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The Gene by Siddhartha Mukherjee

The Gene by Siddhartha Mukherjee

11/06/2018
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M.Mulligan


With DNA it gets personal

Most people are familiar with the image of the DNA molecule. The two intertwining helices, connected by molecular rungs, like on a ladder. But, most people are not familiar with just how long it is, Siddhartha Mukherjee writes. If DNA were as wide as sewing thread, it would be 200 kilometers long. To see its shape is to understand its basic function. As a repository for information. The double strands of DNA in your body contain three billion chemical base pairs, and are divided into roughly 20,000 discrete protein encoding genes. The resulting proteins are the basic building blocks from which you are made. The language of DNA is surprisingly simple and universal, and you could take a gene from a whale, Mukherjee tells us, put it into a strand of DNA in a bacteria, and the gene could be transcribed perfectly.

Image of The Gene book cover

DNA, the history of its discovery, and our ability to manipulate it, are the subjects of Mukherjee’s latest book, The Gene. The story of the gene is a journey across time and scale. Mukherjee eloquently animates the intertwining strands of history and science to demystify the gene and its discovery. He shows the idea of the gene proved to be elusive and counterintuitive to early thinkers. Its discovery was both “dangerous and exhilarating.” After Charles Darwin discovered that traits are heritable, it didn’t take long for his cousin Francis Galton to want to perfect the human race. Unravel the language of our genome, and you discover inherent limitations of its perfectibility. Mukherjee manages to bridge conceptual gaps in our understanding of our own source code, and situate the reader in debates on the frontier of biology.

Mukherjee won a Pulitzer Prize for his previous book, The Emperor of All Maladies: A Biography of Cancer. He also has a TED Talk about the future of medicine, and has published an extended essay: The Laws of Medicine. Professionally, he is an oncologist and haematologist, and has studied at Stanford, Oxford, and Harvard. The goal of his writing, it seems, is to demystify the medical practice and its challenges. In his latest book, he succeeds at painting a picture of the gene across time, and close up. Mukherjee’s style is at once approachable.

Image of Merogenomics article quote on schizophrenia genetic causes

In the first chapter, Mukherjee takes the reader to India and describes his family’s history of mental illness. His cousin, and two of his uncles all developed schizophrenia. Mukherjee describes the “gash of suffering” this disease tears in the lives of those who experience it. This entry point immediately humanizes genetic relevance, and schizophrenia serves to illustrate the contradictory nature of the gene. In the later chapters, we learn that schizophrenia is one of the most intractable problems posed by genetics. It is caused by hundreds of genes we know of, and hundreds of others we have not identified. Doubly disconcerting is the fact that some genes that cause schizophrenia might also cause intelligence too.

 

Early inheritance theories

The gene proved to be a counterintuitive idea. Early philosophers noted that a “likeness” was passed down from parents to offspring. Pythagoras, writing in the Sixth Century B.C., believed that semen would move through a man’s body, gleaning the essences from mystical vapours. Semen became a mobile library for a man’s traits that he passed onto a woman during intercourse. According to this theory, man provided nature, and women the nurture. Pythagoras, who discovered universal constants in the dimensions of triangles, thought triangular harmony applied to heredity too. The mother and father were two sides of a triangle, and a child was the third. The “biological hypotenuse.” The Greeks, alas, were not great experimenters, and relied heavily on a priori reasoning--or that which can be deduced without experiment.

Image of Merogenomics article quote on Aristotle beliefs of inheritance

Aristotle, writing two hundred years later, was not the greatest proponent of women’s rights. But he did propose that women may contribute their own “seed” of information to a fetus. He also proposed the then “radical” idea that the information from the parents was like an “architectural plan,” not matter itself. This idea came close to describing the genetic transfer of information, but was lost during the Medieval ages when people instead believed in the homunculus theory of heredity.

There are a variety of Medieval beliefs in folklore and mythology, the predominant theory being that sperm contains a small fetus, ready to be fully inflated. This homunculus itself contains homunculi. There is an infinite chain of humans, or homunculi all the way down. This world view meshed nicely with Christian theology because, since “all future humans are encased in all humans,” we were all encased in Adam’s loins. Therefore we all bear original sin, because we all tasted the fruit.

