Chapter 8: Back to When You Were Just a Fertilized Egg

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You know that feeling, right?

You're on the phone, the other person clearly wants off, but they say, uh, well, I don't want to keep you any longer.

Oh, totally.

Making it sound like it's your fault they need to hang up.

Exactly.

And there's this brilliant cartoon Sapolsky mentions in the chapter we're diving into today.

One scientist says to another, I think I found the gene for that.

Right?

Yeah.

A perfect encapsulation of the myth.

Okay.

So let's unpack this.

Today we're doing a deep dive into a really fascinating chapter from Robert Sapolsky's huge book, Behave the Biology of Humans at our Best and Worst.

It's quite the read.

It is.

And the big question for us today is, what role do genes actually play in shaping our behavior?

You know, from our best impulses to our worst, are they really the code of codes, these fixed blueprints?

Or is that whole gene for that idea mostly just, well, a caricature?

Right.

And that's our mission really.

We need to navigate between two extremes here.

On one side you have the really troubling history, the misuse of genetics,

things like eugenics.

Awful stuff.

We need to acknowledge that.

But then on the other side, there's this modern tendency, maybe over -enthusiasm, to see genes as these unchangeable, essential blueprints for everything.

Sapolsky even mentions people feeling identical twins might share a moral taint just because of shared genes.

Wow.

That's intense.

It is.

So this deep dive, it's going to show that, yeah, genes are incredibly important, foundational even,

but their power, it's much more nuanced.

Much more dependent on context than we usually think.

Okay.

So let's start at the bottom, maybe.

How do genes actually work?

Because they're not really these little commander's barking orders, are they?

No, not at all.

We hear DNA is the holy grail, the instruction manual.

But Sapolsky's point is crucial.

Genes don't decide anything by themselves.

So how does it work, then?

Well, here's where it gets really interesting.

Look at our DNA on coding.

Maybe 95 % of it is non -coding, used to be called junk DNA.

I remember that term.

Yeah, totally wrong.

That 95%, it contains the keys to the kingdom, basically.

These are the promoters and transcription factors.

Think of them as the on -off switches for the genes themselves.

Ah, okay.

So a gene doesn't just switch itself on.

Exactly.

It waits.

A transcription factor needs to bind to its promoter region.

Then the gene gets transcribed, gets read.

It's regulated.

Okay.

So what regulates the regulators?

What flips those switches, the transcription factors?

The environment.

And this is what blows simple genetic determinism right out of the water.

Environment here means a whole lot of things.

Like what?

Well, it could be the intracellular environment.

Say a neuron's working hard, getting tired, low on energy.

Okay.

That internal state activates a transcription factor.

That factor finds the right promoter, flips the switch on a gene that makes, say, more glucose transporters.

Suddenly, the neuron is better at grabbing fuel.

So the cell adapts based on its own state.

Precisely.

Or it could be signals from neighboring cells.

Maybe a neuron nearby isn't releasing much serotonin.

So sentinel transcription factors in our neurons sense this.

Travel to the DNA, find the promoter for the serotonin receptor gene, and turn it up.

Now our neuron makes more receptors, becoming more sensitive to even faint serotonin signals.

Ah, clever.

It is.

And environment can be farther away within the body.

Testosterone, for example, travels in the blood, hits muscle cells, activates transcription factors, leading to muscle growth.

Okay, that makes sense.

But maybe the most striking example is the outside world.

Picture a new mom smelling her newborn baby.

Ah.

Those smell molecules hit receptors in her nose.

Signals travel.

And eventually, a transcription factor gets activated in her hypothalamus.

It turns on the oxytocin gene.

Result, milk letdown.

Wow.

So the smell of a baby can literally turn on a gene.

Yep.

As Sapolsky puts it, genes aren't the deterministic holy grail if they can be regulated by the smell of a baby's cushy.

They're constantly responding.

So it's less about dictation and more about response.

Sapolsky nails it.

Genes are about if -in clauses.

If you smell your baby, then activate the oxytocin gene.

Conditional instructions.

Not commands.

Not commands.

And this creates exponential complexity.

More genes mean exponentially more ways they can be turned on or off, which means you need a bigger chunk of your genome just dedicated to regulating those genes based on the environment.

