In my last update, I obliquely alluded to the events of Operation Epic Fury, of which about one month had elapsed. Events at the time were foggy as we were still in the thick of major combat operations. Those largely ended a week after the post, and the strategic outcome looks less favorable to U.S. interests, but, paradoxically, the questions brought to the fore by events (e.g. terrorist proxies, ballistic missile defense, drone warfare) seem further from resolution; this simultaneously creates reason for hope and dread. Regardless, these events appear to be of at least modest historical significance and will influence the military strategies and politics of many countries. It has my interest. I will continue to monitor the situation.

Otherwise, we’re probably settling into a slower news cycle as celebrations for America’s 250th kickoff and major decisions from the end of the SCOTUS term settle.1

Anyway, the second quarter of 2026 has come to and end, and it is time to recap what I’ve been reading and thinking about.

Books

Here’s my book reading for the second three months of 2026:

• 21 completed books total across all formats (7 fiction titles, 14 nonfiction titles)

  • 3 ebooks

  • 3 print books

• 15 audiobooks

Stetson’s Review of Books Read from Q2

1. The Novelist by Jordan Castro [Audio] → Goodreads Review

2. James and the Giant Peach by Roald Dahl [Print] → Goodreads Review

3. Football by Chuck Klosterman [Audio] → Goodreads Review

4. University: A Reckoning by Lee Bollinger [Audio] → Goodreads Review

5. The Conservative Futurist: How to Create the Sci-Fi World We Were Promised by James Pethokoukis [Audio] → Goodreads Review

6. Primary Colors by Joe Klein [Audio] → Goodreads Review

7. Peter Pan by J.M. Barrie [Print] → Goodreads Review

8. The Netanyahus by Joshua Cohen [Audio] → Goodreads Review

9. Last Branch Standing: A Potentially Surprising, Occasionally Witty Journey Inside Today’s Supreme Court by Sarah Isgur [Audio] → Goodreads Review

10. Dad Brain: The New Science of Fatherhood and How It Shapes Men’s Lives

    by Darby Saxbe [eBook] → Goodreads Review, Substack Review, Podcast

11. Blood and Progress: A Century of Left-Wing Violence in America by Noah Rothman [eBook] → Goodreads Review

12. Empires of the Steppes: A History of the Nomadic Tribes Who Shaped Civilization by Kenneth W. Harl [Audio] → Goodreads Review

13. Gerontocracy in America: How the Old Are Hoarding Power and Wealth―and What to Do About It by Samuel Moyn [eBook] → Goodreads Review

14. Kill Chain: Drones and The Rise of the High-Tech Assassins by Andrew Cockburn [Audio] → Goodreads Review

15. The Wonderful Story of Henry Sugar by Roald Dahl [Print] → Goodreads Review

16. Days of Rage: America’s Radical Underground, the FBI, and the Forgotten Age of Revolutionary Violence by Bryan Burrough [Audio] → Goodreads Review

17. Television by Lauren Rothery [Audio] → Goodreads Review

18. Strange New World: How Thinkers and Activists Redefined Identity and Sparked the Sexual Revolution by Carl R. Trueman [Audio] → Goodreads Review

19. Almost Human: The Astonishing Tale of Homo naledi and the Discovery That Changed Our Human Story by Lee Berger [Audio] → Goodreads Review

20. After the Ivory Tower Falls: How College Broke the American Dream and Blew Up Our Politics—and How to Fix It by Will Bunch[Audio] → Goodreads Review

21. Everybody Loses: The Tumultuous Rise of American Sports Gambling by Danny Funt [Audio] → Goodreads Review

I’m also currently working through/finishing up Wittgenstein’s Mistress by David Markson, The Collected Prose, Volume 1: 1905-1928 by T.S. Eliot, and selected essays of Michel de Montaigne.

Stetson’s Quarterly Book Recommendations

Any book that I took rated well on Goodreads and took extra time in reviewing are likely worthwhile reads depending on one’s interests or familiarity with a topic. From a more general interest perspective, I really think Days of Rage should be more widely read and discussed given some of the historical echoes of we’ve born witness to today.

Of the fiction I read, The Netanyahus by Joshua Cohen stood out. It was an arch way of exploring the pitched battled hosted by the Jewish American pscyhe, the push-andpull between liberal universalism/assimilationism and ethnoreligious particularism. The novel undoubtedly favors the former (it wouldn’t have otherwise won the Pulitzer), which reflects a truth about American Jewishness, but it doesn’t only satirize the fictional “Yahus” and finds their challenge to liberal universalism substantial.

Television & Film

The only television show I watched with much interest this quarter was the third and final season of Euphoria. The show began as a glittery and provocative coming-of-age story for a cast of LA-based teens, where the central figure, Rue Bennett, battles drug addiction in the wake of familial tragedy. The final chapter for the sometimes transgressive, often gratuitously raunchy and interestingly impressionistic show has been received as a disappointment. This has less to do with choices of the creator than critics have alleged and more to do with circumstances beyond the show’s control. Historically, long breaks between TV seasons are fatal for prestige and popular shows alike, at least if we have learned anything from how Game of Thrones and Stranger Things stumbled through their closing seasons. The momentum evanesces.

Relatedly, the change in age and fame of the several primary cast members—Zendaya, Jacob Elordi, Sydney Sweeney—and the untimely deaths of others, Angus Cloud and Eric Dane, created serious logistical and creative challenges. Many of the actors were apparently too busy to even shoot scenes together, giving the show a disjointed and discontinuous feel. Prominently, Sydney Sweeney dominates season 3. She’s risen so substantially and her contract gave Euphoria scheduling priority thus her character, Cassie Howard, moved from the show’s periphery to its center. In this way, the show’s psychological and emotional core shifted dramatically.

Some of the criticism appears to be a function of the seemingly shifting political tone of the show with the final seasons adopting an almost Old Testament moral universe. I think this thematic shift is over-emphasized and was already present in the past two seasons. Sam Levinson, the show’s creator, was less subtle about some of the satirical choices than before, and the post-woke environment in which the show landed made this clearer to viewers. It was merely obscured before by the show’s gonzo visuals and nominal diversity, e.g. Rue’s race and lesbianism, Jules’ transgenderism, etc.

Quick Hits

Remember my usual disclaimers about these recommendations, i.e. they don’t function as endorsements. I’m keeping the list short again as I really have not been able to keep up with Substack reading as much as I’d like.

Stetson’s Reading Recommendations from Substack for Q2

• Progressives Don’t Understand Masculinity by

• how you should feel about my cancer diagnosis by (DLA gets a bit David Foster Wallacean here)

• On Inequality and Socialism by

• The first molecular data from Homo naledi by (related to my reading of Almost Human)

• How human evolution has been speeding up by

• The ballad of TIGIT by (I had wanted to write something similar)

Stetson’s Podcast Episode Recommendations

• David Reich – Why the Bronze Age was an inflection point in human evolution by (This is a must listen)

• Embryo Selection and Frontier Genomics with Dr. Alex Young – Manifold #111

• Chatting with Prester John Andrews from &

• The Notorious R.O.D. from &

• Why Democrats and Republicans want you to pay $50,000 for a car from &

• Dan Hess: the end of Asians and humanity going to the retirement home from & More Births

My Features

Here’s what I’ve published on Substack recently:

• Colossus: An Interview - I talk with about his latest novel.

• Born in Sin, Raised in Iniquity - I review ’s book on the genetics of sin

• Are Great Dads Made, Born, or Selected? How Do We Make More? - I interview about contemporary fatherhood

• The Once and Future Dad - I review Darby Saxbe’s book Dad Brain

Selections from Substack Notes

I’m active on Substack Notes. Here are some recent selections:

Be back with you all soon!

The proverbial argument about fatherhood made by social conservatives is that fatherlessness is a harbinger of social deterioration. There are corollaries to this claim about the importance of traditional gender roles, including the importance of chastity and a division of labor in the home that endorses a “man for the field and woman for the hearth” vision. Around the millennium and afterward, empirical versions of this argument were reformulated by right-of-center wonks and scholars like George Gilder, Christina Hoff Sommers, James Q. Wilson, Harvey Mansfield, Charles Murray, and many others. Today, we are seeing left-of-center academics and wonks warming to the need to promote and support fatherhood and male socialization. One of the indicators of this shift is the recent publication of Dad Brain: The New Science of Fatherhood and How It Shapes Men’s Lives by and the attention it has received from journalists like , , and .

Pro-fatherhood, or ***gasp*** pro-patriarchy, arguments have trended toward a bloodless and technocratic tone, retreating from moral suasion. This has created a permission structure for those left-of-center to climb aboard, contributing significantly to the empirical case for fatherhood, but to many Americans, this rhetorical shift may seem to be coming at a perplexing time.

Although double the rate of five decades ago, the percentage of U.S. children living in single-mother households has stabilized over the last decade-and-a-half or so. Furthermore, data from the American Time Use Survey shows that contemporary fathers are spending unprecedented amounts of time with their children.1 On top of this, the American Time Use Survey data shows that the modern household division of labor is roughly 50:50! A total feminist victory! So why the concern?

One could argue that the concern is related to the type of rhetoric that’s purportedly popular with today’s young men and boys. There’s been an endless amount of handwringing about and admonishment of various fringe and usually internet-related phenomena among young men, including the supposed popularity of provocative new media personalities from the so-called Manosphere, who unabashedly champion misogynistic or chauvinistic talking points while souring on the project of traditional fatherhood themselves. However, I think technocrats have started to care about fatherhood because there is mounting evidence that social dysfunction between young men and women combined with economic hurdles (e.g. high real estate prices) is a threat to posterity. They’re doing what they usually do: following the data.

The data show that fatherhood is in secular decline, increasingly more difficult to access despite no real evidence of a change in preferences.2 The generalized generation-over-generation decline in family formation (i.e. marriage and parenthood), is relatively more concentrated among those without college degrees. Women have obtained bachelor’s degrees at nearly twice the rate of men for awhile now, and there is a strong preference for pairing up along educational and social status line so the matching math ain’t mathing anymore. Another factor to keep in mind is the stagnation of the median male. There have been negligible male wage gains for five decades as the economy transitioned away from manufacturing toward services, high tech, and healthcare and as returns from the density of the urban centers have increased.

Plus, the men who do happen to become fathers outside of wedlock often spend little time with their children, and unmarried women have significantly fewer children today than married women. So despite the relatively high rates of births to single mothers, most of the opportunity to become an involved father, especially to multiple children, is within the confines of marriage.

Without having to belabor the story told by the data, the fundamental problem should be clear. Over the last several decades, we have experienced a shift where the most important milestones of adult life have increasingly become the selective rites of the educated and affluent. Those who are serious about broadly shared prosperity can’t help but be concerned.3

Does This Have Anything to Do with Dad Brain?

Well, I highlighted these data before directly engaging the text of Dad Brain because I’ve have a nagging concern that the psychological and biological study of fatherhood today will be plagued by selection effects, meaning there may be something altogether different about the men who become fathers today and those that don’t.4 If the selection criteria have to do with characteristics that we can do little to change, then we need to need to focus changing the game and aligning with those fixed factors.

Beyond questions of range restriction, the scientific questions about the effects of becoming a father on a man’s brain and behavior and the effects of a father on his wife, kids, and his community are inherently difficult to study. The gold-standard methods for isolating the variables of interest are not really available to investigators. Plus, most of the research will be underpowered and much of it is also new not yet subject to validation: replication, application, etc.

One of the great things about Dad Brain is that Saxbe is very upfront about the limitations here, cautioning readers not to be overly confident about the conclusion of various studies. She still presents the data she believes in, and I’ll recount some of that here, but it is good to keep in mind how provisional some of the claims are.5

Did Human Evolution Improve Fatherhood?

Saxbe orients readers by pointing out that across the animal kingdom fatherhood (paternal care) is facultative. In the jargon of a biologist, this just means that its not required for survival. It is a bonus or a backstop compared to the obligation mothers fulfill. This suggests that external conditions will play an outsized role in how much fathers contribute to parenting and that parenting duties will inevitably fall more heavily upon mothers regardless of external conditions. Some of the most important factors predicting paternal care include the relationship between a mother and father, a proxy of sorts for certainty of paternity. There are many other environmental and social variables that matter too including many that are peri- or postnatal, such as skin-to-skin contact.

Nonetheless, Saxbe asserts that there’s a special role for human fathers, which is likely related to the greater needs of our young. In some ways, she has piggybacked her claim here on top of Sarah Hrdy’s book Father Time, which makes an evolutionary case that humans have been selected for greater paternal care during the Pleistocene by complex social dynamics and harsh environments.6 There is obviously something to the evolutionary argument given that the level of participation from human dads in the care of children is a striking outlier in the mammalian class, which is characterized by… let’s say… distant fathers.

Does Fatherhood Change the Brain?

Perhaps the pivotal or at least most titular chapter of the book spotlights some of Saxbe’s research on changes in the brain volumes of fathers after child birth. She recounts how neuroimaging studies of mothers have found reductions in grey matter volumes in so-called mentalizing regions of the brain. Her own longitudinal study of roughly forty first-time fathers from Spain and California came up with a similar finding (PMID: 36057840). She cautions readers not to read too much into the brain shrinking given that it can be a signal of greater efficiency, and the study is just looking at a snapshot of a dynamic process given the great plasticity of the brain.

Saxbe then reports on her graduate student’s direct comparison of the maternal and paternal brain changes, finding some sex specificity. The maternal volume losses were more widespread across subcortical and cortical regions, while the paternal losses were mostly cortical. She argues this may be related to the facultative role of fatherhood, where fathers “choices” play a larger role in the changes the brain undergoes, and she claims that the magnitude of the brain volume changes in dads is partially explained by the nature of their involvement.

At the close the chapter Saxbe rightly caveats the conclusions of these imaging studies, highlighting that they’re underpowered. Elsewhere, she’s acknowledged that other imaging studies of the brains of dads have reported somewhat contradictory findings, including volume increases.7 Personally, I put little stock in small studies using brain imaging given the limitations of the technology and associated methods, however, I think we should have a strong prior that parenthood is likely to have meaningful effects on our neurobiology and that these are changes facilitate important dimensions of the parental contribution and burgeoning relationship.

Test-22

In The WEIRDest People in the World, Joseph Henrich helped popularize research, namely research by Lee Gettler performed on men in the Philippines, that shows that fatherhood significantly lower testosterone levels in men. The average drop is 25%! Joe Rogan listeners and bodybuilders may find this news shocking and disturbing, but a clearer understanding of the complex relationship between hormones and behavior is clarifying. In fact, men from the same study with higher testosterone when single were more likely to obtain a female partner and become fathers. This implies a tradeoff between life strategies and testosterone levels, where high testosterone is advantageous during mate competition at the cost of pair-bonding. Contrastingly, lower testosterone levels enables a man to stay simpatico with his partner and provide more attentive care to his offspring (and to live a longer healthier life!).

Saxbe echoes this narrative but takes it in a different direction than Henrich, who attaches civilization-level significance to the testosterone suppression effect of marriage and fatherhood. For Henrich, the testosterone control is a cultural adaptation that yokes and leverages our biology, but for Saxbe it is a bit of a conundrum. First, she highlights that despite the pros of low testosterone, there are psychological costs to the decline for new fathers, almost mirroring postpartum depression in some instances, but she also is uncomfortable with the tension among the social costs of high testosterone and its contribution to male desirability. Men are in a bind, a Test-22. Gender egalitarians tend to look askance at or vehemently condemn high T associated behaviors: aggression, lasciviousness, boorishness, competitiveness, etc. These behaviors are cast as toxic and dangerous yet they also may increase the mate value of these men (think Clavicular’s Jestermaxxing). On the other hand, eagerly embracing the testosterone penalty of marriage and fatherhood may put a man’s desirability as a long-term partner at risk, raising the nightmares of divorce, emasculation, cuckoldry, etc.

No Trad-wifey Girls in a Heterofalalist World

At the halfway point, Saxbe has a brief interlude where she pivots from the biological changes of fatherhood to the psychological and social challenges that modern parenthood creates romantically for couples. Despite Saxbe’s equanimity, the book’s discussion of rhetorical touchstones like “invisible labor” and “cognitive burden” are inexorably shaped by the broader cultural context and history of feminist rhetoric, which can’t help but implicitly indict and ridicule laggard men and their malingering or weaponized incompetence. Saxbe isn’t really that guilty of this, even drawing attention too some of the ways in which the behavior of women excludes men from contributing, but there is nonetheless the implicit concern about lazy or incompetent men in the home. Further, the discussion cannot transcend the rhetorical environment that’s likely familiar to the readers of a book like this where the salient tone that percolates through, intentionally or not, when such concepts are raised reveals a palpable amount of resentment towards men for essentially not thinking and acting like women in relational contexts and this feeling is often legitimized rather than questioned. Men have their shortcomings, of course, but we’ve culturally tolerated, entertained, or tacitly endorsed too much male bashing, and it hasn’t forged the men we’ve been searching for, meanwhile this sort of rhetoric has progressively soured from hostility to resignation; the feminist penchant for neologisms has captured this trajectory, devolving from “manspreading” and “mansplaining” to “mankeeping” and “heteropessimism.”

Personally, I find life or relationship advice masquerading as an amalgam of science and therapy off-putting. Again, I don’t think Dad Brain should be understood as this, but it’s just that there are rhetorical parallels in the book to this pervasive tendency. And even if the research and vogue therapeutic modalities on such thorny life questions turns out to be all correct, I’d see myself as some exception, the dipole of a pick-me girl. I’ve yet to find such framings useful and also never really considered the issues as being important enough to merit what can be characterized as medical-grade attention. It’s mundane. It’s the main stuff of life. It is going to messy, frustrating, and uncomfortable. Plus, the prescriptions that do surface tend to be too narrow or too broad, and rarely, does the takeaway message seem to be that it’s simply okay to accept things as imperfect. Soldier on. But I guess, this is stereotypically masculine life advice…

Dads Parenting Differently

The second half of the book examines the modern practice of fatherhood and some of the related sociopolitical context. Relative to the first portion of the book, it contains more normative claims (implicit and explicit), where Saxbe stakes out a progressive or left-liberal view of the place of fatherhood in society (e.g. “Fatherhood as a Public Good”). This portion is also a bit of a grab bag, churning through a wide variety of topics quickly like adoptive fathers, nonresidential fathers, stepfathers, fatherlessness, public policy (e.g. paternity leave), and cultural scripts (e.g. the bumbling dad). I fear Saxbe uses this part of the book to cover every base and be a bit politic about sensitive subjects. This may distract readers from the central normative message that I think this portion of the book actually delivers: children benefit from and thus deserve good dads.

Unlike many of who share her politics, Saxbe openly acknowledges that fathers “aren’t just male mothers” that they have “distinct styles of parenting.” This may seem obvious to readers, but it’s remarkable insofar as it broadly accepts typically right-of-center claims about the social value of the traditional family unit from a left-of-center perspective.8 If fathers are doing something special for children and it helps children, then the optimal childrearing environment obviously is a home in which fathers are present and engaged (along with the mothers of course). There is not really a way to engineer oneself out of this conclusion. Unsurprising though, Saxbe does try to wriggle away from it. She forwards an inclusive conception of the social role of fathers and parries the traditional view with a more capacious understanding of childcare, the alloparenting model aka the “it takes a village” concept, which is consider more ancestral for humans by anthropologists. What isn’t considered is whether a more alloparental model would actually crowd out the very engaged role that married fathers tend to play today. Is this what we want? Further, Saxbe doesn’t really engage with the kind of social change that would be necessary to move back towards more of such a model of childrearing.9

Does the data really show that fathers do some special and essential for kids? Saxbe doesn’t rigorously explore this question, but she does cite research on the topic, starting with findings that go back four decades now and have yet to be meaningfully disputed. This work observed that the dynamic between infants and fathers is more playful and tactile than between mothers and infants. Since then, research has continued to find that father-led “active physical play” has consistently had positive effects on child development, fostering important life skills. She also hints at a “tots for mom, teens for dad” model of parenting where after the critical mom-infant/young child period elapses dads can takeover an engaged mentorship role. This is all intuitive to those who have been parenting awhile, but Saxbe does start to tease out some of the ways common human tendencies and the social realities downstream of them shape the options and opportunities before parents.

Can We Get More Dads By Making Parenting Prestigious?

There is a popular feminist argument that claims that feminized labor, especially domestic work or childcare, is artificially under-valued by our society. This is extended to the idea that the proportion of men in a field is a driver of that field’s prestige and thus its level of compensation. Saxbe believes in some version of this argument and believes that if there was an influx of men into these forms of care work traditionally thought of as feminine then there would be a transformation in the social prestige attached to it. Subsequently, many new avenues for men to achieve status would open up, increasing their marriageability and thus their likelihood of becoming a father or a father to multiple children. She believes in this argument enough to conclude the book with it.

As is probably already clear, I’m quite skeptical of this narrative. I have strong theoretical (related to evolved biological sex differences) and empirical objections. However, the empirical problems alone should be enough to foreclose entertaining it further.10 Almost all of the research that is cited as evidence for this argument lacks rigor, specifically there is a lack of clean causal identification in the studies. Historically, these claims have been supported by cross-sectional data, which suffers from omitted variable bias and the prospect of reverse causality (i.e. Do women preferentially enter low-paying fields rather than their entry leading to wage declines?). Plus, when more rigorous designs have been attempted the alleged effect is either not observed, attenuates, or not causally mediated by the sex composition itself.

Despite my skepticism, I’m worry about the burden of work that many modern mothers face. It is understandable that many feel overworked and stressed out. If there was an easy way for fathers to substitute themselves and give moms a break, I’d be happy to entertain it. I don’t see such an option, especially one that wouldn’t have more costs than benefits. I think the main reasons the burdens differ between the sexes are biological sex differences influencing psychological tendencies. Egalitarian marriages are now the largest plurality of household arrangements and fathers are doing more domestic and care work than ever before, but the burden on women hasn’t let up. In fact, women has preferentially ratcheted up their investments. The reality is that men and women approach parental investment differently, and any mechanism to force women from continuing their intense personal investment in their children would be perverse or illiberal.11

Part of the reason that mothers have opted to invest so much is that there is a parenting arms race. Heavy investment in children is an (upper) middle class American norm that kicked off a generation or two before Millennials even aged into parenthood. So solving for the stress on mothers, requires solving a series of different prisoner’s dilemmas. And even if we all culturally agreed on a parental détente, it would not eliminate the kin-based incentives inherently built into the proposition of parenting. Parental investment is a kind of luxury that many luxuriate in despite how taxing it is. Some people like running marathons after all! Is it ridiculous to believe that women are simply more likely to draw greater meaning and enjoyment from parenting, especially very young children, compared to men? Such a reality seems pretty evolutionarily convenient.

Despite my critique, I found reading Dad Brain a worthy use of my limited time as a parent to three children myself, and I’m happy to recommend it to any curious reader. I care about being a part of the public discourse about fatherhood because I hope to model it as a positive and worthwhile experience to others and to help graduate more Americans into family life. It is a tough problem, and I don’t think any of us have an easy fix. The energizing part is that people like professor Saxbe, who have a different perspective than me, can still largely agree on this vision. It is a basis for continuing to build a culture that is broadly pro-family.

We touch briefly on how fatherhood changes men’s brains, hormones, relationships, and sense of purpose, while focusing most of our discussion on the culturally and politically charged questions attached to marriage, parenting, fertility, and gender roles in America today.

Much remains unaddressed, and Darby and I didn’t resolve all of our disagreements about the best strategies for promoting more men into healthy marriages and constructive fatherhood, but we both agree on the inestimable value of fathers contributing to the care, education, and socialization of children.

I have a ~1500 word review available at Goodreads where I share my immediate reactions to Dad Brain. It concentrates on my disagreements with the second, more prescriptive portion of the book, but I enjoyed the book a lot! I especially appreciated the candor about biological differences between the sexes and humility about what we can learn from the available science.

Look for a polished, updated, and more detailed version of my review here at Substack soon.

What justifies blame and punishment? How free are we to avoid punishment? Are we to blame because we are free, or in spite of the fact that we are not? Is there a tragic element to human life, in which we are born with a predisposition toward those very acts that are punished? Is that tragic element unequally distributed at birth?

~K. Paige Harden, Original Sin

I can say with certainty that some people are born with certain genes that make it more likely for them to do things that are punished. (Whether or not they ought to be punished is a different question.)

~K. Paige Harden, Original Sin

Kathryn Paige Harden has decided once again to wade into the turbulent waters of the nature-nurture debate. She’s chosen an apt time given the recent publication of “Ancient DNA reveals pervasive directional selection across West Eurasia” in Nature, which has potentially re-written our understanding of the history of natural selection in human history.

Harden’s previous foray, The Genetic Lottery (2021),1 covered the unavoidable and growing evidence that variation in genes was meaningfully responsible for differences in cognitive repertoires, educational attainment, and subsequently socioeconomic inequality. To distinguish herself from the genetic determinism or hereditarian pessimism that is frequently associated with Charles Murray or the Human Biodiversity (HBD) movement, she was careful and eager to argue that genes aren’t the whole story. Little-to-nothing is known about how genes closely or even causally associated with cognition actually mechanistically cause the downstream outcomes we can measure nor is it likely that the causal mechanisms are deterministic or even wholly biological. Despite all the caveats, the clear message for Harden’s target audience, the staunch left-liberals and progressives who generally subscribe to the standard social science model (SSSM), remains: our genetic differences must be reckoned with in research, in culture, and in politics otherwise we can say goodbye to whatever hope there is for an egalitarian polity. It may even cede ground to an openly eugenic culture and politics.

Suffice to say, there were plenty, especially in the early 2020s, who were steadfastly unwilling to accept this conclusion. Several accomplished scientists in related research areas were motivated to mount strong rebuttals,2 setting impossibly high epistemological standards for forwarding claims concerning genetic effects on human social and cognitive phenotypes. Some (myself included) would even call these efforts isolated demands for rigor or even scientific nihilism. Nevertheless, Harden has persisted. The result is Original Sin: On the Genetics of Vice, the Problem of Blame, and the Future of Forgiveness.

In Original Sin, Harden interweaves personal vignettes with topical recapitulations of scientific research, including studies she conducted herself. She also integrates some religious and philosophical musings and a broader cultural critique. This all unfolds over 12 episodic, essayistic chapters.3 It is a bit more discursive and confessional compared to her prior book, but her commitments to the science of genetic effects on human behavior and the politics of egalitarianism remain. Altogether the collection still makes for a compelling read, unguardedly engaging the reader on deeply personal and deeply human questions. I was immediately struck by Harden’s candor early on, which I felt was a sharp departure in tone compared to her prior book.