Image of Merogenomics article quote on Medieval science of inheritance

It’s not until Mendel started measuring successive generations of peas that an idea emerges. The idea that there are discrete units of heredity that appear in consistent ratios in nature. After cross breeding several variant pea hybrids, he discovered “unanticipated constancies, conserved ratios, numerical rhythms.” Mendel made such lasting contributions to our understanding of the gene because he actually tested his theories, unlike his Medieval and Greek intellectual predecessors. But, his experiments were criticized for being too empiric, and not rational. Unfortunately, Mendel was not an effective communicator, and despite sending out several copies of his published work, his obscure charts and tables did not enter popular discourse for four more decades, when his ratios of discrete units of heredity were appended to the Darwinian theory of evolution.

Image of Merogenomics article quote on Mendelian inheritance

When Darwin came up with his theory of heredity, with species branching out from a common ancestor, it butted up against the Christian worldview that place God “firmly at the centre” of the tree of speciation, with all animals in universal fixed categories. There was an essence to a species. Richard Dawkins summarizes this Platonic worldview: “A rabbit was a rabbit was a rabbit.” After having the good fortune to spend five years traveling around the world on the HMS Beagle, Darwin witnessed various peoples and species. He saw life forms exquisitely adapted to their environments.

After having his intuitions played with during this voyage, Darwin developed the theory of evolution. Each subsequent generation produces mutations which create bell curves of variation within a species. The mutations are random. But the selective force of nature is anything but random. Nature culls organisms that are least suited to an environment, and the survivors can breed another generation, passing on their heritable surviving traits, thus making the species more adapted to that particular environment. This does not produce superior organisms. Just ones more adapted to survive in that particular environment. By this mechanism, “freaks became norms, and norms became extinct. Monster by monster, evolution advanced.”

Image of Merogenomics article quote on Darwin theory

 

A dangerous idea

The idea of perfecting the human species caught on shortly after Darwin published his discovery. Racist theories abounded and caught the public imagination in Britain, Canada, the United States, and Germany. These countries adopted forced sterilization programs. These programs applied to “idiots,” who were by definition, of a mental state “no older than 35 months.” “Imbecile” and “moron” were harder to define. “Vagrants, feminists, prostitutes, orphans, dyslexics, and rebellious adolescents” were subject to sterilization and forced into colonies where they were not allowed to leave.

Nazi Germany, in pursuit of racial purity, exterminated six million Jews and others they deemed Untermensch (subhuman). The Nazi scientist Josef Mengele carried out morbid experiments on Jews, especially twins, in hope of finding insights into perfecting humans. In Soviet Russia, genetics was dismissed as a bourgeois pseudoscience, and the state promoted the scientific doctrine of Trofim Lysenko. According to Lysenkoism, environment could rewrite the traits of an organism’s future progeny. Humans were a blank slate, and human nature could be reprogrammed by ruthless totalitarian control of every aspect of people’s environments. This line of thinking was used as justification to send millions of Kulaks (rich peasants) to labour camps in Siberia.

Image of Merogenomics article quote on the theory of evolution

The Nazis had the goal of perfecting the human race, with so-called “Aryans” ruling over inferior races. The Soviets tried to deny genetic relevance outright, in favour of a blank slate theory of humanity. Mukherjee could have mentioned that xenophobia and genocide were not invented in the Twentieth Century. But he correctly shows that these behaviours took on a veneer of sophistication as the nascent language of genetics was used to justify racist narratives.

Independent of grotesque ideological experiments, the gene came into greater and greater resolution through a series of ingenious experiments throughout the Twentieth Century. That the gene is a discrete determinant, that the gene is a physical entity, that the language of DNA molecules is read by RNA molecules and translated into proteins from which life is built, all had to be discovered. This discovery process was marked by eureka moments, serendipity, hermeneutic parsing of data, and divergent thinking. Mukherjee captures the human motives of this discovery. And he effectively shows the discovery process was marked by conceptual breakthroughs as doctrines were overturned.

Image of Merogenomics article quote on the perfect human theories

In the early 1950s, Mukherjee points out, there was a popular line of thinking among biologists, that cellular genetic code was “so context dependent, so utterly determined by each particular cell in a particular organism and so horribly convoluted, that deciphering [it] would prove impossible.” In reality, the opposite is true. “One molecule contains the code and just one code pervades the biological world. If we know the code we can alter it in biological organisms and in humans.”

