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Summary and Analysis of The Gene
An Intimate History
By Siddhartha Mukherjee
OPEN ROAD INTEGRATED MEDIACopyright © 2016 Open Road Integrated Media, Inc.
All rights reserved.
Mukherjee's uncles Rajesh and Jagu and his cousin Moni have all suffered from mental illnesses with genetic origins. Their stories serve to introduce the gene, the "fundamental unit of heredity" that holds the key to the physical and emotional characteristics of each human life.
Need to Know: No understanding of human biology — physiology or behavior — can be complete without first understanding the nature of the gene.
Part One: The "Missing Science of Heredity"
The Discovery and Rediscovery of Genes (1865 — 1935)
The Walled Garden
The concept of the gene was first formed by Gregor Johan Mendel in 1865. However, theories of how human traits are transmitted date back to Aristotle, who theorized that they were contained in "instructions" within the body that were passed on from generation to generation.
Aristotle's theories of heredity were surprisingly accurate; but after him, little progress was made in genetics until the 19th century.
"The Mystery of Mysteries"
Charles Darwin's 1831 — 1836 voyage to South America and the Pacific to collect animal specimens and fossils of their predecessors led him to believe that new species were created in a struggle for survival. The ones best equipped to adapt to shifting conditions would endure, in a process of "natural selection."
Need to Know: Darwin's On the Origin of Species proposed the theory of evolution but did not provide an explanation for how heredity works.
The "Very Wide Blank"
Darwin later sought to explain heredity with the theory of "pangenesis." He believed that tiny particles called gemmules, contained within the cells of living organisms, passed on their essential traits to their offspring, blending the characteristics of both mother and father. His colleagues dismissed the theory because it did not explain why some traits disappeared and then reappeared in later generations.
Need to Know: Darwin's failure to explain heredity came about in part because he was a brilliant naturalist, but not adept at carrying out experiments.
"Flowers He Loved"
Gregor Mendel's research breeding hybrid pea plants led him to conclude that the traits of organisms must be contained in single, indivisible units. Although he did not invent the term, Mendel had identified the fundamental qualities of what we call a gene today.
Need to know: Mendel's seminal work on heredity was received with silence; his contribution to science was not recognized until long after his death in 1884.
"A Certain Mendel"
The Dutch botanist and geneticist Hugo de Vries, aware of Mendel's work, observed that plant species spontaneously generated new varieties — ones with longer stems or flowers of different colors. He termed these variants mutants and the process, mutation. Nature, he posited, spontaneously created mutants with specific qualities and the ones best adapted to changing circumstances were able to survive, creating new species.
Need to Know: Hugo de Vries's discovery of spontaneous mutation extended Darwin's theory of natural selection.
Darwin's cousin Francis Galton was an early proponent of eugenics, which advocated the selective breeding of men and women in order to create a superior society. The notion appealed to a British ruling class appalled over the rising power and numbers of the working class, and to sectors in the United States concerned about the effects of massive immigration.
Need to Know: The eugenics movement in the United States and Britain used theories of genetics to justify social experiments that included forced sterilization.
"Three Generations of Imbeciles Is Enough"
During the 1920s, individual states began to pass laws authorizing imprisonment or sterilization of men and women deemed to have genetic criminal tendencies or mental deficiencies. The first legally forced sterilization was performed on Carrie Buck, an impoverished single mother in rural Virginia who, like her own mother, was confined to a penal colony after being diagnosed as a "moron."
Buck, who did not express any objection to the procedure, was sterilized under a 1924 Virginia law that was later upheld by the US Supreme Court, opening the way for thousands of such forced sterilizations.
Need to know: In the United States, eugenics became, if not the law of the land, a powerful tool for people who sought to protect society from what they regarded as moral and social decay.
Part Two: "In the Sum of the Parts, There Are Only the Parts"
Deciphering the Mechanism of Inheritance (1930 — 1970)
Thomas Morgan, a researcher at Columbia University in New York, conducted extensive experiments on fruit flies and found that genes were linked to one another and to chromosomes. Based upon this notion of "linkage," a student of Morgan's, Alfred Sturtevant, constructed the first genetic map.
Need to Know: Thomas Morgan's graphic description of genes' location on chromosomes as "beads on a string" illustrated their linkage to one another, and to chromosomes. This was the first genetic map.
Truths and Reconciliations
Theodosius Dobzhansky, a Ukrainian biologist who immigrated to the United States, discovered that while genes (or genotype) determine traits (phenotype), environment also has an effect, as does chance. He exposed groups of fruit flies to different temperature levels over several generations; the resulting changes in their physical traits showed that environment also influences an organism's genetic makeup.
