A Boomer Geneticist's Approach to Human Enhancement

When I first stumbled upon George Church's fascinating genetic list in an X post, I realized I had discovered what could be described as a blueprint for creating superhuman beings. As a researcher who has spent years immersed in polygenic traits and genome-wide association studies, I had gradually come to think of genetics almost exclusively in terms of thousands of small-effect variants. Somewhere along the way, I had unconsciously dismissed the idea that single genes could have dramatic effects as an old-fashioned, boomer approach to genetics—a relic from simpler times before we understood the true complexity of human traits.

I had fallen into the trap of thinking that the recipe for creating a superhuman would involve simply shifting the frequencies of thousands of alleles, incrementally boosting polygenic scores across multiple traits until we achieved meaningful enhancement. But Church's list served as a powerful reminder that good old Mendel is still very much alive after all. Sometimes, the most profound changes to human biology don't require orchestrating thousands of genetic tweaks—sometimes a single variant can rewrite fundamental aspects of what it means to be human.

As one of the most renowned geneticists of our time, Church has made groundbreaking contributions to genomics and synthetic biology, from developing multiplex genome engineering techniques to advancing the field of personal genomics. But this particular project represents something far more transformative than typical genetic research, precisely because it embraces the power of large-effect variants that the field had somewhat moved away from.

The list I'm referring to, available here , catalogs 51 genes and their associated alleles linked to extraordinary traits—disease resistance that seems almost superhuman, enhanced physical abilities that transcend normal human limitations, and protective capabilities against conditions that plague millions of people.

As I dove deeper into this genetic catalog, I realized it offered a perfect lens through which to explore one of genetics' most fundamental distinctions: the difference between monogenic, oligogenic, and polygenic traits. But more importantly, it forces us to confront an extraordinary question about our species' future: are we looking at the genetic foundation for transcending human biological limitations entirely?

Understanding the Genetic Landscape

Before we dive into Church's specific findings, I need to establish the foundation that will help us navigate this complex terrain. One of the most profound discoveries from genome-wide association studies (GWAS) over the past two decades is that most human complex traits are highly polygenic. For example, height has been estimated to be modulated by as much as 4% of human allelic variation, meaning thousands of genetic variants each contribute tiny effects to determine how tall someone becomes.

This polygenic reality has fundamentally changed how we think about genetics. Yet Church's “boomer” approach represents something qualitatively different— he focused on specific variants within these broader quantitative traits that have dramatically larger effects, creating distinct phenotypes that stand apart from the normal distribution.

Monogenic traits are the simplest to understand—they're controlled by a single gene. When I think of classic examples, sickle cell anemia immediately comes to mind, caused by a specific mutation in the HBB gene. These traits follow Mendelian inheritance patterns that Gregor Mendel would recognize, with clear dominant or recessive effects.

Oligogenic traits occupy a middle ground that I find particularly intriguing. They're influenced by a small number of genes, typically between 2 and 10, working together to produce a phenotype. Certain cancer predispositions fall into this category, where a handful of key genetic contributors combine to significantly alter disease risk.

Polygenic traits represent what GWAS has shown us is the norm for most human characteristics. Across urate, IGF-1, and testosterone, thousands of dispersed variants contribute to heritability, with each individual variant having minuscule effects. Height and intelligence are classic examples—traits that we know are heritable but result from an intricate orchestra of genetic influences.

We can also compare the effect size distributions of genetic varaints for oligogenic and polygenic traits:

• Left (Oligogenic): A few SNPs have moderate effects, while most contribute almost nothing.

• Right (Polygenic): Thousands of SNPs each have very small effects, creating a narrow distribution centered near zero.

What makes Church's work so compelling is how he's identified variants that create qualitatively different phenotypes within these broader polygenic traits.

Church's List: A Curated Collection of Genetic Marvels

What makes Church's list so compelling is its focus on genetic variants tied to protective or exceptional traits.

The list emphasizes rare or synthetic variants with significant effects, which naturally skews toward monogenic and oligogenic traits rather than the subtle polygenic influences that shape most of our characteristics. This focus makes perfect sense when you consider the list's practical applications—these are the kinds of genetic modifications that could have immediate, measurable impacts in therapeutic contexts.

For researchers and clinicians interested in genetic engineering, this collection represents a treasure trove of possibilities. Each entry is a potential target for CRISPR editing, gene therapy, or other interventions that could dramatically improve human health and resilience.