So the regulation is almost as important as the genes themselves?

Arguably more so, evolutionarily speaking.

Mutations in those regulatory parts, the promoters, are more common and often more significant than mutations in the genes they control.

It shows just how deeply intertwined genes and environment are.

Okay.

Let's shift gears slightly.

There's this concept.

It sounds kind of sci -fi, but it's real.

Epigenetics.

I always thought genes were fixed at birth.

Right.

That's the common idea.

But epigenetics challenges that.

It's basically when environmental influences sort of freeze those gene on -off switches.

They lock them in place.

Freeze them?

How?

Mechanistically,

an environmental signal causes a chemical tag, like a methyl group, to attach tightly either to the promoter region of a gene or to the proteins the DNA is wrapped around.

And that does what?

It physically blocks the transcription factors.

They can't get in, can't bind to the promoter.

So the gene is effectively silenced, shut down.

And this lasts?

It can last a long time.

Lifelong, even.

And here's the kicker.

Sometimes these epigenetic tags can be passed down across generations.

Wait, seriously?

Like, acquired traits being inherited?

Sort of.

Think of the studies on the Dutch famine survivor's grandkids or diabetic fathers passing metabolic traits via sperm.

It's this narrow domain where Jean -Baptiste Lamarck, who everyone made fun of for his inheritance of acquired characteristics, was actually kind of right.

Neo -Lamarckian inheritance.

Mind blown.

Okay, another dogma.

One gene, one protein.

Is that still true?

Nope, that one's broken too.

Most genes aren't one continuous code.

They're broken up into coding bits called exons,

separated by non -coding bits, introns.

Exons and introns, okay.

When the gene is copied into RNA, you initially get both, but then enzymes come along and can splice out the introns and stick the exons together in different combinations.

Oh, so from one gene.

You can get multiple totally different proteins.

It's called alternative splicing, and it's incredibly common.

Like, 90 % of human genes that have exons do this.

Massively increases our protein diversity from a limited number of genes.

Hey, the complexity just keeps growing.

What about these jumping genes, transposons?

Uh,

Barbara McClintock's story.

Brilliant scientist.

Back in the 40s, studying corn maze, she saw inheritance patterns that just didn't fit the rules.

What did she propose?

That chunks of DNA were physically copying themselves and then randomly jumping, re -inserting themselves elsewhere in the genome.

Jumping genes.

People must have thought she was nuts.

They did.

She was ridiculed for years.

But then, the molecular biology revolution in the 70s proved her absolutely right.

Nobel Prize, the whole thing.

Our DNA is not static.

So these jumps, are they just random errors?

Sometimes they might seem like small random changes.

Sapolsky uses the funny example.

The fertilized egg is implanted, becomes the fertilized eggplant is implanted.

But they could be adaptive.

In plants under stress, like drought, transposons might jump around more, shuffling the genetic deck, hoping to create a useful new protein variation by chance.

That kind of built -in mutation generator.

Sort of.

And our immune system uses them too.

In the DNA regions coding for antibodies,

transposons help generate the vast diversity we need to fight off new invaders.

That makes sense.

But where else?

Here's the really wild part.

They occurred in the brain.

Especially in stem cells, as they differentiate into neurons.

So, neurons in the same brain don't all have the exact same DNA.

Nope.

We end up with a mosaic of neurons with different DNA sequences.

Our brains aren't genetically uniform.

Even fruit flies do this.

It's not just random noise.

It seems to be part of the developmental plan.

Okay, my head is spinning a little.

Genes regulated by the environment, epigenetic freezing,

alternative splicing, jumping genes.

Don't forget.

Just pure random chance.

Brownian motion, the random jiggling of molecules down at that tiny scale,

actually impacts when and how transcription factors find their targets.

It adds another layer of unpredictability, further chipping away at simple determinism.

So, the picture at the molecular level is messy.

Genes aren't dictators.

They're influenced by everything.

Their effects can be changed long -term.

They can make multiple products.

And they even move around.

Exactly.

They are not autonomous agents.

They're deeply embedded in and responsive to context.

Which makes that idea of a gene for wanting to get off the phone seem pretty silly now.

Pretty simplistic, yeah.

So, okay, moving from that bottom -up molecular view, let's go top -down.