In this way, Dobzhansky also proved that gene selection alone could not be the basis for creating superior beings, as the eugenicists believed.
Need to Know: Dobzhansky's experiments led to the equation "genotype + environment + triggers + chance" as the explanation for physical attributes (phenotype) of living creatures.
Frederick Griffith, a British medical officer seeking a vaccination for the Spanish flu, found that two different varieties of bacteria could exchange genes, with one acquiring the attributes of the other. This meant attributes could be transmitted without reproduction, in a process he called "transformation." Hermann Muller proved that genes could be altered by radiation to produce mutant varieties. This meant that genes were actual, physical matter that could be manipulated by man.
Need to Know: The research by Griffith and Muller marked the first step toward manipulation of human genes.
Lebensunwertes Leben (Lives Unworthy of Living)
The Nazis' mass experiment in "racial hygiene" began with sterilization and quickly moved to the imprisonment and execution of mental defectives, criminals, dissidents, Jews, and Gypsies. The Russian Communists, meanwhile, used theories of gene manipulation to justify a massive program to erase all differences in thought through brainwashing or "re-education."
Need to Know: Both the Nazis in Germany and the Communists in the Soviet Union used the language of genetics, although not exactly the science itself, to justify their atrocities.
"That Stupid Molecule"
In 1944, Oswald Avery, a professor at Rockefeller University in New York, experimenting with virulent and nonvirulent bacteria, proved that the nucleic acid DNA (deoxyribonucleic acid) is the molecule that carries an organism's genetic information. Avery based his discovery on the work done previously by Frederick Griffith.
Need to Know: The identification of DNA (scorned as "that stupid molecule" by one scientist) as the carrier of the genetic code served as a landmark to direct future research in genetics.
"Important Biological Objects Come in Pairs"
Researcher Rosalind Franklin, using an X-ray machine, took the first useful photos of DNA molecules, which permitted her colleagues James Watson and Francis Crick to determine the molecule's structure. After many attempts, they created the iconic double helix model that illustrates the nature of DNA — the "precarious assemblage of molecules" which holds the secret of life.
Need to Know: Watson and Crick's discovery of the structure of DNA in 1953 posed a new set of questions about how to manipulate that chemical structure to the benefit of humanity.
"That Damned, Elusive Pimpernel"
Knowing the structure of DNA, scientists sought to find out how the molecular model actually transmitted characteristics. George Beadle and Edward Tatum proved that the action of a gene is to encode information to construct a protein, which in turn enables the specific form or function — the trait — within an organism.
Later, Watson and Crick discovered their "central dogma," that RNA — ribonucleic acid, DNA's molecular cousin — is used as a "messenger molecule" to transmit copies of the DNA chain to build a new protein.
Need to Know: The "central dogma" of biological information is that DNA is transformed into RNA, a messenger molecule that constructs a new protein.
Regulation, Replication, Recombination
Experiments by the French biologist Jacques Monod proved that genes were not just passive carriers of traits, but were capable of changing the information they held to respond to changes in the environment, He did so by exposing the bacteria E. coli (Escherichia coli) to two sugars — glucose and lactose — and noting the genes' different reactions to each one. Monod showed that genes are able to regulate themselves, to replicate themselves, and also to recombine, creating new gene forms.
Need to Know: The "three R's" of gene physiology: genes can regulate themselves, replicate, and recombine to create new gene forms.
From Genes to Genesis
If proving the existence of the gene solved the problem of heredity, scientists still sought to learn how an entire organism grows out of a single cell. Embryologist Ed Lewis of Caltech concluded that certain genes (effectors) start this process by turning other genes on or off. By experimenting with inchworms, which have a finite number of genes, Lewis discovered that each gene has a specific function to perform within the organism, with some even "shutting off" to cause its death.
Genes, apart from being programmed with certain traits, were also affected by their proximity to, and interaction with, other genes. By way of analogy, the wood used to construct a ship contains certain intrinsic qualities; but it is the way the different sections are combined with the others that creates a floating vessel.
Need to Know: The way genes create a complex organism is determined not only by the traits they carry, but by their proximity to, and interaction with, other genes.
Part Three: "The Dreams of Geneticists"
Sequencing and Cloning of Genes (1970 — 2001)
In 1973, biochemist Paul Berg created "recombinant DNA" for the first time by joining genetic material from different sources and using virus- bacteria hybrids as carriers. Shortly after, however, researchers Herb Boyer, Stanley Cohen, and Stan Falkow discovered a way to create genetic hybrids with bacterial genes — which were far less hazardous than the virus-bacteria hybrids — and reproduce them in large quantities in an incubator. This effectively ushered in "the birth of a new world," in which genes could be manipulated for therapeutic ends.
