Siddhartha Mukherjee’s “The Gene”: Book Review, Notes + Analysis

Poor Ash’s Almanack > Book Reviews > Science + Engineering + Math > biology

Overall Rating: ★★★★ (4/7) (acceptable for its category)

Note: ratings would be much higher except for the major “asterisk” discussed in Lowlights.

Learning Potential / Utility: ★★★★★ (5/7)

Readability: ★★★ (3/7)

Challenge Level: (3/5) (Intermediate) | ~500 pages ex-notes (608 official)

Blurb/Description: Doctor-researcher Siddhartha Mukherjee opines on the history of genetics from Darwin and Mendel through the present.

Summary:  A little-known fact about me is that I’m actually a degreed biochemist, magna cum laude even.  I decided at thirteen that I wanted to be a genetic engineer and four years later, ended up doing genetics research in a laboratory on my college campus, utilizing techniques like PCR to study the mitochondrial DNA of a slime mold, Physarum polycephalum.  Lab work turned out to not be a great personality fit, though, so I started skipping classes to work as an editor for Seeking Alpha and teach myself about business and investing.

Nonetheless, I’ve always harbored an interest (/admiration, fascination) for the field of genetics, and was excited to start reading The Gene when a friend mentioned it.  I was initially excited by the way Mukherjee put the excitement and “story” back into words like DNA polymerase and intron that memorization-driven college classes had sucked dry.  

Unfortunately, a disturbing thread presented itself and grew to take over more and more of the book: Mukherjee’s sociopolitical views are frequently injected into his commentary on the history and future of genetic therapy, and connecting the dots in the book with some research outside the book (as well as a cognitive scientist’s review), it seems that Mukherjee may have let his ideology shape a selective presentation of the science on certain topics.

Highlights: Mukherjee provided me with a better fundamental understanding of the way four simple nucleotides can result in much of the world’s biological complexity (the first 200 pages of The Gene gave me a better understanding of genetics from a practical perspective than my entire undergraduate education).  While some of the book necessarily gets a little technical, Mukherjee generally does a great job of making it understandable.

Lowlights: The “house view” in the Gene, unfortunately, is just too strong.  It colored my reading of much of the book that isn’t discussing the cold, hard facts of long-ago genetic research.  These views are directionally in the left-wing “social justice” camp, but it’s difficult to just adjust for that on a wholesale basis because he also has some anti-scientific-”playing-God” views that are traditionally right-wing, associated with evangelicals rather than scientists.

I happen to disagree with both sets of views, but there are other books where I strongly disagree with the author’s views (ex. Richard Rhodes’ implied wish for nuclear disarmament, which I view as unrealistic) where it nonetheless didn’t get in the way of the author’s objectivity, or off me enjoying and learning from the book.  

It would be one thing if Mukherjee’s ideological bias was restricted to the ethical/moral discussions of genetic medicine – which I mostly viewed as distracting/uninteresting to begin with – but when we get to the state of modern genetics, it’s difficult to differentiate, in some cases, where Mukherjee’s opinion ends and the scientific facts start.  In other words, his ideological viewpoint appears to influence his presentation of science: his claims about the genetic basis of intelligence, for example, immediately struck me as extremely inconsistent with my general knowledge on the topic from previous reading, as did his passing comment calling alcoholism “a social ill[…] that merely reflects inequality” (when in fact it has a genetic basis).

In fact, Stuart Ritchie, a cognitive researcher reviewing The Gene for The Spectator, went so far as to call Mukherjee’s presentation of the genetic basis of intelligence a “lapse in scholarship” – Mukherjee uses a series of unconvincing, social justice-driven arguments to more or less set up a straw man, equivocate on the commonly-accepted definition of intelligence, and call it a “measurement of a hypothetical quality that [a geneticist might have concluded as] barely worth linking to genes.”

On the other hand, Ritchie calls general intelligence “probably the most well-replicated phenomenon in all of psychological science.”  A research paper I reviewed in Molecular Psychiatry (emblematic of several) noted that intelligence is “one of the best predictors of important life outcomes such as education, occupation, mental and physical health and illness, and mortality,” while another research paper notes that “the measurement of intelligence is among the best and most resilient success stories in all of scientific psychology […] after a century of solid, replicated research, intelligence levels, the [APA] report concluded, reliably predict life outcomes…”  I leave it to readers to decide which of these sounds more reasonable.

Mukherjee ultimately claims that intelligence (in the form of g/IQ) is “heritable in a certain sense” but that it’s “not easily inheritable” and that “Mendel’s laws virtually guarantee that the particular permutation of genes will scatter apart in every generation.”  Again, that’s a very strange interpretation of the science.  

The Gene’s conclusions on intelligence are strongly at odds, for example, with the National Institute of Health’s Primer on Genetics, which notes that studies suggest that genetic factors underlie about 50 percent of the difference in intelligence among individuals,” while the previously-referenced paper in Molecular Psychiatry, which fully acknowledges that “all traits show substantial environmental influence, in that heritability is not 100% for any trait,” nonetheless calls intelligence “one of the most heritable behavioural traits” and due to self-selection of similarly-intelligent spouses, notes that assortative mating increases additive genetic variance in that the offspring differ more from the average than they would if mating were random. The increase in additive genetic variance can be substantial because its effects accumulate generation after generation until an equilibrium is reached.”  

Again, you can think through the logic and contextualize it with your own life experience and decide whether Mukherjee – or just about everyone else in the scientific world – is more accurately presenting reality on the issues of whether intelligence is real or a social construct, and whether intelligence has a meaningful genetic component.

The curious presentation of intelligence is a serious flaw in the book: Ritchie, in fact, essentially implies Mukherjee’s presentation of the science is likely to mislead the average reader: from his review in the Spectator,

This disappointing failure to grasp the genetic nettle can be illustrated by a quotation from Mukherjee’s section on IQ tests. ‘Is g [general intelligence] heritable? In a certain sense, yes.’ Alas, the ‘certain sense’ here really means ‘after much qualification’; in fact, after so much qualification that you’ll go away thinking the answer is actually ‘no’, and not worrying too much about it.

Ritchie, who clearly knows more than I do, goes on to note that Mukherjee’s presentation of other issues like the genetic basis of sexual orientation and gender identity also appears to be overconfident (i.e. potentially one-sided or selectively interpreted presentation of the available research data) – a shame, because I would have been deeply interested in a scientific review of those topics, and it’s hard for me to know how seriously to take the data Mukherjee presents.  

