Review & Recap: The Gene by Siddhartha Mukherjee

The Gene is a follow-up to Mukherjee’s amazing Emperor of All Maladies: A Biography of Cancer, and unfortunately doesn’t quite live up to it. It has lots of interesting information and repeats his customary style of intimate history, tackling a huge subject’s scientific, personal, historical and cultural factors by bringing the reader to the scene of the action. On the negative side, it doesn’t seem as natural to the author as the first book (presumably because he’s an oncologist and has more personal experience with the subject), the personal subplot felt unnecessary, and it has some factual errors and misrepresentations that I can’t look past. Let’s look at some highlights first (this part is super long, so if you want to see my complaints about it scroll to the end).

The book was split into six sections, dividing the time between 1865 and the present into the discovery of the concept of a gene and heredity (The "Missing Science of Heredity" (1865-1935)), the discovery of the physical material of genes and how they work … and also eugenics  (In the Sum of the Parts, There Are Only the Parts (1930-1970)), genetic engineering ("The Dreams of Geneticists" (1970-2001)), genetics as applied to understanding humans and the Human Genome Project (“The Proper Study of Mankind is Man” (1970-2005)), what the Human Genome Project has shown about our genome (“Through the Looking Glass” (2001 - 2015)) and genome editing (Post-Genome (2015 …)).

That said, the sections still aren’t very clear -- for example, eugenics features most of the way through in scattered chapters -- so I’m just going to talk about individual highlights.

The Gene Concept

The gene was first discovered as a concept long before people knew it had a physical form, never mind knowing about the double helix. The ancient Greeks had various ideas like that all the information to make a baby was in the man’s sperm, and the woman’s womb was just to provide nurture, and then ideas didn’t really advance much until Mendel, who did crossing experiments with hundreds of thousands of pea plants across seven different traits (wrinkled/smooth seeds, flower colour, tall/short, etc), and discovered various laws like the Laws of Segregation and Independent Assortment. One important thing he did was show that genes are particulate and inheritance is not ‘blending’ (i.e. when two people had a kid their babies were a blend of the parents’ traits and so eventually all traits would blend together and variation would disappear). He crossed true-breeding i.e. homozygous plants with two opposite alleles for a trait (e.g. wrinkled vs smooth seeds) and counted the proportions of the phenotypes (appearances) that resulted. This cross would be WW x SS and would result in all offspring being heterozygotes i.e. WS. Smooth is dominant so all of the seeds would be smooth. But when he crossed these heterozygous offspring with each other i.e. WS x WS, he’d get SS (smooth), 2 x WS (smooth) and 1 x WW (wrinkled). This showed that inheritance doesn’t blend because the wrinkled trait emerged unscathed after a generation just as wrinkled as ever.

Interestingly, Mendel failed his biology exam to become a teacher twice and that’s why he ended up doing the pea experiments in the monastery. I don’t blame him -- I would’ve hated biology at the time, when it was mostly about memorization (natural history) of different organisms and being able to name and classify them. Luckily he failed and contributed to the much more mechanistic and lawful biology we have now.

This section also talked about Darwin and Wallace and their conception of the idea of evolution by natural selection. One big issue with that was that at the time people thought inheritance worked by blending. Variation is needed for the theory of evolution by natural selection because without it there are no mutants for selection to act on via them surviving or reproducing better or worse than others.  Mendel’s discovery was thus very helpful for the theory of evolution, but unfortunately despite being contemporaries Darwin and Mendel never talked and Darwin doesn’t seem to have been aware of Mendel’s idea.

People also used to think people could inherit acquired characteristic a la Lamarck, so Weismann cut the tails off five generations of mice and showed that the baby mice were still born with tails. Pretty cruel way to do it but it worked I guess.

It also features Francis Galton, Darwin’s cousin, who badly wanted acclaim and ended up becoming a biometrician (got a ton of family histories and measured various traits to show that human traits tend to come in bell curves) and eugenicist.

During this period, genes were thought of as units of heredity -- not necessarily something with a physical basis, just a unit of information transfer between generations.

What are Genes?

