(Published version: https://www.the-tls.co.uk/articles/the-enemy-within/)
Siddhartha Mukherjee, The Gene: An intimate history 592 pp. Bodley Head Press. £25.00
It is no ordinary history of genetics where, midway through, we read the following:
In the Bible, Ham’s descendants are cursed because he stumbles on his father, Noah, drunken and naked, his genitals exposed, lying in a field in the half-light of dawn. In the modern version of that story, you encounter your father, demented and naked, in the half-light of the guest bathroom – and see the curse of your own future, illuminated.
Siddhartha Mukherjee is a cancer specialist, whose previous book The Emperor of All Maladies: A Biography of Cancer won the 2011 Pulitzer Prize for general non-fiction. The physician will out: in The Gene: An Intimate History, Mukherjee’s writing and thinking are at their best when his subject is illness. The curse he fears in that bathroom encounter with his eighty-two-year-old father is not the generic infirmity of old age but the genetic tendency to mental illness that, he reckons, runs in his family. One uncle was undone by manic depression, another by schizophrenia. A cousin with schizophrenia lives out his medicated days in an institution in Calcutta. The book opens with Mukherjee and his father visiting poor Moni, the light in whose pupils ‘had dulled and nearly vanished, as if someone had entered his eyes with a minute paintbrush and painted them gray’.
Between these absorbing personal vignettes stretches a very long retelling of the growth of scientific knowledge about inheritance, from Gregor Mendel through to the biotech firm Genentech. Again, the physician will out, though here with less straightforwardly pleasing results. Mukherjee cherishes genetics for having pulled cancer medicine out of the doldrums, and this baseline admiration shines through in his approach to writing history. He treats the past mainly as providing a chronological frame on which to hang the introductory genetics lessons that he wants to impart, together with colourful stories to wrap them up in. There is little concern to avoid anachronism or re-examine received wisdom. Scale up the historical-enrichment passages in a genetics textbook, organize them according to the periodization favoured by the leaders of the Human Genome Project, render the whole in fluent, simile-laden prose, and you have something that reads a lot like Mukherjee’s history. The textbooks deal with eugenics, and so does Mukherjee, unsparingly though not always subtly (he turns Francis Galton, coiner of ‘eugenics’, into a pantomime villain). The Gene is very much what Mukherjee tells us it is: a ‘prequel’ to the cancer biography, telling the tale of the thing which cancer is liable to distort.
Up to that bathroom moment, the history-coated genetics that we get goes roughly as follows. Once Mendel’s unjustly ignored discovery of the gene, understood as an atom of hereditary information, was belatedly recognized in 1900, genes, dominant and recessive, were held to explain inheritance patterns on the model of those Mendel had found at his monastery in Brünn, among his yellow or green, round or wrinkled garden peas. But nobody could say, exactly, what genes were or what they did. That started to change between the 1910s and the 1940s, when genes became known as bits of chromosome responsible for directing the synthesis of proteins, and genetic disease came to be understood as due to chromosomal alterations that disrupt normal protein synthesis. Francis Crick and James Watson’s 1953 paper announcing that DNA – by then under suspicion as the main genetic chemical – has the structure of a double helix ushered in a new molecular era. Talk of ‘the genetic code’ dates from then, referring to the cell’s rule book for translating sequences of DNA bases into the amino acids making up proteins. Disease-causing mutations were now understood as errors arising in a gene’s DNA sequence. It turned out, for example, that behind sickle-cell anaemia lies just one change in one base pair in the gene encoding the oxygen-carrying protein haemoglobin. In the 1960s, in the wake of François Jacob and Jacques Monod’s demonstration that proteins can turn genes on and off in response to environmental cues, there came a new appreciation of genes’ abilities to regulate their own expression. The 1970s marked the start of a new era again, as geneticists learned to cut and paste genes at will and also to read DNA sequences. Out of these innovations came, among other therapeutic marvels, synthetic insulin and, at a time when HIV made the blood transfusions on which haemophiliacs depended dangerous, synthetic blood-clotting factor VIII.
But then we reach Mukherjee’s discussion of his stricken father’s condition – that other intimate history of the gene – and the triumphalism evaporates. The dementia is not, after all, the family madness striking again, but a symptom of something else: a swelling of the ventricles in the brain, probably due to an excess of fluid. To become intimate with the genetics of normal pressure hydrocephalus (NPH) is to be immersed in a world of complication. Mukherjee is an outstanding guide:
It is … quite likely to be a genetic disease – although not ‘genetic’ in the same sense as sickle-cell anemia or hemophilia. No single gene governs the susceptibility to this bizarre illness. Multiple genes, spread across multiple chromosomes, [are involved]…. Variations in any of these genes may alter the physiology of the aqueducts and ventricles, changing the manner in which the fluid moves through the channels. Environmental influences, such as aging or cerebral trauma, interpose further layers of complexity. There is no one-to-one mapping of one gene and one illness. Even if you inherit the entire set of genes that causes NPH in one person, you may still need an accident or an environmental trigger to ‘release’ it (in my father’s case, the trigger was mostly likely his age)…. It is a Delphic boat of a disease – determined not by one gene, but by the relationship between genes, and between genes and the environment.
