The Gene

by Siddhartha Mukherjee

  But there was another story: of normalcy before it tips into malignancy. If cancer, to twist the description of the monster from Beowulf, is the “distorted version of our normal selves,” then what generates the undistorted variants of our normal selves? Gene is that story—of the search for normalcy, identity, variation, and heredity. It is a prequel to Emperor’s sequel.

  There are innumerable people to thank. Books about family and heredity are not so much written as lived. Sarah Sze, my wife, my most passionate interlocutor and reader, and my daughters, Leela and Aria, were daily reminders of my stake in genetics and the future. My father, Sibeswar, and mother, Chandana, are an inextricable part of this story. My sister, Ranu, and her husband, Sanjay, provided moral interceptions when needed. Judy and Chia-Ming Sze, and David Sze and Kathleen Donohue, sustained discussions about the family and the future.

  Extraordinarily generous readers ensured the factual accuracy of this book and provided comments on content, including Paul Berg (genetics and cloning), David Botstein (gene mapping), Eric Lander (Human Genome Project), Robert Horvitz and David Hirsh (worm biology), Tom Maniatis (molecular biology), Sean Carroll (evolution and gene regulation), Harold Varmus (cancer), Nancy Segal (twin studies), Inder Verma (gene therapy), Jennifer Doudna (genome editing), Nancy Wexler (human gene mapping), Marcus Feldman (human evolution), Gerald Fishbach (schizophrenia and autism), David Allis (epigenetics), Francis Collins (gene mapping and the Human Genome Project), Eric Topol (human genetics), and Hugh Jackman (Wolverine; mutants).

  Ashok Rai, Nell Breyer, Bill Helman, Gaurav Majumdar, Suman Shirodkar, Meru Gokhale, Chiki Sarkar, David Blistein, Azra Raza, Chetna Chopra, and Sujoy Bhattacharyya read early manuscripts and supplied immensely valuable comments. Conversations with Lisa Yuskavage, Matvey Levenstein, Rachel Feinstein, and John Currin were indispensable. A passage from this book appeared in an essay on Yuskavage’s work (“Twins”), and another passage in my essay The Laws of Medicine, 2015. Brittany Rush patiently (and brilliantly) compiled all eight hundred–odd references and worked on mind-numbing aspects of production; Daniel Loedel read and edited the manuscript over a weekend to prove that it could be achieved.

  The illustration on the cover, by Gabriel Orozco—a friend and close reader—crystallized the essential ideas in the book into a diagram of continuous, intersecting circles. I could not imagine a more beautiful image for this book.

  Nan Graham: Did you read all sixty-eight drafts? You did—and with Stuart Williams and indomitable Sarah Chalfant, who first saw this book through the pinhole of a two-paragraph proposal, you gave Gene shape, form, clarity, gravity, and urgency. Thank you.

  Glossary

  Allele: A variant or alternative form of a gene. Alleles are usually created by mutations, and can be responsible for phenotypic variations. A gene can have multiple alleles.

  Central dogma, or Central theory: The theory that biological information in most organisms moves from genes in DNA to messenger RNA to proteins. This theory has been modified several times. Retroviruses contain enzymes that can be used to build DNA from an RNA template.

  Chromatin: The material from which chromosomes are composed. Chromatin takes its name from chroma (“color”), since it was initially found by staining cells with dyes. Chromatin may consist of DNA, RNA, and proteins.

  Chromosome: A structure within a cell comprised of DNA and proteins that stores genetic information.

  DNA: Deoxyribonucleic acid, a chemical that carries genetic information in all cellular organisms. It is usually present in the cell as two paired, complementary strands. Each strand is a chemical chain made up of four chemical units—abbreviated A, C, T, and G. Genes are carried in the form of a genetic “code” in the strand and the sequence is converted (transcribed) into RNA and then translated into proteins.

  Enzyme: A protein that accelerates a biochemical reaction.

  Epigenetics: The study of phenotypic variations that are not caused by changes in the primary DNA sequence (i.e., A, C, T, G) but by chemical alterations of DNA (e.g., methylation) or changes in packaging of DNA via DNA-binding proteins (e.g., histones). Some of these alterations are heritable.

  Gene: A unit of inheritance, normally comprised of a stretch of DNA that codes for a protein or for an RNA chain (in special cases, genes might be carried in RNA form).