For what it’s worth, my ideology on those topics even, in a rare twist (broken clocks etc), aligns with Mukherjee’s – i.e., I hold the generally-consensus view there’s a genetic basis for sexuality and that being gay isn’t a choice – but I don’t want to be told there’s well-accepted scientific confirmation for those views if, in fact, the genetics research is not currently as clear as Mukherjee presents it as being.  

It’s certainly possible that Ritchie has his own biases, of course, but the combination of his perspective and my research suggest that his take is likely more accurate than Mukherjee’s.  I end up feeling extremely disappointed that a book that I thought would be wholly objective ends up being so influenced by extraneous, subjective sociopolitical ideology.  (For a deeper discussion see the notes section, for example pages 116 and pages 273.)

Mental Model / ART Thinking Points: trait adaptivity, feedback effects, n-order impacts, incentives, ideology.

You should buy a copy of The Gene if: you want an engaging primer on the history of genetics, and don’t mind wading through distracting social commentary and occasionally using some critical thinking to determine how seriously to take certain sections that may be largely shaped by opinion rather than fact.

Reading Tips: Consider heavily skimming the part of the book after the pictures in the middle (i.e., from somewhere in the mid-200s onward).  Whether or not you decide to read it cover to cover, as discussed above, keep a very careful eye out for where “fact” ends and “opinion” begins.  Ultimately, I don’t view Mukherjee’s The Gene as unworth reading – it’s totally worth it for the accessible history of Mendel/Darwin through Watson/Crick as well as the simple, understandable, engaging descriptions of the process by which genes give rise to proteins which give rise to observed biological phenomena – but I have a hard time trusting his presentation of any science that has any sociopolitical implications whatsoever, which amounts to most of the modern science, and readers are strongly advised to take that into account.

Pairs Well With / You Should Read Instead:

“The Violinist’s Thumb” by Sam Kean.

Genetics and intelligence differences: five special findings.”  A paper in Molecular Psychiatry that’s probably a better use of time than reading most of The Gene beyond the centerfold.

“The Emperor of All Maladies” by Siddhartha Mukherjee

“The Autobiography of Charles Darwin”

Reread Value: 2/5 (Low)

More Detailed Notes + Analysis (SPOILERS BELOW):

Disclaimer: these notes were created for my own personal reference and are not intended to be an abstract or summary of the book; in other words, they don’t substitute for reading the book, and most of their content will not make sense without the broader context of the book.  

These simply represent some of the points that I found interesting / thought-provoking / related to other material that I’ve learned from, and generally speaking, my thoughts and favorite parts don’t even come close to adequately representing the totality of the value that can be derived from reading the book yourself.  

However, hopefully you will find these notes helpful in understanding some of the concepts from the book if you haven’t read it yourself yet, or determining whether it’s something you should read in the near future, or refreshing yourself on some of the key points if you’ve already read it.

Page 7: opening with his family’s own history of mental illnesses such as bipolar and schizophrenia is an interesting way to contextualize things.  Not terribly relevant, but I did appreciate “Like most Bengalis, my parents had elevated repression and denial to a high art form.”

Page 8: marijuana caused Mukherjee’s father to go into two psychotic episodes.

Page 9: Mukherjee compares the gene to the atom and the byte as three of the most powerful ideas of the 20th century, each representing a unit.  I should read more about information theory and computer science (not a topic I’ve delved into.)

Page 18, 48 – 55 Mukherjee makes the history fairly memorable and engaging.  Gregor Johann Mendel entered the monastery in the 1840s… after failing to pass a science exam (there’s a theme here: Mendel, Einstein…), Mendel crossed true-breeding peas to see what would happen.  It was incredibly tedious and time-consuming work, but he ended up discovering the idea of recessive and dominant alleles.  

For those who haven’t taken a bio class in a while, here’s a quick and oversimplified summary of Punnett Squares… let’s assume that hair color has a dominant allele, capital B, which means black/dark hair, while the recessive allele, lowercase b, means blonde hair.

So if you take a true-breeding dark-haired person with a BB gene and cross them with a true-breeding light-haired person with a bb gene, the kids will all have a Bb gene.  Since B “dominates” b, they will all be dark-haired, but they’ll be a “carrier” of the recessive gene.

Now if you cross the kids (note: this is hypothetical, please note that in practice, it is illegal outside of the state of Arkansas and unethical everywhere), you end up with three potential outcomes: the grandkids could get a B from both, i.e. BB – this occurs one-fourth of the time (one half times one half), so 25% of them would end up as dark-haired true-breeding.  The grandkids could get a B from one and a b from the other (Bb), so they’d end up as dark-haired “phenotypes” (what is visible on the outside) but would be carrying the allele.  This would be one-half.  And you’d get one-fourth recessive “bb” kids with blonde hair.

This is what Aristotle observed with traits from previous generations “reappearing,” and what Mendel observed with his peas.

Page 20: Christian Doppler proved the “doppler effect” (of pitch being influenced by location and velocity) by putting some trumpet players on a train and having them hold a note as the train sped past onlookers.  Now that’s a concrete experiment.

Also, at the time, biology was all about classification, not about learning anything – cross-reference the Feynman bit about the name of a bird.

Pages 21 – 23: Pythagoras, who we all know and love for his theorem about hypotenuses, had a less-accurate theorem about heredity: semen traveled all around the body, collecting “mystical vapors from each of the individual parts,” and thereby contained all necessary genetic information, while the womb was nothing more than a glorified incubator.  One flaw with this theory, pointed out by Aristotle: where exactly did semen pick up the mystical vapors of the female genitalia for the half of kids who are born female?  Yeah, oops.  (Also, Aristotle noticed that traits from the maternal side of the family are transmitted too.)

Page 25: like much of early science, ideology was often the biggest driver of theories: one theory, “preformation,” basically held that semen contained tiny, ready-to-go humans that just needed to be reconstituted like a freeze-dried meal.  Of course, within those tiny humans were more tiny humans – tiny humans all the way down! – which was a helpful way of having all of humanity be present inside Adam’s body when original sin became a thing.

