Professional Documents
Culture Documents
Razib Khan
160 14
Dec 19, 2022
Every piece of IKEA furniture comes with a printed instruction manual of diagrams, its
thickness and page count varying according to the complexity of the item’s
construction. Imagine instead that each item required you to lug home another
universal IKEA instruction manual. The manual would be a few meters tall, a
ponderous compendium of every diagram-filled instruction booklet for every item in
the warehouse. Diagrams or processes that apply to hundreds of distinct products
could be cross-referenced and only appear once, but the document would still run to
thousands of pages.
You would sit down to assemble your chest of drawers, your wobbly-legged high
chair, and your pendant lamp, and for each disparate item, you’d consult the same
unwieldy stack of comprehensive instructions. Except each time, you’d quickly find
your way according to a system of personalized Post-It notes. There they’d be: color-
coded tabs sticking out of the relevant tier of your universal manual. Some would
simply mark your specific starting place and you’d be on your own. Others would
include little hand-written notes, corrections, tips: “actually, do this step face-down
on carpet so you don’t dent the veneer”, “do this one twelve times, not the six
prescribed”, “skip this step and come back to it at the end, trust me, it’ll be easier that
way”, etc. They’ll be in a familiar script: notes in your own hand guiding you, based
on previous assemblies. Occasionally the handwriting might be your father’s,
mother’s or even grandmother’s. Some of your Post-Its from earlier moves or IKEA
binges would be more helpful than others. Some would have been revised, refined
and overwritten multiple times. Under current conditions, the panicked ones
scribbled under the stress of a sudden post-breakup move might no longer seem like
the smartest approach, but you’d find yourself bound to follow them just as closely
as the printed IKEA steps they modified.
That massive compilation of IKEA manuals is, of course, the DNA sequence each plant
or animal carries in its every cell. And the colorful accumulation of custom Post-Its
interleaved throughout each individual copy are the personalized marginalia we call
epigenetics.
The mismeasure of molecular biology
In the last decade, sweeping mainstream-media claims about epigenetics’ expansive
role in shaping our world have become hard to escape. I am a geneticist and happy
to stipulate that epigenetics is responsible for a considerable amount of our planet’s
dazzling biological complexity. And yet when someone comes at me with
explanations of anything social and behavioral in humans predicated on epigenetic
effects, I cringe like an astronomer informed that planetary dynamics determine my
personal character (typical Capricorn hubris they might say). The details of your star
chart might be precisely correct, yet I don’t have to tell you that no astronomer
seriously ascribes comparable validity to astrology and astronomy. Epigenetics is a
powerful and ubiquitous process in biology but entails no mechanism equipped to
explain any of the multi-generational psychological phenomena it’s called upon to
legitimize in media coverage, claims about which are both reliably overblown and
entirely speculative. Let’s inventory epigenetics’ actual reach and influence; you can
arrive at your own conclusions about whether it is plausibly, as headlines often claim,
the transmission mechanism for such phenomena in humans as “intergenerational
trauma.”
Epigenetics as an idea has been with us for decades, since embryologist Conrad
Waddington created the term in 1942, combining the words "epigenesis" and
"genetics." He was trying to grasp how one single genetic instruction manual begat
the vast diversity of cell types observed in a multicellular organism and how it shaped
organismic development. Waddington’s concept preceded knowledge of the
structure of DNA by a decade, so he lacked any detailed understanding of the
molecular mechanisms involved. And indeed it is precisely on the scale of molecular
biology that our appreciation of epigenetics’ actual power must begin today. Though
in general discourse, the field has become far more closely associated with
psychology, sociology and genealogy, if you corral a bunch of scientists working at
the cutting edge of epigenetics, I guarantee you any shared appreciation of the
majesty of their topic of research will be denominated in molecules, not sequelae of
ancestral suffering among humans. This public misperception is almost wholly the
outcome of the media’s preference for titillating headlines over science’s concrete
and prosaic realities. And yet, taken for what it is, epigenetics is genuinely magical.
Let’s explore its actual awesome powers.