There follows a further, fastidious unpicking of the ways in which this condition is and is not genetic, is and is not environmental, is and is not the product of chance. It is hard to think how these pages could be improved.
This willingness to give complexity and diversity their due lifts a good deal of the second half of the book. Here, Mukherjee brings his growth-of-knowledge story up to the present, with an emphasis on human genetics and occasional stops around the Mukherjee family tree. The coverage of topics is a little quirky – there is nothing here, for example, about genetically modified foods or the use of DNA fingerprinting – but the author touches on the major medically relevant developments. He makes an attractive hero out of Victor McKusick, founder of a Baltimore genetic medicine clinic and compiler of the standard catalogue of genes involved in human diseases. Just as, in the late 1960s and early 1970s, the arrival of prenatal testing for chromosomal conditions, together with the spread of legalized abortion, turned genetic medicine into an intervention science (and refreshed its eugenic roots), McKusick and colleagues began effectively putting not only ‘genetic’ in quotation marks, but also ‘disease’, which is increasingly understood as a mismatch between constitution and environment. Even haemophilia and sickle-cell anaemia manifest very differently in different individuals depending on what is interacting with what, and how, and when, and where. Mukherjee quotes McKusick in 1991, at a conference on legal and ethical issues surrounding the just-launched Human Genome Project, warning about the ‘genetic-commercial complex’, selling an exaggerated certainty about what genetic tests predict to parents increasingly under pressure to pay for and abide by them. When, ten years later, the full DNA sequence for humans was published, it revealed far fewer genes than expected – considerably fewer than in the genomes for corn, rice and wheat. ‘The difference between “human” and “breakfast cereal”’, writes Mukherjee, ‘is not a matter of gene numbers, but of the sophistication of gene networks. It is not what we have; it is how we use it’. The recent rise of epigenetics, devoted to understanding the biochemical means beyond DNA by which cells regulate gene networks (and more, controversially, the persistence of the resulting patterns across generations), has reinforced the general message that context matters in determining what a gene determines.
Over and over again, Mukherjee makes this message his own, in mini-essays on everything from race and IQ to breast cancer. But he also has a contrary and, as the book proceeds, increasingly thumping message. Underlying all this surface complexity and diversity there is a deep simplicity, just as Mendel found. If a gene is in version A, you get character A; if the gene is in version B, you get character B. In a minor way this dismissiveness of context, and the jarring incoherence it introduces, show up in his mini-essay on the genetics of Moni’s affliction, schizophrenia. Genes are, we learn, part of the causal mix behind schizophrenia, which become ‘genes for schizophrenia’ only with the collaboration of environment and chance. Schizophrenia itself is not one but many, and so are the relevant genes: over a hundred genomic regions have been implicated, and, according to Mukherjee, ‘no single gene stands out as the sole driver of the risk’ – a risk which may in any case be of enhanced creativity as much as of diminished sanity. But then, in a long footnote added at proof stage, Mukherjee appears to take it all back, reporting excitedly about a study from January this year that found a single gene associated strongly with schizophrenia: if you have the troublemaking variant, then you will get schizophrenia, other things being equal; and if you don’t have the variant, you won’t.
The Mendelian binary is pervasive in his coverage of human genetics: male or female; gay or straight; novelty-seeking (‘neophilic’) or novelty-avoiding (‘neophobic’); and so on. The least hedged discussion concerns sex determination. Mukherjee regards it as especially important in exposing the notion that nature and nurture, genes and environment interact at every level as ‘nonsense – an armistice between fools’:
At the top of the [causal] cascade, nature works forcefully and unilaterally. Up top, gender is quite simple – just one master gene flicking on and off. If we learned to toggle that switch – by genetic means or with a drug – we could control the production of men or women, and they would emerge with male versus female identity (and even large parts of anatomy) quite intact.
He knows that his master gene, called SRY, requires a cellular context to function, and that not any cellular context will do. So why the denial, and why the vehemence of it? Partly the answer lies in that physician’s admiration of genetics. The flipside, for Mukherjee, is indignation at those in the past who, for professional or ideological reasons (or both), upheld the all-determining nature of the environment, thwarting progress and sometimes wrecking the lives of vulnerable people (‘he’s gay because of your bad parenting’, ‘just raise the boy as a girl and the botched circumcision will sort itself out’). But Mukherjee could have signalled his disapproval without insisting unconvincingly – and in spite of everything else he writes so well about genes – that sometimes they act all on their own, untrammelled.