Page 31: on how Darwin thought differently from the taxonomists of the time, who just classified stuff: “a natural historian should be able to describe the state of the natural world in terms of causes and effects, Darwin reasoned – just as a physicist might describe the motion of a ball in the air.  The essence of Darwin’s disruptive genius was his ability to think about nature not as fact – but as process, as progression, as history.”  Mendel apparently thought the same way.

Page 35: Darwin’s famous doubt (“I think,”) and also the birth of the idea that animals arose from common ancestors.  (Also, the taxonomists sort of did help a bit after all by figuring out that what Darwin thought were separate species were actually all just finches.  Credit where credit’s due.)

Pages 36 – 37: if we can breed animals with artificial selection, why can’t nature breed animals via some sort of natural selection?  While reading Malthus’s population explosion hand-wringing, Darwin came to realize that death was the selector.

Pages 41 – 42, 45: for Darwin’s theory to work, there had to be a balance between mutation and stability – the mutations had to be transmitted somehow.  Anyhow, the competing ideology was Lamarckism, which was a sort of strength-training theory of evolution: if you keep stretching your neck enough, your kids will have longer necks, and eventually the great-grandkids will become giraffes.  This is mostly untrue but has actually resurfaced to some degree via “epigenetics.”

Page 68: Darwin’s cousin Francis Galton surveyed the heritability of traits like height, and found that not only did the broad distribution of these characteristics end up on a bell curve, but the distribution of kids ended up in a bell curve sort-of centered on the parents but drifting toward the center.  So if you have a parent with a really far-out result (i.e. someone who is really really tall), their kids will be taller than average, but usually not as tall as the parents.

Page 71: just like the logical atom preceded the actual atom, the “gene” was unknown at first, defined by its purpose rather than its form: the gene was whatever contained and passed on hereditary information

Pages 80 – 85: here and elsewhere, Mukherjee points out that eugenics was actually quite a popular notion in the U.S. pre-Hitler, ranging from forced sterilizations of those deemed deleterious to the gene pool to “Better Baby” contests.  This cultural context is touched on in David Oshinsky’s Polio: An American Story, with examples on pages 32 – 33 and 44, and the broader impact of this line of cultural thinking on bioethics is discussed fairly extensively throughout Meredith Wadman’s The Vaccine Race.  Both of those books, it should be noted, have lots of learning lessons, and authors who (unlike Mukherjee) treat their topic in a very thoughtful and unbiased way.

Page 93: chromosomes were discovered when researchers figured out that male worms had Y chromosomes, but female ones did not… they postulated that all genes might be carried on chromosomes

Pages 94 – 96: studying fruit flies, Thomas Morgan noticed that some genes did not function independently, but rather seemed to travel along with their friends – suggesting that they were physically linked (i.e., on the same chromosome).  The closer they were physically to each other, the more tightly they were linked.

Page 99: Alexei’s hemophilia and Rasputin – might be an interesting topic for further reading

Page 102: by the 1940s, it was generally understood how variation and evolution occurred, but nobody yet understood embryogenesis – i.e., how genes could turn an embryo into a fully developed mature adult

Pages 103 – 104: I thought there was a really nice parallel here between the way that a number of discontinuous – i.e. discrete/packetized – on/off genes in biology gives rise to the seemingly continuous variation we see around us.  In physics, it’s the discrete atoms with their protons and electrons and neutrons, and below that quarks…

Pages 104 – 108: this is where the book starts to get pretty technical pretty fast, but in my opinion Mukherjee does a really good job of keeping it accessible (although, I should note, I do have the benefit of several years’ worth of biochem/genetics classes – even if I daydreamed through or skipped half of them!)  

Tying natural selection to genetics: for natural selection to select something, you need something to select from – variability.  How does that arise?  Mutations and (as we’ll see later), recombination.  

This is where Mukherjee introduces the terms “genotype” and “phenotype” that I mentioned earlier.  As I referenced, people with the same “phenotype” can have different “genotypes” – phenotype is what you see, genotype is what your DNA is.  Phenotypes can be affected by the environment (you can dye your hair and put in color contacts), but genotypes can’t be (as easily, anyway.)

Environmental factors, triggers, and chance also play a role – the term “penetrance” is used to discuss the relative tendency of a gene to result in a specific outcome.  For example, if a gene always results in a certain outcome no matter what, it would have absolute penetrance – but if a gene only results in a certain outcome a small percentage of the time, it would have small penetrance.

Interestingly, the environment can only select for genes indirectly – because phenotypes are what matter on a day-to-day basis.  In other words, an environment where stuff is really high off the ground selects for giraffes, but also for humans smart enough to build ladders or stilts.

Pages 109 – 110: the social commentary starts to amp up in volume, but isn’t at full crescendo yet.  I’ll get there later.  Setting that aside and just focusing on the science, this is the core of the “trait adaptivity” mental model: strengths and weaknesses are context-dependent.  The experiments run by Theodosius Dobzhansky demonstrated that whether one type of fly or another prospered depended on the temperature of the container.  

Pages 112 – 115: “transformation” is a horizontal genetic-transfer process that often occurs in bacteria, although rarely in mammals.  Basically, bacteria can eat other bacteria and absorb their genomes.  Even if they’re dead bacteria.  Also, radiation is a mutagen.

Page 116: here’s where Mukherjee starts to inject his ideology into the book in curious ways.  Let me quote at length:

“But unlike Galton, Muller began to realize that positive eugenics was achievable only in a society that had already achieved radical equality.  Eugenics could not be the prelude to equality.  Instead, equality had to be the precondition for eugenics.  Without equality, eugenics would inevitably falter on the false premise that social ills, such as vagrancy, pauperism, deviance, alcoholism, and feeblemindedness were genetic ills – while, in fact, they merely reflected inequality.”

I’m sorry, what?  This deeply disturbed me – at first I tried to give Mukherjee the benefit of the doubt (you could read this passage as him simply being the messenger for Muller’s views), but the context of the rest of the book suggests to me that this is his house view.  While my big quarrel with him is on the issue of intelligence, which we’ll get to later, it is a very strange presentation to call alcoholism a “social ill […] that merely reflects inequality.”  

It is certainly undoubtable that environmental factors strongly influence alcoholism, but there’s also clear evidence that genetics play a role in alcoholism: according to the National Institute of Health, “Research shows that genes are responsible for about half of the risk for [alcohol use disorder].”