An early clue that genes are physical things came from linkage. Some genes violate Mendel’s law of independent assortment, i.e. these genes for different characters are not passed on independently (e.g. gene for eye colour and one for nail texture). Experiments on flies determined that this was because these genes were beside each other on chromosomes  and that you could actually map the position of genes on chromosomes relative to each other by how independently they were inherited. Genes right next to each other are most likely to be passed on together, while recombination can occur between genes that are further apart and they’re more likely to be passed on. If genes could be physically near each other, that meant they had to have some physical basis and location.

Griffith’s transformation experiment showed that injecting a non-pathogenic live bacterial strain mixed with a heat-killed pathogenic strain resulted in a pathogenic strain that killed mice -- this was the ‘transforming principle’, where something from dead cells had passed to live cells and changed them. Poor mice. Apparently Griffith was very shy and his friends would have to force him to go to scientific meetings by stuffing him into a cab with a one-way fare. He published his results quietly in the fairly obscure Journal of Hygiene after some delay  "God is in no hurry, so why should I be?".

So the next thing was to figure out what the genetic material actual was. Originally scientists thought it must be proteins because there are so many different proteins and the incredible variation in them would make sense as genetic material because they could make all the different body parts of organisms. Nucleic acids like DNA surely couldn’t be it because they only have 4 bases (A, C, G, T) that repeat themselves, and how could they give all the diversity we see in organisms? Turns out it’s all in their order, and DNA is indeed what makes up genes. Experiments that used the transforming principles showed that using things like chemotrypsin and ribonuclease that break up proteins and RNA didn’t affect it, but things that break up DNA did.

Once DNA was accepted as the genetic material, its structure and way of working had to be elucidated. James Watson, Francis Crick, Rosalind Franklin and Maurice Wilkins were pivotal in discovering the double helix, and Watson and Crick figured out that A and T and G and C base pair with each other using Franklin’s crystallographic measurements. They also observed that this base-pairing immediately suggesting a way DNA could replicate itself. The central dogma was born soon after: DNA → RNA → protein.

Eugenics

Eugenics was a prominent theme; American, German, Austrian and British. It started with American eugenics and places like the Virginia Colonies, where social undesirables like prostitutes, orphans and poor people were deemed ‘moral imbeciles’ and sterilized to prevent their having kids and creating more imbeciles. One woman was deemed to be a hereditary moral imbecile because of prostitution and because her young daughter (who was doing fine in school) wrote notes to boys in class, and when her daughter had a child a social worker was sent to say the seven month old was an imbecile even though there was no way for her to know that. But the court nevertheless ruled that they were hereditary imbeciles and had them sterilized.

In Germany, before the much more famous genocide of Jews, there was Aktion T4, where disabled people were killed and many others sterilised. As detailed in Neurotribes specifically about autistic children, children were taken from their parents to ‘relieve the burden’ and then starved to death or gassed. Their families were told they died of a variety of causes -- one was said to have died from ‘warts on her lip’. By 1934, nearly 5000 adults were being stabilised every month in Germany, and there were 400,000 forced sterilisations between 1933 and 1943.

Genetic Engineering

The book details how academics and  companies like Genentech discovered how to express genes from other organisms like frogs and humans in bacteria so that the bacteria could pump out insulin, human growth hormone, alpha interferon (to treat blood cancers) and recombinant TPA (blood thinner) to treat human diseases without having to take e.g. the pancreases from millions of sheep as they were doing before.

It also has some pretty interesting stuff about scientists self-regulating as they realised the power of their new abilities to completely alter the traits of organisms and inject, say, a dangerous virus into a bacterium that typically lives in human intestines and could find its way in there easily -- the Asilomar conferences that put strict rules on genetic engineering.

Diseases

The story of AIDS is briefly told, and something I found interesting was that apart from the well-known cases of gay people and IV drug users getting HIV, haemophiliacs very commonly were infected because due to their lack of functional clotting factor VIII they had to get blood transfusions with factor VIII derived from blood from tons of different people, and it was enough for one of them to have HIV.