  Genome: The full complement of all genetic information within the organism. A genome includes protein-encoding genes, genes that do not encode proteins, the regulatory regions of genes, and sequences of DNA with yet-unknown functions.

  Genotype: An organism’s collection of genetic information that determines its physical, chemical, biological, and intellectual characteristics (see “phenotype”).

  Mutation: An alteration in the chemical structure of DNA. Mutations can be silent—i.e., the change might not affect any function of the organism—or can result in a change in the function or structure of an organism.

  Nucleus: A membrane-enclosed cellular structure or organelle that is found in animal and plant cells, but not in bacterial cells. Chromosomes (and genes) in animal cells are contained in the nucleus. In animal cells, most genes are nuclear, although some genes are also found in mitochondria.

  Organelle: A specialized subunit within a cell that is typically dedicated to a specific function. Individual organelles are usually separately enclosed within their own membranes. Mitochondria are organelles dedicated to the production of energy.

  Penetrance: The proportion of organisms that carry a particular variant of a gene that also expresses the associated trait or phenotype. In medical genetics, penetrance refers to the proportion of individuals carrying a genotype that manifest the symptoms of an illness.

  Phenotype: The set of an individual’s biological, physical, and intellectual traits, such as skin color or eye color. Phenotypes can also include complex traits, such as temperament or personality. Phenotypes are determined by genes, epigenetic alterations, environments, and random chance.

  Protein: A chemical comprised, at its core, of a chain of amino acids that is created when a gene is translated. Proteins carry out the bulk of cellular functions, including relaying signals, providing structural support, and accelerating biochemical reactions. Genes usually “work” by providing the blueprint for proteins. Proteins can be modified chemically by the addition of small chemicals such as phosphates or sugars or lipids.

  Reverse transcription: The process by which an enzyme (reverse transcriptase) uses a chain of RNA as a template to build a chain of DNA. Reverse transcriptase is found in retroviruses.

  Ribosome: A cellular structure composed of protein and RNA that is responsible for the decoding of messenger RNA into proteins.

  RNA: Ribonucleic acid, a chemical that performs several functions in the cells, including acting as an “intermediate” message for a gene to be translated into a protein. RNA is composed of a chain of bases—A, C, G, and U—strung together along a sugar-phosphate backbone. Typically, RNA is found as a single strand in a cell (unlike DNA, which is always double-stranded), although double-stranded RNA can be formed under special conditions. Some organisms, such as retroviruses, use RNA to carry their genetic information.

  Traits, dominant and recessive: A physical or biological feature of an organism. Traits are typically encoded by genes. Many genes might encode a single trait, and a single gene might also encode many traits. A dominant trait is one that usually asserts itself when both dominant and recessive alleles are present, while a recessive trait is one that asserts itself only when both alleles are recessive. Genes can also be co-dominant: in this case, an intermediate trait is manifested when both dominant and recessive alleles are present.

  Transcription: The process of generating an RNA copy of a gene. In transcription, the genetic code in DNA (ATG-CAC-GGG) is used to build an RNA “copy” (AUG-CAC-GGG).

  Transformation: The horizontal transfer of genetic material from one organism to another. Typically, bacteria can exchange genetic information with
out reproduction by the transfer of genetic material between organisms.

  Translation (of genes): The process by which genetic information is converted from the RNA message into a protein by the ribosome. During translation, a codon consisting of a triplet of bases in RNA (e.g., AUG) is used to add amino acids to a protein (e.g., Methionine). A chain of RNA can thus encode a chain of amino acids.

  About the Author

  © DEBORAH FEINGOLD

  SIDDHARTHA MUKHERJEE is a cancer physician and researcher. He is the author of The Gene, The Laws of Medicine, and The Emperor of All Maladies: A Biography of Cancer, winner of the 2011 Pulitzer Prize in general nonfiction. Mukherjee is an assistant professor of medicine at Columbia University and a staff cancer physician at Columbia University Medical Center. A Rhodes scholar, he graduated from Stanford University, the University of Oxford, and Harvard Medical School. He has published articles in Nature, Cell, The New England Journal of Medicine, Neuron, The New York Times, and The New Republic. His laboratory works on genes involved in blood cancer and the genesis of bone and bone marrow. He lives in New York with his wife and daughters.