Now that I’ve oriented potential readers of Harden’s latest book, providing background on the rhetorical and intellectual context, the rest of my review will address the ideas, research, and arguments Harden presents. This is a spoiler warning; not that these really apply to nonfiction titles. Nonetheless, you’ve been warned!

Original sin is both a provocative and evocative concept, perhaps even more so to those who are entirely estranged from religion. It’s provocative to those with modern Western sensibilities because our ethical defaults are premised on assumptions about personal autonomy, consent, and sociocultural context, while it’s evocative to those who study human nature because it pithily captures just how inherent and inevitable our proclivity for misbehavior is. Certainly, these notions were on Harden’s mind when she set out to write her book. Indeed, she tells us about the personal experiences that prompted her musings, including a psychedelic experience in the Texan desert, her freighted departure from the church and faith of her upbringing, and a letter from a prisoner convicted of a grievous crime.

The primary way Harden orders the various ideas she explores is by developing a dialectic of sorts concerning the titular concept. In recapitulating a theological debate about original sin between Pelagius and Augustine of Hippo, she is able to contrast common conceptualizations of guilt and normative views about the role and nature of punishment.4 Although enmeshed in religion, these ideas are still live and legible today to secular people. The Pelagian view is that nothing inherited or natural can be a blameworthy even if it appears evil or wrong.5 Instead, sin is chosen by free individuals. This also suggests that perfection can be achieved. The Augustinian view is that the evil of sin is inherent to man, continually transmitted generation after generation. It is inescapable. The battle against sin is interminable and grim. Augustine even argued the mechanism that propagates original sin, sexual intercourse, is itself a sinful act motivated by sinful desires.

Harden, herself, is ambivalent about both thesis and antithesis in her dialectic. The Pelagian position is too near that of libertarian free will, of which no scientific approach to human behavior can countenance without enormous qualification. Meanwhile, the Augustinian view is tragically pessimistic and such a grim view of man is likely to create a permission structure that tends to endorse cruelty as a form of punishment.6 To sort this out, to reach a synthesis, Harden turns to science. What does the best research have to say about human nature? Can it provide us with a way of reconciling the Catch-22 of guilt and punishment?

Written in Blood: Hereditary Sin

Harden is an active behavioral geneticist so she naturally turns to the research she’s done on this question. She participated in work that pooled genomic data from 1.5 million people of European ancestry and constructed genetic predictors (i.e. polygenic scores) for a range of behaviors some may colloquially refer to as sin or the consequences thereof. This included trait outcomes like opioid use disorder, suicide, HIV infections, criminal convictions, and unemployment. What’d they find? Well, one of the most striking findings was that an individual with high genetic risk for externalizing behaviors was twice as likely to be arrested versus one with a low genetic risk. This wasn’t just a large relative difference to an uncommon outcome. It was a large absolute difference: 40% vs 20% (see figure below).

Harden also covers some research from others in her field. She points out that boys who have inherited minor physical anomalies (MPAs) are more likely to show aggressive and hyperactive behavior (PMID: 622559). After recounting, in brief, some of the false positive findings from human genetics research in the early 2000s, i.e. studies that claimed moderate-to-large effects for common genetic variants (polymorphisms) on behavior, she recapitulates the bonafide discovery of a large Dutch family cursed with a rare, high-impact genetic variant affecting a gene called monoamine oxidase A (MAOA). The MAOA gene is located on the X chromosome so the loss-of-function mutation (i.e. c.886C>T p.Gln296Ter) only affects male carriers (i.e. hemizygotes) as female carriers otherwise carry a healthy copy on their other X chromosome. These male carriers were Cain incarnate, raping their own family members, stabbing people with pitchforks, trying to run people down with cars, and setting things ablaze. The male carriers consistently demonstrated impulsive aggression and intellectual deficit (PMID: 8211186).

When skeptics of genetic effects on human behavior argue there isn’t a “gene for” outcomes like criminality, a strong rebuttal is Brunner syndrome. While, of course, a gene can’t encode a social trait, Brunner syndrome is nonetheless a clear monogenic condition with social and behavioral consequences. We often will call CFTR a gene for cystic fibrosis even though that gene encodes a chloride transporter protein not a fibrotic condition. Similarly, Brunner syndrome results when the enzymatic activity of MAOA is completely or selectively disrupted by genetic variation, which in turn disrupts normal brain development and physiology in ways that appear to almost guarantee anti-social behavior at some juncture in the male carrier’s life. Another rejoinder to this argument is typically that these conditions are rare and that, despite this clear evidence that genes are causally linked to social behavior, the finding doesn’t generalize to common variant in the genome writ large. This position has become less-and-less tenable over time. Genomic research has increasingly shown that rare and common variation effects converge. So yes, Brunner syndrome, like almost all monogenic conditions, is certainly rare (<100 individual cases), it also points to the likelihood that the biological pathways it affects are also affected by common variation in a similar way. Further, the genomic era has also taught us that the true prevalence of genetic conditions can be underestimated and that rare disease is uncommon as a specific diagnostic entity but, in aggregate, the totality of rare disease is anything but rare .7

It is hard not to be persuaded by the genetic findings. Not to mention, there are other clear biosocial factors influencing criminality, including age and sex (see chart below). It’s clear biology matters, especially as we decompose the behavioral tendencies that contribute to actions that are socially labeled as criminal or antisocial, such as aggression, risk-taking, disagreeableness, etc. Harden, herself, is convinced that vice has an important genetic contributions. She still strives to show that environments matter too, recounting instances of extreme privation and abuse also coinciding with familial patterns of violence, including some very harrowing accounts.8 These asides segue into Harden’s broader argument about the false dichotomy that sustains the nature-nurture debate. In other words, nature and nurture do not neatly cleave from each other as influences, and, thus, nature and nurture are almost always causally embroiled in every trait of interest. She also reminds readers to think beyond the individual impact of genetic variation. Genetic liabilities for bad behavior can still cash out as positives for the human populations because the causal variants may also associate with more desirable behaviors and outcomes. It is often the risk-takers who are driving the innovation and creativity from which the rest of the population derives benefit. Variety is the spice of life.

So after establishing that genes are going to matter, Harden shifts back to a philosophical and personal approach on questions of blame, punishment, and forgiveness. She returns to a deeper layer of the central dialectic. This time it is less about the nature of guilt and more about what is to be done with those who sin.

The Tragedy of Those Who Trespass

In Behave, Determined, and countless public appearances, Robert Sapolsky has made a name for himself as a popular defender of determinism.9 His empirical case against free will is something he extends to a critique of our modern criminal justice system. He claims that human societies need to move beyond the laws and institutions that deliver unduly cruel and ultimately futile punishments to those convicted of crimes because, as he says, “It makes as little sense to hate someone as to hate a tornado because it supposedly decided to level your house.”

Many have balked at Sapolsky’s argument but have often failed to articulate why his prescriptions for our criminal justice system errs, especially if he’s otherwise right about all human behaviors having physical causes. Without indulging in a digression about physicalist accounts of human agency, Harden is still able to parry Sapolsky’s normative certainty by gesturing to the importance of censure to preserving functional social group dynamics.10 Further, if we accept a world without human agency, then it is unreasonable to expect humans to abandon their evolved natural tendencies for revenge, retribution, fairness, etc. These proclivities will inevitably lead to punitive corrective institutions as societies scale. Building on this idea, Harden recounts some of the famous psychological studies on young children that purport to demonstrate just how innate retribution is.11 There are also large bodies of literature in various realms of social science concerning cooperation that generally underscore how important it has been to ruthlessly reduce free-riding and deception.12

Despite seeing the incoherence and unreasonableness of Sapolsky’s position, Harden still opines that our criminal justice system is too punitive. She casts our retributive urges as themselves sinful. She argues for accountability without pain or cruelty. Implicitly, she appears opposed to the death penalty and the sordid and dangerous conditions of prison. Her criteria for a life sentence is a finding that an individual presents an ongoing lethal danger to others. She extends some of these ideas to parenting, where she advocates against the use of corporal punishment or authoritarian parenting styles, invoking some research on the question to support her assertions.

From the perspective of reckoning with sociobiological realities, I think Harden’s amendments to Sapolsky’s prescriptions for making criminal justice more humane are similarly afflicted by too rosy a picture of human nature. I’m skeptical that the envisioned reforms would result in a stable social equilibrium, especially in a country like America. The Nordic countries are often held up as a place where justice can be cast as more “restorative” rather than “retributive,” but there are many reasons why the social realities and possibilities there are so different than in America. Harden would continue to ascribe the American attachment to retribution as one rooted in popular notions of original sin. Maybe this is true to some extent. America is a more religious place than many other wealthy countries. However, this specific cultural history can’t be overwritten overnight either. It’s part of who we are.

Original Synthesis

Harden never quite resolves the Pelagian and Augustinian dialectic on original sin that runs throughout her book. Her successive essays tend to walk into new but related dialectics that also cannot be confidently resolved by some grand synthesis. She is clearly comfortable with this dissonance and committed to continual reflection and revision. This is welcome epistemic humility emblematic of a scientific mindset, though it is also challengingly postmodern.

However, this isn’t to say that Harden is inconstant and unsure about everything. She believes in the fundamentals of her discipline. Original Sin is still a re-assertion of the first law of behavioral genetics or the idea that all human phenotypes are heritable, meaning the genetic variation in human populations will explain some meaningful portion of variation in trait outcomes for humans. It is also a robust rejection of the false dichotomy that sustains the nature-nurture debate. In reality, genes and environments cannot be neatly separated from each other because they’re in a reciprocal dance across the history of life on our planet.

Despite having a number of disagreements with specific claims or even Harden’s worldview, I was ultimately buoyed by reading Original Sin. It was a wonderfully candid effort to reconcile a mixture of common left-liberal and progressive aspirations with the realities of human nature. This has become rare and sometimes taboo in our public and intellectual discourse, and this often restricts the range of acceptable policy proposals available to left-of-center wonks and encourages the taking of entirely absurd positions (e.g. police and prison abolition). A loosely shared understanding about the shape the human nature is likely to help encourage more constructive political disagreement and compromise.

I encourage anyone vaguely interested in human behavioral studies or scientific memoirs to read Original Sin. It is a provocative, interdisciplinary exploration of human behavior that pushes readers to reconsider their reflexive ideas about blame and moral responsibility by integrating genetics, psychology, and life experience. It invites a more nuanced and compassionate framework for understanding why people behave as they do and how we might respond more justly.

Ross and I discuss the significance of the novel’s title, the novel’s Midwestern and small town setting, and his interest in American identity and reinvention, including its political ramifications.

Related Links:

• My Goodreads Review of Colossus

• My prior interview of Ross concerning his novel Glass Century

• My review of Glass Century: A New Entry in Post-9/11 Literature

Colossus: A Novel by Ross Barkan has an expected publication data of April 28th, 2026 and is available for pre-order: Amazon, Barnes & Noble, Skyhorse Publishing.

Obviously, there is a lot going on in the world—there always is—but whether or not you are living through an important moment in history, it is more likely than not that your fingers aren’t the ones turning the dial of destiny. You, like me, are a hobbit and, unlike Frodo, the Ring of Power has not come to us and likely never will.

Instead we have the privilege of sampling from a manifold of hyperrealities, where whatever we want to be happening is happening. Nevertheless, in this venture, we remain only spectators. Most of the time this is okay. We should tend to the details of our lives and those of our loved ones. These ideas remind me of a lovely, oft-quoted passage from the closing paragraphs of Middlemarch:

“..for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.”

And so, here’s a snapshot of my hyperreality from the last three months while I otherwise tended my own garden:

Books

Counting the books one reads can feel like vulgar posturing for intellectual status or an embrace of insatiably solipsistic consumerism. There is a box-checking-self-improvement dimension to it that is designed to be seductive because it cranks certain dopaminergic dials up and down, especially those related to chest-thumping about being more urbane or informed than one’s peers. I like to tell myself that I count the books I read, write reviews about them, and share the stats publicly because it helps crystallize my reading takeaways. It’s up to you to judge from there.

Here’s my book reading for the first three months of 2026:

• 29 total books across all formats (8 fiction titles, 21 nonfiction titles)

  • 3 ebooks

  • 5 print books

• 21 audiobooks

Stetson’s Review of Books Read from Q1

1. Enemy Feminisms: TERFs, Policewomen, and Girlbosses Against Liberation by Sophie Lewis → Goodreads Review

2. When We Cease to Understand the World by Benjamín Labatut → Goodreads Review

3. Economics in America: An Immigrant Economist Explores the Land of Inequality by Angus Deaton → Goodreads Review

4. Status and Culture: How Our Desire for Social Rank Creates Taste, Identity, Art, Fashion, and Constant Change by W. David Marx → Goodreads Review

5. The Genome Odyssey: Medical Mysteries and the Incredible Quest to Solve Them by Euan Angus Ashley → Goodreads Review

6. We Have Never Been Woke: The Cultural Contradictions of a New Elite by → Goodreads Review

7. The Right Word in the Right Place at the Right Time: Wit and Wisdom from the Popular “On Language” Column in The New York Times Magazine by William Safire → Goodreads Review

8. The Genius Myth: A Curious History of a Dangerous Idea by Helen Lewis → Goodreads Review

9. Kill All Normies: Online Culture Wars from 4chan and Tumblr to Trump and the Alt-Right by Angela Nagle → Goodreads Review

10. The BFG by Roald Dahl → Goodreads Review (read aloud to my eldest daughter)

11. The Myth of Left and Right: How the Political Spectrum Misleads and Harms America by Hyrum Lewis → Goodreads Review

12. Hunt, Gather, Parent: What Ancient Cultures Can Teach Us About the Lost Art of Raising Happy, Helpful Little Humans by Michaeleen Doucleff → Goodreads Review

13. Read Write Own: Building the Next Era of the Internet by Chris Dixon → Goodreads Review

14. The Witches by Roald Dahl → Goodreads Review (read aloud to my eldest daughter)

15. Better Living Through Criticism: How to Think About Art, Pleasure, Beauty, and Truth by A.O. Scott → Goodreads Review

16. Colossus: A Novel by Ross Barkan → Goodreads Review

17. Proto: How One Ancient Language Went Global by Laura Spinney → Goodreads Review

18. A Hollywood Ending: The Dreams and Drama of the LeBron Lakers by Yaron Weitzman → Goodreads Review

19. Charlie and the Chocolate Factory by Roald Dahl → Goodreads Review (read aloud to my eldest daughter)

20. American Contradiction: Revolution and Revenge from the 1950s to Now by Paul Starr → Goodreads Review

21. Medium Rare by → Substack Review & Goodreads Review

22. Blank Space: A Cultural History of the Twenty-First Century by W. David Marx → Goodreads Review

23. Original Sin: On the Genetics of Vice, the Problem of Blame, and the Future of Forgiveness by → Goodreads Review

24. Charlie and the Great Glass Elevator by Roald Dahl → Goodreads Review (read aloud to my eldest daughter)

25. Humanly Possible by Sarah Bakewell → Goodreads Review

26. Fantastic Mr. Fox by Roald Dahl → Goodreads Review (read aloud to my eldest daughter)

27. The Origin of Politics: How Evolution and Ideology Shape the Fate of Nations – Social Disintegration, Birth Rates, and the Path to Extinction by Nicholas Wade → Goodreads Review

28. A Room of One’s Own by Virginia Woolf → Goodreads Review

29. Shamanism: The Timeless Religion by Manvir Singh → Goodreads Review

Stetson’s Book Recommendations

The first quarter was replete with good reads, but reading to my children, namely my eldest daughter, of the Roald Dahl’s oeuvre has been immensely enjoyable. The favorite among these titles is The BFG. The ungrammatical, quirky patois of the titular character is accessible even to extremely young children. They immediately latch onto the silly vocabulary of “whizzpoppers,” “snozzcumbers,” and “frobscottle." I can’t recommend that enough for parents looking for books to read to young children that will encourage them to engage with language. Make sure to avoid the bowdlerized versions of Dahl books too.

I also finished several new, as in 2026, titles from authors/writers from Substack. These have either just been published or will arrive soon. I, of course, have reviews available on Goodreads but have also published a meatier review of ’s Medium Rare here at Substack. I also recently interviewed about his upcoming novel Colossus. For those involved in the neverending and always fiery debates about human nature, behavioral geneticist ’s new book, Original Sin, examines the genetics influences on human vice and violence in a personal register.

Television & Film

I tend to watch more television series than films because as a parent to younger children, it can be difficult to find an uninterrupted block of ninety-plus minutes for a film, and it’s harder to examine a film fairly and in the same mood if the watching is broken into chunks. I also have a preference for sitting with characters for longer periods of time. For instance, I’ve spent the whole first quarter with Mad Men’s Donald Draper and the rest of his family, colleagues, rivals, and paramours. At first, the show’s commentary on gender was over-the-top, but, as the show continues, the psychological portraits deepen and the Madison Avenue ad-man life feels more lived in than caricatured.

I’ve sprinkled in some other shows like the second season of Severance, which I finally got around to finishing, and the second season of The Pitt. The Pitt is a high octane emergency department drama (definitely entertaining) that ratchets up the level of freshmen medical student 101 exposition and progressive political pieties to a level that even Law & Order SVU couldn’t compete with. Both the second seasons of these shows have lost some of the shine of their breakout first seasons but remain entertaining.

Quick Hits

Remember my usual disclaimers about these recommendations, i.e. they’re not necessarily endorsements. Second, I tried to keep these links notably shorter than my prior updates.

Stetson’s Reading Recommendations from Substack for Q4

• Does genetic evidence really increase drug success by 2-3×? by

• On the Ivy Red Queen’s Race by

• The fascinating insights of Robert Trivers by

• Endlessly mocking “the manosphere” won’t solve the bigger problem by

• Attention is all we have by

• Someone is deeply wrong about Iran right now by

• Did Levallois Tools Make Neanderthals Human? by

Stetson’s Podcast Episode Recommendations

• Conversations with Tyler - Harvey Mansfield on Machiavelli, Straussianism, and the Character of Liberal Democracy

• Out-of-Africa is Not Dead but Hybridization Lives from

• Ancient DNA: The Good, The Bad, and The Ugly - Razib Khan interviews Dan Tabin

• Machiavelli and Rational Control at The Remnant with Jonah Goldberg

• When ‘Good Kids’ Go Radical at Breaking History

• Weapons Free at Very Bad Wizards

My Features

Beyond reviews I published a couple pieces to Substack, including a critique of Cormac McCarthy’s only nonfiction essay, The Kekuele Problem. I also wrote about the potential for assaying ear wax for cancer biomarkers, and commented on the clinical approach used to the philosophical question of lumping and splitting.

I also appeared on a couple podcasts in the last three months. Feel free to take a listen!

• ’s peppered me with great questions about genetics, evolution, technology and culture: Spotify, Youtube, RSS

• I appeared on the Speaking of Women’s Health Podcast to discuss some of the new advances in testing circulating tumor DNA (ctDNA) in cancer patients for molecular/minimal residual disease (MRD): Spotify, Buzzsprout, Youtube, Apple

Selections from Substack Notes

The latest knight-errant in our Waste Land is with her novel Medium Rare. One would be forgiven for thinking that the novel might be concerned with how Jordan Peterson and Joe Rogan like their steak, but it’s really a re-telling of the Icarus myth.

For those who have forgotten, the fullest surviving account of Icarus comes from the Roman poet Ovid in Metamorphoses (Book VIII).1After slaying the Minotaur, the great hero Theseus escapes Crete, but the master craftsman Daedalus, the designer of the Labyrinth, remains trapped there by King Minos. Unable to leave by land or sea, since Minos controls both, Daedalus resolves to escape through the air. Being an engineer extraordinaire, he skillfully fashions two pairs of wings, one for himself and one for his son, Icarus. Before taking flight, he instructs Icarus to follow a middle course. If he flies too low, the sea’s dampness will weigh down the wings. If he flies too high, the sun’s heat will melt the wax that holds the wings together.

Together, father and son rise into the sky, astonishing onlookers below who mistake them for gods. But Icarus, exhilarated by flight, abandons his father’s warnings and soars upward. The sun softens the wax, and the wings disassemble. Icarus beats his bare arms in vain and falls into the sea, crying out for his father. Daedalus, calling repeatedly for his son, finds only debris from the wings floating on the water, and he curses his art. The sea into which Icarus falls thereafter bears his name, the Icarian Sea.

The Icarus myth concerns the tradeoffs inherent to creative striving and, its frequent companion, transgression. In the words of the bard, "These violent delights have violent ends." Daedalus represents technical mastery and foresight, while Icarus embodies youthful daring that dips into recklessness. Ingenuity is most brilliant and beautiful in the young, but, when they have it, they rarely exercise it prudently. The image of melted wax and falling feathers, memorably shaped by Ovid’s poetic telling, is an enduring emblem of the dangers of excess and the fragile boundary between aspiration and ruin. These are ideas that have resonated with artists ever since. Clearly, this tension was at the forefront of Joukovsky’s mind as she crafted Medium Rare.

But before I really turn my attention to Medium Rare, it is worth disclosing that this is not my first rodeo with Joukovsky’s writing. I read and reviewed her 2021 novel, The Portrait of a Mirror, which was a modernized retelling of the Narcissus and Echo myth that followed two overlapping yuppie love triangles in an Age of Innocence sort of way and experimented some with textual formats. I also have stayed current with her periodic posts on her Substack , which provides a clear picture of her interests as a writer.2 Suffice to say, I can lay claim to a modicum of authority when it comes to understanding her style and preoccupations as a writer. My verdict? Well, I think if you've watched and enjoyed series like the White Lotus or films like The Materialist, then you will probably enjoy Joukovsky's novels. In other words, her target audience is quite similar to the subjects of her writing, affluent urbanites (or what Musa Al-Gharbi calls Symbolic Capitalists) who would like the pretense and plausible deniability of critical self-reflection and self-parody but would otherwise like a left-liberal coded permission structure for their insatiable striving and hedonic appetites.

What does threading the needle on dissonant sensibilities in Medium Rare look like? Well, Joukovsky returns to mapping the finer details of contemporary class and status dynamics among America's symbolic capitalists or professional managerial class (the PMC, the bourgeoisie, the upper middle class, or whichever your preferred term is), while pulling in elements from classical Greek myths. Sometimes these classical elements are symbols that function as guides to plot developments or foreshadowing of a kind, but other times they function as a shortcut for psychologically layering the characters. Unlike in many Greek myths, her characters have very legible and very modern psychological motivations, which she is loath to disguise, detailing them explicitly for readers. Her characters are strivers, eager to improve their position relative to others and chase more, more, and more. The skeleton key for the divining the motivations of her characters is Girardian "mimetic desire," which tracks neatly back to Icarus’ reckless aerial reveling. Instead of the allure of oneself spilling out as illicit desire for similarly modeled others (as in The Portrait of a Mirror), Medium Rare explores the simpler desire to be recognized as special, to rise above the masses, and how a little taste of specialness can be the prelude to disaster. But beyond Joukovsky's spin on Icarus, she also uses the novel as a vehicle to revel in her idiosyncratic interests: NCAA men's basketball, visual art, statistics, and real estate voyeurism.

The novel is narrated by a character named Cassandra, modeled after the ignored prophet, who recounts the rapid ascent of a moderate Republican lobbyist named Phil from a mediocre everyman to a “rare medium,” in the fortune-telling sense of the term. Phil miraculously completes a perfect NCAA March Madness bracket, wins a billion dollars for it, and then launches an all-too-brief career in the public eye, which includes exploring a career in reality TV and politics. Cassandra is enmeshed in Phil's story, like a Nick Carraway figure, first as a college friend turned work acquaintance turned close friend of Phil's wife, Raleigh. Phil's ascent incidentally pulls Cassandra into Raleigh's world of domestic tranquility and Southern hospitality, while his rapid descent pushes her right back out.3

The actual basketball in the novel faithfully follows the actual events of the 2019 tournament in which the University of Virginia (UVA) Cavaliers did indeed win after being embarrassingly upset as a 1-seed in the year prior, an inverse Icarus arc, if you will. The coverage of these games, even the March Madness scenes in general, are among the most electrifying portions of the novel and, unfortunately, comprise only its first half. So, I do feel that the second half of the novel loses steam. It is a bit shapeless, which to some extent mirrors Phil's frantic efforts to maintain relevance after his fifteen minutes of fame elapse, but it also seems like a bit of a missed opportunity. Further, the climactic scenes that trigger and then complete Phil's downfall and the rupture between Cassandra and Raleigh are rushed, even a bit melodramatic, though omitting most of the actual drama. We only see these events indirectly as readers. It’s like a Macbeth take on a wife-mistress confrontation that murders the husband’s social position, but, given that this is so heavily foreshadowed throughout the novel, the reader is expecting something a lot more like Real Housewives.

Although Joukovsky appears to understand herself as loosely working within the literary lineages of Jane Austen, George Eliot, Edith Wharton, Henry James, and F. Scott Fitzgerald, there are aspects of her novels that are distinctly Randian and Nietzschean. In fact, she perhaps presents a more realistic version of what a Randian hero(ine) could actually look like. It could perhaps be carried off a bit more trenchantly, but it definitely seems like it’s there. Her lead characters may not be able to stop the motor of the world, but they can make the scramble to the top of America’s unforgiving meritocracy look effortless and self-fulfilling all while not entirely interring their youth. Of course, there is still some vestigial moral gravity, such that characters who strive with abandon and hedonistically seize the day do eventually pay some kind of price.