It is true on one level that “selecting” for alcoholism genes, or lack thereof, would not be as simple as selecting for peas with a certain color flower: this presentation by Howard Edenberg at the Indiana University School of Medicine notes that alcoholism, like diabetes, is a complex disease influenced by multiple genes and environmental factors.  Nonetheless, Mukherjee’s phrasing implies that there’s no genetic influence on alcoholism beyond “inequality” – it’s, in Mukherjee’s presentation, purely a “social” issue like “pauperism” – and no matter your views on inequality, I don’t think the two are comparable at all.  

There are plenty of rich people in AA; alcoholism is not only a working-class disease.  I know several people with top-tier educations and extremely high-paying jobs who have struggled with substance abuse.  At best, Mukherjee’s argument is poorly phrased, at worst, it’s wrong.

While we’re at it, let’s address Mukherjee’s general, vague “but our humanity” arguments against negative eugenics that are peppered all over the book: they’re tenuous and, in my view, annoying because they detract from the otherwise scientific tone of the book, and Mukherjee doesn’t do a good job, in my opinion, of clarifying when he’s presenting opinion and when he’s presenting fact (I often had to reread passages multiple times to differentiate the two).  There are much better fundamental arguments.  For example, on Page 74: note “defective geniuses” … Darwin’s depression … many people with desirable characteristics in one area have undesirable ones in another.  

There’s also the already-referenced Dobzhansky experiments, which Mukherjee references at the top of the page and could have taken further: “good” genes are contextually-dependent.  Mukherjee later references, for example, the gene for sickle-cell anemia, which (can’t remember if he mentions this, actually) offers protection against malaria for recessive carriers.  Mukherjee brings up this issue in context of the cystic fibrosis gene.  At the top of the page, he calls natural variation a “vital reservoir,” an asset that outweighs its liabilities – and he should’ve stopped there.

Also, Mukherjee’s own later points about “chance” and “triggers” mean that even perfect equality wouldn’t allow for perfect selection: twin studies (of twins with identical genomes and, presumably, as-identical environments as you can find in nature) demonstrate that randomness plays a big role in genotype → phenotype as well… so equality would reduce the variation between genotype and phenotype, but not eliminate it entirely.

So, ultimately, the potential for unintended consequences via n-order impacts is a reasonable and sound scientific argument against intentionally destroying biodiversity… but unfortunately, Mukherjee spends a lot of time providing sociopolitical arguments that are neither interesting nor convincing.

Page 127: I mostly view the discussion of Nazi Germany and Soviet Russia as a distraction because, as Mukherjee rightly points out on page 128, it was “junk science” that I don’t think has any real bearing on real genetics other than the twin studies… and there are other places I can get much better and more thorough reads on those horrors.  (I voluntarily spent two or three days in the Holocaust Museum when I was 12 or 13, and probably read The Diary of Anne Frank two or three times.  I get it.  But it doesn’t add anything here, unlike Rhodes’ discussions of the war context in The Making Of The Atomic Bomb.)  

Nonetheless, perhaps some readers will find it a good example of the (sometimes twisted) power of ideology.

Pages 130 – 131: Mukherjee echoes Rhodes’ point in The Making of the Atomic Bomb about the exodus of Jewish scientists; “Germany’s loss was genetics’ gain.”  This part is relevant.

Pages 134 – 135: lots of great stuff here.  First, Mukherjee notes how finely calibrated biological reactions are:

“Cells depend on chemical reactions […] none of these reactions occurs spontaneously (if they did, our bodies would be constantly ablaze with the smell of flambeed sugar).  Proteins coax and control these fundamental chemical reactions in the cell […] organisms exist not because of reactions that are possible, but because of reactions that are barely possible.  Too much reactivity and we would spontaneously combust.  Too little, and we would turn cold and die.”

That’s worth thinking about.  

Now, scientists wanted to focus on proteins because they were sexy: on the other hand, nucleic acids like DNA and RNA are rather monotonous chains of four bases – adenine, guanine, cytosine, and thymine (A, C, G, T) – in RNA, the thymine is replaced by uracil (U). This was so boring as to lead one scientist to call DNA a “stupid molecule” – but of course, similarly to how a brief alphabet can ultimately encode human language, these four bases encode genes.

Pages 136 – 137: more good examples of the scientific method / inversion: using the earlier-discussed horizontal-transfer practice of “transformation” by which bacteria “eat” other genomes, scientist Oswald Avery and his two assistants basically systematically eliminated each component of the “soup” to see what would happen.  No lipids?  No problem.  No proteins?  No problem.  No RNA?  No problem.  But get rid of DNA, and all of a sudden transformation didn’t happen.

Also, on what DNA looks like when precipitated: “a white fibrous substance… that wraps itself about a glass rod like a thread on a spool.”  

On what it tastes like: “the faint sourness of the acid, followed by the aftertaste of sugar and the metallic note of salt.”  

Avery (page 140) still wasn’t given the Nobel Prize because one Swedish chemist literally refused to believe DNA was the genome.

Page 141: an example of the previously-referenced way in which proteins enable reactions: hemoglobin A has four leaves; each leaf clasps an iron-containing “heme” that binds oxygen – Mukherjee calls this “a reaction distantly akin to a controlled form of rusting” (see Jonathan Waldman’s excellent Rust: The Longest War for more on the more traditional form of rusting.)

Pages 142 – 143: on how x-ray crystallography (also discussed in The Making of the Atomic Bomb) works: you’re trying to figure out the shape of a tiny three-dimensional object; if you shine light at it from different angles, you can eventually stitch together a composite of the shadows that tells you what the molecule is shaped like.  However, if the molecules are liquid or gaseous, they move around, which messes up your shadows.  If you lock them in a crystalline form, they don’t move.

Page 144: Mukherjee calls Rosalind Franklin the rare “independent female scientist in a world dominated by men,” and cites New Zealand scientist Maurice Wilkins, who noted Franklin “grew up in a household where her brothers and father resented [her] greater intelligence.”  Wait, I thought intelligence was just a social construct and the genes were too complicated to separate out from environment?  Yet in an environment that would seem to discourage her education and intelligence (a family that didn’t like her intelligence, in a time when females weren’t really respected in science), Franklin nonetheless managed to rise above those environmental challenges.