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  Notes

  Epigraph

  An exact determination of the laws of heredity: W. Bateson, “Problems of Heredity as a Subject for Horticultural Investigation,” in A Century of Mendelism in Human Genetics, ed. Milo Keynes, A.W.F. Edwards, and Robert Peel (Boca Raton, FL: CRC Press, 2004), 153.

  Human beings are ultimately nothing but carriers: Haruki Murakami, 1Q84 (London: Vintage, 2012), 231.

  Prologue: Families

  The blood of your parents is not lost in you: Charles W. Eliot, The Harvard Classics: The Odyssey of Homer, ed. Charles W. Eliot (Danbury, CT: Grolier Enterprises, 1982), 49.

  They fuck you up, your mum and dad: Philip Larkin, High Windows (New York: Farrar, Straus and Giroux, 1974).

  In 2012, several further studies: Maartje F. Aukes et al., “Familial clustering of schizophrenia, bipolar disorder, and major depressive disorder,” Genetics in Medicine 14, no. 3 (2012): 338–41; and Paul Lichtenstein et al., “Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study,” Lancet 373, no. 9659 (2009): 234–39.

  “In the sum of the parts, there are only the parts”: Helen Vendler, Wallace Stevens: Words Chosen out of Desire (Cambridge, MA: Harvard University Press, 1984), 21.

  “The whole organic world”: Hugo de Vries, Intracellular Pangenesis: Including a Paper on Fertilization and Hybridization (Chicago: Open Court, 1910), 13.

  “Alchemy could not become chemistry until”: Arthur W. Gilbert, “The Science of Genetics,” Journal of Heredity 5, no. 6 (1914): 239.

  “That the fundamental aspects of heredity”: Thomas Hunt Morgan, The Physical Basis of Heredity (Philadelphia: J. B. Lippincott, 1919), 14.

  “the quest for eternal youth”: Jeff Lyon and Peter Gorner, Altered Fates: Gene Therapy and the Retooling of Human Life (New York: W. W. Norton, 1996), 9–10.

  PART ONE: THE “MISSING SCIENCE OF HEREDITY”

  This missing science of heredity: Herbert G. Wells, Mankind in the Making (Leipzig: Tauchnitz, 1903), 33.

  JACK: Yes, but you said yourself: Oscar Wilde, The Importance of Being Earnest (New York: Dover Publications, 1990), 117.

  The Walled Garden

  The students of heredity: G. K. Chesterton, Eugenics and Other Evils (London: Cassell, 1922), 66.

  the Augustinians, fortunately, saw no conflict: Gareth B. Matthews, The Augustinian Tradition (Berkeley: University of California Press, 1999).

  In October 1843, a young man from Silesia: Details of Mendel’s life and the Augustinian monastery are from several sources, including Gregor Mendel, Alain F. Corcos, and Floyd V. Monaghan, Gregor Mendel’s Experiments on Plant Hybrids: A Guided Study (New Brunswick, NJ: Rutgers University Press, 1993); Edward Edelson, Gregor Mendel: And the Roots of Genetics (New York: Oxford University Press, 1999); and Robin Marantz Henig, The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, the Father of Genetics (Boston: Houghton Mifflin, 2000).

  The tumult of 1848: Edward Berenson, Populist Religion and Left-Wing Politics in France, 1830–1852 (Princeton, NJ: Princeton University Press, 1984).

  “Seized by an unconquerable timidity”: Henig, Monk in the Garden, 37.

  he applied for a job to teach mathematics: Ibid., 38.

  In the late spring of 1850, an eager Mendel: Harry Sootin, Gregor Mendel: Father of the Science of Genetics (New York: Random House Books for Young Readers, 1959).

  On July 20, in the midst of an enervating heat wave: Henig, Monk in the Garden, 62.

  On August 16, he appeared before his examiners: Ibid., 47.

  In 1842, Doppler, a gaunt, acerbic: Jagdish Mehra and Helmut Rechenberg, The Historical Development of Quantum Theory (New York: Springer-Verlag, 1982).

  But in 1845, Doppler had loaded a train: Kendall F. Haven, 100 Greatest Science Discoveries of All Time (Westport, CT: Libraries Unlimited, 2007), 75–76.

  But these categories, originally devised by the Swedish botanist: Margaret J. Anderson, Carl Linnaeus: Father of Classification (Springfield, NJ: Enslow Publishers, 1997).