The part on tracking the Huntington’s gene was interesting. The person who started it had a family history of Huntington’s so was very invested in it. She wanted to figure out where the gene might be so needed a bunch of affected family trees but it was too rare in America to get that so she went to a village in Venezuela where 10-20% of people carry the Huntington’s gene (have or will develop it), i.e. about 2000 people in total in that one village. Something particularly interesting was a phenomenon called anticipation, in which Huntington’s onset comes earlier with each affected generation. It seems to be caused by a gene repeat, and the first person in the family to have it might have 30-40 repeats, but then some of these Venezuelan kids had 70-80 copies because the number of repeats increases with each affected generation and were developing the disease aged 12.

A footnote discussed ideas on why cystic fibrosis has not been selected out of the population and is in fact quite common. One factor is that it’s recessive; another, related one is that humans with one copy of the CF gene are partially protected from the worst effects of cholera thanks to a slightly diminished ability to lose salt and water through their cell membranes. This may have protected them during the Middle Ages and caused the gene to persist.

A really creepy aspect was the concept of ‘wrongful life’ -- parents suing a doctor on behalf of their child for not telling them their child would be born with a severe disability, saying that they would have aborted the child and it should never have been born. These cases don’t typically win because people say a disabled life is better than no life at all, but sometimes they do. I get wanting money because it can be very expensive to raise a severely disabled child, but it must feel awful for the child to hear their parents saying they should never have been born, and so I find it pretty creepy.

Sort of on that note, a quote from Francis Crick, co-discoverer of the double helix: 'no newborn should be declared human until it has passed certain tests regarding its genetic endowment'. Also, man, so many Nobel Laureates in the sciences were huge eugenicists. Okay I’ve read quote like that from like two or three, but that’s still a lot for humanity’s ‘best and brightest’.

The Human Genome Project

I learned that the project to sequence the human genome (all genes) involved competition between the government-sponsored scientists and Craig Venter’s startup called Celera. If this company had achieved it faster, it would’ve been a PR nightmare for the government, so Bill Clinton, who was president at the time, send an aide a note saying ‘Fix this!’ and the heads of both projects were brought to dinner and convinced to agree to announcing the completion of the project together whoever finished it first, and publishing their papers back-to-back in the same journal (due to further spats over Venter wanting to commercialise parts of the genome the second part didn’t end up working out).

It was also interesting that they got one of their computer scientists (James Kept) 100 desktop computers so he could run his code simultaneously on all of them, and had him icing his wrists every night from all the work.

Identity

This section was quite interesting, talking about the relation between genetics and various aspects of identity like race, gender identity, sex, sexuality and human evolution.

The first chapter, on race, was about the book The Bell Curve and how African-Americans consistently have an average IQ of 85 whereas whites have an average IQ of 100, even when these studies were carefully done outside the South and only taking results from after 1960. A typical explanation, and one I would have believed before, is that this is due to socioeconomic disparities (since poverty decreases performance on IQ tests), but the gap between average black IQ and white IQ (in America) actually widens at the top of the income bracket apparently. One explanation is that IQ tests are not actually good measures of intelligence, and that changing the weighting of different subtests within them dramatically changes results; another is that there seems to be some psychological/internalised racism factor affecting performance, because African-Americans do badly on IQ tests when told it’s to test their intelligence but do fine when told it’s to test a new electronic pen or to refine the test.

On human evolution, Mukherjee discusssed Mitochondrial Eve, a woman who lived 200,000 years ago in Africa to whom we can all trace our mitochondrial ancestry.

I found the sex determination stuff interesting. It wasn’t known for quite a while what determined maleness. Eventually the Y chromosome was discovered, but how did it work? What were the genes for ‘maleness’? It seems that the SRY gene is a master regulator for maleness: two illustrative lines of evidence are that forcibly activating SRY (by putting it into the X chromosome) makes mice with all XX (female) chromosomes that develop a penis and testicles and mount females. Women with Swyer syndrome are chromosomally male (XY) but have mutations in SRY and develop with a female phenotype.

Interestingly, XX mice that are exposed to a drug that blocks signalling of ‘femaleness’ to the brain have all the anatomical and physiological features of femaleness but are behaviourally male including mounting females.