Pages 146 – 147: a 23-year-old James Watson, seeing a preliminary x-ray diffraction picture of DNA,w as instantly entranced.  “The fact that I was unable to interpret it did not bother me.”  Francis Crick, twelve years older, was highly intelligent and somewhat Munger’like: “thought nothing of invading the problems of others and suggesting solutions.  To make things worse, he was usually right.”

Pages 148 – 149: Watson and Crick thought it was “absurdly laborious” to determine the structure of DNA experimentally: Crick memorably called it “like trying to determine the structure of a piano by listening to the sound it made while being dropped down a flight of stairs.”  Their alternative: deducing it via building a model that made sense.

This reminded me a bit of the Feynman quote in The Pleasure of Finding Things Out about figuring out how things work roughly before figuring them out precisely:

“I spent a few years trying to invent mathematical things that would permit me to solve the equations, but I didn’t get anywhere, and then I decided that […] I must first understand more or less how the answer probably looks.  […] I had to get a qualitative idea of how the phenomenon works before I could get a good quantitative idea.  In other words, people didn’t even understand roughly how it worked, and so I’ve been working on […] understanding roughly how it works, not quantitatively yet, with the hope that in the future that rough understanding can be refined into a precise mathematical tool.”

The counterpoint is on pages 148 – 149 of How Doctors Think by Jerome Groopman, where the brilliant Dr. James Lock discusses some challenges he faced with a beautiful, elegant theory.  My notes from those pages:

While Groopman seems to take a generally skeptical tone toward “evidence-based” or statistical medicine earlier, here he defends it a bit: more or less, Lock discusses a few instances in which “impeccable logic” failed to reach the right conclusions.  

Peter Thiel would be sad: “My mistake was that I reasoned from first principles when there was no prior experience.  I turned out to be wrong because there are variables that you can’t factor in until you actually do it.”  Lock goes on to point out that the complexity of human biology means that you can’t predict everything; he doesn’t explain this explicitly but here you could dive into n-order impacts, feedback effects, etcetera.

Pages 151 – 153: on the ability of brilliant people to make elementary mistakes (perhaps a good recommendation for The Checklist Manifesto): both Watson/Crick as well as, independently, Linus Pauling, made the mistake of putting the phosphate backbone of DNA in the center, creating an energetically unstable molecule with strong repulsion forces; a colleague of Pauling’s later noted that “if that were the structure of DNA, it would explode.”

Page 155: biochemist Erwin Chargraff finds something interesting: the base composition of DNA has nearly identical proportions of A/T and G/C.  Nobody had yet figured out why…

Page 156: here is where the double-helix structure, with the pairing of A/T and G/C, becomes evident  the duplicate nature is what allows for reading and repair of DNA.

Page 157: nice contextualization: biologist John Sulston notes that every cell in our bodies has two meters of DNA; if DNA was as thick as a sewing thread, one cell’s worth would be 200 km long (?!)

Page 158: Watson and Crick continue on the “grand tradition” (starting with Darwin’s I think) of “counterposing the most significant discoveries in biology with supreme understatement.”

Page 163: probably the closest to the central theorem of genetics; it gets a little more complicated for now, but the general rule is: genes encode proteins, which enable cellular and biological functions.  Proteins are composed of twenty amino acids strung together in a chain, and it’s often the shape of proteins that leads to their function (recall hemoglobin “clasping” oxygen.)

Pages 165 – 167: proteins aren’t encoded directly from DNA; instead, it’s transcribed into RNA – this allows for variable expression

Page 168: triplets of DNA encode amino acids, as well as stop codes and introns (more on that later)

Pages 170 – 171: Mukherjee here references sickle cell disease, but doesn’t (unless I’m just zoning out) mention the malaria-protective side-benefit that has led to it being selected for over time

Page 173: the next big question: how did genes figure out where to turn on or off?  Why did your liver, with the same genome, do different things than your eyes?

Pages 174 – 175: doing some nifty experiments on feeding E. coli different types of sugars, Jacque Monod discovers that genes were being turned on and off: the DNA doesn’t change, but the environment (via feedback effects) leads to RNAs disabling or enabling production of certain things by binding to the DNA

Page 180: more on feedback effects

Pages 181 – 182: why does sexual reproduction even exist?  Why not just asexual reproduction?  The answer is because recombination generates variation.

Page 183: one of my friends viewed the central point of this book as “mechanisms,” i.e. the processes by which things work.

Pages 185 – 186: to solve the problem of embryogenesis, inversion was once again utilized.

Page 189: maternal factors (mostly proteins, but some other chemicals) are deposited asymmetrically in fly eggs, which activates certain genes in certain places, thus leading to the development of heads and tails.

Page 193: on apoptosis, or programmed cell death… the malfunction of which can lead to cancer

Page 196: Mukherjee quotes a scientist: “individual genes are not particularly clever – this one only cares about that molecule, that one only about some other molecule… but that simplicity is no barrier to building enormous complexity.”  The scientist continues with the example of an ant colony.

Here, Richard Feynman’s question on page 145 of The Pleasure of Finding Things Out is answered.  Feynman asks:

“what is this mind, what are these atoms with consciousness?  Last week’s potatoes!  That is what now can remember what was going on in my mind a year ago – a mind which has long ago been replaced.”

Mukherjee answers, with an analogy to a Delphic riddle:

“Consider a boat on a river whose planks have begun to rot [and are] replaced [///] after a decade, no [original] plank is left […] how can the boat be the same boat?  […]  The answer is that the “boat” is not made of planks but of the relationship between planks.  […] the relationship among genes allows physiology.”

Page 199: again, not particularly topical, but interesting look at Asian “shame culture” (I grew up within a much lower-key version thereof) – once people find out about Mukherjee’s uncle’s mental illness, Mukherjee’s father is embarrassed because “the fragile varnish of class and normalcy that he has struggled so hard to seal is being cracked open […] my father has been shamed in [neighbors’] eyes: he is cheap, mean, hard-hearted, foolish, unable to control his brother.  Or worse: defiled by a mental illness that runs in his family.”  I’ve seen the same sort of culture among Southern evangelicals; to borrow a phrase from Mukherjee earlier in the book, “elevating repression to a high art form” is not something I’ve ever seen end up healthy.