How did scientists even start trying to figure out genetic influences on behavior by looking at people and families?

Because early on, that must have been tricky, right?

Families share genes and environment.

Absolutely.

That was the big confounder.

If kids resemble their parents, is it nature or nurture?

You can't easily tell just by looking at families.

So, how did the methods get better, more sophisticated?

The big leaps came with twin studies and adoption studies.

Twin studies are classic.

You compare identical twins, monozygotic, MZ, who share 100 % of their genes, with fraternal twins, dizygotic, DZ, who are like regular siblings, sharing about 50 % of their genes on average.

But both types usually grow up in the same house, same time.

Exactly.

So, the environments are pretty similar.

If identical twins are significantly more similar for a trait than fraternal twins, that strongly suggests a genetic influence on the differences between people for that trait.

Okay, that makes sense.

And adoption studies.

Similar logic.

You look at kids adopted early in life.

They share genes with their biological parents, but their upbringing environment with their adoptive parents.

So, you see who they resemble more.

Right.

If they're more similar to their biological parents for a certain trait, despite not being raised by them, that points towards genetics.

And the ultimate version of this.

The gold standard, though rare and ethically complex, is identical twins separated at birth and raised in different environments.

Like that famous case Sapolsky mentions,

Jack Youth and Oscar Storr.

Exactly.

One raised Jewish in the Caribbean, the other as a Nazi youth in Germany.

Utterly different upbringings.

And yet.

And yet, they share these incredibly specific, quirky mannerisms, like flushing the toilet before using it, enjoying sneezing loudly in elevators.

Bizarre stuff.

It's hard to explain that purely by environment.

It dramatically highlights genetic influences.

And using these kinds of methods, researchers have found genetic links to, well, almost everything, it seems.

It's a huge range.

IQ scores, definitely.

Risk for mental health conditions like schizophrenia, depression, anxiety, personality traits, the big five, like neuroticism, extraversion, even things like religiosity,

political attitudes, how often people text, whether they have dental phobias.

Dental phobias?

Seriously, there's a genetic link.

Apparently so.

It seems genes cast a very wide net.

But it's probably not one single gene for dental phobia.

Oh, almost certainly not.

For any complex behavior, it's likely many, many genes interacting, and often indirectly.

Like, maybe genes influence general anxiety levels, which makes someone more prone to all phobias, including dental ones.

Or the voting example you mentioned earlier.

Right.

Voter participation might link to genes influencing personality optimism, maybe.

Or a sense of agency, which then affects whether you feel your vote matters.

Because taller people might get treated differently, leading to more confidence.

Exactly.

It's often these complex, indirect pathways, not a single voting gene or confidence gene.

Okay.

But these twin and adoption studies, they aren't perfect, are they?

There are criticisms, arguments, that maybe they overestimate the genetic part.

Absolutely.

They're powerful tools.

But there are important caveats and ongoing debates.

Critics raise valid points.

Like what?

Well, for twin studies, maybe identical twins aren't just genetically identical.

Maybe their environments are more similar than fraternal twins' environments.

Parents might treat them more alike, dress them alike, etc.

Okay, that seems plausible.

Researchers have tried to control for that, and often find the effect is smaller than you might think, but it's a fair point.

Another is the shared prenatal environment.

Most identical twins share a placenta, which fraternal twins don't.

That could make a difference.

Hmm.

And for adoption studies?

A big one is selective placement.

Adoption agencies might try, consciously or unconsciously, to place kids with adoptive families who are somewhat similar to their biological families in background, SES, etc.

Which would muddy the waters, making it harder to separate genes and environment.

Exactly.

And experts really disagree on how much of a problem this is.

You have researchers like Bouchard, Plowman, Kendler, who think it's manageable, and fierce critics like Lee Ann Kamen, who think it significantly distorts the findings.

Sapolsky basically says, if these super smart people who live and breathe this stuff can't agree, it's clearly complex.

So it's not perfectly clean cut.

Definitely not.

Oh.

These methods give us valuable information, but we have to be aware of the potential limitations.

This leads us to something really important and often really misunderstood.

Heritability.

I hear that term thrown around a lot.

Oh, hugely misunderstood.

And it's crucial to get this right.