  “Not the true parent is the woman’s”: Aeschylus, The Greek Classics: Aeschylus—Seven Plays (n.p.: Special Edition Books, 2006), 240.

  “She doth but nurse the seed”: Ibid.

  from Indian or Babylonian geometers: Maor Eli, The Pythagorean Theorem: A 4,000-Year History (Princeton, NJ: Princeton University Press, 2007).

  A century after Pythagoras’s death: Plato, The Republic, ed. and trans. Allan Bloom (New York: Basic Books, 1968).

  In one of the most intriguing passages: Plato, The Republic (Edinburgh: Black & White Classics, 2014), 150.

  “For when your guardians are ignorant”: Ibid.

  The result, a compact treatise: Aristotle, Generation of Animals (Leiden: Brill Archive, 1943).

  “And from deformed”: Aristotle, History of Animals, Book VII, ed. and trans. D. M. Balme (Cambridge, MA: Harvard University Press, 1991).

  “just as lame come to be from lame”: Ibid., 585b28–586a4.

  “Men generate before they yet have certain characters”: Aristotle, The Complete Works of Aristotle: The Revised Oxford Translation, ed. Jonathan Barnes (Princeton, NJ: Princeton University Press, 1984), bk. 1, 1121.

  Aristotle offered an alternative theory: Aristotle, The Works of Aristotle, ed. and trans. W. D. Ross (Chicago: Encyclopædia Britannica, 1952), “Aristotle: Logic and Metaphysics.”

  “[Just as] no material part comes from the carpenter”: Aristotle, Complete Works of Aristotle, 1134.

  biologist Max Delbrück would joke that Aristotle: Daniel Novotny and Lukás Novák, Neo-Aristotelian Perspectives in Metaphysics (New York: Routledge, 2014), 94.

  In the 1520s, the Swiss-German alchemist Paracelsus: Paracelsus, Paracelsus: Essential Readings, ed. and trans. Nicholas Godrick-Clarke (Wellingborough, Northamptonshire, England: Crucible, 1990).

  “floating . . . in our First Parent’s loins”: Peter Hanns Reill, Vitalizing Nature in the Enlightenment (Berkeley: University of California Press, 2005), 160.

  In 1694, Nicolaas Hartsoeker, the Dutch physicist: Nicolaas Hartsoeker, Essay de dioptrique (Paris: Jean Anisson, 1694).

  “In nature there is no generation”: Matthew Cobb, “Reading and writing the book of nature: Jan
Swammerdam (1637–1680),” Endeavour 24, no. 3 (2000): 122–28.

  In 1768, the Berlin embryologist Caspar Wolff: Caspar Friedrich Wolff, “De formatione intestinorum praecipue,” Novi commentarii Academiae Scientiarum Imperialis Petropolitanae 12 (1768): 43–47. Wolff also wrote about essentialis corporis in 1759: Richard P. Aulie, “Caspar Friedrich Wolff and his ‘Theoria Generationis,’ 1759,” Journal of the History of Medicine and Allied Sciences 16, no. 2 (1961): 124–44.

  “The opposing views of today were in existence centuries ago”: Oscar Hertwig, The Biological Problem of To-day: Preformation or Epigenesis? The Basis of a Theory of Organic Development (London: Heinneman’s Scientific Handbook, 1896), 1.

  “The Mystery of Mysteries”

  They mean to tell us all was rolling blind: Robert Frost, The Robert Frost Reader: Poetry and Prose, ed. Edward Connery Lathem and Lawrance Thompson (New York: Henry Holt, 2002).

  Charles Darwin, boarded a ten-gun brig-sloop: Charles Darwin, The Autobiography of Charles Darwin, ed. Francis Darwin (Amherst, NY: Prometheus Books, 2000), 11.

  He had tried, unsuccessfully, to study medicine: Jacob Goldstein, “Charles Darwin, Medical School Dropout,” Wall Street Journal, February 12, 2009, http://blogs.wsj.com/health/2009/02/12/charles-darwin-medical-school-dropout/.

  Christ’s College in Cambridge: Darwin, Autobiography of Charles Darwin, 37.

  Holed up in a room: Adrian J. Desmond and James R. Moore, Darwin (New York: Warner Books, 1991), 52.