Pages 204 – 207, Page 209, Page 213: on the process of inserting genes via viruses, using enzymes like DNA polymerase to cut and paste genes.  Bacteria like e. Coli, with this genome embedded, can then be used to clone the new gene.  I did this in a research lab.  I didn’t fully understand it at the time, even though I actually wrote a thesis paper about it.

Pages 210 – 211: here is, for once, some useful scientifically-based (rather than socially-based) discussion about whether or not to proceed with experiments with SV40 and E. coli: biochemist Erwin Chargaff notes “you cannot recall a new form of life.”

Page 219: on introns and the structure of DNA: much of DNA doesn’t code for anything, but that allows bits and pieces of DNA to be combined in interesting ways, similar to the kid’s game of “how many words can you make out of these letters.”

Page 223: reverse transcriptase allows you to build DNA from active RNA in cells, so you can catalog what genes are related to ongoing cell activity

Pages 232 – 233: an analogy to the “secrecy” agreed upon by nuclear physicists leading up to the Manhattan Project: in the case of genetics, scientists decided to self-regulate on important issues of genetics research.  [later, on pages 478 – 479, Mukherjee discusses the challenge of an “arms race” with China.]

Page 239 – 240: insulin, which regulates blood sugar and is normally produced by the pancreas, was one of the first proteins to be synthesized via bacterial production.  Previously, it had been purified from mashed-up cow and pig organs.

Page 250: on the chemistry of medicine and biology: even though there are millions of different types of molecules in the human body, only 250 are targeted by current medicines.  

Page 255: on the famous Indian frugality: after suffering a fall that caused his arm to break bloodily, Mukherjee’s father was upset that his wife cut off his shirt since she couldn’t pull it over his head

Pages 263 – 265: First of all, the relation between genotypes and phenotypes is complex.  We’ve already discussed “penetrance” – i.e., having a gene and having it expressed are two different things (with the environment and randomness acting as modulatory factors).  Second, conversely, many different genes could lead to the same result, such as high blood pressure – somewhat similar to how many types of failures (bad gas, bad spark plugs, ???) could lead to the same phenomenon: a car not starting.  

Then trait adaptivity is discussed: “mutation” is just another word for “variation,” and none are necessarily intrinsically good or bad – that’s dependent on the environment.

Pages 268 – 271: genetic testing, combined with Roe v. Wade, allowed for prenatal screening and led to meaningfully decreased births of children with terminal illnesses or severe disabilities such as Down Syndrome.

page 273: In attempting to debunk IQ, which is entirely a social argument and not a scientific one, incidentally, Mukherjee presents information in some pretty strange ways.  Let’s start with page 110: here, Mukherjee calls intelligence, like height, a “complex phenotype” and states selecting for it would be a “flawed mechanism to guarantee genetic selection.”  

Later, on page 273, Mukherjee – again, very bizarrely – states the following:

But these attributes are complex, and their link to genes cannot be simply captured.  “Intelligence,” [airquotes are Mukherjee’s!] for instance, may have a genetic component, but it is much more evidently a consequence of genes, environments, gene-environment interactions, triggers, chance, and opportunities.  Selecting “intelligence” [again, airquotes Mukherjee’s] therefore, cannot guarantee that genes for intelligence will be selected any more than selecting ‘richness” guarantees that a propensity for accumulating wealth will be selected.”

Okay, let’s break this down into three parts.  First, the “airquotes” – as we’ll see later, Mukherjee is “equivocating” on the commonly-understood, commonly-understood definition of “intelligence” – the commonly understood definition among both laymen and professionals is a psychometric variable, g, that is, as Wikipedia describes it, “closely linked to the ability to learn novel material and understand concepts and meanings.”  Mukherjee basically claims much later in the book (by the time readers have already interpreted the word intelligence in the normal sense) that this is a social construct and that intelligence should be measured in other ways than just analytical capability – which, setting aside whether or not that’s a useful argument, is not a scientific discussion about the heritability of “intelligence” as commonly understood.  It’s a purely sociopolitical argument about what we should value as a society.  It has no place in, or bearing on, this book about genetics, and its inclusion in an otherwise very thoughtful and engaging book about genetics is both astonishing and disappointing.

Second, the question of whether or not “intelligence” is heritable.  Mukherjee says that airquotes-”intelligence” “MAY” have a genetic component; later (page 345, he calls it heritable “in a certain sense” – Ritchie (the cognitive scientist who reviewed Gene) notes that that “in a sense” basically means with so many caveats that the average reader will think the answer is no.  

But the answer is, in fact, not no.  The answer is a resounding YES.  The National Institute of Health notes in its genetics primer that “studies suggest that genetic factors underlie about 50 percent of the difference in intelligence among individuals.”  This paper in Molecular Psychiatry goes on to note that:

Intelligence is one of the most heritable behavioural traits. […] (i) The heritability of intelligence increases from about 20% in infancy to perhaps 80% in later adulthood. (ii) Intelligence captures genetic effects on diverse cognitive and learning abilities, which correlate phenotypically about 0.30 on average but correlate genetically about 0.60 or higher.

So, using “may” to describe the heritability of intelligence is ridiculous.  On pages 343 – 349, Mukherjee launches what I view as a mostly incoherent argument against our standard definition of intelligence.  Why do I call it incoherent?  He very briefly addresses and dismisses g by calling it “a hypothetical quality invented to serve a particular context – might be a trait barely worth linking to genes,” without providing ANY sort of concrete alternative whatsoever for what would be a good standard scientific measure of “intelligence,” then spends the rest of the section focusing primarily on a very narrow subset of the data (i.e. the supposed racial disparity in IQ discussed in books like The Bell Curve), making social-justice arguments that end up discussing how society gives black children low self-esteem.  

He also notes on page 347 that – unsurprisingly – “genes play a rather minor role in determining IQ in severely impoverished circumstances […] genes that control IQ only become significant if you remove [poverty, hunger, and illness],” which is obvious, but again, doesn’t prove in any way that in normal environments, IQ/g is an irrelevant factor.  Let’s use height as an analogy: using Mukherjee’s logic, his argument would be that genes that control height would only become significant if kids weren’t starving.  Sure – it’s unlikely that someone malnourished is going to end up being 6’2.  But that doesn’t, in any way, have any bearing on whether or not height is strongly genetically influenced (it obviously is).

