Siddhartha Mukherjee

Every genetic “illness” is a mismatch between an organism’s genome and its environment. In some cases, the appropriate medical intervention to mitigate a disease might be to alter the environment to make it “fit” an organismal form (building alternative architectural realms for those with dwarfism; imagining alternative educational landscapes for children with autism). In other cases, conversely, it might mean changing genes to fit environments. In yet other cases, the match may be impossible to achieve: the severest forms of genetic illnesses, such as those caused by nonfunction of essential genes, are incompatible with all environments. It is a peculiar modern fallacy to imagine that the definitive solution to illness is to change nature—i.e., genes—when the environment is often more malleable.

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1 Response to Siddhartha Mukherjee

  1. shinichi says:

    The Gene: An Intimate History

    by Siddhartha Mukherjee


    The task of writing that complete manifesto belongs to another generation, but perhaps we can scribe its opening salvos by recalling the scientific, philosophical, and moral lessons of this history:

    1. A gene is the basic unit of hereditary information. It carries the information needed to build, maintain, and repair organisms. Genes collaborate with other genes, with inputs from the environment, with triggers, and with random chance to produce the ultimate form and function of an organism.

    2. The genetic code is universal. A gene from a blue whale can be inserted into a microscopic bacterium and it will be deciphered accurately and with nearly perfect fidelity. A corollary: there is nothing particularly special about human genes.

    3. Genes influence form, function, and fate, but these influences typically do not occur in a one-to-one manner. Most human attributes are the consequence of more than one gene; many are the result of collaborations between genes, environments, and chance. Most of these interactions are nonsystematic—i.e., they occur through the intersection between a genome and fundamentally unpredictable events. And some genes tend to influence only propensities and tendencies. We can thus reliably predict the ultimate effect of a mutation or variation on an organism for only a minor subset of genes.

    4. Variations in genes contribute to variations in features, forms, and behaviors. When we use the colloquial terms gene for blue eyes or gene for height, we are really referring to a variation (or allele) that specifies an eye color or height. These variations constitute an extremely minor portion of the genome. They are magnified in our imagination because of cultural, and possibly biological, tendencies that tend to amplify differences. A six-foot man from Denmark and a four-foot man from Demba share the same anatomy, physiology, and biochemistry. Even the two most extreme human variants—male and female—share 99.688 percent of their genes.

    5. When we claim to find “genes for” certain human features or functions, it is by virtue of defining that feature narrowly. It makes sense to define “genes for” blood type or “genes for” height since these biological attributes have intrinsically narrow definitions. But it is an old sin of biology to confuse the definition of a feature with the feature itself. If we define “beauty” as having blue eyes (and only blue eyes), then we will, indeed, find a “gene for beauty.” 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.

    6. It is nonsense to speak about “nature” or “nurture” in absolutes or abstracts. Whether nature—i.e., the gene—or nurture—i.e., the environment—dominates in the development of a feature or function depends, acutely, on the individual feature and the context. The SRY gene determines sexual anatomy and physiology in a strikingly autonomous manner; it is all nature. Gender identity, sexual preference, and the choice of sexual roles are determined by intersections of genes and environments—i.e., nature plus nurture. The manner in which “masculinity” versus “femininity” is enacted or perceived in a society, in contrast, is largely determined by an environment, social memory, history, and culture; this is all nurture.

    7. Every generation of humans will produce variants and mutants; it is an inextricable part of our biology. A mutation is only “abnormal” in a statistical sense: it is the less common variant. The desire to homogenize and “normalize” humans must be counterbalanced against biological imperatives to maintain diversity and abnormalcy. Normalcy is the antithesis of evolution.

    8. Many human diseases—including several illnesses previously thought to be related to diet, exposure, environment, and chance—are powerfully influenced or caused by genes. Most of these diseases are polygenic—i.e., influenced by multiple genes. These illnesses are heritable—i.e., caused by the intersection of a particular permutation of genes—but not easily inheritable—i.e., likely to be transmitted intact to the next generation, since the permutations of genes are remixed in each generation. Instances of each single-gene—monogenic—disease are rare, but, in sum, they turn out to be surprisingly common. More than ten thousand such diseases have been defined thus far. Between one in a hundred and one in two hundred children will be born with a monogenic disease.

    9. Every genetic “illness” is a mismatch between an organism’s genome and its environment. In some cases, the appropriate medical intervention to miti
    gate a disease might be to alter the environment to make it “fit” an organismal form (building alternative architectural realms for those with dwarfism; imagining alternative educational landscapes for children with autism). In other cases, conversely, it might mean changing genes to fit environments. In yet other cases, the match may be impossible to achieve: the severest forms of genetic illnesses, such as those caused by nonfunction of essential genes, are incompatible with all environments. It is a peculiar modern fallacy to imagine that the definitive solution to illness is to change nature—i.e., genes—when the environment is often more malleable.

    10. In exceptional cases, the genetic incompatibility may be so deep that only extraordinary measures, such as genetic selection, or directed genetic interventions, are justified. Until we understand the many unintended consequences of selecting genes and modifying genomes, it is safer to categorize such cases as exceptions rather than rules.

    11. There is nothing about genes or genomes that makes them inherently resistant to chemical and biological manipulation. The standard notion that “most human features are the result of complex gene-environment interactions and most are the result of multiple genes” is absolutely true. But while these complexities constrain the ability to manipulate genes, they leave plenty of opportunity for potent forms of gene modification. Master regulators that affect dozens of genes are common in human biology. An epigenetic modifier may be designed to change the state of hundreds of genes with a single switch. The genome is replete with such nodes of intervention.

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