Epigenetics as the dance of molecules
Your genetic code at different molecular scales, from the coarsest to the
most zoomed in
While classical genetics began with the Mendelian pedigrees tracing the transmission
of traits, epigenetics unfolds through the physicality of molecular biology. Mendelian
genetics manifests across generations, while epigenetics makes its mark, literally, on
the time scale of cell divisions and DNA replications. Epigenetic processes are
necessary to drive phenomena on a molecular scale, which ultimately build up to the
level of complexity that gives us biology’s numerous disparate, rich fields, from
neuroscience to physiology to developmental biology. In genetics, when we consider
the transcription of genes and their ultimate translation to proteins, the classical DNA
→ RNA → protein explanation is a highly stylized reduction of extremely complex
molecular phenomena. If Mendelian genetics is like the history of car makes and
models, molecular genetics is the nuts and bolts of engineering and physics that
power them.
Since we live in the age of genomics, people usually imagine DNA’s A’s, C’s, G’s and
T’s in one of two ways. There’s the elegant DNA helix, a polymer backbone spanned
by nucleotide bases, and then there’s the bland sequence of letters often represented
in plain text, line after line. But these are both reductionistic depictions. You usually
find DNA wrapped around proteins called histones, which allows the long strands to
be packed compactly within the cell’s nucleus. There, the 1.8 meters of a complete
DNA sequence collapses down to 0.09 millimeters and winds together into structures
called nucleosomes. During cell division, as DNA is replicated, these nucleosomes are
condensed further into the chromosomes visible under the typical light microscope.
Epigenetics operates at the interstices of these molecular structures repackaging
DNA in the seemingly blank margins that are airbrushed out of colorful double-
stranded helix visualizations.
Happily, for us, molecular biology as a field lends itself well to the possibilities of
animation. The first two minutes of the below YouTube video illustrate the
interactions that define the epigenetic process:
Humans have about 19,000 genes, but only a subset are expressed at any time in any
cell. Numerous mechanisms drive epigenetic modifications, from the methylation of
CpG islands of DNA promoter sequences that result in gene silencing to the more
recent discoveries of the role of noncoding RNAs in gene regulation. But foremost
among epigenetic mechanisms are the numerous chemical modifications (as in the
video above, which focuses on methyl and acetyl groups in particular) to the histone
proteins that shepherd and package DNA to control and regulate the differentiation
of tissues and organs. For a single biochemical and developmental pathway, DNA
supplies the orchestra musicians in the form of genes, while epigenetics plays
conductor, bringing them together to summon a complex symphony of mechanisms
and structures from the sequence of interacting chemicals. Summed together over
tens of thousands of instances, this yields the elaborate and synchronized structural
and physiological diversity of life on earth.
But epigenetics does not always run as a simple deterministic program; these
dynamic molecular processes can be modified through environmental insults and
stresses. Transcriptional factors, proteins that bind to DNA and regulate the reading-
out of the sequence that ultimately produces proteins, are nudged and modulated
dynamically by epigenetic forces receiving inputs from signals within the cell.
Through this chain of molecular processes that runs from receptors on the cell
surface all the way to proteins interacting with DNA, epigenetics even allows for an
element of improvisation in the expression of the genome and activation of specific
genes to tackle unexpected conditions. To wit, when nearly all organisms are exposed
to very high temperatures, epigenetic forces turn on heat shock genes in direct
response to physical changes to the structure of proteins on the cell surface. Think of
an emergency response team swooping in to reduce inflammation and repair
misfolded proteins and rip apart broken molecules for recycling at the site of your
steam burn. These environmentally responsive epigenetic marks may then be
inherited down the cell lineage, resulting in cellular-scale adaptation.
Histone modifications, and DNA methylation, are not the only epigenetic
mechanisms. But the dynamics outlined above take you much of the way toward
explaining how a single fertilized egg cell transforms into a complex organism with
fantastically diverse, specialized tissues that can change and evolve over your lifetime,
a miracle for which epigenetics deserves some author credits. Media reports highlight
sensational and often spurious results of intergenerational and transgenerational
epigenetics, focusing on the impact of this mechanism across generations. But
molecular epigenetics as an instrument of gene regulation is constantly in play within
the human body’s 200 distinct cell types across a human lifetime’s 10 quadrillion cell
divisions. Yes, that’s 10,000,000,000,000,000 cell divisions or mitoses across which
epigenetic phenomena are essential. The script of epigenetic changes replays
endlessly in every individual, in every organism, and is therefore usually highly
deterministic. This is why humans look like humans and potatoes like potatoes. This
reality rather than nebulous speculations about intergenerational trauma should
frame how we understand epigenetics.