Even if you accept his arguments as true, none of this has any relevance to the general understanding of intelligence: g clearly measures something important inside of racial groups (i.e., white kids with higher G do better than white kids with lower G, and black kids with higher G do better than black kids with lower G).  Going back to the Mol Psych paper cited earlier:

Intelligence is a core construct in differential psychology and behavioural genetics, and should be so in cognitive neuroscience. It is one of the best predictors of important life outcomes such as education, occupation, mental and physical health and illness, and mortality.

Another research article by Joan Freeman noted that:

The measurement of intelligence is among the best and most resilient success stories in all of scientific psychology, according to the American Psychological Association’s task force (Neisser et al., 1996). After a century of solid, replicated research, intelligence levels, the report concluded, reliably predict life outcomes in education and the workplace,as well as aspects of health, such as how long people live. For example, a step up of just one standard deviation in IQ in 11-year-old girls improves their chances of reaching the age of 76 by 25% (Whalley & Deary, 2001)

I pulled up plenty of other papers confirming the same, which lends support to Ritchie’s statement that general intelligence is “probably the most well-replicated phenomenon in all of psychological science.”

So “one of the most important predictors of life outcomes” is, and I quote Mukherjee again, something he thinks a geneticist would look at and find “barely worth linking to genes.”  Wow, okay.

Ultimately, Mukherjee’s extremely ideological, partisan, selective, one-sided approach to discussing this issue massively damaged his credibility in my eyes as I was reading the book: reading the rest of it, now I have to wonder where his opinions end and the facts begin.  I might expect this from a book about, say, climate science, but I didn’t expect this from a book about genetics, written by a cancer researcher.  Very disappointing.

The issue doesn’t stop there, though.  The next question is whether or not one of the “most heritable behavioural traits” can be selected for.  Mukherjee, as a reminder, says on page 346:

“The most logical conclusion from these facts is that while some combination of genes and environments can strongly influence g, this combination will rarely be passed, intact, from parents to their children.  Mendel’s laws virtually guarantee that the particular permutation of genes will scatter apart in every generation.  And environmental interactions are so difficult to capture and predict that they cannot be reproduced over time.  Intelligence, in short, is heritable (i.e., influenced by genes), but not easily inheritable (i.e., moved down intact from one generation to the next.”

And on page 273:

[intelligence] is much more evidently a consequence of genes, environments, gene-environment interactions, triggers, chance, and opportunities.  Selecting “intelligence,” therefore, cannot guarantee that genes for intelligence will be selected any more than selecting ‘richness” guarantees that a propensity for accumulating wealth will be selected.”

The use of “guarantee” renders this statement technically true, but that is a tautology that is, in practice, completely irrelevant.  It’s pretty easy to select for height and intelligence: just look around you.  Smart parents tend to have smart kids, while tall parents tend to have tall kids.  “Select for” smart parents and, on average, you’ll end up with smart kids.  People actually do this, by the way: whereas Mukherjee states that intelligence from generation to generation will be fleeting, in contrast, the Mol Psych paper notes something different.  Early on, it discusses that, obviously:

No traits are 100% heritable

For some areas of behavioural research—especially in psychiatry—the pendulum has swung so far from a focus on nurture to a focus on nature that it is important to highlight a second law of genetics for complex traits and common disorders: All traits show substantial environmental influence, in that heritability is not 100% for any trait.

Nonetheless, the paper goes on to note that:

because there is strong positive assortative mating, children with highly intelligent mothers are also likely to have highly intelligent fathers, and the offspring themselves are likely to be more intelligent than average. The same thing happens for less intelligent parents. In this way, assortative mating increases additive genetic variance in that the offspring differ more from the average than they would if mating were random. The increase in additive genetic variance can be substantial because its effects accumulate generation after generation until an equilibrium is reached.

So it turns out not only can you select for intelligence theoretically, but practically, in the real world, people (by themselves) actually do select for intelligence.  Mukherjee’s weird phrasing about “moved down intact from one generation to the next” is very odd – no genetic trait is moved down intact from one generation to the next.  I don’t literally have my father’s exact eyes, or my mother’s exact shortness of height.  That doesn’t mean that I didn’t get a lot of those respective characteristics genetically from my mom and dad.

Yes, there are plenty of outliers, and no, you can never “guarantee” 100% selection – but reductio ad absurdum, if you followed Mukherjee’s line of thinking to its logical end, we’d almost never be able to selectively breed any plant or animal, especially considering how heritable intelligence is for a “complex” behavioral phenotype.  All selection, natural or otherwise, is a “flawed mechanism to guarantee genetic selection.”  50% of something being genetically influenced is actually pretty strong, and with enough iterations, you get where you want to go.  (See also my comparison to schizophrenia on the notes for page 300.)

It would certainly be reasonable to say that selecting people who are intelligent or tall or whatever would not perfectly guarantee the optimal genes for those traits: but this has already been established in the discussion of nature only indirectly selecting genes via phenotypes.  Farmers and ranchers have been doing the same thing “artificially” for a long time, and it seems to work pretty well, so it’s a tough sell and Mukherjee’s logic, taken to its end, basically implies you can never select for anything because of randomness and environmental factors.

Ultimately, then, Mukherjee’s arguments are unconvincing on all levels based on a review of available research that I invite any reader to conduct on their own.

Pages 279, 281: linked genes can be used to identify the location of genes: if you know where a certain gene is, and you find that it’s statistically linked to another gene by transmission through generations, then those genes are likely to be nearby.  As such, per MIT geneticist David Botstein, the real key wasn’t finding the gene – but finding the humans.  (Researchers used Mormons in Utah because of their big, branching family trees.)

Pages 284 – 291: I really enjoyed the discussion about how scientists identified the genetic basis of Huntington’s and cystic fibrosis.

Page 295: interesting discussion of genetic vs. genomic diseases – often it’s not as simple as Huntington’s/CF and there are multiple genes that play a role

Page 300: Mukherjee notes that when a schizophrenic parent’s child is adopted by a nonschizophrenic family, “the child still has a 15 to 20 percent risk of developing the illness – about twentyfold higher than the general population – demonstrating that genetic influences can be powerful and autonomous despite enormous variations in environments.  These patterns strongly suggest that schizophrenia is a complex, polygenic illness, involving multiple variants, multiple genes, and potential environmental or chance triggers.”

This is a thoughtful and balanced view.  