Medium Rare felt like a progression for Joukovsky in terms of moving her dramatis personae from an earlier portion of young adulthood (i.e. the carefree DINK life of The Portrait of a Mirror) to a more mature portion of adulthood (i.e. adulting as a parent). That said, parenting is not immediately a compelling source of drama, so it is mostly background for the novel, serving instead as a springboard to dramatize a very Millennial version of the perennial sociopolitical friction between men and women. Phil, as a character, is ostensibly a bit of a satirical jab at the much abused "mediocre white man" who somehow manages to shirk domestic and emotional obligations and stumble and bumble his way to the top of every social hierarchy yet never develop the self-discipline to keep it in his pants.4 Phil’s Icarus arc could be understood as wish fulfillment or revenge fantasy on the part of Millennial women, a symbolic realization of what turned out to be the ill-fated vision of 2010s feminism as represented by publications like Feministing, Jezebel, or The Cut or political movements like #MeToo. However, I think this would be a bit of a slight misread. There is maybe even some subtle yet wry acceptance of male unruliness, “boys will be boys,” in the work. On the other hand, there are some palpable feminist yearnings, but certainly not bitter misandry. For instance, Cassandra's periodic maternal ambivalence is nonchalantly asserted as a kind of female rebellion against social and biological expectations and are cast as still compatible with being a loving and “good” mother. The perspective on the battle of the sexes is colored by the wisdom accrued with age and experience, but this same process creates new problems to confront, the cost that the movement of time extracts. Subsequently, Medium Rare may implicitly function as a generation- and class-defining cri de coeur for professional Millennial women, who are, perhaps, the novel’s unacknowledged Icarus figures.

Anyway, I’m happy and eager to forgive and forget some of the minor shortcomings I’ve identified because Medium Rare is an engaging and exceedingly smooth read. It doesn’t tax the attention spans of readers. It’s immersive with enough frisson of gossip, adultery, riches, and schadenfreude to stave off the incessant pull of doomscrolling or a carousel of reels. I think these are legitimate terms on which we can positively judge contemporary fiction that genuinely attempts to have an audience of readers while maintaining enough self-respect not to embrace smut or other forms of sensationalism.5

Medium Rare by A. Natasha Joukovsky will be published by Melville House on March 3rd, 2026. It is 304 pages and can be purchased at the usual places. Check it out!

I call it the Kekulé Problem because among the myriad instances of scientific problems solved in the sleep of the inquirer Kekulé’s is probably the best known. He was trying to arrive at the configuration of the benzene molecule and not making much progress when he fell asleep in front of the fire and had his famous dream of a snake coiled in a hoop with its tail in its mouth—the ouroboros of mythology—and woke exclaiming to himself: “It’s a ring. The molecule is in the form of a ring.” Well. The problem of course—not Kekulé’s but ours—is that since the unconscious understands language perfectly well or it would not understand the problem in the first place, why doesnt it simply answer Kekulé’s question with something like: “Kekulé, it’s a bloody ring.” To which our scientist might respond: “Okay. Got it. Thanks.”

~Cormac McCarthy in “The Kekulé Problem”

There are influential persons among us—of whom a bit more a bit later—who claim to believe that language is a totally evolutionary process. That it has somehow appeared in the brain in a primitive form and then grown to usefulness. Somewhat like vision, perhaps. But vision we now know is traceable to perhaps as many as a dozen quite independent evolutionary histories. Tempting material for the teleologists. These stories apparently begin with a crude organ capable of perceiving light where any occlusion could well suggest a predator. Which actually makes it an excellent scenario for Darwinian selection. It may be that the influential persons imagine all mammals waiting for language to appear. I dont know. But all indications are that language has appeared only once and in one species only. Among whom it then spread with considerable speed.

~Cormac McCarthy in “The Kekulé Problem”

The spontaneous eureka moment is a clichéd trope from the historiography of scientific progress. It’s generally understood that most of these moments are fictionalized for the very purpose of dramatizing a moment of insight: Archimedes’ tub, Newton’s falling apple, Fleming’s open petri dish, etc. These are great stories. We need great stories for instruction, inspiration, and coordination. But stories aren’t the same thing as reality. Let us never confuse these.

The less glamorous, more realistic yet still imperfect account of scientific progress is that there are lots of ideas in circulation that scientists can select from and mix together as needed to account for trends that emerge from systematic or serendipitous observation. After a model of a particular phenomenon is developed, something that is usually the product of many minds over time and catalyzed by a propitious confluence of social and material factors, it is then demonstrated to have validity, typically through prediction or technological development. And in this way, the ratchet of scientific progress keeps turning.

However, it is hard to entirely dismiss the brilliant force of intuition. Most have the experience of a Sisyphean struggle with a particular mental puzzle, only to walk away from it for a while and suddenly be struck by the answer. An invisible and beneficent Wile E. Coyote seems to be stalking our thoughts on a high wire. But how does this actually work? Presumably, unconscious processes in our brain solved the problem that our conscious mind could not and then somehow surfaced that solution for our consciousness using some unknown mechanism, though some believe visceral metaphors and images are its preferred medium. It seems that the unconscious brain is remarkably efficient, though temperamental, when it comes to manipulating symbols without declaring its activity, though when it wants to declare itself, its avenues for doing so appear indirect by design. So, huh, what’s going on here?

The Kekulé Problem

At least, this is how Cormac McCarthy in his sole work of nonfiction describes the Kekulé Problem. The eponymous locution he coined derives from the chemist August Kekulé, who claimed that a dream about a snake coiled upon itself, the ouroboros, helped him understand that the chemical structure of benzene was ringed. McCarthy believes examples of unconscious insight like this raise fundamental questions about the origins of the unconscious and what language is, especially the relationship between the two. Why doesn’t our unconscious with a solution in hand simply provide us (our conscious brain) the answer in plain language? Why would it default to an image in a dream?

McCarthy’s explanation basically comes to "bad habits die hard," meaning the unconscious is a brain thingy that’s been there way longer— part of all animals—than we’ve been here with our consciousness and system of symbols, language.1 He also goes on to argue there are a lot of features of language that indicate it’s not really a natural thing. It is at a remove from our biology, only feeding back into our biology at a great cost after colonizing us.2 He extends this point by analogizing the spread of language in ancient human populations to parasitism rather than something that gradually emerged piecemeal like other adaptations.3 McCarthy immediately dismisses the slow convergence of vocalization, symbolic representation, and grammar into language as a normal but powerful biological and social process because it doesn’t appear in any other species. Of course, there are other adaptations besides language that are more or less the sole purview of our species too: our obligate bipedalism, our brain-to-body size ratio, our long childhoods, etc.4

Is McCarthy Right About the Kekulé’s Problem?

To review, McCarthy conceptualizes the unconscious processes in the human brain as a unitary and ancient biological system that has been shaped by evolution into an all-purpose problem-solving apparatus. He even calls it “a machine for operating an animal.5” Contrastingly, he conceptualizes language as an invented module, a product of conscious thought, that became so important it immediately became ubiquitous and then was backdoored into our biology over time but imperfectly so.6 His timeline on this is somewhere between two million and one hundred thousand years, though he prefers the shorter timeline.

These distinct evolutionary histories and the somewhat non-biological character of language impairs direct communication between conscious and unconscious mind. The workaround is that the unconscious, due to some unknown impetus (McCarthy defaults to “moral compulsion” and immediately undercuts it in an aside just like this), uses metaphor and images when conscious processes are quieter or shutdown, like dreaming, in order to communicate. So numinous of it.

This explanation is compelling in a lot of ways because it merges an antediluvian mysticism with a streamlined view of our evolutionary history that at least superficially lines up with some important mile markers. However, I see a couple issues.

My first gripe is with McCarthy’s somewhat Freudian conception of the unconscious. It’s not a unitary thing. We have plenty of neuroscience to back this up. And virtually all of brain activity is unconscious. It’s not hidden away. It’s the neural origins of consciousness that are the greater mystery, and even then the “hard problem” itself may be a bit invented...

McCarthy doesn’t venture a theory of consciousness in his essay, accepting it as is phenomenologically and operationalizing it only as language. The other issue embedded here is that conscious thought doesn’t have to use language either (i.e. mentalese), which has been popularly demonstrated by psycholinguists like Steven Pinker.7 We need language because we need communicate clearly about complex subjects with other people. We are a social species after all, and the intensity and capacity of our sociality is itself biologically distinct.

My second gripe concerns McCarthy’s false framing of some human capacities as being biological and others as non-biological. Everything we are, everything we can be, and everything we do is in some way informed, enabled, or constrained by our biology. There is no escape. All our behavior is under evolutionarily review even if its but a dim projection of the genome, the only substrate on which evolution can ultimately act. In my frame, language has clearly added to human fitness. It’s rudiments have origins in deep biology. It is something we acquire via socialization like many behaviors and forms of knowledge and probably required reciprocal interaction between our biology and the human culture that has organically emerged from socialization under different conditions over time. But our biology anticipates that we will acquire language (something McCarthy does acknowledge but doesn’t entirely reckon with), which is why children pick up language so easily and why, when this critical developmental period has passed, full language acquisition has been lost.8

McCarthy is right to plumb the mysterious depths of conscious and unconscious processes. He does so with an unadorned philosophical profundity that speaks to a brilliant mind. He is right to wonder about how something as seeming arbitrary and abstract as language came to be and how it could possibly be part of our evolved biology. However, along these lines of thought, language itself has become a trap. It pushed him toward a conception of distinct and diverse neural processes as a unified entity, quite a literary turn there, and it induced him to draw a hard line between the biology that occurs within an individual and the extended biology shared by a population of social animals, quite a reductionist turn there. Nonetheless, “The Kekulé Problem” is a thought-provoking essay that more or less makes a defensible argument for the origins of language and the mysterious powers of the unconscious that have taken others many thousands of words more to make.

Related Reading at Holodoxa

• Homo Largiloquus

• Phonemes and Genes

Source

• The Kekulé Problem

"Alas! Earwax!"

~Albus Dumbledore in The Sorcerer’s Stone after eating a Bertie Bott's Every Flavor Bean

Until I stumbled across this tweet (see the embed below), I was ignorant of the diagnostic potential of assaying earwax. The tweet, from an apparently MAHA-curious account, asserts that cancer can be accurately detected via biochemical analysis of the metabolites in earwax, and earwax may be superior to “other biological fluids” or biomatrices for early cancer detection due to “a lower turnover rate” and for the obvious reason that it is very easy to obtain. These were intriguing claims I wanted to evaluate.

First, some background.

What is Cerumen?

Earwax is the oft forgotten little brother of biological substances despite being pretty accessible via Qtip (Of course, the recommendation is to never use these to clean your ears!). We carefully remove it in private, discard, and quickly forget. The medical term for earwax is cerumen from Latin, cēra, meaning "wax" and"-umen" being a suffix that indicates a substance.

Cerumen is quietly complicated—the usual story in biology. It’s not just simply a recrudescence of grime that simply protects the ear drum. It’s a layered secretion, rich in lipids and other molecules, shaped by glands, microbes, skin chemistry, and genetics. Lots of factors shaping its content. Its properties vary between individuals and within individuals over time.

In fact, on the genetics front of earwax consistency are actually surprisingly well-described, a bit of an exception from the failures of the candidate gene era. There is a famous variant in ABCC11 that influences whether an individual has “wet” or “dry” earwax, ABCC11 (rs17822931, 538G>A). The G allele (GG/GA genotypes) results in wetter earwax, linked to body odor, while the A allele (AA genotype) produces dryer earwax, with little odor. The allele frequencies differ across populations, with dry earwax being much more common in East Asian populations than in many others, a pattern likely caused by natural selection.1

Of course, earwax is sticky partly by design. There to trap dust, pollen, spores, and whatever else drifts into the ear canal. But in trapping the outside world, it may also preserve an imprint of the inside one, potentially making it a great source of easy-to-access clinically useful biomarkers.

If diagnosing a seemingly distant or unrelated disease in the body from earwax sounds too much like science fiction, let’s try to dispense with that reflexive skepticism. We’re living in the era of precision medicine powered by next-generation diagnostic technologies, the hunt for ever more sensitive and specific biomarkers that can be assessed from specimen obtained non-invasively or minimally invasively has been intense and successful. Many of these approaches are now standard-of-care for numerous indications with a commercial assays at the ready. For example, Exact Sciences' Cologuard, a stool DNA-based screening test for colorectal cancer, already does billions in sales as does Natera’s Signatera, a bespoke assay that analyzes a patient’s blood for circulating tumor DNA after effective treatment.2

The idea that various diseases may leave a signature in earwax that can be reliably detected with a diagnostic assay is very plausible and potentially exciting. The question is whether it actually works!

Is Earwax A Window into the Body?

As of 2019, this is what a team of Brazilian scientists has claimed. They pioneered a method dubbed the “cerumenogram.”3 Their published paper appeared in Scientific Reports4 with the bold assertion that earwax contains a chemical fingerprint capable of distinguishing people with cancer from people without cancer. They also reported remarkable results, perfect discrimination between cancer and non-cancer patients.

In this retrospective case–control study, the authors present evidence of their proof-of-concept “cerumenogram” by analyzing earwax (cerumen) as a diagnostic biomatrix for cancer. Cerumen was collected at an oncology unit in Goiás, Brazil from 102 volunteers, split into a cancer group (n=52; ages 33–83) and a cancer-free control group (n=50; ages 2–65); cancer cases included carcinoma (n=28), lymphoma (n=11), and leukemia (n=13), spanning a range of times since first diagnosis (0–6 months, 6–12 months, and 1–5+ years) and including patients with and without chemo/radiotherapy. Samples were collected with a metallic curette, frozen at −20 °C, and analyzed within 7 days using headspace gas chromatography–mass spectrometry (HS/GC‑MS). The authors identified 158 volatile organic metabolites (VOMs) across several chemical classes. To reduce potential confounding from ethnicity/race and other variability, they transformed the dataset into a binary presence/absence matrix and applied a genetic algorithm–partial least squares (GA‑PLS) feature selection, which yielded 27 VOMs as a candidate biomarker set. Using these 27 features, hierarchical cluster analysis (HCA) perfectly separated all samples into cancer vs control groups (reported as 100% discrimination/efficiency in this dataset), while not separating samples by cancer type or by treatment status. Their additional analyses suggested the separation was not driven by patient sex. The authors conclude that cerumen volatilomics could provide a fast, low-cost, noninvasive preceding test (they estimate ~3 hours and ~$50 per sample). The makings of a holy grail diagnostic. But wait!

As proof-of concept results go, these are initially exciting, but we shouldn’t immediately declare victory for the cerumenogram. Beyond the obvious design limitations like the small sample size derived from a single center and the use of a retrospective case-control design, there are other issues that should give us pause. Without digging into every detail, suffice to say, there are a lot of alternative explanations for their results such as confounders, artifacts, contamination, and modeling mistakes (i.e. overfitting) and the methods themselves may simply have overfit a model to their data.5 Taken together, the study is best viewed as intriguing, warranting replication rather than as evidence that cerumenograms are already “highly accurate” and or anywhere close to clinical primetime. A prospective, matched, multi-site trial is needed big time.

What Has Follow-up Work on Cerumen Analysis Found?

Unsurprisingly, the story changes when datasets grow and mature. There was almost no chance the 100% discrimination between cancer and non-cancer patients was going to stand. Unfortunately, there are just two papers that further pursue cerumen analysis in a diagnostic context, e.g. as a potential cancer biomarker, in the last six years. One is a follow-up on the original 2019 work from the same Brazilian team lead by João Marcos Gonçalves Barbosa. The other is point-of-care cerumen analysis from a German team.

Follow-up #1

The paper form the Brazilian scientists is large, mostly internal follow-on case series that keeps the same core cerumenogram assay (i.e. cerumen collection → HS/GC‑MS volatiles → binary feature matrix → multivariate/statistical classification) but changes the modeling narrative and the way its performance is reported. Methodologically, they analyze cerumen from a much larger sample of 751 volunteers. including 531 individuals with a “proven diagnoses of cancer” and 203 individuals “without a prior diagnosis of cancer,” plus a small “precancer/benign” groups. The authors explicitly frame the output as “oncological risk” vs “oncological risk‑free.” They retain the same high-temperature headspace extraction conditions (i.e. 160 °C for 60 min) and essentially the same long GC program as the 2019 work, and they still convert the HS/GC‑MS output into a presence/absence matrix. Compared with 2019, they do add some practical rigor around operations, e.g., instructing participants not to clean ears or use products around the ears for 15 days, having otolaryngologists screen out acute otitis media, using an internal standard, randomizing vials in batches, and placing QC blanks spiked with internal standard across batches to monitor drift. These are meaningful, more grown-up lab steps that the 2019 paper either did not emphasize or did not document as clearly.

Statistically, the 2025 paper arguably improves on some of the weaknesses of the original work, i.e. no out-of-sample validation attempt. For instance, they provide a logistic regression classifier with standard tenfold cross‑validation, reporting an area under the curve (AUC) of 0.916 (0.858–0.974), sensitivity of 0.904 (0.904–0.984), and specificity of 0.880 (0.790–0.970). The cerumenogram appears to distinguish between cancer and non-cancer cases well, though most of the prior caveats still apply, meaning this may still mean nothing.

So in the loosest sense, this is a clear replication, but in the stricter sense of forwarding an assay that could someday plausibly meet the standards of used for identifying valid clinical biomarkers, this work is still nowhere near that rigor.6

Follow-up #2

The independent follow-up from the German team is also very tentative and proof-of-concepty. It shows that a workflow using surface-enhanced Raman spectroscopy (SERS) plus machine learning (i.e. principal component analysis and linear discriminant analysis or PCA-LDA) can discriminate head and neck cancer (HNC) from controls. The authors use individual-level cross-validation, but the sample is extremely small (N = 13) and the topline claims are presented as stronger than what the design can reasonably support. Nonetheless, the approach, if scaled and controlled properly, looks a bit more promising than what the Brazilian group was attempting. It seems mechanistically more plausible given the proximity of HNC to the ears and the known microbiomic association with HNC.

Together, it is clear that cerumenogram development is still in its infancy and could easily be a dead-end. Even from a proof-of-concept perspective, there are some missing fundamentals and biomarker validation is always hard. For instance, it would be great to see the identified predictive metabolites in the cerumen be biologically connected to the condition for which they discriminate. Nevertheless, I won’t entirely give up on the zany hope that cerumen could be a source of clinically meaningful biomarkers. However, the apparent lack of research interest beyond these few papers may suggest there are even more reasons to be pessimistic about this possibility despite how easy it is to dig out a little earwax.7

“It is good to have hair-splitters and lumpers”

~Charles Darwin in a letter to J.D. Hooker in 1857

“The time has arrived for discarding imaginary species, and the duty of doing this is as imperative as the admission of new ones when such are really discovered. The talents described under the respective names of ‘hair-splitting’ and ‘lumping’ are unquestionably yielding their power to the mightier power of Truth.”

~Naturalist Edward Newman in 1845

In a previous post titled “A Gene For… You,” I described the conceptual framework that is used to establish a causal relationship between a gene and a disease. This is a pre-requisite for drawing diagnostic conclusions about the effects of a given variant in a gene and then acting clinical. Within the gene-disease validity framework, I also demonstrated some of the formal process that is performed by medical geneticists to evaluated the validity and strength of such an alleged relationship, walking through an example based on the gene FAS and the disease autoimmune lymphoproliferative syndrome (ALPS), before a gene is included in a diagnostic assay. However, I didn’t tell the whole story, and I’m back to provide some more insight on a question central to medical genetics: how do we decide what the “disease” in the gene-disease relationship is?

A notable omission from my previous post concerns the question of what qualifies as the relevant disease entity in a proposed gene-disease relationship. Without clearly defining which clinical features (aka phenotypes) count toward a particular diagnosis, any asserted gene-disease, or more generally genotype-phenotype, relationship can become quite fuzzy. The set of relevant features can grow and grow to include dubious associations or be sliced and diced thus obscuring a varied but otherwise unambiguous and unitary biological relationship. This is a dangerous problem when a medical geneticist is trying to design and use a diagnostic assay and then interpret the testing results.

Classification questions have an obvious practical importance, but also animate deep philosophical debate. They have bedeviled many intellectuals across many fields. But instead of wandering into that quandary, I want to explore why classification problems are so important in medical genetics.

Broadly, medicine is of course responsible for a systematic attempt at disease classification, which goes by the term nosology. A physician needs to be able to distinguish between who is diseased and who isn’t and which disease a patient has versus all the other possible diseases. However, the question of concern here is where to draw the line between the sets of phenotypes counting as condition X and the sets of phenotypes that don’t with respect to those observed in association with disease-causing changes in a given gene. Can this gene of interest cause distinct conditions or are there just different presentations within same condition? Given some amount of variation in a condition caused by changes to a gene of interest, when is it appropriate to create distinct diagnostic entities? What will be gained or lost by making such distinctions?

These questions can be condensed down to a general problem known as the lumper-splitter problem, sometimes just called lumping/splitting. Ironically, it has its own self-aware taxonomy where people with different classification tendencies fall in either the “lumper” or “splitter” camp, where a “lumper” is someone who classifies generously based on observed similarities eliding observed differences, while a “splitter” is someone who classifies fastidiously drawing distinctions on the basis of subtle differences.

An Introduction to Lumping and Splitting

Modern medical genetics approaches the lumping/splitting question using a structured evaluation of evidence, guided by explicit criteria and discussed and agreed upon by panels of experts. The Clinical Genome Resource (ClinGen) has articulated a formal framework to inform decisions about whether a gene should be associated with a single disease entity or with multiple entities. This framework emphasizes four domains of evidence: prior disease assertions, molecular mechanism, phenotypic variability, and inheritance pattern. It also provides guidance on how evidence in each of these domains should be evaluated and then collated in order to make a final lumping-splitting decision.

Disease Assertions

The process begins with the identification of existing assertions of some relationship between a gene and one or more diseases. Whether or not a gene-disease relationship has been alleged can be ascertained by searching various public resources that catalogue such data whether in a nosological way such as OMIM, Orphanet, or Medline do or an ontological way as MONARCH does. If only one disease entity can be found, that entity becomes the default target for evaluation and this averts the need for a challenging lumping-splitting decision. Multiple assertions, however, raise the question of whether these different assertions represent genuinely distinct biology or are merely different faces of the same underlying disorder. This is where the real lumping/splitting evaluation begins. Nevertheless, it is good to be thorough and assess things carefully even when only one condition is asserted. There still may be underlying complexity related to the other evidence domains or broader questions about the etiology of the condition, including whether other genes or environmental factors together or separately may cause it. However, these other questions are generally assessed in the normal workflow of gene-disease validity assessments.1

Molecular Mechanisms

Next, it is important to assess the putative or definitive mechanism by which changes in the gene of interest contribute to the associated condition(s). Such differences can include the distinction between loss-of-function (LOF) versus gain-of-function (GOF) variants, the effects of variants in distinct transcripts, or the effect of variants occurring in distinct functional domains or gene regions. The type of variation itself may matter too. Ostensibly null alleles have a hard time exerting dominant negative effects, for example. These mechanistic evaluations start at the gene level and work up through biochemical, protein, and cellular levels. Ultimately, the definitive determination as to whether distinct mechanisms exist relies on the availability of functional evidence. It can be difficult to ascertain this evidence from the literature alone, though increasingly multiplex assays of variant effect (MAVEs) have helped increase the amount of functional evidence available to evaluate variants across a gene.

When different classes of variants in the same gene clearly act through different biological mechanisms this provides strong justification for splitting. This is always the case, but it is a good heuristic. Conversely, when the molecular mechanism is shared or poorly understood, lumping is generally favored, at least provisionally.

Phenotypic Variability

Pleiotropy, when a gene influences many traits, and variable expressivity, when the same alleles associated with a range of effects on a trait or many traits, are common characteristics of many genetic disorders. Genetics would certainly be a lot easier without them, but alas, biology is confoundingly complex. These properties can create the appearance that different variants within the same gene produce distinct sets of phenotypic features and, consequently, separate conditions. To assess this possibility, it is helpful to compare phenotypes among related individuals carrying the same variant (intrafamilial variability) with those observed in unrelated individuals carrying the same or related yet different variants (interfamilial variability). Consistent and specific phenotypic patterns within families, or among unrelated individuals with the same variant, may support classification as a distinct disease entity (splitting), even in the absence of evidence for differing molecular mechanisms. In contrast, inconsistent or nonspecific phenotypic differences are more suggestive of variable expressivity, likely influenced by additional genetic or environmental modifiers. Handling phenotypes is notoriously thorny given the limitations of phenotyping itself. The phenotypes reported in the research literature represent a particular snapshot in time and are shaped by clinical biases and measurement or technological limitations. A clinical report can easily be incomplete in critical ways and often patient are not followed in a longitudinal way.

Pattern of Inheritance

Finally, inheritance pattern is considered. Some genes appear to cause different diseases depending on whether variants are inherited dominantly or recessively or their zygosity/dosage (i.e. heterozygosity, homozygosity, hemizygosity, compound heterozygosity), but even here caution is warranted. Differences in inheritance may reflect a dosage continuum rather than distinct biological entities (e.g. semidominance).

The pattern of inheritance, specifically whether disease expression requires monoallelic or biallelic variants, is often the most readily identifiable feature of a monogenic disorder. Many genes have been proposed to exhibit distinct disease relationships depending on variant combinations or modes of inheritance. When this is the case, splitting may be warranted.

A prospective lumper-splitter should assess whether the available evidence indicates that different inheritance patterns observed within families correspond to clearly distinguishable phenotypic features and/or differences in clinical management. Alternatively, the evidence may support a model in which these seemingly distinct inheritance patterns reflect a single disease spectrum, characterized by variation in severity and/or age of onset. In such cases, phenotypic manifestations and disease risk are correlated with variant zygosity, and thus gene dosage. There are many such example including low-density lipoprotein receptor (LDLR) variants associated with familial hypercholesterolemia.

FAS: A Case for Lumping

When I performed a lumping/splitting evaluation for FAS, I first sought out what assertions existed for the gene. Most of the sources indicated only autoimmune lymphoproliferative syndrome (ALPS) as a robustly associated condition, but some other immune conditions like juvenile idiopathic arthritis and cancers were also asserted. So, I proceeded with a full lumping and splitting evaluation. Next, I thoroughly reviewed the literature reporting FAS-ALPS, assessing the mechanisms that pathogenic FAS variant caused disease, the pattern of inheritance of disease, and the associated phenotypic features. It immediately became clear that there were co-occurring and complementary molecular mechanisms at play that accounted for differences in the penetrance and severity of ALPS. However, there was no persuasive evidence that another condition should be split off on this basis alone. The best way to frame the gene-disease relationship was to assert that disease-causing variants in FAS cause ALPS in a semidominant inheritance pattern with incomplete penetrance. Monoallelic cases consistently show less severe presentations compared to biallelic cases, but this is merely variation in severity within a single phenotypic spectrum. Further, loss-of-function variants affecting the extracellular domain of FAS show reduced penetrance with about 30% showing disease due to the need for a second somatic hit or loss-of-heterozygosity to cause clinically manifest disease, while missense variants that disrupt the FAS-FADD interaction act in a dominant negative manner and show higher penetrance, affecting about 80% of carriers. Importantly, the cellular phenotype associated with a reduction in apoptotic capacity shows complete penetrance when functional examined across all disease-associated variants in FAS. Altogether, FAS-ALPS represents a great case for lumping despite some distinctions existing across all the lumping/splitting evidence domains.