How then to explain results like those from Sweden where grandfathers’ and
grandmothers’ food deprivation was correlated with increased mortality of grandsons
and granddaughters respectively? The p-values in these studies were below 0.05, so
they were statistically significant (in other words, even if the default hypothesis is
true, the probability is less than 5% that you’d get that result, so perhaps consider the
alternative). Studies like this can see print because the design and results fall within
scientific guidelines, so they technically meet a journal’s gatekeeping standards. But
at this point, as most readers are aware, just because a study is statistically significant
does not mean it will stand the test of time or its results be broadly replicable; the p-
value tells you only the probability of the given outcome assuming a certain model,
and sometimes unlikely things do happen. But it doesn’t tell you anything about all
the comparable studies that never saw print because the statistics didn’t cooperate,
nor does it reveal all the datasets selectively discarded because they turned out to be
junk. A study, or studies, may show something, but the truth of a matter is
established through many replications, ideally with controls for confounding variables
that may be driving some of the intergenerational associations (obviously, more than
genes are transmitted within families; folkways, customs and habits are acquired
through imitation).
In addition, trite though the chestnut that correlation does not equal causation might
be, in the case of transgenerational epigenetic transmission it cannot be avoided.
Extraordinary claims contradicting over a century of established Mendelian genetics
and seventy years of scientifically validated molecular biology require extraordinary
evidence. In humans, many roadblocks remain to establishing that inherited
characteristics in subsequent generations are due to environmental shocks in prior
ones, not least that you cannot perform randomized controlled experiments.
Inferences must be from observation studies, correlational or indirect (“natural
experiments” like famines). Deeper digging reliability shows that cases where
epigenetic marks seem to have been inherited transgenerationally actually turn out
to be conditional on the existence of a conventional DNA mutation being passed on
within the family. These mutations may induce a byproduct of distinctive epigenetic
marks, so they are caused every generation by variants natural selection or drift
favors. The causal role of the epigenetic variant in a trait may hold, but its
transmission across generations due to the epigenetic mark is a mirage. Epigenetics
in this case is downstream of conventional Mendelism. It is like some fine print
addendum automatically regenerated anew by a DNA mutation every generation. A
mere footnote to a well-characterized classical genetic process of inheritance.
In plain English, any case for the mechanism required to posit the inheritance of
human epigenetic variation is a royal mess. That doesn’t mean that transgenerational
epigenetic transmission doesn’t happen; it is well documented in plants and C.
elegans (“worms”). A small body of candidate studies in humans also require further
follow-up, but even these remain the object of strong skepticism from most
biologists. Contrary to what headline writers and pop psychotherapists might like you
to believe, thus far, epigenetics is terribly implausible as a factor in theories of human
intergenerational trauma.
Descriptions like the above blur the fundamental difference between epigenetics and
Mendelian genetics, misconstruing both as mechanisms of inheritance across the
generations. Reality is a bit different as noted earlier. Epigenetics is defined by
concrete biophysical changes to your DNA packaging and marks that impact how
genes express themselves rather than changes to the heritable genes themselves.
These changes can be temporary or persist across many cell divisions. Within cell
lines, like muscle tissue, the epigenetic marks determining which genes are expressed
or repressed can be passed on to new muscle cells throughout your lifetime. This is a
feature; you don’t want muscle cells randomly transforming into brain cells. In most
animals, especially mammals, this is the sum total of epigenetic transmission,
modifiers shepherding specific cell types within an organism’s lifetime.
But in some rare cases in some organisms, epigenetic marks persist for generations
(but remember, even these results have alternative explanations). Intergenerational
epigenetic transmission means that the changes affect both the offspring and the
parent (and perhaps also the grandchildren, in the case of a female fetus whose eggs
are impacted during in utero development). The theory of transgenerational
epigenetic transmission extends it a step further, with offspring passing the
epigenetic marks down to multiple future generations. This is the form of epigenetic
inheritance requisite for hypothesized intergenerational trauma, because it is not a
correlation due to the same stress event occurring to the parent and fetus
simultaneously, but an event whose impact is transmitted biologically across many
generations. A cause that echoes down through the generations.