It's a bruising, difficult, but immensely important subject, as Sapolsky says.

Okay, break it down for us.

Inherited versus heritable.

Right.

An inherited trait is simply one influenced by genes.

Like having five fingers is highly inherited.

It's in our genetic blueprint.

Okay.

Basic biology.

But heritability is different.

Heritability measures how much of the variation you see among individuals in a population for that trait is due to genetic differences among those individuals.

Variation.

That's the key.

That's the absolute key.

So think about finger number again.

Almost everyone inherits the plan for five fingers.

The variation in finger number in the population of people having fewer than five is mostly due to accidents, not genetic differences.

So finger number is highly inherited, but has very low heritability.

I see.

The differences aren't usually genetic.

Exactly.

And the big mistake people make is confusing the two.

They hear a trait is inherited and assume differences must be highly heritable, meaning strongly driven by genetic variation.

That leads to massively overestimating the role of genes in explaining why people differ.

Can you give an analogy?

Sapolsky uses one, right?

Yeah, the plant analogy is brilliant.

Imagine a geneticist studying one type of plant.

She grows clones, genetically identical plants in a perfectly uniform, optimal rainforest environment.

They all grow to pretty much the same height.

Now she takes other clones and grows them in a perfectly uniform but harsh desert environment.

They also grow to a uniform height but much shorter.

Right.

Environment matters.

Now, if you only looked at the plants within the rainforest, all the tiny variations in height would have to be due to subtle genetic differences or random chance.

Let's say heritability is near 100 % within that group, same if you only look at the desert group.

But now, combine the data.

Look at all the plants, desert and rainforest.

What's the main reason for the huge difference in height between the two groups?

The environment.

Desert versus rainforest.

Exactly.

Suddenly, the overall heritability of height across both groups plummets.

Environment becomes the massive predictor of height differences.

Studying genes in just one context artificially inflates their apparent importance.

Neon lights.

This is crucial, as Sapolsky says.

Totally.

And he argues that, for humans, with our incredibly diverse environments, heritability scores likely plummet the most when you go from a specific subgroup to considering the full range of human habitats and experiences.

Think about wearing earrings heritability in 1950s men versus today.

Environment changed everything.

So heritability isn't a fixed biological constant.

It depends entirely on the group and the environments you're looking at.

Precisely.

Which leads directly to the next crucial concept,

gene -environment interactions.

GXE.

We've touched on this, but let's dive in.

It's ubiquitous.

Basically, if the effect of a gene depends on the environment, or the effect of an environment depends on the gene, you have a GXE interaction.

So you can't ask what the gene does in isolation.

It's meaningless.

Sapolsky emphasizes sizes.

Ask not what a gene does.

Ask what it does in a particular environment.

Give us some examples.

PKU.

Classic one.

Phenylketonuria.

It's a genetic mutation.

If you have it and eat a normal diet, you get severe brain damage.

But if you have the mutation and eat a special diet, low in phenylalanine from birth.

No brain damage.

The gene's effect is entirely dependent on the diet of the environment.

Okay.

What about behavior?

Loads of examples.

A variant of the serotonin transporter gene 5 -HTT.

It increases the risk of depression.

Only if.

Only if the person also experienced significant childhood trauma or stressful life events.

No trauma.

No increased risk from that gene variant.

It takes both.

Gene plus environment.

Another one.

A gene called FADS2.

A particular variant is associated with higher IQ.

But only in kids who are breastfed.

If they are formula fed, that gene variant made no difference to IQ.

Wow.

These interactions are everywhere.

They really are.

Sapolsky even mentions a study with genetically identical mice raised in obsessively standardized lab conditions across three different top labs.

Should be identical results, right?

You'd think.

But for many gene variants, they found massive GXE interactions.

The same gene variant had different, sometimes opposite effects on behavior in the different labs.

Due to incredibly subtle, still unidentified environmental differences between the labs.

That's incredible.

Even tiny environmental variations matter.

It really underscores the point.

It's like the neurobiologist Donald Hebb said, asking whether behavior is more nature or nurture.

It's like asking if a rectangle's area is more due to its length or its width.

Both are essential.

You can't separate them.

Exactly.

And we see this play out in the real world.

Remember the heritability finding.

Cognitive development heritability is high, like 70 percent, in high socioeconomic status families.