Behind that insistence are two further misapprehensions. One is the idea that if genes were, in some fundamental way, dependent on context for their effects, then humans could never manipulate genes in reliably, and of course they can – so genes must, in some fundamental way, be context-independent. Mukherjee puts this view most plainly in his chapter on epigenetics. When a version of the chapter appeared in the New Yorker in May, ahead of The Gene’s publication, it provoked online criticism from scientists who judged it as misleadingly demoting genes from a position of influence. But the thrust in the book is very much the opposite. For Mukherjee, what is most exciting about epigenetics is that humans have learned to strip its encumbrances away, thus opening the path to the most powerful form of gene therapy. Research in this area got more or less shut down after the death, in Philadelphia in 1999, of Jesse Gelsinger, a young man with a non-terminal genetic disease whose body went into immunological meltdown in reaction to genetically modified viruses designed to deliver functional copies of the faulty gene into his cells. But a chastened and cautious comeback is underway. In the meantime, scientists have learned how to wipe away the epigenetic marks that make a mature cell into a liver cell or a heart cell or whatever, restoring it to the blank-slate condition of an embryonic stem cell: the ideal vehicle for delivering genes into an embryo, thus making any genetic fixes permanent, hereditary. In Mukherjee’s estimation, the availability of such cells, in conjunction with the greater speed and precision of gene editing made possible by a new system called CRISPR/Cas9, has put ‘germ-line’ gene therapy tantalizingly close.
That may be so, but not because genes are, after all, autonomous in their functioning. Suppose that you and I suffer from haemophilia, and we participate in the same viral-delivery gene therapy trial. A few months later, you report a dramatic reduction in the number and nastiness of bleeding episodes. I report no discernible difference. On studying me further, the drug company learns that there is something in my genome or epigenome or wider environment (my diet, my stress-inducing work, the smog-choked air I breathe in my city) that has inhibited gene uptake or expression at the needed levels. In the future, the company will package up the clotting-factor gene along with whatever extra will, as it turns out, bring people like me into the therapeutic loop. The expansion of that loop will be a marvellous achievement, to be celebrated. But it will not in any way vindicate the context-independence of genes. Rather, it will vindicate all the further research and clever engineering needed to multiply the worldly contexts in which the therapy – like so many lab-originating technologies before it – can be made to work. As for the SRY gene, the fact that inserting the mouse form of the gene into the genome of an otherwise female mouse will induce her to grow testes and a penis and to mount female mice is, for similar reasons, no badge of the gene’s autonomy. There will be mice in which that works and, especially outside the lab (because lab mice are genetically standardized and live in standard environments), mice in which it doesn’t. Context will make the difference to the gene’s making a difference or not.
The other misapprehension concerns the history of knowledge about inheritance. On the textbook version that Mukherjee takes over wholesale, Mendel got it right in his 1866 paper when, by dividing pea characters into neat binaries, he discovered that hereditary information is atomic in nature. (Mukherjee’s Mendel is not just brilliant but angelic, in contrast to the dimwit, demon Galton.) Likewise the Cambridge biologist William Bateson got it right in 1900 in backing Mendel, proclaiming that an ‘exact determination of the laws of heredity will probably work more change on man’s outlook on the world, and in his power over nature, than any other advance in natural knowledge that can be foreseen’ – a line that serves as an epigraph to the book. For Mukherjee, we owe to Mendel and his followers the gene’s joining the atom and the byte on the top tier of twentieth-century scientific entities: the fundamental units organizing the most powerful theories and enabling the most powerful technologies. A stirring vision – but also a profoundly ahistorical one. Mendel wrote nothing about information (a mid-twentieth-century concept) or even about inheritance (an early twentieth-century reading). As the historian Robert Olby showed, the alleged atomism too is a mirage, projected from later times onto Mendel’s words. Mendel was rightly proud of his meticulously conducted experiments, the new mathematical regularities that they had made visible among the offspring of his hybrid pea plants, and the way that his conjectures about cellular materials neatly explained the distribution of characters in those plants. But he never regarded his paper as laying down new laws of heredity – and his contemporaries read him accordingly. When, after Mendel’s death, inheritance and its laws became a lively topic, Bateson read the paper differently. He met with sharp criticism – far more potent than the textbooks, and Mukherjee, let on. Not even peas, as Bateson’s Oxford rival W. F. R. Weldon demonstrated, come in the supposed Mendelian binaries of yellow or green, round or wrinkled. They display characters all over the spectrum, depending on the varied interactions of chromosomes, context and chance. Dominance, for Weldon, was not absolute but relative: a view whose pioneering figure he took to be none other than Galton.
Better history would have made The Gene a better, and a bolder, book. But even with its limitations, it is a remarkably instructive, stimulating and, at every level of its generous construction, artful work of popular science. It begins with that quotation from Bateson nestled alongside one from Haruki Murakami. It ends with father and son returning, in reflective mood, from their visit to Moni’s institution. En route they stop at the family’s former house. His father wants to talk about the social and political past: about Partition and its rupturing of the country’s life and the family’s life. Siddhartha Mukherjee’s own thoughts take a different and – for the reader by this point – distinctive tack. The real tragedy that befell his uncles, he muses, was that they were born too soon, in advance of the genetic medicine that might have saved them from themselves.
Gregory Radick is Professor of History and Philosophy of Science at the University of Leeds and Director of the Leeds Humanities Research Institute. He has published widely on the histories of Darwinism, genetics and the behavioural sciences. A new book, Disputed Inheritance: The Battle over Mendel and the Future of Biology, is in preparation for the University of Chicago Press.