But want to know something funny?

This 2016 paper in Schizophrenia Bulletin noted that for schizophrenia, “Heritability, the degree of genetic contribution to phenotypic variance, has been estimated to range between 41% and 87%.”

The 2016 Mol Psych paper I referenced noted that, “The heritability of intelligence increases from about 20% in infancy to perhaps 80% in later adulthood. “

Obviously there’s some variability in estimates and so on… but it’s interesting to me that Mukherjee focuses on the “powerful and autonomous” genetic influences for the “complex, polygenic illness” of schizophrenia “despite enormous variations in environments,” while for intelligence, which is also highly heritable, he doesn’t take the same approach.

Ideology, man.

Pages 302 – 303: While working on the Human Genome Project, Kary Mullis discovers “an ingenious shortcut.  He made a copy of a human gene in a test tube using DNA polymerase, then used that copy to make copies of the copy […] each cycle of copying amplified the DNA, resulting in an exponential increase in the yield of a gene.  The technique was eventually called the polymerase chain reaction, or PCR.”  

This (PCR) is much of what I did in my research lab – we were sequencing the mitochondrial DNA of the slime mold Physarum polycephalum.  (Don’t ask me why we were doing that, because I never figured that out.)

And as for anyone wondering why I ended up being an investor rather than a genetic engineer, well, Sydney Brenner jokes on page 303 that “the sequencing of the human genome would perhaps ultimately be limited not by cost or technology, but only by the severe monotony of its labor.”  Yeah – I can relate to that!

Page 310: the idea of “shotgun sequencing” is interesting – rather than the tedious/laborious process of doing it one by one, you could just get a bunch of genes, beat them into little bits, and then put together the overlaps to figure out the whole gene.  This was frustrated on page 320 by the fact that a lot of the human genome is not very unique – repetitive sequences that Craig Venter called “equivalent to a big stretch of blue sky in a jigsaw puzzle”

Pages 316 – 317: more complex animals don’t always have more complex genomes; complexity is often a function of organization rather than size.

Pages 322 – 324: Mukherjee gives bullet points about the human genome.  Easily one of the best chapters in the book.

Page 329: a reminder about the nature of variation: “to a biologist the nomenclature [of mutations like BRCA1, cystic fibrosis, Huntington’s] is absurd: the function of the BRCA1 gene is not to cause breast cancer when mutated, but to repair DNA when normal.”

Page 335: the mitochondrial genome comes only from our mothers, and is thus a self-contained way to date things back.  Pages 337 – 338: apparently we all at this point have one common female human ancestor.

Pages 344 – 349: skip these

Page 359: the Y chromosome is unpaired, so it “cannot be fixed, repaired, or recopied from another chromosome,” and is thus one of the most easily mutated chromosomes.  

Page 360: Mukherjee’s note on sex/recombination is very much worth reading and thinking about

Page 362: the “SRY” gene determines maleness

The chapters on gender identity and sexual orientation: I was really excited about / interested in these, but given Mukherjee’s treatment of intelligence, the sociopolitically-charged nature of these topics, and Ritchie’s commentary in his review, I unfortunately couldn’t bring myself to take Mukherjee too seriously here and will have to do my own research.

Page 401: so epigenetics (which kinda goes back to Lamarckianism – the idea of a permanent environmental stamp on the genome) is a fascinating topic.  However, again because of Ritchie’s review, it’s difficult for me to know how much credit to give this section, although it’s certainly somewhat less sociopolitically charged than other topics.

Page 410: here is the completed organizing rule of genetics: genes encode RNAs that build proteins that form/regulate organisms that sense environments that influences proteins/RNA that regulates genes.  In a nice circular flow.

Pages 423 – 424, 428 – 435: the David Vetter “bubble boy” story and the story of Jesse Gelsinger are very interesting studies of biological complexity in the real world that harkens back to the “unintended consequences” quote by Dr. Lock that I have in the earlier notes

Page 439: geneticist Mary-Claire King of the National Cancer Institute noted that one of the lessons on BRCA1 was “being comfortable with uncertainty for years”

Page 445: interesting footnote on how the C4 gene encodes a protein that eliminates viruses, bacteria, and cellular debris, and is also used to prune synapses

Page 449: this is perhaps one of the best single pages in the book that Mukherjee could’ve used to support his anti-playing-God viewpoint if he had wanted: certain forms of mental illness are strongly correlated with creative abilities or genius.  More broadly, given the complex genetic nature of many phenotypes, selecting for one trait may mean leaving behind another one that you want: it reminds me of why roses don’t smell like roses anymore.  (Select for looks and longevity, and you’re not selecting for scent…)

Page 454: a good reminder of the nature of randomness and chance/environment; in a business context, Phil Rosenzweig’s The Halo Effect is good here – it’s tempting to tell a clean A causes B story, but reality is often much more complicated.

Page 457: an example of Mukherjee’s over-the-top social commentary: “[genetic screening] technologies have also enabled stifling definitions of abnormalcy, partitioned the weak from the strong […]”  In context, I take objection to the word “stifling” – that’s a social opinion.  Here and elsewhere, Mukherjee too easily makes the leap here from modern genetics to Nazis; there are a number of other examples.  

On pages 460 – 461, for example, he puts down a proposition to direct publicly-funded therapeutic resources to children more likely to see a benefit based on their genetic tendency to respond as “genotype-driven social engineering.”  

Well, if it results in fewer kids going down the wrong road without spending more dollars, isn’t that fantastic public policy?  Mukherjee is far too quick to view the majority of genetically-driven medicine as suspect and directionally akin to Nazi Germany forced sterilization or murder of anyone viewed as an undesirable.  The two are far, far apart.

Page 466: the Gelsinger intervention did not go well, but on the other hand, an injection of a virus-loaded gene helped some hemophiliacs pretty well.

Page 481: one final example of Mukherjee’s irritating injection of his own viewpoint into the book: “If we define ‘intelligence’ as the performance on only one kind of problem in only one kind of test, then we will, indeed, find a ‘gene for intelligence.’  The genome is only a mirror for the breadth or narrowness of human imagination.  It is Narcissus, reflected.”  

I don’t think I even need to annotate that one at this point.

 

First Read: early 2018

Last Read: early 2018

Number of Times Read: 1

 

Review Date: early 2018

Notes Date: early 2018