But low.

Only 10 percent in low SES families.

Poverty, stresses, and lack of opportunity basically overwhelm the genetic variations.

The environment becomes the dominant factor.

Similar findings for alcohol use.

Heritability is lower in strongly religious communities that forbid drinking.

Social environment trumps genetics.

Okay.

This framework is crucial.

Genes aren't solo actors.

They're always interacting with the environment.

Now let's look at some specific genes people have studied, keeping these interactions firmly in mind.

Absolutely.

We have to remember the caveats.

Generally small effect sizes,

context dependency is key.

But let's start with the serotonin system.

We heard earlier that low serotonin is linked to impulsive aggression.

Right.

So the prediction would be gene variants causing less serotonin activity should link to aggression.

That was the logical prediction.

Maybe genes that make less serotonin, or genes that break it down faster, or transport it a little quicker.

But that's not what they found.

Surprisingly, no.

Studies on genes like the serotonin transporter, 5 -HTT,

and especially MAOA, monoamine oxidase A, which breaks down serotonin and other neurotransmitters, found kind of the opposite.

Opposite?

How?

Well, high activity variants of 5 -HTT, meaning more transporter, clearing serotonin faster from the synapse, technically lower signaling duration, were linked to more impulsive aggression.

And the really big one was MAOA.

The warrior gene.

That infamous label came later.

The landmark study was in 1993 on a Dutch family where some men had a rare mutation that completely knocked out the MAOA enzyme.

So serotonin and others would build up higher levels.

Exactly.

And these men showed patterns of impulsive aggression, arson exhibitionism, other antisocial behaviors.

High serotonin seemed linked to problems.

So why the contradiction?

Drugs lowering serotonin seem to reduce aggression in some contexts, but these genetic studies link higher serotonin activity or accumulation to aggression.

The key difference is likely the time scale.

Drug effects are temporary, genetic influences are lifelong.

Ah, so lifelong high serotonin might change brain development?

That's the thinking.

It could lead to structural changes, different receptor sensitivities over time, plus the warrior gene idea itself is super flawed.

How so?

Well, first, the effect size of common MAOA variants is tiny.

Second, MAOA affects dopamine and norepinephrine too.

Not just serotonin, it's nonspecific.

Third, that original Dutch family had varied issues, not just aggression.

Could have been called the drop your pants gene just as easily.

Ah, fair point.

And most importantly, remember GXE.

The CASPY study from 2002 was huge.

Followed kids for decades.

Found that the low activity MAOA variant, the warrior one, leading to higher serotonin, only tripled the risk of developing antisocial behavior if those individuals also suffered severe childhood maltreatment.

Only with the environmental trigger.

Exactly.

No history of abuse.

The gene variant didn't predict anything, warrior gene, not so much.

It's environment interacting with the vulnerability.

Okay, that really drives home the GXE point.

What about the dopamine system?

That's tied to reward motivation.

Right.

Reward anticipation, goal -directed behavior.

Yeah.

Here the pattern seems a bit more consistent, though still context dependent.

Variants generally leading to lower dopamine signaling, less dopamine released.

Fewer receptors, less sensitive receptors are often linked to things like sensation seeking, risk taking, impulsivity, ADHD.

Then specific genes.

The DRD4 gene, coding for dopamine receptor, is a famous one.

Particularly a variant called the 7R allele.

It's linked to novelty seeking, impulsivity, ADHD,

financial risk taking.

A whole cluster of traits.

But wait for it.

But wait for it.

Don't ask what the gene does.

Ask what it does in a particular context.

The GXE interactions are crucial here, too.

Examples.

Okay, kids with that 7R variant.

They tend to be less generous unless they have secure attachment to their caregiver.

Securely attached 7R kids are actually more generous than average.

Wow, flips the effect.

Totally.

Or 7R kids are worse at delaying gratification unless they grew up poor.

If they grew up poor, the 7R variant makes them better at it.

Maybe because they learned resourcefulness.

Context changes everything.

It's always context.

Quickly, what about other systems?

Oxytocin, vasopressin, hormones?

Similar story.

Variants in oxytocin and vasopressin receptors.

Linked to things like empathy, pair bonding, trust.

But again, context matters.