SCN8A: A Case for Splitting

Few genes illustrate the necessity and the justification of splitting more clearly than SCN8A, which encodes the voltage-gated sodium channel Nav1.6. SCN8A sits at the intersection of neurodevelopment, neuronal excitability, and epileptogenesis, and over the past decade it has become a paradigmatic example of how a single gene can give rise to genuinely distinct disease entities.

At first glance, SCN8A looks like a textbook case for lumping. It is a neuronal sodium channel expressed broadly in the central nervous system, particularly at the axon initial segment and nodes of Ranvier, where it plays a critical role in action potential initiation and propagation. Unsurprisingly, pathogenic variation in SCN8A is associated with neurological disease. Early reports emphasized a severe phenotype, early infantile epileptic encephalopathy (EIEE), characterized by neonatal-onset seizures, profound developmental delay, movement disorders, and high mortality. As additional cases accumulated, however, the story became more complicated.

What ultimately compelled splitting was not phenotypic variability alone, but distinct molecular mechanisms, which is the most common and strongest basis for splitting. Functional studies revealed a striking pattern that tracked with molecular effect. Many variants associated with SCN8A-related epileptic encephalopathy exhibited gain-of-function (GOF) effects, including increased persistent sodium current, impaired channel inactivation, or hyperpolarizing shifts in activation. These biophysical changes directly increase neuronal excitability, providing a compelling mechanistic explanation for early-onset, intractable seizures.

In contrast, a growing number of individuals were identified with loss-of-function (LOF) variants in SCN8A, such as nonsense variants, frameshifts, or missense variants shown to reduce channel activity. These individuals often had intellectual disability without seizures, or with seizures that were mild, later-onset, or entirely absent. Some presented primarily with hypotonia, ataxia, or cognitive impairment rather than epilepsy.

This clear mechanistic bifurcation, GOF versus LOF, provided a strong case for splitting. Unlike many genes where mechanism is inferred or ambiguous, SCN8A offered direct electrophysiological evidence that different classes of variants perturb neuronal function in opposite directions even though the clinical presentations show overlap.

Inheritance patterns further supported splitting. Most SCN8A GOF variants associated with epileptic encephalopathy arise de novo and act dominantly. LOF variants, by contrast, often behave as haploinsufficient alleles, sometimes showing reduced penetrance or milder dominant effects. In model organisms, complete loss of SCN8A function is lethal, underscoring the gene’s dosage sensitivity and reinforcing the idea that partial loss and excessive activity are not simply opposite ends of one linear disease continuum.

This pattern is precisely what lumping/splitting frameworks are designed to detect. The differences were not simply a matter of severity or age of onset along a single spectrum. Instead, they reflected qualitatively different though subtle clinical distinction that aligned with distinct underlying biology. Further, the decision to split SCN8A-associated conditions has had tangible clinical consequences. From a therapeutic standpoint, it matters enormously whether a patient’s variant increases or decreases channel activity. Sodium channel blockers may benefit individuals with GOF variants but could worsen symptoms in those with LOF variants. Lumping these conditions together would obscure this distinction and risk inappropriate treatment.

Lumping/Splitting Decisions Are Provisional

As with any scientific conclusion, lumping and splitting decisions are not final verdicts, and there isn’t systematic evidence for its effects on diagnostic yields, though the theoretical basis is strong. They are best understood as working hypotheses that reflect the current state of knowledge. As new functional assays, genotype-first studies, or longitudinal clinical data emerge, today’s lumped entity may tomorrow warrant splitting or vice versa. Nonetheless, using an evidence-based framework to inform these judgements is critical to standardizing clinical genetics and guaranteeing sensitive and specific diagnostic assays.

Who Needs Nosology Anyway?

Human genetics is constrained by ethical, practical, and historical realities. We cannot conduct reverse genetic screen at will on human population. In other words, we can’t systematically mutate human genes in a randomized population and comprehensively observe outcomes. Instead, we study natural experiments that biology has already incidentally run and compare this to systematically collected data from other empirical systems or computational models. The rare disease-causing genetic variants that arise spontaneously in individuals who present to medical attention are what we depend on. This means that the phenotypes we see are filtered through layers of happenstance, such as who gets tested, which symptoms are noticed, which specialists publish case reports, and which features are considered worth naming.

Nosology, imperfect as it is, becomes a necessary scaffold rather than an optional luxury. Genotypes and phenotypes without the framework would be an even greater practical challenge. Moreover, the clinical relationships among and between diagnostic entities, what’s referred to as disease ontology, increasingly needs to reflect underlying molecular and biological relationships rather than historical idiosyncrasies and the exigencies of clinical practice. Without some working classification of disease entities, we simply cannot design useful diagnostic tests, accurately interpret variants, or effectively counsel and treat patients. The alternative to this sometimes ad hoc yet coordinated nosology is not a clean, theory-driven taxonomy, but confusion.

At a deeper philosophical level, lumping and splitting expose a tension between biological realism and epistemic pragmatism. We want to achieve the former but must often settle for the latter. Diseases are not natural kinds in the same sense as chemical elements. They are patterns, recurring constellations of molecular behavior, developmental (mis)timing, and environmental context. Our classifications attempt to track these patterns, but they are always approximations, shaped by human interests and technological limits. All models are flawed, but some are useful. Undeniably, this is true for medical genetics.

This is also why medical genetics is explicitly provisional and sometimes ad hoc fashion about these judgements. They are the best answers that can be provided given the available data and constraints. The goal is not to discover the one true taxonomy of disease, but to build classifications that are useful, revisable, shared, and transparent about their assumptions. Lumping errs on the side of coherence, guarding against premature fragmentation of knowledge. Splitting errs on the side of specificity, guarding against false generalization. Neither is intrinsically superior or inferior, though medical genetics prefers to err on the side of lumping because of the known limitations concerning phenotype ascertainment and measurement and the inherent variability of biology.

There are obvious limits to what lumping and splitting can achieve. Excessive lumping can obscure meaningful biological differences that matter for prognosis or therapy. Excessive splitting can create a proliferation of named entities supported by thinner bodies of evidence, undermining reproducibility and clinical trust. The art of medical genetics lies in navigating between these extremes while acknowledging that today’s best answer may be tomorrow’s historical artifact.2

Medical genetics is far from the only field to confront crucial classification questions, though they are certainly central in the study of biology. The lumper–splitter problem can also be regarded as a signal of the field’s maturity as it must prioritize the practical impact of its decisions rather than providing a perfect model of the biology that links a genotypes to phenotypes. Nosology, far from being obsolete, remains one of the quiet engines that makes genomic medicine possible—even, and perhaps especially, when it reminds us of its own limitations.

Conclusions

How we classify disease profoundly shapes our understanding of monogenic disorders, the variants that cause them, and the strength of the evidence linking the two. Clear and accurate disease definitions are necessary if patients are to receive diagnoses that genuinely illuminate their condition, guide effective management, and lay the groundwork for therapeutic advances. In essence, medical genetics aims to replace vague clinical labels with precise molecular diagnoses that meaningfully inform prognosis and care. This ambition depends on well-defined gene–disease entities and careful assessment of the evidence supporting their validity, pathogenic mechanisms, and clinical actionability.

The outside is like crunchy and tough but then you bite down on it, it gives way to a gooey, creamy core.

~Steve “The Hair” Harrington in Stranger Things Season 5

In the final season of Stranger Things, there is a moment where the show’s pet-redemption-arc character, Steve Harrington,1 is childishly delighted to obtain a niche 1980s snack, the Peanut Butter Bopper, while trapped in Hawkins, Indiana under military quarantine. The moment is a nostalgia play and product placement that later doubles as a jocular metaphor that explains a small bit of plot action. As as fan of peanut-butter-based treats myself, I’ve latched on this and plan to appropriate the metaphor for my own 2025 content diet. Perhaps all the reading, listening, watching, and thinking that follows looks crunchy and tough on the outside but once you bite in, it’s all creamy goodness.

Reading Recap & Recommendations

I would like to remind my Substack readers that I have over 550 book reviews that can be perused on Goodreads. The length of these reviews varies substantially, but if it is a major title in the natural or social sciences or politics or a splashy “discourse” read from the past few years or a famous work of literature, there is a reasonable chance I have commentary on it there.

Although what follows are books I completed in the past quarter, I’m actively working my way through other books, including We Have Never Been Woke by , The Right Word in the Right Place at the Right Time by William Safire, Enemy Feminism by Sophie Lewis. On deck for January 2026 and in the form of advanced reader copies, I have Gerontocracy in America by , Colossus by , and Medium Rare by .

Here are the totals for what I read or listened to in last three months:

• 17 total books across all formats (3 fiction titles, 14 nonfiction titles)

  • 2 print books (including The Secret Garden to my eldest daughter)

  • 2 ebooks

  • 13 audiobooks

And here are the totals for what I read or listened in 2025:

• 82 total books across all formats (20 fiction titles though this is mostly children’s literature read aloud to my kids, 62 nonfiction titles)

  • 17 print books

  • 11 ebooks

  • 54 audiobooks

As an aside, it is worth noting that many are concerned that book reading has become outdated, even impossible for young people who have been irrevocably stunted by ubiquitous screens and AI chatbots. I don’t harbor dour projections about the fate of literacy as I think the intellectual life has always been for the few, but it is hard not to notice things are in a sorry state. Anyone who reads a full book a month is firmly ensconced in the top quintile of readers in America.2 Anyone working at five-times that one-book-a-month rate is certainly in the top centile of readers. This is before we even consider the quality of that reading material or the comprehension of the readers. If we’re being honest with ourselves, it is evident that most of the reading that does happen includes either throwaway airport titles (e.g. self-help, celebrity memoirs, or the softest pop-sci) or pulpy fiction (e.g. Romantasy, YA titles, bodice rippers, etc). To rephrase, the bar for being literate in a sustained way with worthwhile material is several layers under bedrock. Substack is fortunately a community that helps promote reading and thinking seriously about ideas so please join and support us, if you haven’t already!

Stetson’s Review of Books Read from Q4

1. American Educational Excellence: The Foundation of Our Values, Democracy, and Market Capitalism by Kenan E. Sahin → Review at Goodreads

2. After the Spike: Population, Progress, and the Case for People by

   & → Review at Goodreads

3. The Captured Economy: How the Powerful Enrich Themselves, Slow Down Growth, and Increase Inequality by & → Review at Goodreads

4. Rules for Reactionaries by Lee Bebout → Review at Goodreads

5. The Storm Before the Storm: The Beginning of the End of the Roman Republic by → Review at Goodreads

6. Boomers: The Men and Women Who Promised Freedom and Delivered Disaster by → Review at Goodreads & Substack Piece

7. What It Took to Win: A History of the Democratic Party by → Review at Goodreads

8. Fellow Travelers by Thomas Mallon → Review at Goodreads

9. The Two-Parent Privilege: How Americans Stopped Getting Married and Started Falling Behind by → Review at Goodreads

10. Shadow Ticket by Thomas S. Pynchon → Review at Goodreads

11. The Secret Garden by Frances Hodgson Burnett → Review at Goodreads (read to my eldest daughter)

12. The Spike: An Epic Journey Through the Brain in 2.1 Seconds by Mark Humphries → Review at Goodreads

13. Furious Minds: The Making of the MAGA New Right by → Review at Goodreads

14. American Canto by Olivia Nuzzi→ Review at Goodreads

15. Nations Apart: How Clashing Regional Cultures Shattered America

    by → Review at Goodreads

16. The Rest in History by & Dominic Sandbrook → Review at Goodreads

17. Selfish Reasons to Have More Kids: Why Being a Great Parent Is Less Work and More Fun Than You Think by → Review at Goodreads

Stetson’s Book Recommendations

I was somewhat dissatisfied with the reading selections I made to close out the year, especially when it comes to being able to provide quasi-generic recommendations. I had significant criticisms of almost every title, and I wish I enjoyed reading them more. I can say that if you have a young child, it is definitely worth reading The Secret Garden to them. It is fun to introduce children to naturalistic dialogue, especially something a funny sounding as early 20th century broad Yorkshire. Sadly, the yield on this recommendation is quite low given that The Secret Garden is already a children's classic.

The most entertaining of the bunch was probably Helen Andrews’ Boomers, though I agree with her polemical analysis less than I anticipated, and, to the extent I do agree, I think her criticisms would be as much or more applicable to the generations that have followed the boomers.

I found Melissa Kearney’s book on the beneficial economic and social consequences of raising children in two parent households compelling, though she wasn’t able to convincingly and entirely demonstrate that the benefits married parents confer on children aren’t mostly selection effects and/or endogenous to the children. Of course, I’m normatively for two-parent households for raising children, but I worry the effort and political capital required to raise marriage rates may not result in meaningful improvement in the long-run outcomes for children from these unions and may have secondary consequences (backlash). The cultural levers to increase marriage may also no longer exist. At the very least, we should probably do some serious thinking about how such mechanisms could be rebuilt in ways that would be acceptable to most Americans.

I thought Mark Humphries’ The Spike was an excellent work of popular science writing that both refreshed my knowledge of neuroscience and taught me several new things. The Spike impressively bridges experimental and theoretical neuroscience using a systems approach to the electrical physiology of neurons. However, this is unlikely to ever be anyone's preferred topic for pleasure reading and following chats of stark action potential traces or abstract representations of neural circuits is going to feel a bit arcane to most readers. So even though I found it valuable as someone who has taken a graduate-level course in neuroscience based on Kandel’s Principles of Neural Science (a very ephys forward text), I can’t, in good conscience, strongly recommend in a nonspecific way.

Bryan Caplan’s Selfish Reasons to Have More Kids was amusing and a good reminder that parents should avoid overly taxing or painful investments in parenting, especially if it comes at the cost of family size. The book is largely a review of the findings of behavioral genetics (mostly twin studies). It was published in 2011 and we’ve learned a lot about the limitations of such research since then because of the advances of the genome era, but Caplan was already taking a somewhat softer line on these studies despite being confident in their nominal findings. The main takeaway here is that it is difficult for any parent to exert substantial influence on any long-run outcome for their child. Nevertheless, parents should be loving, attentive, and dutiful parents with high expectations; they just shouldn’t feel compelled to go overboard or be perpetually racked with guilt.

Laura K. Field's Furious Minds is generating a lot of attention and garnering a great deal of praise among political writers of the left and anti-Trump center-right. There are useful and interesting portions of the work. It is a good introduction to Straussianism and typology of “New Right” intellectuals, but it elides the most interesting and pressing questions about why “New Right,” especially illiberal, ideas have proliferated and found such fertile footing. This question seems all the more pressing given that Field prudently avoids smugly deriding these thinkers as troglodytes and toadies.

Stetson’s Reading Recommendations from Substack for Q4

As I shouldn’t need to say, my recommendation isn’t a comprehensive endorsement. I’m purposefully highlighting recent written work on Substack that I found plain ‘ole interesting for one reason or another. I could include many many more, but I did my best to keep the list limited in size. These pieces are not listed in any particular order.

• The Lost Generation by

• English has become easier to read by in

• America has already differentiated into castes by

• Completed Family Size Will Soon Plummet to Unprecedented Depths by

• Hating Stranger Things During the Death Rattle of Criticism by

• Top 10 discoveries about ancient people from DNA in 2025 by

• What is Heather Cox Richardsonism? by

• What’s Missing from the New Cross-Disorder Genetics Paper? by

• Elite Colleges Should Try Harder to Stay Elite by

• To Get More Effective Drugs, We Need More Human Trials by

• Of course motherhood drives the gender wage gap by

• Why I teach Conservative Social Thought by

• Why I Write About the Jews by

• Does inequality undermine democracy? The evidence is weak by

• Review: Shadi Hamid’s The Case for American Power by

• Ezra Klein’s Blindspot by

• The Neoliberal Era Was Not Pro-Market Enough by

• In Defense of Men by

• Stop Trying to Pretend that Feminism Isn’t a Class War by

• ‘Why Is The Incel Narrative So Popular Then?’ by 3

• The missing heritability question is now (mostly) answered by

• Monogamy is good, actually by

• It’s Hard to Be God by

• When grades stop meaning anything by in

• Writing For The AIs in

• Announcing the world’s most powerful genetic predictor of cognitive ability by

• Speak So They Can Hear You by

• Being a Writer in the Age of the Influencer by

• Acting Is Not That Hard by

• Further Arguments Against Jared Diamond by

Stetson’s Podcast Episode Recommendations

Save caveats as my article recs. Some of my recs here stray from the Substack platform itself:

• Alex Young: IQ, disease and statistical genomics at

• The Eugenics Debate - vs at

• The Meaning of Norman Podhoretz from Commentary Magazine

• The Secrets of Joan Didion at

• Intellectuals of the New Right | Interview: Laura Field

• Donald S. Lopez Jr. on Buddhism from Conversations with Tyler

• Sarah Paine – Why Russia Lost the Cold War at

• A Spark of Literary Genius By Christopher J. Scalia + Frances Wilson

• Joseph Heath on the Psychology Behind Modern Populism from

• Did Liberal Feminism Ruin the Workplace? | Interesting Times with

What to Watch… or Not

While it feels like cinema is dying, I worked to get through some of the more critically celebrated films of this year, including Sinners (2025), The Materialists (2025), Eddington (2025), Weapons (2025). I thought all four were fairly entertaining, though none were particularly subtle and perhaps only Eddington was conceptually sophisticated and possibly culturally memorable.

I think critical appreciation for Sinners is way out-of-step with what that film is. In fact, I thought it was the weakest and least engaging of the four I watched in the last three months.

The dialogue in The Materialist was wildly stilted, non-naturalistic. In the pivotal scenes, the main characters adopt solemn visages and discourse in an unironic incel patois. In fact, I was surprised when terms like “gonial angle” or “looksmaxxing” didn’t find their way into the film. Although this is consistent with film’s central concept, justifiable—even interesting— as an artistic choice, and suited for Dakota Johnson’s wooden acting, it’s ultimately a thin way to make a provocative play for very online theater goers, especially on a perennial topic (the battle of the sexes). Celine Song, the writer-director, also has to pull a deus ex machina of sorts (SPOILER: discovery of a leg lengthening surgery) and shoehorn in a sexual assault side plot in order to make her point about the commodification of the sexual marketplace. There’s a big casting problem too. The low status ex-boyfriend can’t be Captain America (Chris Evans) even as an alternative to a looksmaxxed finance bro (Pedro Pascal), who was also ill-suited for that role. At least, Chris Evans does look like he’s had the super soldier serum sucked out of him in the film.

Ari Aster’s Eddington is a surrealistic and satirical neo-Western set in the COVID era. It hits every hot button issue from that miserable moment and predictably has been more warmly received by right-of-center film critics than left-of-center ones. In fact, Ross Douthat sought to explain this phenomenon by reversing the woke left’s favorite zinger, “When you’re accustomed to privilege, equality feels like oppression." into “When you’re accustomed to caricature, evenhandedness feels like bias.” Despite the criticism of the cultural left, the actual politics of the film are not reactionary, but are quite cynical and fatalistic, perhaps a bit conspiracy minded itself. Regardless, I’m confident in asserting that Eddington was the most thought provoking of the films I watched.

Weapons is a horror film intended as an allegory about the social and psychological consequences of mass gun violence perpetrated against school children. It is a decently executed and entertaining film that makes some goofy choices. Considered together, it seems conceptually and tonally inconsistent. It bounces between differently flawed though sometimes sympathetic point-of-view characters while vacillating between a serious and sardonic view of events. In fact, the mixture of darkly satirical and irreverently absurdist humor often cuts against my expectations about where the creator’s sympathies lie with the exception of one or two characters. These choices make Weapons a banal, though visceral, commentary on the aftermath of trauma while being resolutely confused about exactly where the blame for that trauma should go.

In television, I watched two Netflix limited series, Black Rabbit and Death by Lightning. I enjoyed both. I also completed the first season of Mad Men, a show I have been woefully behind on watching. I have found the depiction of midcentury misogyny too on-the-nose and extreme which sometimes takes me out of the show. Finally, as the title of this piece suggests, I have been keeping up with the latest season of Stranger Things. It is a mess like many critics have pointed out, but I just try to enjoy the end of the ride. I strongly recommend the first two seasons of the show without reservations.

My Own Substack Recap

Here’s what I ended up publishing this quarter:

• A Gene For... You

• Ok, Boomer

• The Progressive Case for American Power

• Paradoxes of the Genome

This was certainly less than intended, though my pace is consistent with my prior quarter. It is difficult to assess what is worth pushing out as a newsletter post, though I do feel that I should at least write 1000 words, and I should try to do something more substantial than provide critique of something I’ve read or do basic science communication. I plan to push my production up in 2026 and, of course, have many ideas sitting around in draft form.

Selected Stetson’s Notes from Q4

I’m also quite active on Substack Notes so I encourage those who read Holodoxa to download the mobile app and follow me there. I’d like to reserve sending out email posts for longer form content (1000+ words at least, as mentioned above) so I have shifted to sharing commentary on science, literature, and politics there.

Here are some selections from my Notes this quarter:

Here's to looking forward to a great 2026! Heartily bite into it like a peanut butter bopper.

This story begins more than 20 years ago with the observations of the Vendrely’s and of Mirsky & Ris that different species contain different amounts of DNA in their nuclei. This harmless information caused some discomfort when it was learned that primitive amphibians and fish contained more than 20 times as much DNA per nucleus as did man. It was argued that mammals display a greater developmental complexity than primitive fish, therefore, they must have more genes, yet why should the lower forms have more DNA, if DNA is the chemical basis of the gene? Early opponents of the DNA-theory of heredity drew strength from the misinterpretation of these observations and they continue to inspire some. Others contented themselves with interim interpretations such as: maybe those animals and plants having huge amounts of DNA per nucleus were highly polyploid. In this way the c-value (the amount of DNA per haploid set of chromosomes) could still be a reasonable number. When this proved not to be true, some suggested that these chromosomes were polytene—that is, having multiple chromatids per chromosome. When it was shown that these chromosomes replicated semi-conservatively and that the sperm cells contained about half the huge amount of DNA found in the somatic cells, some retreated to the uncertain refuge of polynemy—that is, many strands of DNA per chromatid. But, as discussed in the previous section, this interpretation creates more problems than it solves. Here the matter rested, for who could be certain that the lower forms did not in fact require more genes to conduct their dreary affairs.

-C. A. Thomas, JR on the C-Value Paradox in “The Genetic Organization of Chromosomes” (1971)

The above passage is the original codification of various empirical observations into the “C-value paradox.” I’ve always found it (and the related G-value paradox) intriguing. It focuses the mind on one of the most motivating reasons for studying biology: the relationship between genomic information and the complexity of life. If genomic information is not the answer, what is? Are we thinking about the information in the genome in the wrong way?

So for those who want to come along for the ride and learn about genomic paradoxes, buckle up! Today, I’ll cover some of the latest thinking on the so-called C-value paradox and the related G-value paradox. I’ll explain why these aren’t actually paradoxes at all. Along the way, I’ll try to persuade you that it is the amount of functional information encoded in the genome, rather than its sheer size or gene number, that actually accounts for the complexity of an organism. The lay intuitions were right all along, but the encoding of complexity in the genome is not itself straightforward. This doesn’t mean that genomic information alone can account for what makes humans special in the eyes of many, but it can help account for why behavioral complexity is accessible to us. As always, the devil is in the details and no one has time for those, so I will do my best to keep the discussion at a high level as well as short and sweet. To make my case, I’ll recap what the C-value and G-value paradoxes actually are, how subsequent research has since resolved them, touch on why the framing persists, and why our intuitions can lead us astray when we try to provide casual explanations of our complexity via biological reductionism.

What is the C-value Paradox?

The term C-value paradox refers to the puzzling historical observation that an organism’s haploid DNA content (the “C-value”) does not correlate with intuitive understandings of organismal complexity. A classic example is that certain amoebae carry over 200 times more DNA per cell than humans do. Early geneticists expected that more complex organisms would require more genetic information, so these findings were perplexing enough to be dubbed the “C-value paradox” in the 1970s (PMID: 26323762). Subsequently, as the genomics era blossomed and scientists began assembling whole genomes, a related surprise emerged: even the number of protein-coding genes (sometimes called the G-value) does not scale with organismal complexity (PMID: 39874285). The tiny nematode and famous model organism C. elegans (~1,000 cells total) has ~20,000 genes which is roughly the same number as humans (~30-40 trillion cells total), layering a G-value paradox on top of the existing C-value paradox. These paradoxes prompted deeper study of the genome. What truly drives organismal complexity if not raw genome size or gene count?

In recent decades, we’ve learned a lot about genomes thanks to pioneering work from the Human Genome Project, advances in the cost and throughput of DNA sequencing technology (aka the genomics cost curve), and other methodological developments and the continued progress of empirical research. This research has demystified the C-value paradox. Today, we understand that genome size variation is mostly due to non-coding DNA, and these non-coding, often repetitive, elements typically have little to do with building a more complex organism. This realization reframed the problem: rather than a paradox, it became more of an enigma. Why do some genomes carry so much extra DNA? What (if anything) do these non-coding sequences contribute? In parallel, to resolve the G-value paradox, biologists identified multiple genomic and molecular mechanisms that let complex organisms do more without needing more genes (PMID: 32445179). These include factors like alternative splicing, multitasking proteins, and notably the sophistication of gene regulation networks that amplify and tune the informational output of a limited gene set.

The Paradox that Wasn’t

The C-value paradox emerged from the basic expectation of a simple linear and transitive relationship between genome size, informational content, and organismal complexity. In other words, more complex organisms should be expected to have more DNA because more DNA is required to specify a greater level of developmental and morphological complexity. If we understand the primary role of DNA to be encoding proteins then certainly more proteins must be needed to make a large multicellular animal than a single-celled protozoan. However, this doesn’t straightforwardly check out at least in the ways scientists initially tried to measure it.