The chapter on sexuality was interesting mainly for the quotes showing the extraordinary vitriol people have shown towards gay people. A psychiatrist in the late 1960s is quoted as saying:  'the homosexual's real enemy ... is not so much his perversion but [his] ignorance  of the possibility that he can be helped, plus his psychic masochism which leads him to shun treatment"; another, in 1956: 'permanent homosexuals, like all perverts, are neurotics'.

Dan Quayle, Vice President, in 1992 said: 'homosexuality is more of a choice than a biological situation ... it is a wrong choice"

A (gay, as it happens) scientist later showed that there is a chromosomal region associated with homosexuality (he carefully checked it wasn’t ‘sissyness’ or other things it could be confused for, and was very thorough with his experiments according to the book). The Daily Telegraph then said that now that the ‘gay gene’ was known: 'science could be used to eradicate it'. The scientist was attacked by both gay activists for fuelling people’s ideas of eradicating homosexuality via in utero testing, and by anti-gay activists for giving a biological ‘excuse’ to homosexuality. It’s just absolutely bizarre how hateful people are and especially were towards gay people. Like, obviously they don’t need treatment.

Epigenetics - how the environment affects our genomes

I was shocked to discover that during the Dutch Hongerwinter at the height of the famine they were down to 400 calories a day, or the equivalent of three potatoes. Someone said about that that a human being is ‘a stomach and certain instincts’, which I guess shows how intense it was and how dehumanising, when you’re so hungry you can’t think about anything else or really think much at all.

Children born to mothers who were pregnant during the Hongerwinter grew up more obese, as if their systems had figured they’d need to hold onto every piece of food it could get, and so did their children -- so clearly some chemical memory had been left of the event.

Gene Therapy

I found two of the gene therapy stories really compelling. The first was Ashanti DeSilva, a small girl with a non-functioning adenosine deaminase enzyme causing a form of Severe Combined Immunodeficiency resulting in severe damage to her T cells and frequent life-threatening infections. Some of Ashanti’s T cells were removed, had the functional gene inserted and were injected back into her, and the treatment seems to have worked -- but we can’t know for sure, because she was allowed to continue with the usual treatment of injecting the enzyme once a month, which confounded the results. The really sad part of that story is the quote from Ashanti, aged 4: “Mommy, you shouldn’t have had a child like me”.

The other story was that of Jesse Gelsinger, a teenager who lacked ornithine transcarbamoylase, a crucial enzyme in the urea cycle and thus couldn’t metabolise ammonia properly. He had a ‘mild’ variant of it -- he ‘only’ had to take 32 pills a day to keep his ammonia levels in check to stay alive and functioning, and when he broke his no-protein diet and ate a peanut butter sandwich he went into a coma -- because his gene mutation had occurred in one of his cells as an early embryo and gone into all the mitotic descendants of that cells so he was a human chimera and only had the deficiency in some of his cells. But still, y’know, pretty bad. So he was happy to volunteer for gene therapy to try to insert the OTC gene into his genome. The researchers wanted to use a virus to insert it and needed it to not be dangerous, so they used a stripped-down version of an adenovirus, the type that causes flu, since that type is well understood and not very harmful. Unfortunately, they didn’t do their due diligence and didn’t realise that precisely because this virus was so common it was an issue -- when they injected it, Jesse’s body raised antibodies against it and after an overwhelming immune response he died.

A more successful story of gene therapy is in the treatment of Haemophilia B; they used a virus to insert the gene for the missing clotting factor IX and were able to restore the concentration of factor IX to 5% of its normal value, which was enough because it resulted in a 90% decrease in the haemophiliacs’ bleeding episodes and requirement for injected factor IX.

Genetic Screening

I’d never heard of preimplantation genetic diagnosis before -- it involves screening IVF embryos for certain disorders before implantation to not only prevent disordered babies being born, but to prevent the need for even an abortion -- to prevent them from even growing in the womb at all. An example of this was a couple where one had a family history of X-linked ‘mental retardation’ and the other had a history of an X-linked immunological syndrome, both of which only affect males, so they screened the IVF embryos and selected only female ones.

Mukherjee makes the point that the largest ‘negative eugenics’ (killing or sterilising the undesirable; ‘positive eugenics’ is encouraging the ‘best’ to procreate with each other) project in history wasn’t the Holocaust; it’s the 10 million girls missing from adulthood in China and India due to abortion, infanticide and neglect of daughters.