The Power of Single Genes: Monogenic Traits in Action

Some of the most striking examples in Church's list demonstrate the remarkable power of single genes to transform human experience. Take natural short sleep, where mutations in genes like DEC2/BHLHE41 or ADRB1 allow people to function perfectly well on just 4-6 hours of sleep per night without any of the cognitive or health detriments that would affect the rest of us.

While most people's sleep needs follow a polygenic distribution—with thousands of variants contributing tiny effects to whether you need 7, 8, or 9 hours—these rare variants create a qualitatively different phenotype. These natural short sleepers don't just need slightly less sleep; they've essentially bypassed one of the most fundamental human requirements.

Another compelling example is pain insensitivity linked to the SCN9A gene—a mutation that can render someone completely unable to feel physical pain. A single genetic change can alter one of the most fundamental aspects of human experience.

These monogenic traits follow clear Mendelian inheritance patterns, making them relatively straightforward to understand and potentially modify. The therapeutic implications are staggering. Imagine being able to temporarily "switch off" pain during medical procedures or chronic pain conditions, or helping people function optimally on less sleep.

Large-Effect Variants: Beyond Simple Monogenic Traits

While many of the most dramatic examples in Church's list are truly monogenic—single genes with large effects—some traits may involve multiple genetic variants that, while not necessarily interacting with each other, collectively contribute to the phenotype.

The Polygenic Reality: Understanding the Background

GWAS studies have revolutionized our understanding of human genetics by revealing that the vast majority of complex traits are highly polygenic. This means that traits like height, intelligence, disease susceptibility, and even sleep duration in the general population are influenced by thousands of genetic variants, each contributing tiny effects that collectively shape the phenotype.

This polygenic architecture explains why most human traits follow normal distributions—why most people cluster around average heights, sleep needs, or cognitive abilities, with gradual tails extending toward the extremes. For example, while natural short sleepers represent a distinct monogenic or oligogenic phenomenon, the normal variation in sleep duration across the population (typically 7-9 hours) is influenced by hundreds of small-effect variants identified through GWAS.

The contrast with Church's list is illuminating. Where his variants might allow someone to function on 4 hours of sleep or increase bone density by 30-50%, the hundreds of polygenic variants identified through GWAS each contribute tiny fractions of a percent to these same traits. It's the difference between genetic changes that create qualitatively different human phenotypes and the subtle genetic tuning that creates normal human variation.

This distinction is crucial for understanding why Church's approach is so valuable for therapeutic applications. While polygenic scores can help us understand disease risk or predict traits across populations, the high-effect variants in his list provide clearer, more dramatic targets for intervention. They represent the rare exceptions where single genes or small gene networks can override the complex polygenic background that typically governs human traits.

Looking Toward the Future: Implications, Risks and Applications

The medical applications alone are breathtaking, but there's an elephant in the room that we need to address: what would happen if someone actually combined multiple variants from this list?

Imagine a hypothetical individual who inherited or received several of these protective variants simultaneously. They might sleep only 4-5 hours per night while maintaining perfect cognitive function, possess bones so dense they're virtually unbreakable, be naturally resistant to HIV and other pathogens, have enhanced muscle development, experience no physical pain when needed, and maintain youthful cellular function well beyond normal human lifespan.

We must remember that genetic variants often exhibit unexpected correlations, meaning manipulations can trigger unforeseen side effects. Church lists some known risks: for instance, reducing muscle atrophy might cause hypertrophic cardiomyopathy, while selecting for norovirus resistance could increase Crohn's disease risk. Crucially, countless unknown negative consequences likely exist because we don't yet understand the function of all the genetic variants we carry.

Current gene therapies and CRISPR technologies are making these possibilities increasingly realistic. We're moving from theoretical discussions about genetic enhancement to practical questions about implementation, safety, and ethics. But the potential to stack multiple enhancements creates entirely new categories of ethical considerations.

Should there be limits on how many enhancements one person can receive? Would enhanced individuals have unfair advantages that could fracture society? How do we ensure equitable access to these technologies?

The future likely holds an integration of approaches—combining the targeted power of Church's high-effect variants with the nuanced understanding that polygenic research provides. We might develop therapies that address major genetic risk factors while also fine-tuning polygenic scores to optimize outcomes.

The distinction between monogenic, oligogenic, and polygenic traits isn't just academic when viewed through this lens. By focusing on large-effect variants rather than the subtle polygenic influences that create normal human variation, this list identifies the specific genetic changes that could redefine what it means to be human.