Eukaryotic genome sizes vary over 60,000-fold—from tiny genomes of a few million base pairs in certain microsporidian parasites to gargantuan genomes of >100 billion base pairs in some plants—yet these differences show no consistent relationship to the organism’s morphology or developmental complexity. As early as the 1950s, it had already been noticed that closely related species could have huge differences in genome size with no obvious effect on function or complexity. It didn’t even necessarily create reproductive barriers. In 1971, geneticist C.A. Thomas coined the term “C-value paradox” to label this confusion (PMID: 16097657).

Not long after, the alleged paradox was putatively resolved by the discovery that the variation in C-values was explained by variation in the amounts of non-protein-coding DNA. Susumu Ohno famously called these nonfunctional regions “junk DNA.” This now refers to genomic features like repetitive elements, regulatory regions, introns, and pseudogenes. It is also widely known, even among many lay people, that only a small portion (~1–2%) of the human genome encodes proteins, while the rest is junk or of dubious import.1 This finding was easy to reconcile with the existing evolutionary paradigms and its related popularized narrative, Selfish Gene Theory. Genome size can quickly bloat because non-coding elements are good at playing the selfish evolutionary game of amplifying themselves and persisting. Unfortunately, this phenomenon obscured the relationship between the genome and complexity and raised puzzling questions about why genomic bloat was an acceptable energetic cost to these organisms if it wasn’t doing anything functionally.

Despite the non-coding DNA findings, the C-value paradox didn’t quite go away. There were a couple reasons for this:

1. Better and broader sampling of the entirety of life’s genomes does evince a general relationship between C-value and organismal complexity. It is more precisely re-stated as an inverse relationship between gene density or genomic constraint and organismal complexity (see the figure below). Thus, the C-value paradox is restricted to a particular range—that of multicellular eukaryotic life. This is arguably the most interesting slice of life there is, which perhaps accounts for why the C-value paradox hangs around as a term (PMID: 20548290).

   

2. Rhetorically, it is difficult to walk away from compelling, attention grabbing language. After the Human Genome Project, the demand for scientific communication about genomics expanded so naturally the popularity of the term exploded despite the underlying scientific question departing from the original C-value paradox. Who can resist the indulgent pomposity of calling something a “paradox?”

Anyway, as mentioned, the scientific literature started to reframe the questions concerning the relationship between genomes and organismal complexity, renaming the C-value paradox as the C-value enigma (PMID: 11325054). The new focus became investigating the non-coding elements themselves and honing in on the relationship between genomic content and organismal complexity. The former problem was more tractable. The study of these bloated genomes suggested a yin-vs-yang dynamic at play, where expansion or contraction can be favored in the same genome depending on the necessities of an organism’s evolutionary niche. Thus, one of the competing tendencies, whether for expansion—repeatome copying, polyploidization, and whole-genome duplication—or contraction—diploidization, illegitimate recombination, and nonhomologous end joining (NHEJ) after double-strand breaks (DSBs)—is usually downstream of the selection pressure of a particular niche, where intense selection drives streamlining and weaker selection accommodates bloating. Once again the Theodosius Dobzhansky’s proverb rears its head: “Nothing in biology makes sense except in the light of evolution.”

The G-Value Layer

As mentioned above, the G-value paradox is a second order question following on the the heels of the C-value paradox solution (i.e. variation in non-coding, often repetitive, DNA elements). It asks a more trenchant question, digging further into the relationship between the functional information content of the genome and organismal complexity. Why doesn’t gene quantity simply account for organismal complexity? How can gene density go down while organismal complexity goes up, especially if the reason gene density is going down, non-coding element expansion, is not itself a sufficient account of complexity either?

First, the G-value paradox is also a bit of a misnomer. It results from being definitionally imprecise due to the limitation of measurement tools and paying a bit too much attention to the exceptions to a general trend within selected ranges of life. In fact, this is quite a bit more true for the G-value paradox than the C-value one. Gene number (sometimes referred to as gene content), especially in terms of unique gene families, does correlate with complexity, and it doesn’t vary much within related species in a taxa. The range of variation in gene content (here quantified by the transcriptome) is dramatically smaller than genome size, 17 fold versus 66,000 fold (PMID: 12004964).

Second, the G-value paradox is resolved by sophisticated mechanisms of gene regulation which enable the genome to do more with less. Gene regulatory mechanisms are able to amplify the functional content contained by genes and control when, where, and how this functional information is used without increasing gene number or gene density. Gene regulation is the ability to take pieces of genes and cut and paste them in many different ways and in different tissues and at different times and produce them in different amounts.2 The dimensionality introduced by these mechanisms is easy to gesture toward when confronted with the uncomfortable questions raised by the C/G-value paradox.

But is it actually the case? Is gene regulation the real solution to the questions that motivate observations like the C/G-value paradoxes? Does it provide for a scientific version of the “Great chain of being”?3

Although the genome alone is an insufficient account of the total behavioral, cognitive, and collaborative capabilities of our species,4 the genome does appear to explain why some lifeforms are more complex than others, where complexity refers simply to the collected number of parts and the number of levels at which these parts are organized. A good demonstration of this is that we can produce some simple and clear linear relationships within eukaryotes for proxies of organismal complexity, i.e. cell type number or CTN, and proxies of gene regulatory complexity, i.e. alternative splicing prevalence and level or ASP/L (PMID: 34819032). This along with the aforementioned relationship between unique protein families and organismal complexity restore some confidence in the intuitive idea that the amount of unique functional information in the genome explains organismal complexity. Measuring that functional content just isn’t straightforward as the way in which genomic features increase organismal complexity is multidimensional.

Why Do Things Still Feel Paradoxical?

This resolution of the C/G-value paradox unfortunately elides why we’re interested in the question in the first place. People want to know what about our human genome makes us special. There are of course ways of examining genomic regions and features that are enriched or even unique to humans (i.e. human accelerated regions) but studying these things will likely result in the same dissatisfaction; the answers will never feel like enough. In some ways, the things that make humans special—the great complexity evolution has bequeathed—has also enabled us to take control of our biology. We’re in an era where parents can combine gametes externally in greater number that nature would typically allow for and use genomic information to choose from this pool of zygotes. Eventually, engineering of the human germline may become commonplace. These technologies were never anticipated by our genomes or evolutionary forces. Nevertheless, they arose from them de novo. It is always difficult to fully account for these seemingly enormous phase shifts (nothing to something; abiotic to biotic; non-conscious or unconscious to conscious; etc), especially when we look into the details and the plausible story looks so incremental and modest.

Today, the world needs American power, it needs more of it—and it needs it now. But power on its own isn’t enough. The world needs American dominance, too. This mean maintaining America’s political, economic, and cultural edge over its competitors. This is not because competition itself is bad; it is because the only country that comes close to competing with the United States is a brutal authoritarian regime that has only grown more brutal with time.

~Shadi Hamid, The Case for American Power

If American power declines—and if such a decline is accepted without resistance—other countries will step into the void. Seen through this comparative lens, America’s dominant role, for all its very real faults, becomes more attractive. The alternative to America isn’t some morally perfect superpower of our own imagination. Such an alternative does not exist and never will.

~Shadi Hamid, The Case for American Power

In June of this year, Gallup polled Americans about their national pride and published the results along with the past two-and-a-half decades of data on the same question. The results came back at a record-low, and the low figure was largely explained by a sharp drop in national pride reported among Democrats.

From a broad American perspective, the trend is disheartening. Why has national pride fallen so much among Democrats? Why are independent trending in a similar direction? Precise and complete answers will elude us given the data we have, but some of the story is clear. Among Democrats, reported national pride shows a sensitivity to the partisan identity of the president, especially when that president is Donald Trump. Although Democrats have always reported lower national pride in the history of survey data and there were already signs of decline prior to 2016, Trump’s first term coincided with a near 30 point erosion in national pride among Democrats. That pride showed a brief recovery during the Biden administration, only to crash even lower after Trump’s re-election in 2024.

Being able to read the tea leaves, left-liberal and progressive pundits and operatives, often motivated by a desire to keep Democrats competitive in national races, have sought to reverse this trend among their co-partisans.1 Some of the shifting vibes have resulted in genuine conversions too. can be slotted in somewhere among these left-of-center figures who are trying to find new, solid footing. Although I’m not deeply familiar with his work, his evolution appears to have really begun in the mid-2010s in the wake of the collapse of the Arab Spring, the lost promise of the Obama administration, and the twinned rise of The Great Awokening and Donald Trump. Given Hamid’s background, a scholar of Middle Eastern politics, his focus is more international than domestic politics, and, on this front, Hamid has undergone a near complete reversal from a postcolonial anti-imperialist in the vein of Noam Chomsky to a reserved champion of American power in the vein of Dean Acheson. This has culminated in a book called The Case for American Power.

At its core, The Case for American Power is a refutation of the reflexive oikophobia2 of the American left3 and a critique of its naivety about the nature and consequences of political power. It isn’t an uncritical defense of American power though. Hamid retains skepticism about some of the ways America has used its power on the world stage, especially in the Middle East, but he insists that the best and only available option for a leader of our international system is America. There are real mechanisms for reforming and improving America. He also believes that America will likely remain in the position of world leader despite the increased prevalence of narratives of American decline.

Hamid’s argument is straightforward. It has two basic components: 1) American hegemony is actually good for the world and 2) There are no superior alternatives. Hamid’s first contention rests upon both philosophical and empirical grounds. Interestingly, the philosophical premises are likely stronger or at least easier to believe in, while the available historical datasets are inherently limited and comparatively small, precluding high-confidence analysis of cause-and-effect and projections about the future.

On the philosophical front, Hamid makes the persuasive yet ungainly (to many Western ears) assertion that democracy is a morally superior form of governance. Democracy embeds a mechanism of self-correction, enables the peaceful transition of power, and diffuses existential conflict. In an imperfect world of competing trade-offs, it offers a modest, sometimes chaotic, way to optimize freedom and equality for all.4 I think most readers will be inclined to demurely agree, especially if the only alternative system on offer is autocracy. However, for the potential skeptic, Hamid goes on to provide a pragmatic and empirical case for democracy arguing that democracies have historically been better at delivering peace, stability, and prosperity.5 Despite the many caveats involved with drawing causal inferences from observational, retrospective, and messy data, I think his claims are generally substantiated. Hamid’s argument, however, does overlook the cultural or institutional constraints on democracy that have historically helped it flourish, liberalism.6

On the empirical front, Hamid briefly marshals some evidence to show that Pax Americana has been a boon for the world. One prominent data point comes from a 2018 study by Aaron Clauset. Clauset observes that the rate of large wars before and after World War II (WWII)—arguably the moment of indisputable American hegemony—shows an unmistakable decline in the rate of conflict, where the incidence of large wars dropped from roughly every 3 years to every 13 years. However, Clauset’s paper also acknowledges that the sampled years prior were notably enriched with conflict and the current trend of peace could be a statistical fluke. He argues that another 100 or so years of future time is needed before we can be confident in the post-WWII liberal peace argument. Hamid omits the conclusion of the paper. I don’t raise this as a critique of Hamid. I raise it to highlight that there is a lot of uncertainty about the takeaways we should draw from the last 80 years of history. It is easy to fall into interpretations that make us look good. At any moment, our brilliant theories of how great we are can be falsified, which seems like good motivation to strive harder for greatness.

Hamid’s laudatory treatment of democracy is essential for his argument about American power on the world stage. Hamid concedes that an unchecked hegemon is likely to abuse power, but instead of another great power needing to check the hegemon, Hamid believes restraint should emerge from within. That check is America’s imperfect and contentious democracy. He insists upon this because the alternatives eligible to participate in great power competition, China and Russia, are autocracies. He spends an entire chapter cataloguing the weaknesses of autocracy, offering a refutation of arguments made about China or even Singapore figuring out how to run “smart autocracies.” He identifies two fatal weaknesses in autocratic governance: 1) They preclude organic discovery of public sentiment both among citizens themselves and between citizens and the government and 2) The dilemma of succession inherently compromises stability.

I’m less confident that certain forms of government are inherently more stable and more effective for all peoples in all contexts.7 There is substantial material, geographical, and cultural variability that likely impinges on this question. Will China be able to supplant America as world hegemon? I think it is somewhat unlikely in the short-term for a number of reasons, but I also don’t think it is inevitable that China will fail to because it is autocratic.8

The Balance of Power Alternative

Let’s take a very brief look at an alternative to Hamid’s perspective. I want to avoid spending too much time on alternative views, which of course there are many, because they’re largely beyond the scope of the book and enjoy greater popularity and prestige among Hamid’s ideological compatriots. So, I will simply provide a brief look at the strongest version of what Hamid’s argument doesn’t directly address, a “balance of power” thesis.

The main alternative to Hamid’s position of American unipolarity often comes from members of the realist school of international relations. They often argue that a single global hegemon makes for an unstable world, and many already argue that American hegemony has ended. The realist view is informed by the belief that nations will act ruthlessly in their self-interest and naturally pursue power. Subsequently, the realists only see a stable international system sustained by power sharing or a balance of power, ideally between two main power centers. The two power centers could police smaller players in their spheres of influence while checking and restraining each other on the broader world stage given that their interests would be easy to understand and coordinate around. In some ways, this is an extension of Enlightenment political philosophy, features of which have been constitutionally built into American governance. These ideas have long been championed by famous figures like Henry Kissinger.

The problem with this form of realism is that it appears to assume national interest is both discoverable and rational and that governments can effectively and coherently act upon these interests. Any examination of the history of great power conflict or American foreign policy would strongly militate against such beliefs. Instead, an examination of historical follies would likely underscore Hamid’s point concerning the weaknesses of autocracy and the strength of democracy when it comes to governing legitimacy and mechanisms for assessing the government’s gaining legitimacy, maintaining stability, and promoting prosperity. Unfortunately, I fear theoretical models and the lessons of history will be insufficient guides to the future of great power conflict. Unpredictable things will undoubtedly occur.

The Seductive Trap of Declinism

Hamid only indirectly addresses the “balance of power” alternative, which comes through his adversarial engagement with the popularity of narratives of American decline. He does offhandedly reject the idea that a multipolar world is emerging, but this never comes up again in the book outside of the introduction.9 On the question of whether American empire is itself in decline, Hamid somewhat demurs from an empirical refutation and opts to cast belief in decline as a comforting, fatalistic trap ensnaring too many Americans.10

He traces a brief history of notorious prophets of Western decline, starting with Oswald Spengler and then moving to James Burnham and finally to Christopher Lasch. By the 1970s, Hamid argues Americans had inherited a penchant for decline due to a mixture of cultural forces and basic psychological defaults (i.e. threat sensitivity, loss aversion, etc). Our healthy tendency for self-critique devolved into self-contempt, nurturing a “pessimism that discounts [our] own society while elevating less familiar societies.” Hamid really emphasizes the psychological appeal of decline:

Decline is, more than anything else, a feeling. If you think that the past was great, you’re more likely to believe that the present is worse. These feelings are subjective things. Declinism, the state of fear and fretting in which decline seems inevitable, has been something of a national past time, with each generation of Americans rediscovering what it means to lose faith.

And he relies on the claim that our attachment to stories and subjective states of mind have been common throughout history, and that even if history can be rightly modeled as cyclical rises and falls that our beliefs are not necessarily attached to the reality of our location in that cycle. In fact, our beliefs themselves may play a causal role in where we are and where we go, a dangerous self-fulfilling prophecy.

Hamid, A Champion of American Hypocrisy

No one is wearing a mask because it is no longer possible to see what there is to mask.

~David Runciman, Political Hypocrisy

Perhaps the most intriguing part of the book is Hamid’s chapter-long defense of American hypocrisy. It is very much along the proverbial lines of “hypocrisy is the tribute vice plays to virtue,” where Hamid accepts America’s expressed idealism as genuine are compromised by the tragic limitations of reality, which inevitably generate actions inconsistent with heartfelt values. Hamid stresses over and over that the world is brutal and that the use of power is inherently sullying but the burden must be born. America is the right choice because it is exceptional in that it is the one powerful nation organized by ideas. We often fail to live up to our ideals in practice, but at least we’re trying.

This is, of course, a revolting sentiment to those in the postcolonial or Chomskyite traditions. To them, American ideals are a veneer painted upon ugly power plays and sinister conspiracies executed by special-interest and political elites so as to dupe brainwashed members of the broader American public. The litany is long and includes American support for right-wing dictators in Latin America and the Middle East, covert action to topple democratically elected socialists and communists abroad, and exploitation of the resources and people of the Global South.

Hamid, both literally and figuratively, holds trump cards against the anti-imperialist left’s criticism of American hypocrisy. First, he recounts how Barack Obama’s unimpeachable postcolonial credentials, including close personal connections with pro-Palestine figures like Edward Said and Rashid Khalidi, failed to deliver significant change in U.S. foreign policy towards Israel, showing that intentions and outcomes can diverge for many reasons. Second, he trots out Donald Trump as an example of a less hypocritical version of American foreign policy. Trump forgoes paying deference to American idealism and just acts in whatever way he sees fit. This is meant to contrast, for Hamid’s intended left-of-center audience, how some amount of hypocrisy can be preferential to none. Additionally, Hamid also draws attention to the hypocrisy of many on the anti-imperialist left, highlighting how little they have had to say about Russian imperialism in Ukraine and how they have ignored how many eastern European countries voluntarily sought alliance with America as a bulwark against Russia.11 Hamid goes so far as to assert, “So many anti-war voices are not, in fact, anti-war at all; they are anti-American war.”

A Verdict on the Progressive Case for American Power

To be sure (a phrase Hamid, like many political writers, loves), Hamid presents a reasonable argument for America, the benevolent hegemon. However, the argument is more of an attempt to move sentiment among Americans, especially left-of-center Americans, than an attempt to actually analyze the state of American power and the current dynamics of great power politics. Thus, I’m judging it as a rhetorical object. And I do think it is necessary to make this popular case against self-destructive manifestations of oikophobia or self-loathing because they probably have warped our politics for the worse, having long ensnared academics and activists on the left and currently gained purchase among some of the paleoconservatives who staff Trump’s administration and run intellectual periodicals.

Insofar as Hamid is speaking to those to his left, it behooves his argument to avoid a rah-rah tone, meaning the praise for America is never delivered in an entirely unqualified or unconscious fashion. The strongly pro-American argument is consistently positioned against the common left-wing criticisms of American foreign policy and accompanied by an acute awareness of the stigma attached to unreflective patriotism. Nonetheless, the fact that Hamid is willing to regularly profess a love for both the idea of America and the America he lives in today is something I greatly appreciate. It appears genuinely felt. I hope Hamid’s sentiments are contagious among his co-partisans.

Now, it can simply be exciting to see this sentiment at all.12 And yes, I’m excited to see a left-of-center Muslim political figure come around to this position, a position that many former liberals and left-wingers have come around to again and again in the wake of the world wars, the rise of the Soviet Union, and the anti-war agitations of the New Left.13 However, the message is somewhat marred by Hamid’s residual ambivalence. Hamid is deeply troubled by the recent conflict between Israel and Hamas in Gaza, and he sees that conflict, which has for now been resolved, as a deep threat to the thesis of his book. However, I fear his read on those events is blinkered my his own particularism—commitments to an ethnic-religious group identity which themselves are often understood as inconsistent with or in tension with the liberalism of America.14 Understandably, it is difficult to decouple from such intimate commitments in order to favor more abstract ideas. In fact, I was actually surprised that Hamid struck a more sober tone on the subject than he has sometimes done when commenting more extemporaneously.

Altogether, I agree with the broad version of Hamid’s argument. I, too, think power must inevitably be used in world affairs. I, too, think America is the best available option to be trusted with that power. I, too, believe that Pax Americana has been salutary for the world. I, too, think we should work to preserve and extend American power. But, I’m not sure these beliefs can be accurately labeled as “progressive” despite how I’ve framed this review. Nonetheless, Hamid does clearly believe that progress is a political choice, and it’s one that the American electorate is capable of making together.15 This suggests a profound trust in Americans, which is a bit surprising from someone on the left-of-center in the wake of Donald Trump’s re-election. Admirably, Hamid has taken the long view. Let’s pray he’s right about American resilience and that his co-partisans start similar journeys back to a faith in the American project and optimism about its future.

We’ll end with some final commentary from Hamid on American power:

When American power seemed uncontested after the Cold War, a growing number of Americans could afford to imagine a world with less of it. It was peacetime. The United States had no real competitors, and political elites in Western democracies took for granted their own permanence. Around the globe, Americans saw more friends than enemies, but even our enemies—weak as they were—could be transformed into friends. Or so the thinking went. Those easy assumptions are now lost to history.

Every generation is dealt its own challenges and handles them as well as it can. The boomers were dealt an uncommonly good hand, which makes it truly incredible that they should have screwed up so badly. They inherited prosperity, social cohesion, and functioning institutions. They passed on debt, inequality, moribund churches, and a broken democracy.

~Helen Andrews in Boomers

Drugged up, divorced, ignorant, and indebted, but at least they did it out of idealism. That has been the baby boomers universal alibi: our intentions were good. Later, they will admit, perhaps that idealism curdled, motivation flagged, the weaker-willed sold out. Still, the original impulse was altruistic. It would be quite a blow to their self-image if it were discovered that the boomers’ various crusades were selfish from the very beginning.

~Helen Andrews in Boomers

Helen Andrews recently sent shockwaves through contemporary political discourse with her piece in Compact Magazine titled “The Great Feminization” wherein she provocatively argues that “wokeness” was precipitated by shifting sex ratios—from male-dominant to female-dominant—in major social institutions because men and women have innate average differences in their communication and management styles. I’m not here to adjudicate these scorching hot claims (though of course sex differences are real) because many other are already doing this (just scan some Substacks) and before this piece ran I had serendipitously picked up Helen Andrews’ polemic tilted Boomers: The Men and Women Who Promised Freedom and Delivered Disaster.

Andrews chose to model Boomers after Lytton Strachey’s Eminent Victorians (1918), a title that I imagine is wholly new to most readers; it was new to me at least. Apparently, Strachey’s Eminent Victorians was a collection of short biographical sketches that doubled as an ironic takedown of both the figures profiled and the ethos of the epoch.1 It was apparently a big hit. Doesn’t hurt to offer up a sequel.

In Strachey’s case, he was an aesthete looking to flambé pomposity and prudery. It’s more of the opposite in Andrews’ case, though it would be somewhat unfair to call her pompous and prude. She’s eager to hold the boomers accountable for what she identifies as “irreparable harm to Western civilization”—to take them to task for cloaking their normal but base and selfish appetites as high-flown moral crusades. Boomers were handed the world, aspired to great things, and even accomplished some great things, but due to their vanity, arrogance, and rapaciousness they also managed to suck the vitality out of the institutions that made America special. For that, she acerbically asserts, “The boomers should not be allowed to shuffle off the world stage until they have been made to regret [it].”

Oof! Andrews’ case against the boomers is harsh. She is, perhaps, a bit of a bitter aging Millennial, though her bitterness is mixed with some fondness and ambivalence, which is sometimes just enough of a salve for the lacerations left by her cutting wit. This set of mingled emotions and Eminent Victorians has provided important shape to the book with the former guiding her choice of subjects and the latter giving the work its episodic structure. She has selected six eminent boomers, individuals born between 1946 – 1964: Steve Jobs, Aaron Sorkin, Jeffrey Sachs, Camille Paglia, Al Sharpton, and Sonia Sotomayor who respectively hail from the fields of technology, entertainment, economics, academia, politics, and law. She claims each of these figures is neither “altogether a villain or a victim” but exemplify important aspects of the boomer ethos. These characters also present her with an opportunity for comparison. More than half of the biographical chapters include historical foils, sometimes major ones: Tim Cook for Jobs, Larry Summer for Sachs, Susan Sontag for Paglia, and Jesse Jackson for Sharpton.2 She also flanks the sketches with an opening chapter on the boomers and a closing chapter on the millennials, individuals born between 1981 - 1996.3

As I read the book, it became clear that many of the subjects weren’t necessarily of deep interest to Andrews or as emblematic as she frames them, but they are convenient for the commentary she wants to deliver. The device also helps her avoid assembling a sociological treatise where she can plausibly pin blame on an abstraction (i.e. a generational cohort).4 Thus, the portraits don’t even attempt to be comprehensive, and the use of facts and figures to support claims is ad hoc. Instead, the sketches allow her to use these characters as symbolic anchors for polemical episodes about connected social phenomena. Andrews’ primary grievances concern economic displacement (i.e. the two-income trap, student loan debt, etc) and social decay (i.e. divorce rates, marriage rates, sexual anarchism, etc). Even then, she spends little time harping about why such things are harmful and bad and rather more time ardently lambasting the follies of the boomer that comprise her cast of characters.

The Boomer Bunch

The peculiar structure of the book lends itself to a similarly structured review, meaning I’ll summarize Andrews’ takes on each eminent boomer in her cast. I’ll keep my digressions to a minimum, and I will include some direct excerpts I find striking for one reason or another.

Steve Jobs

The Jobs chapter very neatly supports Andrews’ contention about the paradoxical mélange of vice and virtue in the stereotyped boomer that she sees as ultimately coming at too great a cost to America’s social fabric and future. It is unfortunately the least compelling of the profiles given how familiar most of the content is and how the underlying economic analysis on which the critique is ultimately built is shortsighted in important ways. The basic message is Jobs was an incredible builder. He drove the creation of amazing products at Apple, but he was not a responsible enough steward for posterity. The succession plan was botched. He let his creation be passed on to someone, Tim Cook, who compromised his vision for short-term gains. Cook’s errors are identified as indulging cheap consumerism, starkly utilitarian business ethics, giving away jobs and intellectual property to China, and politicizing the brand.

Aaron Sorkin

The chapter on Sorkin, a perennial bête noire of conservatives, opens immediately with an anecdote about staffers in the Obama administration believing in a fictional political tradition (i.e. pro forma cabinet resignations between the first and second term of a president) invented by The West Wing. Its intended as emblematic of what Andrews sees as television’s ability to make people feel knowledgeable without actually being knowledgeable (Neil Postman, anyone?). Despite his admirable dedication and idealism, Sorkin is faulted for being an earnest believer in the power of television as an educational and informational medium in addition to an entertaining one. I think a lot of what Andrews is working through in the chapter is that she’s a fan of Sorkin’s work too but finds his politics nauseating. Admittedly, I cringe up when I see that Jeff Daniels clip from The Newsroom circulating on social media too.