He also discusses the criteria for genetic screening and intervention: highly penetrant genes (that gene has a strong effect and someone with that gene has a very high likelihood of having the negative phenotype); high suffering; justifiable interventions (aborting a foetus with Down Syndrome and performing a double mastectomy on someone with the BRCA1 gene, which makes your chance of breast cancer around 80%). It was kinda chilling how he just casually put the bit about Down’s in there; I don’t know if he’s reflecting his own beliefs or just describing the consensus, but it seems like a weird example of something when there are other things that would less controversially be considered ‘justifiable interventions’.

environment incongruity.

He describes the interesting concept of a ‘previvor’ e.g. someone who’s discovered that they have the BRCA1 gene knows they will most likely develop breast cancer but it hasn’t actually started yet, and someone with the Huntington’s gene knows they’ll develop Huntington’s later -- but for now, they’re previvors.

THE BAD & THE UGLY

First of all, a small gripe -- he didn’t have a table of contents with the chapters in it? It just had the six sections and their pages, not the many chapters within each. Anyway, onto the more important stuff.

Firstly, he says something that I’m not certain is correct, though I could be wrong. He says 'most evolutionary biologists agree that sex was created to enable rapid genetic reassortment" when from my study for schols everyone says the origin of sex is a mystery, and the rapid genetic reassortment argument (in which sexual organisms do better because they can more rapidly combine multiple good mutations in one organism rather than having to wait for each mutation to come up sequentially in the germline) only works if positive mutations occur  frequently enough that it actually makes a difference, which is not certain. There’s a whole literature on this but yeah seemed weird that he didn’t qualify that statement much.

What annoyed me the most was his treatment of autism. Some quotes:

• 'polygenic illnesses -- schizophrenia or autism, say' autism is not an illness
• 'Shockley...afflicted by a syndrome of paranoia, aggression and social withdrawal that several biographers have suggested was a form of high-functioning autism' suggested by others, yes, but this isn’t representative of autistic people and since he gives so little representation anyway I think he should’ve chosen not to include it
• Said most autistic children are peeling their skin off or smearing shit or something but some ‘rare’ children might maybe even possibly be ‘functional in most situations, and possibly hyperfunctional in some (a chess game, say, or a memory contest)' this is promoting stereotypes of what autistic (including Aspergers) people can do. Out of the ones I know, I’d say most of them actually prefer arts to the stereotypical maths/computer science tropes, and I’ve never met any who are typical ‘savants’. That’s not to say they don’t exist, but to say they are very much less common than they’re assumed to be, and autistic people are much more variable than we’re given credit for. This is especially irritating because he writes it in a way to suggest that this is the very pinnacle of what autistic people achieve. It’s in a section about how illnesses are actually about a mismatch between genetics and the environment, so it had the potential to be very woke (I subscribe to the social model of disability when it comes to autism) but he lets himself down by using stereotypes.
• Said high-functioning autists might do well in an environment that required the ‘sorting of objects by the subtlest gradations of color’ probably the least bad here because it does at least have some truth to it in terms of autistic sensory characteristic, but not exactly aiming high when that seems to be the point of the section.

I looked in the acknowledgements and his source on autism is a researcher whose lab looks for genetic ‘risk’ factors for autism and is explicitly looking for a cure. Why didn’t he consult autistic people instead, or in addition? Of course he was going to get a skewed picture of autism if he only consulted someone who wants to eradicate them.

Finally, I wasn’t a huge fan of the family thread he wove through the story. He inserted a couple of random chapters about his family history of schizophrenia, about his mother being a twin and about his family during Partition in India. They were fine, and the first chapter was pretty good, but they felt unnecessary since I was there for the science. They could also be very overdramatic; he describes his father and uncles spending all day solving a puzzle in the most incredibly dramatic way, with a lot of unnecessary metaphors. Maybe other people liked them though.

OVERALL

There was lots of interesting information here, and Mukherjee is talented at making us feel like we’re right there where it happened -- but a small bit of factual error and bad representation of autism make me dock it to 3 stars out of 5.