Need to Know: The creation of recombinant DNA and hybrids opened a world of possibilities for genetic manipulation.
The New Music
British biochemist Frederick Sanger learned how to read genes by "copying" a DNA sequence; rather than break down the DNA into its component parts, he slowed its reproductive process so he could observe the order in which the parts appeared. This brought science another step closer to altering genes. For decades, scientists had managed to do so only by bombarding genes with X-rays and producing mutants; by the late 1970s, however, gene cloning and gene sequencing (determining the order of DNA nucleotides in a gene) were a reality.
Need to Know: The capacity to alter genes created a divide in the science of biology, between the old guard who merely sought to describe and classify organisms, and the new biologists who studied ways to change them.
Einsteins on the Beach Scientists who gathered at Asilomar, California, in 1975 drew up a scheme to rank the risks of biohazards of experiments with recombinant DNA and restrict research accordingly. The conference espoused self- regulation by scientists in order to avoid having restrictions imposed later by governments.
Need to Know: The Asilomar conference recommended self- governance by scientists in gene experiments, but did not address the ethical dilemmas raised by the nascent science of genetic engineering.
"Clone or Die"
During the 1970s, genetic science began to move inexorably into the realm of technology and, by extension, into business. Researcher Herb Boyer and venture capitalist Robert Swanson formed the genetic engineering company, Genentech, which in 1978 manufactured insulin from recombinant DNA.
Need to Know: The founding of Genentech and its success in creating recombinant insulin marked the start of the biotechnology industry.
Up until then, insulin was still being obtained by a crude and inefficient method which consisted of crushing pig and cow pancreases. Genentech patented the recombinant insulin and went on to invent many other genetic-based medicines.
Part Four: "The Proper Study of Mankind Is Man"
Human Genetics (1970–2005)
The Miseries of My Father
Late in life, Mukherjee's father fell from a rocking chair; this accident caused him to suffer from confusion, urinary incontinence, and difficulty in walking. He was diagnosed with Normal Pressure Hydrocephalus (NPH), a condition thought to be genetic, although it requires external circumstances to trigger the symptoms.
Need to Know: The experience of Mukherjee's father illustrates how genetic science must address human illness: by considering genetic structure, its variants, the environment, and chance, all of which influence human pathology.
The Birth of a Clinic
As genetic research in laboratories advanced, clinical studies were establishing the links between genetics and human illness. Victor McKusick founded the Moore Clinic in 1957 to study hereditary disorders; by 1998, he had discovered 12,000 gene variants linked to different medical disorders and traits.
Need to Know: The ability to detect genetic illnesses such as Down syndrome in fetuses created a "medical industry" in the 1970s, with the abortion of affected fetuses as one of its activities.
"Interfere, Interfere, Interfere"
Genetic testing on fetuses in the 1970s and the legalization of abortion was, in effect, a return to eugenics, which was now called neogenics, or newgenics. The difference was that in newgenics, genes were used as the basis for selection by individual choice.
Need to Know: In the "newgenics" that arose in the 1970s, the genetic testing and medical procedures were carried out by individual choice, not mandated by governments.
A Village of Dancers, an Atlas of Moles
By the 1970s, many diseases had been classified as genetic, but scientists were still unable to identify the specific genes that caused them. By compiling data on the affected families and using new mapping techniques — which pinpointed a gene's location through its linkage with other genes — researchers were able to identify the single gene that causes Huntington's disease. The same techniques were later used on cystic fibrosis. By the late 1990s, many genetic diseases could be detected through prenatal screening.
Need to Know: Scientists' ability to map genes allowed them to detect genetic illnesses, opening a new horizon in man's ability to control human nature.
"To Get the Genome"
The successful mapping of disease-provoking genes gave impetus to a much larger project: mapping the entire human genome, with its more than 3 billion base pairs of DNA. Estimates of the cost and the time it would take were huge, but so were the potential rewards in diagnosing diseases, particularly cancer. The Human Genome Project got underway in 1989.
Need to Know: Starting in 1989, the Human Genome Project began to map the human genome, the entire "encyclopedia" of genetic information in the body.
Microbiologist Craig Venter decided to shortcut the process of mapping the human genome by examining only fragments of each gene. His company, Celera, entered into a race with the National Institutes of Health's Human Genome Project. In June 2000, the leaders of the two efforts announced jointly that they had made a "first survey" of the entire human genome.
Excerpted from Summary and Analysis of The Gene by Siddhartha Mukherjee. Copyright © 2016 Open Road Integrated Media, Inc.. Excerpted by permission of OPEN ROAD INTEGRATED MEDIA.
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Table of Contents
Cast of Characters,
Direct Quotes and Analysis,
What's That Word?,
About Siddhartha Mukherjee,
For Your Information,