Jeffrey Sachs

The Sachs chapter is Andrews’ most oblique attack on the boomers. It’s certainly a critique of the left-of-center approach to developmental economics, but a similar critique would appear to apply to a number of Chicago school economists who advised other foreign governments too. She casts such efforts as a bake-your-cake-and-eat-it-too type of anti-imperial imperialism. It’s no less imperialistic yet can plausibly be dressed in humanitarianism and post-colonialism garment because ultimately all the United States economists are doing is advising.

She spends most of the chapter following the many different international projects Sachs has engaged in across the world and some of the rougher aspects of his personality. She’s also eager to call attention to the hypocrisy and paternalism of those who feel self-important enough to meddle with the world in this way and received praise and credit for it.

Andrews doesn’t exactly state how she sees this as exemplary of boomer psychology or why the consequences have been disastrous. The reader is left to infer that this is Andrews further dissecting the internal hypocrisy built into the boomer political mode—always adopting the mantle of the moral crusader but never willing to take responsibility for the difficult choices.

Camille Paglia

Andrews’ chapter on Paglia was the one I anticipated most and also was the most invested in. I agree that she’s an incredibly important cultural figure.5

Andrews is quite hard on Paglia despite her evident respect for her. She implicates her in the degradation of high culture, the infantilization of higher education, and the sexual anarchy subsequent to women’s liberation, including the proliferation of pornography. These attributions sting because Paglia positions herself as a defender of aesthetic brilliance, intellectual rigor in the academy, and even Western civilization. I can see why Andrews and Paglia diverge on sexual politics, but they, in important ways, both agree on the chthonic depths of sex. Andrews thinks the proper response is restraint and containment, while Paglia wants Pandora’s box open so that the truth of sexuality is understood and enlightened reason guides us to a healthy homeostasis. Given the benefit of hindsight, Andrews thinks this permissiveness has been shown wanting.

Andrews’ critique of Paglia rests on being even more based about human nature. Yes, Paglia saw men and women were different. Yes, Paglia saw through many liberal pieties and the stuffiness of PC culture. Yes, Paglia was an incisive aesthetic observer. But, Paglia was still too naïve about the freeing dark urges and too optimistic about the edifying and uplifting possibilities of mass culture.

Al Sharpton

The chapter on Sharpton was intriguing. It makes Andrews’ collectivist stripes clear. She endorses machine politics, patronage, representationalism, and ethnic self-interest. The chapter is centered on a distinction that Sharpton himself has drawn between transactional and transformational leadership. Despite Sharpton seeing himself as the latter type of leader, Andrews sees Sharpton as a transitional figure in the middle of these two paradigms. She prefers the former mode as it delivered material benefits to ethnic factions that inevitably develop in a diverse democracy and forged durable compromises across ethnic divides. The latter mode contributes to rhetorical excesses and rash, dramatic action that invite backlash and eventually move questions beyond the reach of normal politics.

Sonia Sotomayor

Andrews makes a perfunctory effort to sketch Sotomayor, focusing on her college activism, confirmation process, and behavior as a justice of the Supreme Court. The portrait emphasizes Sotomayor’s learned pugnacity—in less polite terms, Sotomayor’s ability to be a bully for her causes.

Andrews seems to have chosen Sotomayor because she helpfully embodies a synthesis of several strains of failure in America’s legal profession and system while being robust to the typical critiques levied against her, i.e. that she was an affirmative action appointee.6 Given Sotomayor’s leading role, the focus is appropriately directed at the courts, where Andrews argues that judicial activism married to professionalized legal advocacy designed to foster precedent testing cases has run roughshod over the deep “constitutional doctrine of parliamentary supremacy.” Andrews is most invested in a 1963 case Abington School District v. Schempp which barred mandatory Bible reading and prayer from public schools. Andrews sees this as a policy that permanently disrupted the social transmission of religiosity from one generation to another. However, this change largely pre-dates boomers rise to political power so it was an interesting inclusion as a watershed case.

This chapter presents the likely least resonant of the critiques of boomers. The prior chapters does offer, even if meager, some things to those with variable ideological predispositions. Sotomayor represents the culmination of cultural and legal trends that have been less than salutary for conservative policy goals and perhaps the continuity and strength of the institutions of civil society have suffered because of this if we accept some of Andrews’ premises. However, to be completely persuasive, this critique requires that the reader is invested in a particularly conservative Christian view of American life, and thus is unlikely to be resonant with conservatives (the classically liberal kind) with secular worldview, let alone those with ones that are left-of-center commitments.7

The Boomers and Our Discontents

There were many highly entertaining moments in Boomers. Andrews writes with a dry, sharp wit and is unrestrained by many of the norms of polite political discourse. However, I fear Boomers suffers from the same purported weakness as Eminent Victorians; it’s all critique without a clear alternative set of values that are defensibly articulated. Andrews does actually have an alternative worldview to replace the one she identifies as synonymous with boomers or perhaps more accurately boomer inflected liberalism. Unfortunately for Andrews, though she is probably well aware of this, is her particular set of values are not broadly popular among Americans and don’t appear to have a bright future given current trends.8 Her rejoinder would perhaps be that the boomers are to blame for stigmatizing Christian family values and more nationalistic iterations of Americanism, but, even if this is the case, the reader is left to ponder what path millennials, zoomers, and alphas should try to forge in the boomer’s wake, whenever the boomers do in fact exit the stage.

So are the boomers to blame for our discontents?

If one is familiar with Jean Twenge’s theory of generational change and we take it as a good model, then we are to believe boomers are the way they are because of the technological change they experienced in their formative years: contraception, television, mass media, personal computing, etc. Using this or any more scientific approach to the material causes of sociopolitical change, it is unreasonable to believe that boomers themselves should bear the blame for today’s social outcomes whether we like them or not. They’re simply unlikely to be any more psychologically problematic on average than any generation before or after unless some vast and diffuse material cause, likely beyond their immediate control anyway, is to blame. If we review every policy or important decision made by boomers maybe we could identify some critical failures of will or some particular stumble, but this isn’t the moral case Andrews wants us to believe in. She wants us to believe boomers had more of a clear choice between paying down a debt owed to their forebears or skimming funds from future generations to forge some dark bargain with Mephistopheles, and boomers, reflecting carefully on these two choices, repeatedly went full Doctor Faustus.

Maybe I have a blinkered moral imagination, but I’m willing to forgive the boomers their decisions and even their foibles, where Andrews correctly identifies them, because I think these are failing shared by all Americans today, and it is unclear how we are to constructively grow beyond our increasingly solipsistic and cosseted way of life. The old, tried-and-true methods are almost certainly gone forever. Nevertheless, I, like Andrews, yearn for a zeitgeist that believes in the American project enough that it induces individuals to act in ways that contribute to stronger institutions and a more robust version of communal life.

More on Helen Andrews’ Boomers:

Fortunately, there’s a pragmatic alternative to the approach of philosophers of biology and science educators that has been developed by medical geneticists, gene-disease validity (GDV). The standards for establishing the validity of an asserted gene-disease relationship are published by the Clinical Genome (ClinGen) Resource, which uses a qualitative framework with seven classifications: Definitive, Strong, Moderate, Limited, Refuted, Disputed, and No Relationship.3 Classifications of Moderate or greater are considered evidence of a causal relationship and provide a rationale for including a gene on a diagnostic panel which can result in a molecular diagnosis provided a pathogenic variant is identified in that gene.

This approach isn’t an absolutely perfect method. It works best for classical presentations of genetic disease; the kind caused by mutations in a single gene where the associated phenotype is distinct in some way.4 The common case under this genetic paradigm is rare autosomal recessive conditions, where loss-of-function variants affecting both maternal and paternal alleles of a gene are inherited by an individual who then presents with a specific set of symptoms that are related to the affected gene’s function. These affect ~1.7–5 in 1000 neonates, and there are many famous of examples: CFTR and cystic fibrosis, PAH and phenylketonuria, and HEXA and Tay-Sachs Disease.

The limitations for this approach emerge in situations where a condition is substantially polygenic, meaning it is under the influence of many “genes” in the genome, or when the relationship between variants in a given gene and the condition of interest are inconsistent (what geneticists call penetrance), or when the relationship between variants in a given gene and the associated phenotypes is multifaceted (what geneticists call expressivity).5

Gene-Disease Validity: A Case Study

I figured it would be more edifying to see an example of how a given gene is demonstrated to have a valid relationship with a given clinical condition rather than just describing the process at a high-level. I have picked a clear but non-classical example. So I’ve chosen the gene FAS. SPOILER: Genetic variants in FAS cause a condition called autoimmune lymphoproliferative syndrome (ALPS) in semi-dominant inheritance pattern, a pattern which is accounted for by the different effects of variants affecting different parts of the gene.

Before exploring conditions associated with a gene, the first step is simply to get one’s bearings by gathering some basic information on that gene: cytogenetic location, genomic coordinates, gene aliases, gene structure, gene size. This information can quickly be obtained using publicly available resources like OMIM, NCBI, HGNC, Ensembl, DECIPHER, etc. FAS, for instance, is located on the long arm of chromosome 10, has a number of aliases, and its primary functional transcript is 9 exons. Those 9 exons are roughly 3,700 nucleotides long, which translates to 335 amino acids.

This basic information gather extends to learning the basic function of the gene. The scientific literature is indispensable here, which can be accessed via PubMed or Google Scholar, as are the aforementioned resources, especially a guide to the often robust literature associated with a gene.

Continuing our example, my look into FAS found that the it encodes a transmembrane receptor protein that is a member of the TNF-receptor superfamily. Part of this FAS protein contains a “death domain” or, in other words, a consistent sequence of amino acids that is known to function as a recruitment module for a complex of other proteins that facilitate cell death, apoptosis. The complex includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic (self-chopping-up) of the caspase is what triggers cell death.

Further, it is worth taking a look at what can be learned from genomic resources like gnomAD, which hosted the results of population sequencing efforts on putatively healthy individuals. This is done to assess the frequency of disease-causing variants in human populations, an essential aspect of determining whether a variant is possibly disease-causing in the first place.6 From these resources, one can quickly gather how sensitive the gene is to variation, a concept called evolutionary constraint, and thus disease-causing variation in the gene may look like. For FAS, the population sequencing data show that it is at least somewhat constrained against variants that are predicted to result in loss-of-function (pLOF).

Now, it is finally time to proceed to look at associated conditions. This entails returning to some of the aforementioned online resources and looking at what conditions research scientists and medical laboratories have argued are associated with variants in the gene. One may find many assertions that a given gene is associated with a number of different conditions. If this is the case, this ends up triggering a deeper dive in the literature to assess if these asserted gene-disease relationships are valid and whether they have to be treated as separate or can all be lumped together.7 Fortunately, in the case of FAS, there is really just one associated condition, autoimmune lymphoproliferative syndrome (ALPS).

The obvious next step is to do some background reading on the association condition. There are many resources for this, including those already mentioned, but an additional resource worth recommending is GeneReviews. The GeneReviews page for ALPS is extremely useful for our purposes, covering all the clinical essentials. It defines ALPS as a condition of defective lymphocyte homeostasis characterized by non-malignant lymphoproliferation that improves with age, autoimmune disease, and elevated lifetime risk of lymphoma. The diagnostic workup should identify biomarkers like elevated levels of double-negative T cells, defective apopotosis as measured by in vitro assays, and elevated levels of soluble interleukin-10 (IL-10), Fas ligand (FasL), IL-18, and vitamin B12.

After review of GeneReviews, one should have some idea of the likely strength of gene-disease relationship. The next step is to dive into the deep pool of the clinical literature and to start assigning points to the variants found in reported cases based on the ClinGen guidelines/SOP. However, before engaging in the wonky details of curation a gene-disease relationship, it can be helpful to assemble a high-level summary of the clinical literature. This can be done by identifying critical papers using the GeneReviews references and confirming the details there. The quick summary I put together below for FAS makes it clear that there is substantial amount of clinical evidence associating FAS variation with ALPS and thus a good reason to suspect a causal relationship. Despite genetic heterogeneity in the condition, meaning mutations in other genes can recapitulate ALPS, and the reduced penetrance associated with some variants in FAS, the cellular and molecular features of ALPS are fairly specific and it appears that the disease mechanism can be elucidated from the gene to all the way to the clinical phenotype.

Next, comes the scoring of clinical evidence. This is most important part of establish gene-disease validity, bonafide instances where disease-causing variants in the gene of interest associate with the clinical condition of interest. There are several evidentiary threshold or criteria that have to be met in order for a variant to be scored as clinical evidence, which are there to reduce the risk that scoring passenger variants (false positives) or risk alleles as something that is causing disease. This processes involves identifying individuals who fulfill the clinical criteria for ALPS (referred to as probands) while also having germline variants in FAS that are sufficiently rare to cause disease and, if possible, have orthogonal evidence to support pathogenicity. The methods used to make the molecular diagnosis is also of interest as it indicates if other molecular causes of the condition have been ruled out among other things. If available, it should also be assessed whether a variant of interests co-segregates with the condition of interest in a family. These factors contribute to how the variant is scored with the ClinGen framework. There is a minimum of six variants scored at full points needed to reach a Strong classification on clinical evidence alone.8

In the case of FAS and ALPS, it was trivial to reach the maximum threshold for scoring clinical evidence despite other complexities with the gene. Below, I provide an example of the structure and scoring of evidence from a case report of FAS-ALPS (PMID:23524443), where a start-loss substitution variant observed in a six-year old female individual affected by ALPS is shown to disrupt FAS-mediate apoptosis and segregates with symptomology consistent with ALPS in 11 other family members who also carry the variant. Family member who do not carry the variant do not show ALPS-related symptomology.

After a comprehensive review of clinical evidence is performed, it is time to turn to functional evidence. There are many different kinds of possible functional data, but the gold standard is animal modeling. For FAS, there is a wealth of animal modeling. Part of this is due to a bit of a fluke of nature. There are two natural hypomorphic alleles affecting Fas in mice, one on the MRL strain (PMID:19110678) and another on the CBA/K1Jms strain (PMID:7930845). Both have been well-characterized and generally recapitulate human ALPS. Plus, a mouse engineered to have a complete Fas knockout presents as a several model of ALPS (PMID:8700897). This is significant functional evidence that supports the gene-disease validity of FAS-ALPS.

When the genetic/clinical and functional evidence are totaled for the FAS-ALSP gene-disease pair, the Strong classification is met and due to multiple replications over time, three decades in fact, the classification can be upgraded to definitive. This scoring is shown below on the gene-disease pair scoring rubric used by ClinGen.

It is also customary to draft a summary of the evidence supporting the classification of the relationship between the gene-disease pair. I have provided an example for FAS-ALPS below:

FAS was first reported in relation to autoimmune lymphoproliferative syndrome (ALPS) in 1995 (Fisher et al., PMID: 7540117). ALPS is caused by defective lymphocyte homeostasis, which is characterized by the following: 1) non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. 2) Autoimmune disease, mostly directed toward blood cells. 3) lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma.

Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found distinct but complementary molecular mechanisms, haploinsufficiency and dominant negativity, in a semidominant inheritance pattern with incomplete penetrance, where monoallelic cases consistently show less severe presentations compared to biallelic cases. Additionally, loss-of-function variants affecting the extracellular domain of FAS shown reduced penetrance (~30%), appearing to require a second somatic hit or loss-of-heterozygosity to cause clinical disease, while missense variants that disrupt the FAS-FADD interaction act in a dominant negative manner and show high penetrance (~80%). Therefore, a single disease entity has been curated autoimmune lymphoproliferative syndrome (OMIM: 601859).

More than 100 distinct variants (missense, nonsense, frameshift, splice site, and large deletions) have been reported in more than 200 probands in several publications (PMIDs: 21490157, 34171534, 7540117, 15459303, 9028321, 9821419, 23524443) are included in this curation. For example, Hauck et al., 2011 reports on a four generation kindred with 12 heterozygous carriers of a start loss variant (c.3G>T) that presents as ALPS in a daughter and father. The proband was shown to have a loss of heterozygosity in their double-negative T-cells (PMID: 23524443). The other heterozygous carriers are affected by milder, mostly sub-clinical phenotypes, though all show impaired apoptosis in cellular assays. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be both loss-of-function or dominant negativity depending on where the FAS variant falls in the gene.

This gene-disease relationship is also supported by robust animal modeling (PMID:1910678, 7930845, 7533326, 8700897). There is a natural partial knockout allele on the MRL murine background caused by a retrotransposon insertion in intron 2 which present as lymphadenopathy and splenomegaly when in a homozygous state (PMID: 1910678). Complete Fas KO mice have also been engineered and exhibit more severe and earlier symptoms than the natural models [PMID: 8700897].

In summary, there is definitive evidence supporting the relationship between FAS and semidominant autoimmune lymphoproliferative syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over three decades of research.

As is clear from the summary, there is additional information included to demonstrate the gene-disease validity that was not covered in the walk-thru I provided above. The notable difference is the attention paid to the pattern of inheritance, penetrance, and genotype-phenotype relationships concerning the type and location of variants in FAS. These complexity were glossed over along with some of the deeper mechanistic details that account for how loss-of-function or dominant negative variants in FAS drive ALPS pathology. These details are covered in a excellent review (PMID: 34171534), which I encourage readers to check out.

A Gene For…

And so, let’s give our picky philosophers of biology their due, FAS is not literally a gene for autoimmune lymphoproliferative syndrome. It is a segment of the genome that carries information for the cellular production of a specific transmembrane receptor. That transmembrane receptor participates in a cellular pathway that coordinates programmed cell death in response to extracellular cues. This, for reasons we won’t entirely get into, is especially important in the lifecycle of T cells early in our lives. This lifecycle is disrupted by changes to the normal sequence of FAS, whether that disruption works by decreasing expression of FAS or by interfering directly with its normal function, because the T cells cannot be culled, like they normally are, after they proliferate in response to immunological insults. Thus, these T cells accumulate, causing tissues that house T cells in the body to swell, and these zombie T cells can get up to no good, i.e. attacking other healthy cells in the body.

Alternatively, we should also understand the other side of the coin here. Instead of requiring the acknowledgement of all this complexity, which I’ve also simplified in many ways, in everyday language, we should accept that it is fine to claim that FAS is a gene for ALPS in particular contexts where such claims help people understand the causal relationship that is there.

6

Famously, the population frequency and phenotypic impact, especially with respect to traits that are related to health/fitness, are inversely coordinates.

For now we see through a glass, darkly; but then face to face: now I know in part; but then shall I know even as also I am known.

— 1 Corinthians 13:12 (King James Version)

[F]or the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill… as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs.

― George Eliot, Middlemarch

There’s a part of me that vainly yearns to be a witness to all of time. It’s an insatiable curiosity about what was, what’s happening now that I know nothing of, and what will come in the future when I’m gone. I have another tendency, to systematize. This desire and this tendency conspire. They induce me to author a story in my head about the events of the present— the story of now. I know I’m not alone in this. We need stories to make sense of the world and to work together with others.

The story I can tell about my small corner of the world is one I can tell vivdly. I’ve plotted it all out. Even when the unforeseen emerges, I can edit and revise with confidence. However, I have limited authority or ambition to author a story for the larger world, and though my own private assessment does include a growing sense of uncertainty, volatility, and suspense, I’m worried others are telling themselves similar stories but in an agitated register. Meanwhile, there’s an ever growing contingent of those who live as heroes (or even anti-heroes) in fantastical narratives erected upon clouds rather than upon earth, who insist we must also be part of their story. And whether because the stories of others may interfere with my own or because I can’t help myself, I gather these fragmentary threads so that I can weave an expanded tapestry of the many stories I contain.

And now to the quarterly update!

Reading Recap & Content Recommendations

Here’s are the totals for what I read or listened to in last three months:

• 16 total books across all formats (1 fiction titles, 15 nonfiction titles)

  • 4 ebooks

  • 12 audiobooks

  • Reading of primary research publications and other forms of commentary and journals as well as to children have been left untracked for this quarter.

Stetson’s Review of Books Read from Q3

I was able, as I aspire to, produce brief reviews for all of the books I read or listened to this past quarter:

1. Abominations: Selected Essays from a Career of Courting Self-Destruction by Lionel Shriver → Review at Goodreads

2. Power And Prediction: The Disruptive Economics of Artificial Intelligence

   by Ajay Agrawal, Joshua Gans, and Avi Goldfarb → Review at Goodreads

3. Elite Capture: How the Powerful Took Over Identity Politics (And Everything Else) by Olúfẹ́mi O. Táíwò → Review at Goodreads

4. When Everyone Knows That Everyone Knows...: Common Knowledge and the Mysteries of Money, Power, and Everyday Life by Steven Pinker → Review at Goodreads & Substack Piece

5. 1848: Year of Revolution by Mike Rapport → Review at Goodreads

6. Power, Sex, Suicide: Mitochondria and the Meaning of Life by Nick Lane → Review at Goodreads

7. The Origin of Language: How We Learned to Speak and Why by Madeleine Beekman → Review at Goodreads & Substack Piece

8. Transformer: The Deep Chemistry of Life and Death by Nick Lane → Review at Goodreads

9. Oxygen: The Molecule that Made the World by Nick Lane → Review at Goodreads

10. The Joy of X: A Guided Tour of Math, from One to Infinity by Steven H. Strogatz → Review at Goodreads

11. The Curse of Cash by Kenneth S. Rogoff → Review at Goodreads

12. The Case for American Power by → Review at Goodreads

13. Breakneck: China's Quest to Engineer the Future by Dan Wang → Review at Goodreads

14. Lions and Scavengers: The True Story of America (and Her Critics) by Ben Shapiro → Review at Goodreads

15. The Prime Minister (Palliser #5) by Anthony Trollope → Review at Goodreads

16. Kindred: Neanderthal Life, Love, Death and Art by Rebecca Wragg Sykes → Review at Goodreads

Stetson’s Book Recommendations

Although there were many amazing reads from this quarter, including a close look at the corpus of popular science writing from the biochemist Nick Lane, the book of the moment is definitely Dan Wang’s Breakneck. The great power rivalry between America and China is on the minds of many power players, public intellectuals, and armchair experts. We’re all a part of this story. Many are attempting to light a fire under America’s metaphorical bum so that it isn’t overwhelmed (in the Pacific) by China’s engineering and manufacturing capacity. I have many of my own thoughts, but they are held in reserve for now (or can to some extent be gleaned from my review of Wang’s book).

I also strongly recommend Steven Pinker’s latest book When Everyone Knows That Everyone Knows... to readers who want to take a detailed and somewhat technical look at how common knowledge can facilitate or preclude social coordination. There really are very few, if any, other titles this one out there. In addition, Pinker is one of our more talented public intellectuals.

I fell behind on fiction reading this quarter, only tackling a fairly lengthy Anthony Trollope novel in an audio format. It was I only picked up because of the illustrious recommendations it has picked up from figures like Robert Caro. Hopefully, I can introduce a bit more fiction this coming quarter.

Stetson’s Reading Recommendations from Substack for Q3

All the usual caveats once again apply! My recommendation isn’t a comprehensive endorsement. I’m purposefully highlighting recent written work on Substack that I found valuable or provocative or just plain ‘ole interesting. I could include many many more, but I did my best to keep the list limited in size. These pieces are not listed in any particular order.

• PhDs are easy by

• Building Better Scores For Embryo Screening by

• The Remnant by in

• Beneath the surface of the sum by

• Psychiatric Genetics Beyond Heritability: Q&A with &

• Litigation Nation, Engineering Empire by

• Bullets and Ballots: The Legacy of Charlie Kirk by

• An aesthete of controversy. Who was William F. Buckley? by

• How the West was wrought by

• The four fathers of Four Mothers by

• Conservative closet cases by

• Illiteracy is a policy choice by

• Education Doesn’t Work 3.0 by

• Did Romans Have Blue Eyes? by

• What We Find in the Sewers by

• Geography of Housing Costs by and

• The Bluesky-ization of the American left by

• If Self-Awareness Is a Phase Change, There Was an Eve by

• Unbundle the University by

• Agustín Fuentes’ Book ‘Sex is a Spectrum’ Fails to Refute the Binary by

• High fertility on the Faroe Islands by

• Building in the world of flesh needs regulatory transparency by

• A shorter, sharper Out-of-Africa story is emerging by

• Is hereditarianism wrong yet? by

• Getting closer to understanding mechanisms behind GWAS signals by

• Your Parents Aren’t Being Rude, They Just Don’t Remember Parenting by

• The Two Mearsheimers by

• Dating Men In The Bay Area hosted by Astral Codex Ten

Stetson’s Podcast Episode Recommendations

Same disclaimers as above but this time for podcasts. Also, my podcast recommendations stray a bit beyond the confines of the Substack ecosystem, though I still try to highlight Substack natives or those with an ethos consistent with the platform. I also have tried to keep this list shorter so as to encourage more reading than listening. The latter can’t quite compete when the content has high information density or visual/mathematical content.

• Barbarians at the Gate | Interview: Allen C. Guelzo at The Remnant with Jonah Goldberg

• John Hawks: varieties of humankind all mixed-up at

• Coffee, Cherry Pie, and the Nostalgia Trap with &

• Left Behind at with , , and

• Non-Zionism Returns with &

• Paying the Toll of the Infinite Scroll with &

• hosts Ezra Klein, Matt Yglesias, and Derek Thompson: what happened to Liberalism and who shot first?

• hosts Should We Encourage Our Daughters To Be Feminists? - Bryan Caplan vs Holly Lawford-Smith

• 100 years of insulin in 15 minutes with and

• Stephen Kotkin — How Stalin became the most powerful dictator in history with

Film & Television Recap

I wasn’t particularly ambitious about what I watched this past quarter. Nearing the end of her pregnancy, my wife was particularly averse to anything with intensely dark themes. So we stopped halfway through season two of “Yellowjackets” (Eww, cannibalism) and switched to “Desperate Housewives” (Yay, gossiping about neighbors).

We made it through two seasons and maybe halfway through the third season (somewhere in Orson Hodge’s Hitchcockian arc) and then our interest petered out a bit. By the time, the show had turned more than once to a character-in-a-coma plotline, we figured it may be time to bow out even discounting the plot histrionics that come with the soap opera package. I also watched the latest Steven Soderbergh film Black Bag.

Arguably, both “Desperate Housewives” and Black Bag are very interested in the psychological and logistical demands of marriage albeit the latter’s dynamic, a childless marriage between British spies, is obviously less immediately relatable. So I guess there’s an accidental theme to my watching. I can’t say I didn’t learn anything or didn’t find occasion to reflect upon the content.