But we don’t even need to take this line of hopeful speculation seriously, because
epigenetic transmission across multiple generations almost certainly does not occur
in humans at all. Mammals generally would be unlikely to exhibit transgenerational
epigenetic transmission due to the simple facts of our reproductive biology. Though
transgenerational epigenetic transmission grabs the public spotlight, it accounts for
far less than 1% of the research published that can be classed as “epigenetics” (and
this is on any species, least of all humans!). Instead, for humans and all complex
organisms, epigenetics remains both incredibly important and ubiquitous, but solely
as a cellular and developmental phenomenon. To understand epigenetics in its full
power, you talk to a molecular biologist that works with DNA, not a therapist probing
the pain points of your family history.
What the media says matters because few laypeople read scientific papers; they get
their information on science from the likes of The New York Times, which has put the
total weight of its sober-minded reputation behind such tantalizing headlines as
“Fathers May Pass Down More Than Just Genes, Study Suggests” and “The Famine
Ended 70 Years Ago, but Dutch Genes Still Bear Scars.”
Watch the whole episode, and you can’t avoid the rather deflating (or reassuring,
depending on your goals) conclusion that realistically, trauma probably cannot be
inherited. But 45 seconds into the episode, the host is still asserting that “trauma can
affect future generations, too,” without a trace of hesitation, caution, or
foreshadowing that he will soon reverse himself on precisely this point. Speculations
about epigenetics and intergenerational trauma without caveat take up fully two
minutes and 30 seconds out of five ( leaving aside that he misdefines epigenetics as
the “study of what can be inherited from parent to child biologically, but outside of
the actual letters of your DNA”) before the host begins dutifully bringing the
narrative back to earth, deflating all those balloons he floated to get the party
started. For anyone who peeled off early, the video looked like a full-on epigenetics-
is-the-mechanism-behind-intergenerational-trauma fest.
For the broader public, tantalizing suggestions frequently encountered enough risk
swiftly mutating into rock-solid facts and theories that can be taken as givens in
serious discussions. Members of the lay public who have heard about epigenetics are
likely to associate it with neo-Lamarckian ideas about the transmission of acquired
characteristics (a giraffe routinely stretching its neck out and then passing on a long
neck to its offspring who in turn do the same in the next generation, etc.) rather than
the workaday nuts and bolts of the body’s molecular machinery.
In 2021, Canadian Prime Minister Justin Trudeau released a statement about the
controversy around Catholic schools for Aboriginal Canadian children where he
stated:
…we must continue to learn about residential schools and the intergenerational
trauma they have caused. It is only by facing these truths and righting these
wrongs that we, in partnership with Indigenous peoples, can move toward a
better future.
What jumped out at me was the casual deployment of the concept of
“intergenerational trauma,” which seems out of nowhere to have become ubiquitous.
Google Books’ Ngram search feature tells us that the term did not exist before 1985,
with its use increasing gradually until 2012 when it hit an inflection point and began
to shoot up.
Searching Wikipedia for “intergenerational trauma” will take you to the page
“transgenerational trauma.” The edit history shows that the entry was created in 2012
(transgenerational and intergenerational trauma chart the same Ngram pattern). The
definition section clarifies the scope and mechanism:
Our genetic code remains that tower of universal IKEA instructions, faithfully copied,
plonked down and consulted anew at each cell replication. And we are lucky to have
epigenetics’ confetti of handwritten Post-Its interleaved among its thousands of
pages; they guide and customize our development as incredibly complex organisms.
But hopeful rumors that these little marks, these bits of marginalia, these ephemeral
scraps of advice, are running the show, as heritable as the tome they annotate, are at
best a motivated fantasy. Transgenerational trauma may well meaningfully exist, but
pinning its validity on a system of Post-It notes that flutter away at the slightest
breeze (or at each meiotic event) is a non-starter. And all to the good. Ultimately,
epigenetics is a case where you can’t take it with you.
14 Comments
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Thanks for writing this! Finally a primer we can send to all of our friends
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Great work Razib. I shared this in all those groups where this should he shared. (You know
the ones I am talking about)
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