A variant linked to seeking emotional support had different effects in Americans versus Koreans.

Presumably due to cultural differences in interaction styles.

Fascinating.

And hormones.

Testosterone receptor gene variants can interact with circulating testosterone levels to predict violent crime risk.

But again, the predictive power is small overall.

Glucocorticoid genes stress hormones show big interactions with childhood abuse.

Affecting things like amygdala reactivity to threats later in life.

So these candidate gene studies focusing on one gene at a time have taught us a lot.

Especially about GXE.

But they're only looking at a tiny piece of the puzzle.

Like Sapolsky says, we're plugging away trying to understand interactions of two genes at a time.

It's like looking for your keys only under the streetlight because that's where the light is.

We're missing the genes hidden in the dark.

So how do scientists try to find those?

That's where genome -wide association studies, or GJOES, come in.

Instead of picking one candidate gene,

GWA surveys the entire genome.

The whole thing?

How?

They look at hundreds of thousands, even millions, of tiny variations across the genome.

These are usually single -letter differences in the DNA code called SMPs, single nucleotide polymorphisms.

Okay, SMPs.

And they do this in huge populations, thousands, sometimes hundreds of thousands of people.

They see if any particular SMP is slightly more common in people with a certain trait, like being tall or having schizophrenia,

compared to people without it.

Sounds powerful.

What have they found?

The results have been, well, humbling.

Very humbling for anyone looking for simple genetic answers.

How so?

Take height.

Seems pretty genetic, right?

Huge GWAs with over 180 ,000 people found hundreds of SMPs linked to height.

But the single SMP with the biggest effect explained only 0 .4 % of the variation in height.

0 .4%.

That's tiny.

Tiny.

And all the hundreds of SMPs together only explained about 10 % of the height variation.

Same story for BMI.

Biggest SMP hit was 0 .3%.

So lots of genes, each doing almost nothing on its own.

Exactly.

And for complex behaviors, even more so, educational attainment.

A massive GWS found the most predictive SMP explained.

Wait for it.

0 .02 % of the variation.

Wow.

Okay.

It confirms that behaviors are incredibly polygenic, influenced by vast numbers of genes, each having a minuscule effect.

No single gene for anything complex.

And this leads to another issue, right?

Non -specificity.

Huge non -specificity.

Because so many genes are involved in everything and they work in overlapping networks, any single gene variant is likely involved in lots of different processes and linked to lots of different traits or disorders.

Like the serotonin transporter gene.

Right.

That 5 -HTT gene variant isn't just linked to depression risk.

It's also implicated in anxiety disorders, OCD, maybe schizophrenia, bicolor, Tourette's, borderline personality.

It's part of many different brain circuits, not a dedicated depression switch.

So after all this, this deep dive into the weeds of genetics and behavior, what's the big takeaway for you, our listener?

Well, it's clear that genes are foundational.

Absolutely.

They build the machinery.

But they were so far from destiny.

That gene for that cartoon.

It's funny because it captures a common misconception, but scientifically, it's just way too simple.

Genes give us tendencies, potentials.

Tendencies, propensities, potentials, vulnerabilities.

Yes.

Right.

They specify the proteins, the enzymes, the receptors, but how those play out, that is supremely context dependent.

So the mantra is...

Ask not what a gene does, ask what it does in a particular environment, and when expressed in a particular network of other genes.

That's the core message.

It really forces us to move beyond those simple deterministic ideas and appreciate this incredible complex dance between our biology and everything else, our internal state, our cells, our upbringing, our culture, even chance.

It's not about inevitability.

It's about this intricate, constantly interacting fabric of life.

And maybe thinking about that, how does recognizing this profound context dependency change things?

That's the big question to ponder, isn't it?

If genes aren't destiny, if environment and interaction are so critical, how does that shift how we think about individual responsibility, or how society tackles huge challenges like crime or mental health or inequalities in education or health?

Does it change the focus?

Definitely something to mull over.

It suggests that changing the context, the environment, might be just as, if not more, powerful than focusing only on the biology.

It certainly opens up that possibility in a big way.

Well, thank you for joining us on this deep dive.

We really hope you're leaving with a richer, more nuanced view of this incredibly complex world of genes and behavior.

Thanks for listening.