I can also say that the DH creator Marc Cherry at least put together a somewhat sympathetic, though still too Freudian, portrayal of a Republican WASP, Bree Van de Kamp. Bree is evidently inspired by Cherry’s own mother as Andrew, Bree’s early primary antagonist, is evidently stand-in for himself and a manifestation of his own id.

Stetson’s Writing Recap

Given limitations on my time, and the ever growing population of Substackers producing writing worth reading, I’ve slowed my output. Nonetheless, I’ve aimed to make my contributions more substantial. Here’s a recap:

• Phonemes and Genes - I ask explores research that treats phonemes, the basic sound units of language, like genes and what this can and can’t teach us.

• Homo Largiloquus - I review the thesis of a recent pop-sci entry in the storied debate about the evolution of language.

• Solving the Problem of Uncertain Significance - I provide an accessible summary of one of the most important challenges facing medical genetics and how it may be resolved.

• Reading the Mind of the Mind Reader - I review the major claims presented by Steven Pinker concerning common knowledge in his latest book.

A New Addition to the Family!

This past week, my wife and I were blessed with our third child. He’s our first boy and is wonderful and healthy. His older sister are enchanted too.

Nevertheless, the similarities between genes and phonemes are so tantalizing to those who study evolution, they beg a comparison. In chapter 7 of her book, Beekman confidently asserts that genes and phonemes show the proverbial “Out-of-Africa” pattern:

Modern African languages are the most phonemically diverse. The smallest phonemic language diversity is found in South America and Oceania—some of the most recent areas to be colonized by our species. !Xun, a language spoken in southern Africa, has 141 phonemes. Rotokas, a language spoken in New Guinea, and Pirahã, a Sotuh American language, both have only 11 phonemes.

The assertion was striking to me as I was also aware of similar claims about cultural variation.3 Despite their plausibility and Beekman’s confidence, I felt compelled to follow-up on the claim, especially because there were not any immediate citations or footnotes in the book. Based on some Googling around and some assistance from the latest generative AI tools, I was able to identity the probable paper that served as the basis for Beekman’s claim, Q.D. Atkinson’s 2011 report in Science Magazine; the conclusion from the author of the report is quite clear:

[T]he number of phonemes used in a global sample of 504 languages is also clinal and fits a serial founder–effect model of expansion from an inferred origin in Africa. This result, which is not explained by more recent demographic history, local language diversity, or statistical non-independence within language families, points to parallel mechanisms shaping genetic and linguistic diversity and supports an African origin of modern human languages.

It does appear Beekman is correct in broad strokes. The diversity of sound units in a language appears to bear an important imprint from the rapid global dispersal of anatomically modern humans from Africa between 70-50 kya.4 However, there is a substantial difference in the magnitude of variation explained by the model between genes and phonemes. The Out-of-Africa (OOA) model accounts for 80-85% of the variation in neutral genetic markers in the genome but only 19%-30% of the variation phonemes in global languages.5 Why the difference?6

The Atkinson paper doesn’t immediately have a great explanation for why the serial founder model of the OOA dispersal is better for genes than phonemes. However, the author gestures at the similar levels of variation OOA explains in mitochondrial DNA (mtDNA) and some phenotypic measures.7 Due to the maternal transmission of mtDNA, this observation is intriguing given Beekman’s hypothesis that language evolved due to the intense pair-bonding and caretaking demands of parenthood, though it also suggests a significant modification to Beekman’s model: maybe it is just mothers and children creating the selection pressure and driving the social learning involved in language rather than the broader social group.

Although I’m not entirely sure how Beekman would respond to this modification of her theory, I do think she would be disinclined to embrace it. She makes some less than laudatory claims about the cultural effects of the nuclear family with respect to the sophistication of language and socialization:

Cultural evolution brought us the nuclear family. Most of the time, we see cultural evolution as a positive force, trumping biological evolution in the speed with which it can effect positive change. But the emergence of the nuclear family was far from an unalloyed good, and it has pushed us too far from our biological roots. Thanks to language, our species could raised more children by recruiting helpers. As modern parents become more isolated from their extend family, raising the next generation becomes an even bigger challenge. Many children in the Western world grow up without grandparents, either because they no longer live nearby or they died owing to the later age at which many women now become mothers. I had a fortunate childhood. Not only did I have my grandparents, but I also had my great-grandparents until I was well into my teens. They were of great help to my parents, emotionally and, when the need arose, financially. For me, they were repositories of knowledge, my emotional soundboards. They spoiled me, too, knowing well that my parents would have to deal with the consequences. Grandparents and other elders have played such roles throughout most of human history and prehistory.

Now, I personally don’t see an enormous distinction between the ideal of the Western nuclear family and significant alloparental contributions from grandparents or even great-grandparents. This looks like a distinction of degree rather than kind. It’s a narrow slice of the same genetic lineage, and this wouldn’t implicate the broader social processes that Beekman gestures to as important to the need for complex language in other parts of her book (i.e. a communal model of caring for the young).

I think Beekman’s concern with respect to language and general social sophistication and the historical increase in Western atomization, the partitioning into what Edmund Burke referred to as “little platoons,” is misplaced, emerging from more primitive Rousseauan moral instincts that don’t map constructively onto today’s W.E.I.RD. societies. Some of her concerns may also be informed by the same phoneme research, which identifies population size as an important determinant. However, Beekman presents no evidence that atomization in Western societies is affecting phoneme diversity. Heck, Beekman doesn’t bother to show that phoneme diversity has any relationship with the content or sophistication of what can be communicated. It is just implicitly assumed that more sound units equals greater and more refined communication. Is this actually true?

What is the Relationship between Phonemes and Linguistic Complexity?

It is often argued that the sophistication of human language is so great because of a design feature called “duality of patterning” or “double articulation,” which is just the idea that arbitrary, meaningless yet distinct sounds (phonemes) can be combined into meaningful units (words), which can be further arranged syntactically (sentences). Extending this further, it follows that the complexity of a language must arise due to some interaction among these three levels of variation. What’s the verdict on this?

Unsurprisingly, it is hotly debated. It is quite unclear if the phoneme inventories really have any relationship at all with linguistic complexity, especially in terms of what is actually being communicated rather than just having a lot of ways to potentially communicate the same things. There is perhaps some relationship between phoneme variation and syllabic complexity, but even here there are conflicting results. Here’s a quick summary of this debate excerpted from 2021 analysis:

Phoneme inventory size and its relationships with linguistic and nonlinguistic variables remains a matter of debate. The literature about cross-linguistic associations between phoneme inventory size and other linguistic components starts with a paper by Nettle (1995) who reports for a sample of 10 languages an inverse relationship between phoneme inventory size and the average length of a word. Nettle (1998) could repeat this finding for 12 West-African languages and Wichmann et al. (2011) for a sample of more than 3,000 languages averaged over families and macro-areas. Moran and Blasi (2014) likewise replicated a negative correlation between number of segments and word length and demonstrated, moreover, that this inverse relationship shows particularly with the number of vowels. As to syllable complexity measured as number of phonemes Maddieson (2006), Fenk-Oczlon and Fenk (2008) and Easterday (2019) report a positive correlation between inventory size and syllable complexity. Concerning the relationship between phoneme inventory size and the nonlinguistic variable population size, the finding of Hay and Bauer (2007) that languages with more speakers tend to have larger phoneme inventories attracted a lot of interest and has been the subject of extensive debate. Atkinson (2011) and Wichmann et al. (2011) could replicate Hay and Bauer's finding, but Donohue and Nichols (2011) and Moran et al. (2012) could not find such a correlation.

As already hinted above, the whole question of phoneme variation, while engrossing, may be entirely divorced from what can actually be communicated with language. There may be some lower bound of required phonemes needed for a full slate of human communication, but it would likely be irrelevant to actually understanding the linguistic complexity of present day languages or those of human prehistory.8

For those familiar with Chomsky’s work on universal grammar, they are likely jumping up and down while reading this, frantically yelling “RECURSION.” They’re right to draw attention to this design feature in human grammar — something that can refer to itself or embed an existing relationship can do so ad infinitum. Language’s recursive nature makes it trivial to generate an infinite number of distinct sentences from even just a small number of words.9

Now, recursion itself doesn’t necessarily mean all ideas can easily be communicated from a limited set of phonemes, but it also seems trivial to see the route to linguistic innovation without even needing more phonemes given the aforementioned duality of patterning. As anyone with young children knows, they’re wont to combine the sounds they already know into all kinds of nonsense words or even invent private neologisms. Thus, returning to the global pattern of average phone diversity, the more pressing question concerns the actual conditions that increased phoneme diversity in the first place? And why did the phoneme diversity expand so much seemingly just prior to modern human dispersal from Africa? Were there any actual consequences when phoneme inventories reduced during the dispersal? Unfortunately, it is unlikely that we’ll ever be able to confidently answer any of these questions.

Do Phonemes Actually Behave Like Genes?

Despite some of the similarities between genes and phonemes, I think the short answer is no. The differentiating factors are how and why phonemes and genes change over time. There are biochemical and other biological factors that govern the stochastic process of genomic variation, which also accumulates over time. While it’s a bit unclear where phoneme actually emerge from, they change because of social, demographic, and technological processes (contact, prestige, isolation, literacy, etc) rather than random processes. Moreover, these social processes can be non-linear, reversible and rapid. While not impossible in biological evolution, the fidelity and mutability of the phoneme is much lower over generational time than the information content in genomes. These fundamental differences mean that the “molecular clock” model is reliable for genes and unreliable for phonemes.10

There is a nice empirical demonstration of the divergence of genes and phonemes in a 2015 study published in PNAS. It partially recapitulate, though questions, the findings from Atkinson’s 2011 papers, but shows that genetic and phonemic diversity do not universally track:

Global genetic and phonemic patterns were not universally concordant: the most genetically polymorphic populations [top fifth percentile for number of microsatellite alleles observed] are all in Africa, whereas the largest phoneme inventories in the Ruhlen database (top 5% of 2,082 languages, corresponding to at least 43 phonemes) (SI Appendix, Table S4) were globally distributed, predominantly in Africa (41 languages), Asia (32 languages), and North America (18 languages).

Further, the paper shows that in contrasts to the genetic repertoires of isolated population, the phonemic inventories of isolated populations tend to vary substantially:

[A]lthough geographically isolated populations lose genetic diversity via genetic drift, phonemes are not subject to drift in the same way: within a given geographic radius, languages that are relatively isolated exhibit more variance in number of phonemes than languages with many neighbors.

The authors of the 2015 paper assert their findings contradict the serial founder OOA model, suggesting some other mechanism must account for the low resolution trend in global phonemic inventories. However, these studies appear to be very sensitive to which languages are getting included in the analyses and other methodological differences. The conflicting data and models underscore the fact that map between genes and phenotypes, especially higher order phenotypes, is non-linear. The use of crude measures like assessing the total amount of average variation and its regional patterns doesn’t necessarily really tell us much unless we have an existing, established genotype-phenotype map.11

After diving into this literature thanks to an somewhat offhanded claim from Beekman, I’m left disappointed. Borrowing assumptions and methods from population genetics to study the prehistory of language is fraught. It would be lovely if we could entirely rely on these genetic models to pinpoint when language originated, how it dispersed, and how it changed over time. However, I think we should be wary of this. Nonetheless, my prior remains that human language did emerge in Africa prior to the OOA dispersal of modern humans, but unlike Beekman, I also think that archaic humans already outside of Africa’s border also possessed human language, though it was unlikely to be complex. Further, I think following the regional patterns of phonemic variation is misleading and is unlikely to tell us a great deal about the linguistic and cultural sophistication of human populations in prehistory. It may be more reliable to use the archaeological record, though this has other limitations. The best measure may just be using estimates of population sizes (to whatever limited extent we can accurately predict these) at certain time and places as a proxy for cultural complexity. Regardless of the challenges, I hope to see more interesting and daring work on questions about our deep history.

See Additional Commentary from Me on Phonemes and Genes:

The stakes of this debate are understood as quite high as the status of language cuts to the core of metaphysical understandings of mankind. Are we special or merely another mean and small species in the vast but doomed kingdom of Animalia?

I’ve always flippantly looked past this question, viewing it as a false dichotomy perpetuated by a lobby of insecure proponents of faith and a lobby of reactively juvenile atheists — the latter often comprising a meaningful segment of departments of anthropology and evolutionary sciences at universities and thus, perhaps, deserving a larger share of the blame. However, language, as in a generalized system that allows for the infinite recombination, according to a set of rules (syntax), of a finite number of symbols (words), does clearly appear to be a capacity unique to the human lineage (wherever we want to place the origin point exactly, whether 2 million or 60 thousand years ago).

Given my interests in evolution, my inveterate curiosity, and the high stakes of the language debate, I decided to dip a toe into these waters. Conveniently, I noticed a new release on the very subject: The Origin of Language: How We Learned to Speak and Why by Madeleine Beekman. So I picked up a copy, figuring that it would at least provide one explanation of the origin of language and, in doing so, likely shed some light on alternative theories.4

Just-So Stories Can Be Feminist Too

Although I can’t claim that there is a bonafide trend, I’ve increasingly noticed a growing interest in revising our understanding of the role women in human evolution. The push here is to move beyond female mate choice (sexual selection) to other behaviors like pair-bonding, parenting, caretaking, and cooperation (sometimes called social selection).5 Concurrently, the same tendency aims to degrade received narratives about selection on traits associated with dominance or competence which themselves are traditionally associated with maleness or understood to have been performed by men at a greater frequency: hunting, fighting, tool-making, provisioning, etc. Some recent examples include Father Time by Sarah Hrdy, Eve by Cat Bohannon, The Social Instinct by Nichola Raihani. There are even reactionary examples like Selective Breeding and the Birth of Philosophy by Costin Alamariu.6 I would also be remiss not to mention psychometrician and Substacker and his Eve Theory of Consciousness here. His explanatory model of consciousness is meant to account for the Sapient Paradox and argues that consciousness was an adaptation that occurred in women first and was something they transferred to men.7

If I’m to do a bit of mind-reading, the recent revisionism in evolutionary theories is often partially motivated by a need to reconcile commitments to egalitarian feminism with scientifically demonstrated differences between the sexes. This reconciliation project is seen as increasingly salient given the social gravity of bro-forward podcasts and the manosphere. Personally, I don’t share these concerns. I think only a misplaced insecurity about the persuasiveness of the naturalistic fallacy, i.e. the conflation of what is natural with what is good or better., sustains concerns about the social consequences of the popularization of sociobiological or evo-psych theories. But I recognize the power of story (being a reluctant yet passionate Yuval Noah Harari stan after-all) so I’m very willing to hear the evo-feminists out.8

Beekman Blames Language on Parenting Demands

Madeleine Beekman enters the storied yet ignominious debate on the evolution of language by arguing that the intensive nature of caregiving for the young created a selection gradient for complex language. The nature of this selection was mostly “tinkering” as it occurred after a handful of high impact genetic changes differentiated us morphologically from our common ancestor with chimps and created the conditions for runaway brain growth (We’ll circle back to these changes later in my review, but, in the meantime, see my review of Max Bennett’s A Brief History of Intelligence for a long-run view of brain evolution, including the tripling of brain volumes in roughly 2.5mya in our lineage).

More controversially, she contends that complex language ability occurred only in our lineage, excluding our archaic brethren, and happened fairly recently, specifically within the last 100kya. Most scholars of human evolution would place the emergence of complex language between 150-200kya and acknowledge that it is highly likely that Neanderthals had comparable though probably somewhat less sophisticated language ability. It is usually a pretty wise move to bet on longer timelines than whatever is currently proposed today. As our ability to sample the archaeological record continuously improves, many of the timelines of human evolution have been moved back and the picture grows ever more complex (see ’s “The longer I live, the wronger I get to be”).

Given the compressed timeline and the Sapiens-specificity to her model, some readers may expect that Beekman forwards a strongly innate theory of language. However, she’s more in the safer gene-culture co-evolution camp though. For Beekman, language is only partially innate with a substantially acquired component. Her position splits the difference between two historical giants in the cognitive sciences: Noam Chomsky and B. F. Skinner. Chomsky famously argued that language arises from the activation of an innate capacity (the Language Acquisition Device or LAD) and that language has a natural and universal grammar. Contrastingly, Skinner argued that language is a special type of conditioned behavior. In other words, children learn the meaning of arbitrary symbols by association and then are rewarded for manipulating these arbitrary symbols properly, i.e. when the manipulation facilitates effective communication. Beekman basically combines these positions, metaphorically arguing that language is a virus and the brains of children are a very susceptible and hospitable hosts. The metaphor doesn’t exactly account for why adult brains would be less susceptible and hospitable, but she just assert this as true. She has no way around this fact; it’s blatantly the case that language acquisition is superior in childhood.

There is some unexplained dissonance in Beekman’s position on the importance of children and language with respect to her viral metaphor. This becomes quite apparent when she mentions how children help stabilize pidgin languages as creole languages. Pidgins are simplified languages invented impromptu by adults who need to find ways to communicate across different language backgrounds. Pidgins mature into creoles across generational time as children are brought up by the pioneers of the pidgin language. Beekman jumps at this example as showing that childrearing is important for developing sophisticated language, but she overlooks how pidgins are independently devised by adults. Pidgins very much look like a point in Skinner’s column, though it is unclear how much this extrapolation is relevant to the ancestral environment in which language actually arose. It also doesn’t negate the clear receptivity of the developing brain to language acquisition. If anything, I see this as evidence toward the necessity of a robust proto-language substrate emerging in ancestral species in our lineage. I guess one could argue this substrate was only gestures rather than syntactically organized groups of phonemes, but come on, this strains credulity, right? Nonetheless, Beekman is leaving some ideas on the cutting room floor, dedicating really just part of the sixth chapter of her book to this crucial argument. She simply doesn’t fully examine the ways in which the phenomenon of pidgin languages complements and complicates her thesis about parenting and language.9

Even though there are some out-there aspects to Beekman’s thesis — namely consigning our archaic cousins to inarticulateness and her often hand-wavy account of the evolution related to language, which again I’ll get to in more detail soon — her model is still arguably mainstream. It accounts for language without adding special epicycles in to existing accounts of human origins, requires just a few big shifts in phenotype early in our evolutionary trajectory, and doesn’t make human seem too special (i.e. all the special sauce is classed as little tweaks to primate biology that were refined and scaled by culture). On this last point, Beekman reveals herself as one of the somewhat sophomoric and misanthropic members of her discipline, making periodic asides about the ecological destruction wrought by humans. Looking past this gauche self-loathing, here’s her conclusion to the pivotal chapter on language:

Neither [Alfred Russel] Wallace nor Chomsky could see how a little bit of language would give us a leg up in evolution. But I have argued that our childcare problem was incentive enough to keep climbing. Our tiny babies are in need of extraordinary levels of help. They compete with siblings and others for attention and for resources. Being slightly better at vocalizing your needs than the others may just be enough to put you ahead of your competitors. Mothers, too, would benefit from being just that little bit better at enticing others to help with raising children. With every improved fragment of speech, and every moment of shared understanding, we raised the likelihood our babies— and our species—would survive. Yes, human language makes us fundamentally different from other apes and animals. But all the innovation required for abstract, compositional language can be explained by natural selection. What makes us special simultaneously confirms that we’re part of the natural order.

But What About the Social Brain Hypothesis?

My primary gripe about Beekman’s theory as presented is that she puts very little effort into its core, answering questions like why, how, and when language evolved in mostly an oblique fashion. Why questions are of pre-eminent importance in popular evolutionary narratives. The why holds the story together. So that is why it is strange that Beekman spends almost no time exploring the intensive nature of caring for our young in a comparative way. It is uncontroversial that caring for young among humans is more intensive than it is for chimpanzees, but this still leaves 7 million years of evolution in parenting demands in which the emergence of language could fall either before or after these demands ratchet up. The empirical record is perhaps too thin. Our view of deep history obscured. However, this is no excuse for Beekman just punting on this core issue.

There are also a number of competing explanations for the evolution of intelligence and language alongside parenting demand. The one I find persuasive is the social brain hypothesis (sometimes modified into the cultural brain hypothesis). The basic thrust of the SBH is that brain size is a function of group size in social species. In other words, the demands of the social niche are the selection pressure that mostly drive brain growth. Additionally, this model is dependent on the “high transmission fidelity” of social learning and predicts that species along this trajectory experience a treadmilling where the importance of social learning increases the importance of transmission fidelity to maintaining adaptive gains. Subsequently, the emergence of language as a product of gene-culture co-evolution falls right out of the SBH/CBH.

One would think then that Beekman would resonate with the SBH/CBH, but instead she dismisses it based on her interpretation a single study in birds. The study found that among ~1000 species of birds the amount of energy invested in the young is a strong predictor of brain size. Even though this seems like it could be perfectly compatible with SBH/CBH, she argues that the correlation explained by the SBH/CBH has the causal arrow backwards between brain-size and sociality. She thinks “big-brained species are social because they can be.” I can’t explain how outrageous this claim is, especially coming from a behavioral ecologist who studies Hymenoptera. Eusociality is a species-level adaptation that independently emerges over and over again in evolution, given that its found in insects, crustaceans, trematoda, and mammals. Perhaps Beekman is using the word “social” in a very specific way here and perhaps the “big-brained” comment is meant only to apply to larger fauna or within taxonomic orders, but whatever she is thinking here looks wildly incorrect. It’s much more plausible to believe that the conditions of sociality in our lineage created selective pressures for larger brains or at the very least preceded them rather than our larger brains inducing us to become more social. This doesn’t exclude parenting from being an important part of our social niche; it obviously is. However, the broader view also means that other social behaviors and organizational structures, such as competing for mates, hunting, tool-making, gossip, social loafing, female-female hierarchies, and male-male hierarchies, could also have played important roles in the selection for bigger brains and better communication.

I don’t want to obliterate Beekman’s theory. I think it has some merit. The helplessness of our young is an important dimension of human sociality, and it created pressures that likely played an important role in the evolution of our modern phenotype. Nonetheless, it is one among many important social behaviors. It would also be an evolutionary process that sidelines men a bit, making them somewhat superfluous to the emergence of language. Their participation in the process would be limited to their childhoods and the extent of their participation in childcare, which there is reason to believe our lineage didn’t see men taking on a great deal of fatherly duties until recent times. However, the evolution of fatherhood, whether it is actually a biological or cultural adaptation or a mixture is up for debate (it’s a subject I’ve addressed before — see my review of Sarah Hrdy’s Father Time).10 So does is helplessness of our young the x-factor that explains the emergence of language in humans? My guess is no.

Were a Few Lucky Tweaks All It Took to Become Human?

Now, it’s time to circle back to some of the actual evolved biology at play here. An important part of Beekman’s theory concerns the constraints and capacities that preceding adaptations in our lineage, such as bipedalism and increasing brain volumes, contributed to the evolution trajectory in a way that fostered human language. In this way, Beekman’s book ends up mostly being a recapitulation of important milestones in human evolution, foregrounding the alleged handful of major genetic events that are responsible for these obvious adaptations. The whole story is of course just that, a frequently speculative narrative, but some portions of Beekman’s tale are taller than others.

This isn’t to label The Origin of Language as wholly unscientific or even to claim that its chock full of misleading claims (though any ambitious book of popular science will inevitably whither some under a fastidious fact-checking). It is just to call attention to the epistemic hurdles that evolutionary sciences confronts. Studying evolution, especially human evolution, is mostly retrospective. We can’t recapitulate ancestral conditions with an ancestral model hominid and see if the adaptation in question re-emerges. It is difficult to even come up with a good proximal model to study these questions. This places limits on what can be confidently known, but, more importantly, it makes precise and rigorous communication about evolutionary science to a public audience fraught. Beekman shirks this burden some and makes confident yet unjustifiable assertions sometimes. I think this is defensible in popular science so long as there is some deference paid to epistemic humility somewhere, and the author prudentially avoids sniping at scholarly rivals or competing theories. Beekman doesn’t hew closely enough to my standard. She dismisses and criticizes a lot of alternative theories (e.g. the social/cultural brain hypothesis) flippantly, while also providing close readers little evidentiary basis to be invested in the greater plausibility of her theory. Beekman would have made her book more valuable if she had considered alternative models with greater consideration.

Now, I think it is worth walking through the evolved biology because the fact that major adaptations occurred in our lineage is inescapable and begs for explanation. Relative to other primates, our nakedness, endurance, dexterity, cooperation, and intelligence have to be accounted. Insofar as popular science on human evolution is telling just-so stories, the factual bounds of these stories are highlighted in neon. Solipsistically, any narrative of how-we-came-to-be is inherently exhilarating to a curious mind. We can’t help but indulge.

As a geneticist, I found Beekman’s evolutionary account thorough in that it often married specific genomic changes to specific adaptive milestones— usually these narratives recap adaptations and speculate about the selection pressure and population dynamics that brought them forth. However, I was also surprised by the simplicity of the molecular details. In the introduction to the book, she plainly asserts, “Our descent from other apes in the last few million years or so boils down to a mere handful of genetic and morphological turning points.” Discounting the fact that the work is one of popular science where simplifications and generalization are necessary, I was still made apprehensive by this claim, especially because it was ironically accompanied by several skeptical and sometimes sardonic expressions about claims from the fields of behavioral genetics and sociogenomics, i.e. fields that allege that genetic variation can account for meaningful differences in the variation in social and behavioral phenotypes in human populations. If relatively small genetic changes can explain the phenotypic differences between other primates and humans, then it should be trivial to believe that other variation in genes account for a smaller degree of intraspecies variation in behavioral phenotypes. There is perhaps a way to reconcile these beliefs by somehow differentiating among the types of genotypic variation and their phenotypic impact, but logically there’s a contradiction to believe in one of these claims but not the other.11

Contrastingly, a different story was told by David Reich in his 2018 book Who We Are and How We Got Here. In a section titled “The Siren Call of the Genetic Switch,” Reich recounts the rise and fall of Richard Klein’s theory of a rapid transition into behavioral modernity circa 50,000 years ago and highlights the rare example of recent and purportedly high impact evolution in the FOXP2 locus with respect to human language ability. Reich concludes the section humbly (emphasis mine):

The sad truth is that it is possible to count on the fingers of two hands the examples like FOXP2 of mutations that increased in frequency in human ancestors under the pressure of natural selection and whose functions we partly understand. In each of these cases, the insights only came from years of hand-to-hand combat with life’s secrets by graduate students or postdoctoral scientists making engineered mice or fish, suggesting that it will take an evolutionary Manhattan Project to understand the function of each mutation that we have and that Neanderthals do not. This Manhattan Project of human evolutionary biology is one to which we as a species should commit ourselves. But even when it is carried out, I expect that the findings will be so complicated—with so many individual genetic changes contributing to what makes humans distinctive—that few people will find the answer comprehensible. While the scientific question is profoundly important, I expect that no intellectually elegant and emotionally satisfying molecular explanation for behavioral modernity will ever be found.

