwrite the mother’s genes for eye color in the embryo, thus guaranteeing that their child will have blue eyes. But the real kicker is that the child will pass on the targeting system to their children in turn. All of their children will now have blue eyes too, and so on. Within a few generations, the gene drive will pervade the entire population – and the natural, unedited copy of the gene will be wiped out completely. All Homo sapiens will have blue eyes.”

(He doesn’t explain that the edit would need to affect the embryo’s primordial germ cells, which give rise to sperm or eggs, to be passed on. That’s important.)

Logan leaves prison, after many years. And his mother Miriam has disappeared. Or has she?

Before we find out what’s happened to Miriam, a description of this strange, genetically modified world unfurls.

Zootopia
Scythe leaves CRISPR in the dust, enabling creation and propagation of populations of creatures with selected genetic changes. These include the expected designer pets, ultra-strong cannabis, spider-silk clothing, and GMO foods, plus the more inventive “exotic synthetic creatures” nurtured in lab-grown, free-standing uteri. The syn beasts include

• giant hornets that make taipan snake multi-venoms
• “an eel with a head at each end”
• Pompeii worms adapted to deep-sea hot thermal vents
• tiny pink gorillas as toys
• “sex dolls wrapped in synthetic human muscle and skin”
• “four biology undergrads at Brown who had simply wanted to see if they could make a dire wolf”- prophetic years before Colossal Biosciences made this very claim, providing the inspiration for my post De-extincted Dire Wolf Pups Have a Few Genetic Tweaks – That’s It).

Miriam is able to take her technology to humans, thanks to her 23andMe-like company and its millions of stored human genome sequences.

Evading the Gene Protection Act
All genetic tinkering has gone underground since evocation of the Gene Protection Act, which outlawed genetic research and made geneticists and molecular biologists instant criminals. Editing one’s own genes also became verboten.

Miriam Ramsay’s plan went far beyond engineered insects and skewed eye color. Her goal: building a better human.

But “better” is a highly subjective term, and genetic manipulations tend to have unforeseen consequences.

To start, she arranges for son Logan to have his genome enhanced in a dark lab, without his knowledge, just as hers has been enhanced. That takes the form of a sudden shower of tiny, glowing ice shards, each delivering into his unsuspecting cells a slew of genes carried aboard viruses. As the story unfolds, these genes unspool his enhancement.

A Menu of Genes
Blake Crouch traipses through an impressive laundry list of genes to tweak (with assistance from real-life geneticist Michael Wiles):
• SKI, PGC-1alpha, and IGF-1 pack muscle cells with mitochondria.
• Altered LRP5 builds denser bones.
• A slew of genes enhance brain function: GRIN2B regulates early learning and memory, GluK4 synaptic plasticity, and NLGN3 molds synapses.
• PDE4B, encoding an enzyme involved in inflammation and cell division, is implicated in COPD, asthma, cancer, and schizophrenia.
• TERT, which controls telomere length, affects rate of aging.

Oddly, protagonist Logan is flummoxed by one of the best-known genes, FOXP2, which gave our species speech.

The roster includes some targeted genes that don’t seem obviously to provide enhancement – the mutation behind the inborn error of metabolism PKU, a cystic fibrosis gene variant, an interleukin variant here, hemoglobin variant there, a tumor suppressor and oncogene thrown in.

A clever interlude complete with sequences of A, T, C, and G – the DNA bases – reveals how genetic code, read backwards and forwards, from one strand or the other, can be tweaked to hide information. This becomes important later on, when characters meet up.

Alas, the accurate gene descriptions lapse into classic anti-science word choices. Logan’s genome, for example, has the “primary goal of survival of the species.” That’s not at all how mutation and natural selection affect evolution.

So what can the genetically enhanced Logan do? The changes unfold slowly.

Logan’s Run
The first improvements are barely noticeable. Beating his daughter in chess (like Larry suddenly beating me in Scrabble). Remembering details of journal articles and books he read decades ago. Ultra speed-reading; “You’re turning a page, like, every thirty seconds,” says his wife one night.

Logan suddenly recalls events from years past in excruciating detail.

He reads tiny, subtle facial cues that convey instantly how people will act – that’s invaluable, especially when gambling, for example. Senses sharpen, as pain tolerance soars. He’s stronger, and takes multitasking to a new level. Perhaps most importantly, Logan’s focus, concentration, and ability to ignore unimportant stimuli – collectively called sensory gating -skyrocket.

“I hadn’t been capable of this intensity of concentration and focus in, well, ever: Something was different. As I closed my eyes, a quiet voice whispered from the further corner of my mind. Not something. It’s you that’s different,” Logan muses.

In short, Miriam was attempting to use her Scythe superior gene editing to alter how humans think, and her son was a guinea pig. She told him before committing her crime against humanity, “It’s one thing to build a new life-form, cure illness, or even attempt the work we’re doing now with our locusts. But to change how members of a fully sentient species THINK is surely the ultimate expression of the power of gene editing.”

(I’m glad that our president doesn’t know how to read and most certainly doesn’t know anything about genetics, or any science.)

A rather convoluted plot complete with the requisite chase scenes, perhaps a requirement for an eventual film adaptation, finally reveals that Miriam and her two offspring, Logan and his sister Kara, have had their genomes enhanced. But the classic unpredictability of gene expression and interaction turns Kara to the dark side.

Collateral Damage
If a technology seems too good to be true, it generally is.

I guessed the Achille’s heel of Miriam’s technology when the narrative settles on Glasgow, Montana, a small town where everyone has been enhanced. Some of the guinea pigs suddenly break out in “maniacal laughter,” for no apparent reason, and soon perish. If you’re familiar with protein folding (hint), it is an ingenious and plausible plot point. The explanation rhymes with “scion,” but I won’t give it away.

The second half of the book takes place a year later. Miriam had been planning to upgrade all of humanity, to make up for her killing millions, but she died before she could do so. Meanwhile, Logan struggles with the challenges of the genomically enhanced, struggling with too many stimuli.

How will he stop his evil sister from disseminating the genome enhancement?

Can he preemptively save the millions who will be collateral damage, spiraling into the deadly laughter?

I won’t give away the ending, but it does wrap up all the dangling plot tendrils.

CODA
Alas, much as I loved Upgrade, near the end it devolves into a prolonged chase, presumably to ease translation to the big screen and satisfy adolescent viewers with Y chromosomes.

The action becomes a traipse through what was once lower Manhattan, the skyscraper pinnacles poking up from what was submerged, with remnants of human culture dotting the apocalyptic landscape. I skimmed about 50 pages of it.

I awoke when the last two pages suddenly evoke a pair of sci-fi classics.

“Music effervesced from the crowd” of survivors brought me instantly back to the brilliant Station Eleven’s band of scorched-earth traveling troubadours. And Logan catching “a glimpse of the Statue of Liberty” of course conjured the final scene of Planet of the Apes, as a stunned Taylor gazes at the ruined crown of the great statue and instantly sees the past and the future.

End-of-the-world scenarios, split humanity, genome tinkering, good versus evil – they’ve all been done many times. Upgrade is a thought-provoking take on a classic theme.