Beekman, a behavioral ecologist whose primary model organism appears to be Hymenoptera (especially honey-bees), alternatively forwards a handful of major genetic events that have differentiated the human lineage from the nearest extant primate lineage (Pan) after divergence from a common ancestor around seven million years ago. This is, of course, distinct from differentiating humans and Neanderthals, which is a subtler venture. Debatably, the Reich and Beekman positions can be reconciled. However, Reich was speaking to a very similar question, especially because many consider Neanderthals and other archaic humans to be members of our species and thus quite comparable on human-specific traits, including symbolic and recursive thought. So the question becomes about what molecular changes account for the suite of phenotypes, mostly cognitive and social abilities, that are considered specially or saliently human.

Here’s a summary of the evolved biology in that forged modern humans according to Beekman:

• Exquisite Developmental Timing - Wind the clock differently and the whole world changes.

  • Ontogeny doesn’t recapitulates phylogeny, but nature can repurpose and iterate on inherited developmental programs thanks to the cumulative nature of evolution. One of the ways this is done is by subtle tweaking of the timing of developmental processes. These programs are typically signaling pathways linked gene regulatory programs linked to cascades of gene expression, which in turn feedback into the same or different signaling pathways. Beekman doesn’t exactly finger a major specific change that was essential to humans, but she selects a number of flashy examples12 and summarizes some fundamental findings in developmental biology so the reader can fill the picture in themselves. The takeaway from the picture she paints — mostly with respect to Sonic Hedgehog (SHH), Hox genes, the Notch pathway, and bHLH transcription factor 7— is that small modifications to regulatory elements in the genome, which turn genes on and off at different times, facilitated large changes to the overall developmental program, impacting phenotypes in dramatic ways too.13

• From 24 to 23 — Losing a chromosome to become human.

  • Beekman points out that our chromosome 2 resulted from a “head-to-head fusion of two ancestral chromosomes that remained separate in chimpanzees and gorillas and in all other primates.” This fusion creates issues during meiosis in the hybrids who inevitably form both 24-chromosome gamete and 23-chromosome gamete. Subsequently, Beekman presents two explanations for how evolution may have skirted around the reproductive barrier created by lower hybrid fertility: 1) A subpopulation of individuals with 23-chromosome gametes (the fusion event would have had to happen many times), and these individuals paired off only or largely with each other. Eventually, this matching would entirely isolate the population making only 23-chromosome gametes from the population making 24-chromosome gametes. 2) A small, spatially isolated population led by an alpha-male with the fusion event founded our lineage. The latter possibility seems more likely to me. Both scenarios in part explain the reduced levels of genetic diversity in the human population compared to chimp populations.

  • The fusion event certainly happened in some way — that’s not in question. Compared to other types of genetic changes, a fusion event is monumental and immediately creates a potential reproductive barrier that requires a solution if a lineage is to survive. Thus, it likely played a crucial role in differentiating our species from the lineage that led to chimps, though it is ambiguous what it meant phenotypically. Beekman doesn’t speculate on the total phenotypic consequences of the fusion, somewhat implying that there were unlikely to be many beyond the impact on fertility. For more on the fusion resulting in chromosome 2 check out ’ piece: “When did human chromosome 2 fuse?”

• An Inversion of Part of the Long Arm of Chromosome 1 - Turn the genes around and speed up evolution.

  • In molecular evolution, a chromosomal inversion, or when part of a chromosome breaks off, flips around, and reconnects, is known for dampening recombination, which in turn creates "gene nurseries" or regions where genes are marooned and destined to accumulate variation over time.

  • Beekman claims that after the human and chimp lineages split, an inversion event occurred on part of chromosome 1 and that this was responsible for an important part of the increase in brain growth in our lineage. Beekman points out that the inversion revived a pesudogene called NOTCH2NL, itself the result of a botched duplication of NOTCH2. NOTCH2NL then experienced two more duplications and became involved in regulating NOTCH2, an important gene developmentally that also happens to regulate the rate of maturation in the cells that become neurons (radial glia). This NOTCH2NL triplet is critical to large cranial volumes evidenced by the relationship between copy number variation and head circumferences— a loss of one of the three copies results in microcephaly, while a gain of a single copy results in macrocephaly.

• Aquaporin Gene Duplication - Always need to keep one’s cool.

  • Most people are familiar with the claim that only humans sweat. Though it is a bit misleading, the truth is that human thermoregulatory adaptation is amazingly efficient. It keeps our metabolically demanding brains from overheating. Beekmen argues that the multiple duplications of the Aquaporin 7 or AQP7 gene are responsible for our prolific ability to perspire. She points out that this is likely a pretty old adaptation likely present in Homo erectus (2.5 mya - 1.1 kya).

• Skull Shape is Everything - Phrenology but do it right this time.

  • Beekman recounts how research performed on skulls derived from an ossuary in Hallstatt, Austria has shown that the face, cranial base, and cranial vault are an integrated structure and thus selection pressure likely works on all three at once. She then argues that changes in the angle of cranial flexion occurred as bipedalism emerged which in turn created an opportunity for the cranial vault to swell (our now bulbous heads) which in turn flattened our faces. Our face of course are an essential social interface.

  • Beekman argues that no novel genes were needed to facilitate the changes to the skull. These seemingly massive differences could be accomplished by some molecular fine-tuning.

  • She also tacks on the fact that Neanderthals likely did not go through quite the same modifications as they exhibit less cranial flexion, suggested the packing of similarly sized brains was less efficient than ours. Our faces are also shorter, making room for a descending larynx.

• Dying to Speak - The descent of the larynx.

  • Evolutionary biologists love bringing up the tradeoff between molding sounds and choking created by the location of the larynx in humans. Beekman is not different on this front. Though she has little to say about the molecular changes that enabled the descent of the larynx and tongue, lamenting that soft tissue doesn’t fossilize and as such it becomes a harder question to tackle. Instead she turns to methylome data, arguing there isn’t much genetically that distinguishes us and archaic human (Neanderthals and Denisovans), which imperils her claims about the unique possession of complex language in Sapiens. So it must be epigenetics in her view. To this end, she cites a 2020 study by David Gokhman and colleagues that found that ~900 regions of differential methylation distinguish Sapiens from archaic humans and that may of the affected regions implicated the soft tissue involved in speech.14 Why based on these data alone, does Beekman think archaic and modern human couldn’t speak to each other despite many instances of interbreeding?15 It is unclear.

    

  

There are a number of morphological and behavioral adaptations that Beekman identifies as crucial in the trajectory to becoming human and being able to speak that she avoids providing much molecular insight on, namely bipedalism and neoteny (“underbaked babies” as a solution to the obstetrical dilemma created by narrow pelvises). Arguably, she would explain these along the lines of “small changes, big effects,” gesturing toward the gene-regulatory-tweaks-in-development story she sets up early in the book. She also generally gestures toward a gene-culture co-evolution story to explain human or human-like behavioral adaptations like cooking or other forms of social cooperation. This is pretty standard evolutionary fare.

Despite some of the clear flaws, such as the paradox concerning genotypic change and phenotypic effect, I think this is a decent recapitulation of human origins. More of the pop-sci books on evolution should address themselves to the evidence in the molecular record even when it is fraught. Some of the limitations here aren’t Beekman’s fault either. There simply aren’t clear answers yet. As the passage from David Reich’s book highlights, the real story behind what makes us who we are is probably unsatisfyingly complicated. It is too piecemeal and incremental to be understood by any one person. Additionally, it would behoove the field of genetics to have a systematic way of distinguishing between “small” and “big” genetic change, specifically with respect to how a trait under prodigious genetic control is constructed. It would mean mapping all of the genotype-to-phenotype possibility space and understanding how to traverse its various dimensions. Unfortunately, mechanistically elucidating the genetic architecture of all human traits anytime soon feels far-fetched. As Reich said, it is a Manhattan-Project-level venture, and, at this moment, there is little urgency to make it happen.

Mixed Recommendation

It is hard to give an unqualified recommendation to The Origin of Language. It is a bit of a mixed bag. Different readers will get different mileage. It contains tantalizing tidbits on the molecular genetics of human evolution and cross-species comparisons of social behavior, but they’re wrapped in a half-baked theory in a domain that already teeming with such offerings. It is especially thin when it comes to thinking about language itself. Plus, it is served alongside a perspective that some readers may find indigestible. Despite the limitations, it is still competent as a primer on the human origins, especially insofar as various adaptations were relevant to the development of language. Alas, language remains a mystery.

Imagine a young woman who has recently undergone genetic testing after her father’s sudden cardiac death in his forties. This young woman is obviously first hoping for her genetic risk for sudden cardiac death to be assessed at near zero, but second she is hoping for clarity about her future health — a definitive yes or no and/or a high-confidence, quantitative estimate that describes her individual risk along with a plan of action to manage that risk. Instead, she is likely to be presented with set of opaque and confusing results: a variant of unknown significance, abbreviated VUS. Various medical professionals, including genetics professionals, may be able to provide some additional context or clear up some confusion for her, but, after the visit, this young woman is still left in limbo. Did this DNA variant kill her father? Will this DNA variant kill here and, if so, when? Can she even do anything about this?

This predicament is all too common, and it stems from a fundamental tension at the heart of our genomic age. The (haploid) human genome contains roughly three billion base pairs of DNA, and every individual harbors millions of genetic variants. Most are harmless, some are well-understood, but an enormous fraction reside in a gray zone. These so-called variants of unknown significance (VUS) call attention to the chasm between our technological capability to detect genetic variation and our ability to understand the biological importance of it.

When a VUS inevitably finds its way into a patient’s lab results1, what are reporting laboratories to do? How should this information be communicated to patients? Suffice to say, even the professionals come to different conclusions on various facets of VUS-related reporting questions. Whether to report or not is a longstanding debate in clinical genetics. I will spare readers the details here (though I can return to it another time if there is interest). Personally, I like to err on the side of transparency, but I recognize that more information is often only beneficial to those who possess the faculties for processing it.2 So instead of a digression on the ethical and epistemic quandaries in genetics, let’s re-direct to some of the emerging strategies for solving the problem altogether.

Scales Falling from Genomic Eyes

When a VUS is identified, it means that a coding difference, typically a missense variant (meaning a DNA substitution that causes one amino acid to be substituted for another) in a protein-coding gene, has been detected by a specific type of assay that reads the DNA sequence, but despite the best efforts of genetics professionals to evaluate the effect of that coding difference, there simply isn't enough evidence to make a confident call (see the visual for the evidence thresholds below). The usual reason for this is simply a lack of information. Any given VUS may be incredibly rare and therefore has never been observed before. Hard to say anything about a complete unknown. Alternatively, it may have been observed in a few individual during the DNA sequencing of a large population, but there isn’t a literature on the effects of that variant. Or, the most frustrating of all, there may be conflicting reports on the variant — some providing evidence that it is disease-causing (pathogenic) while others providing evidence it is not disease-causing (benign).3

All of the above VUS scenarios can usually be resolved with more data. For instance, if more evidence emerges from classical family studies showing the variant of interest associates with a disease phenotype of interest in a patient and segregates with that disease in the patient’s family, then this evidence would likely push the classification from VUS to pathogenic. Evidence of this kind is unlikely to be available for a given variant, especially when the variant is itself rare. Subsequently, we have to rely on prediction tools or functional studies. I won’t describe all the in silico predictors out there; there are a lot! Although the predictors are improving, including with some help from developments in the field of artificial intelligence, they are still not reliable enough for use to solely rely on them to make diagnostic classifications. This leaves functional evidence as the last reserve of the clinical geneticists.

Functional evidence is unfortunately expensive and sometimes arduous to collect and publish. It isn’t full-proof as a final arbiter of deleteriousness either.4 However, methodological advancements have recently enabled researchers to collect functional data on a massive amount of gene variants simultaneously. This experimental approach is referred to as a multiplexed assay of variant effect (MAVE) or sometimes as deep mutational scanning (DMS). Simply, these assays try to generate every possible missense variant in a gene, introduce them into a functional assay, and then efficiently measure and visualize the impact of these variants.

One of the exciting things about MAVEs is that they can leverage some of the same technology that has powered our genomic era, next-generation sequencing (NGS), making generating functional data more efficient and inexpensive (the cost of NGS has fallen at a rapid pace).5 The data has already begun to accumulate since the first low-throughput MAVEs were carried out in the late 2000s. Currently, the database of record for MAVE data (MaveDB) includes ~2,000 datasets comprising ~7 million variant effect measurements. Additionally, these data already inform VUS re-classification efforts. Across twelve previously published studies, a total 937 of 1,711 (55%) VUS classifications have been reclassified due to MAVE-derived findings (summarized in the figure below).

The prospects for MAVE work informing variant classification are bright as not only is the functional data itself immediately informative, but the data can be used to refine the output of in silico predictors of pathogenicity as well as serve as input for the training of new and better predictors. Given the low-cost of generating predictions, the quickest path from MAVE work to ending the VUS problem may be mediate by improving prediction tools.

An immediate solution for the VUS problem is not on the horizon, but at least we can see some of the vague outlines of a solution. While we wait, there will be minor tweaks and short-term patches that will hopefully provide some remedy. This will likely include the risk tiering of VUS, where high-risk VUSes will be reported while low and intermediate risk VUSes will be withheld from reports. This re-opens the reporting debate I alluded to earlier, but it likely represents some improvement over throwing the overwhelming majority of observed variant during genetic testing in the gray zone. Let’s have the debate and take action fast!

I hope clinical genetics is able to reach the National Human Genome Research Institute’s optimistic goal of solving the VUS problem by 2030. Regardless, we know MAVE data will play an important role. We cannot rest on our laurels. Biology is a field that needs more data! Although MAVE progress has been substantial and is already affecting variant classification, only a fraction of the protein-coding genome has been assessed in a high-quality, comprehensive way and an even smaller fraction of the non-coding genome has been evaluated.6 This needs to change. There is a long road ahead.

However, by way of introduction, I do feel compelled to mention that he is currently a professor in Harvard’s psychology department, has conducted research on topics in cognitive sciences for nearly five decades, and spent over three decades in the public eye as an author of classic titles in popular science or the “Big History” genre. This prominently includes The Language Instinct (1994), The Blank Slate (2002), and The Better Angels of Our Nature (2001). It also is difficult to understate the influence he has had on important corners of our public discourse.

In September, Pinker is debuting a new book on the topic of “common knowledge” titled When Everyone Knows That Everyone Knows...: Common Knowledge and the Mysteries of Money, Power, and Everyday Life. Although I have to admit it is likely to be a lesser work in the Pinker Pantheon, it was still a very edifying and entertaining read. Pinker cleverly weaves together insights from several different academic fields to give readers a perspective on a cognitive phenomenon of simultaneously mundane and monumental importance. Common knowledge is an often misunderstood and overlooked state that Pinker deftly argues is the foundation of everything that makes humans special.

What is Common Knowledge Anyway?

It’s easy to think one is familiar with the idea of common knowledge; after-all it is a common refrain, “Oh yeah, that’s common knowledge…” Pinker’s usage is distinct, specific, and a bit technical.1 To clarifies his usage he defines it while contrasting it with a different epistemic state, private knowledge:

With private knowledge, person A knows something, and person B knows it. With common knowledge, A knows something, and B knows it, but in addition, A knows that B knows it, and B knows that A knows it. On top of that, A knows that B knows that A knows it, and B knows that A knows that B knows it, and B knows that A knows that B knows it, and so on, ad infinitum.

Pinker draws on the famed and often cited Hans Christian Andersen’s story “The Emperor’s New Clothes” to helpfully dramatize the concept, calling attention to two of its key features:

1. “[C]ommon knowledge need not be deduced from an infinite chain of musings about other people’s mental states, which no mortal could ever think [through].”

2. “[T]he difference between private knowledge, even when widely shared, and common knowledge is not a mere logical nicety but can unify knowers in coordinated action and sometimes explode a social status quo.”

The big deal of common knowledge is that it facilitates coordination that wouldn’t otherwise occur even when everyone has the same knowledge but aren’t aware that everyone also knows that. Further, Pinker alleges that the recursive loops of knowledge that catalyze coordination (or conflict) is what “empowered our species to coordinate our behavior in social networks like communities, economies, and nations."

Given the boldness of Pinker’s claim, he opts to contextualize it with respect to other popular theories that explain the successful trajectory of human social development. He explicitly raises Yuval Noah Harari's claims about inter-subjective myths, popularized in Sapiens. Harari argues "our world is built on fictions," specifically the power of belief in various human narratives like the state, private property, currency, individual rights, etc. In Harari’s view, this is the X-factor that explains human success. Pinker doesn’t really question this model but rather points out that it must sit on top of common knowledge in some way. Thus, the Pinker-cum-Harari thesis, itself mostly a narrative, is that common knowledge must emerge at various civilizationally critical junctures so conventions (Harari’s myths or Henrich’s cultural adaptations) can be built that in turn power the cooperation that power progress and sustain successful human institutions.

Taking the thesis as is, it immediately prompts several questions:

1. What are the mechanisms that give rise to common knowledge?

2. As common knowledge emerges and people become aware of competing interests and the possibility of coordination, what are the dynamics that govern resulting coordination equilibria? How stable are these?

3. What distinguishes between common knowledge dynamics that promote human flourishing versus those that promote human misery? Knowledge of other minds can’t always be a socially positive or generative thing.

Pinker does try and tackle the first couple questions in his book (we’ll return to this later), but he generally punts on the third one. He has a good reason for this even though it makes the book seem like he shied away from trying to prove his big bold claim; but Pinker has simply answered this question in his two prior books: Enlightenment Now! and Rationality. In these books, he lays out his worldview: his epistemology is scientific rationality, his politics are liberal, and his ethics are broadly utilitarian. Additionally, in this book, Pinker is generally working from the assumption that most readers agree with a generalized version of his worldview where material growth, competent participatory government, individual liberty, and stable, peaceful international relations are good things. Readers will invariably have more specific disagreements with Pinker’s politics, but understanding his worldview does help enrich one’s reading of When Everyone Knows That Everyone Knows.

Alternatively, if you’re feeling a bit galaxy-brained, you can invent an answer to the question yourself. Simply reach for other titles on the “Big History” or “Big Idea” shelf and select answers for the human success sequence à la carte. There are a wealth of popular theories of civilizational success that are in circulation that can be woven fairly neatly into the Pinker’s claims about common knowledge: Acemoglu & Robinson's Why Nations Fail, The Social Brain by Robin Dunbar, and Joseph Henrich's The Secret of Our Success, The Theory of Everyone by Michael Muthukrishna, etc. Whatever the exact best model is is of course unknown; so run wild. Nonetheless, it’s exciting and generative to have an assemblage of these ideas in the back of one’s mind as one thinks about how simple interactions among close kin in hunter-gatherer groups of ancient humans eventually scaled into bustling megalopolises of strangers.

Do We Really Need Common Knowledge?

Being a member of a social species is a blessing and a curse because the outcomes of our decisions often depend on the choices of others. We’re compelled to play social “games” repeatedly. Taking a strategic perspective, we can map the outcomes of all possible permutations of decisions in these games, allowing us to definitively know (or solve) which combination of choices result in the best outcome for all players. There is a common and fortunate tendency of social games where cooperative forms of coordination can result in win-win outcomes for all players. Unfortunately, even when win-win outcomes are available, a win-lose outcome is often easier to reach due to the individual incentives involved. The textbook example of this, derived from game theory, is The Prisoner’s Dilemma, where despite the optimal solution being both prisoners remaining silent in an interrogation scenario (top left corner of 2-by-2 table below), the incentives of the game encourage both prisoners to betray their partner in crime, resulting in a harsher punishment for both perpetrators (bottom right corner of 2-by-2 table below). The amazing thing about The Prisoner’s Dilemma is that it’s more than an abstract exercise. The phenomenon of omertà is a real-world solution to transcending its default solution or “Nash equilibrium” (i.e. mutual betrayal).

The dynamics of our real-world social games are not always as easily grokked as The Prisoner’s Dilemma. This is for obvious reasons, and, even if they were, the ongoing dynamics of even simple games compel players to think about what is going on in the minds of other players. When we can’t know for sure, we have to work off assumptions about others (e.g. assuming self-interest). When we do have knowledge of others’ minds, like in instances of common knowledge, then strategic or cooperative action becomes easier.

Common Knowledge… How?

Pinker takes several chapters to actually specify common knowledge and account for its emergence. I fear some reader will find it a bit laborious. As part of this careful effort, Pinker reaches for the work of the political scientist and Nobel laureate Thomas Schelling:

Schelling’s classic example was a separated couple who had to reunite somewhere, anywhere, in New York. They’d be wise to get themselves to the big clock in Grand Central Station at noon, even if it wasn’t particularly close to where they had lost sight of each other, because each can expect it to pop into the other’s mind.

Schelling’s example is meant to illustrate the how focal points or the salience of something in human psychology, a given culture, or the environment is critical to solving coordination problems. Pinker refines this point by asserting that focal points themselves catalyze common knowledge as part of facilitating coordination or governing competitive choices. As is done robustly throughout the book, Pinker covers several examples of how this works theoretically and in the world. In the chapter addressing itself most directly to concepts from game theory, Pinker covers games like Rendezvous (Schelling’s discussion of focal points is nested within an example of this game), Chicken, and Stag Hunt.2

Of course, having a recognized focal point isn’t enough for an infinite regress of awareness about shared knowledge. Pinker pulls in additional phenomena like self-evident knowledge, the dynamics of joint-attention during the witness of some public happening, and recursive metallization to round out how common knowledge emerges. He then goes to great lengths, drawing on numerous studies and thought experiments, to demonstrate that it is really recursive mentalization, thinking about the thoughts of others including their thoughts about your thoughts, that is the key cognitive capability in common knowledge. This puts Pinker in favorable company on Substack, which includes many champions of the powers of recursive thought.3

Counterintuitive Common Knowledge

Before I rush ahead to my verdict on Pinker’s book, it is worth pointing out some tricky things that arise when thinking about how common knowledge functions in social settings. It can be a slippery but powerful thing— sometimes even a bit of an insult to common sense.

By way of hooking in casual readers, Pinker highlights several counterintuitive things that the study of common knowledge has happened upon and yet again walks through many examples. Below I’ve excerpted two passages that describe and tease some of the intriguing examples of the counterintuitive takeaways:

The first is that you can deduce facts about the world from what people don’t know. The second is that two people really do need to think an infinite vortex of “I know that he knows that I know that he knows...” thoughts to be sure they will coordinate their plans; two or three, or any finite number, aren’t enough. The third is that rational agents with the same understanding of the world, after examining evidence and sharing their assessments, must arrive at the same conclusion: they cannot agree to disagree.

&

Common knowledge can make frivolity important, aesthetics practical, powerlessness empowering, profligacy efficient, and arbitrariness systematic.

Evolving for and because of Common Knowledge

It wouldn’t be a Pinker book without some sort of evolutionary tie-in. It comes in the latter half of the book. By way of exploring different models of human social relationships, which he draws from Alan Fiske, Pinker alleges that common knowledge is enmeshed in human physiology. Not only has symbolic communication (language) evolved to facilitate common knowledge, but also our bodies. This perhaps sounds a bit weird, but, if you think about for a moment, it is self-evident. The obvious thing to mention here is our eyes. We have colorful irises surrounded by white sclera; these allows us to share attention and track the attention of others. Pinker also covers how emotional states are physically expressed and what they mean in various social setting. He covers an array of conspicuous emotional expressions that are hosted by our faces: laughing, crying, blushing, staring, and glaring.

He then expands from this focus on interpersonal dynamics to social ones, covering common-knowledge-based insights on the role of innuendo and euphemisms, censorship, cancellation, and hypocrisy. The final chapter is in part dedicated to a provocative defense of Plato’s Noble Lie. It is hard to disagree with Pinker’s conclusion after thinking carefully through all the downsides of making certain knowledge common knowledge.4 Our social media epoch, having created various kinds of epistemic chaos, reinforces Pinker’s closing arguments.

My Pet Criticisms

Although When Everyone Knows That Everyone Knows… makes for a compelling read, it is also a demanding read given that Pinker asks readers to follow him several layers deep into recursive loops and play out the dynamics of various games given different epistemic states. It isn’t the most breezy popular science read available. I think many readers will find this valuable though. I certainly appreciated Pinker’s fastidiousness and rigor even when I tired of it.

I do wish Pinker invested more in demonstrating the claim that animates his interest in common knowledge - that it's foundational to human success because it is the basis for social conventions that power our modern world. A lot of this boils down to how language functions, but, surprisingly given his expertise in language, Pinker spends little time focusing on it.

More generally, I remain a bit confused about how Pinker sees something like written language fitting into his common-knowledge-to-human-success model. Written language is almost certainly an important technology that catalyzed human development, but it would appear to side-step a need for recursive mentalization. Perhaps Pinker would argue that communication through written language is a convention that emerged on top of common knowledge concerning other more fundamental aspects of language. It’s just not immediately clear how he’d game that out. There is also a conspicuous omission of artificial intelligence and the implications thereof in the realm of common knowledge and social coordination. It would have been interesting to hear Pinker connect some of his insights to these emerging technologies, especially given that they’re likely generating an important amount of the content consumed on the internet today.

Despite the wealth of evidence presented and even given Pinker’s gestures at reliable shortcuts like chunking and conventions, part of me still thinks it strains credulity to put recursive mentalization at the center of all human social coordination. It would seem to make everything very very fragile... Perhaps it is.

Applying Hanania’s Razor: Strong Recommendation

says he uses a three-pronged test to determine whether a book should be read (I’m calling this Hanania’s Razor here). Hanania’s Razor stipulates three types of nonfiction books are worth reading (as opposed to reading a summary of such work): 1) Deep dives on particular subjects, namely history books, 2) Books of social or culture significance, and finally 3) “A Genius Takes You on A Journey.”

Funnily enough, Hanania explicitly uses Steven Pinker as an example of an author whose work falls into the third category, saying “he’s a pleasure to read, he addresses fascinating issues, and I have trust in his judgment and intellect.” I have to agree with this and strongly recommend this book.