As biology entered the era of recombinant DNA, categories of life started to fall apart. “In the 1960s, scientists thought you couldn’t shuttle genes from one species to the next.” In reality, it turned out to be “ridiculously simple,” and scientists made the first genetic chimera using recombinant DNA in 1973.

Image of Merogenomics article quote on first genetic chimera

In 1998, Craig Venter and his team first sequenced the genome of the sub-centimeter Nematode worm, Caenorhabditis elegans, one of the most studied animals of science for its simple features. In 2000, the draft sequence of the human genome was announced, and doors opened up to new frameworks of thinking. As it turns out, you have a lot of genetic overlap with flies and worms. Over 60% of human genes related to disease are shared with flies. Grain has far more genes than you do. Much of your genome is inactive and does not encode proteins. In fact, protein encoding genes make up a tiny minority of your genome.

Some of the most profound discoveries about the gene had to do with its deep influence on the intricate details of our lives. From the 1930s to the 1970s, universities were dominated by environmental theories of identity. But under the weight of experimental data, these blank slate theories gave way to innatist interpretations of identity, that suggest animals, humans included, have pre-wired categories of thought and behavior. Mukherjee does not claim that we should be genetic determinists. Genes are one of many “lenses” through which we can view our identity. But, the role of genes in influencing “our lives and beings is richer, deeper, and more unnerving than we had imagined.”

Image of Merogenomics article quote on fruit fly genetics

In 1979, the behavioural psychologist, Thomas Bouchard, began recruiting twins for studying shared traits. By the end of the eighties he had assembled “the world’s largest cohort of reared-apart and reared-together twins.” These twins were subjected to numerous tests, measuring both physiological and psychological differences. The results were astonishing.

Identical twins share 100 percent of their genes, and while they obviously share physical traits, they also share psychological traits to a startling degree of concordance. “Personality, preferences, behaviors, attitudes, and temperament” were all tested for with various independent tests, and twins reared apart showed nearly the same levels of identity as twins reared together, with strong correlations between 0.50 and 0.60.

Most striking was the correlation between social and political attitudes. Here, the concordance was the same between twins reared apart, as with twins reared together: “liberals clustered with liberals, and orthodoxy was twinned with orthodoxy. Religiosity and faith were also strikingly concordant: twins were either both faithful or both nonreligious. Traditionalism, or “willingness to yield to authority,” was significantly correlated. So were characteristics such as “assertiveness, drive for leadership, and a taste for attention.”

Let’s say you had broken your ankle falling down stairs as a child and developed a consequent fear of heights, and you had met your future husband at a dancing lesson. And let’s say you had a signature giggle, and would burst uncontrollably into peals of laughter, and you enjoyed playing pranks, and you died your hair an unusual shade of auburn. Was that all your own free will? What if you met your genetic clone, and she shared each of those same characteristics, including the same height and IQ? Such was the case with Daphne Goodship and Barbara Herbert, identical twins separated at birth who were profiled in the Minnesota Group Twin Study. In case study after case study, identical twins lived startlingly similar lives.

Image of Merogenomics article quote on identical twins

Environment can play a huge role in the course of someone’s life. But, the fact remains that we have modular brains that are made of proteins that are coded for by our genes. Our decisions are determined, in part, by the modules we inherit from our genetic constitution. A toddler is not a “random access memory onto which any number of operating systems could be downloaded by culture.” But genes alone do not write our destiny. “A genetic predisposition,” Mukherjee explains, “is not a disposition.” And as identical twins age, their lives diverge more and more. They encounter different circumstances, form different beliefs, and make different choices.

Biology, Mukherjee tells us, “is the most lawless of the sciences. There are few rules to begin with, and fewer that are universal.” And “natural,” Oscar Wilde writes, “is a pose.” The essentialism with which we view categories of life starts to fall apart when you turn your attention to the tails of the bell curves. “Mutations are abnormal in a statistical sense. They are only the less common variant.” Nothing about mutations denotes pathology. They are only exceptional with regards to the norm.

Image of Merogenomics article quote on facts about identical twins

A male to female transgender person might have the XY chromosome for maleness. But she has another hypothetical gene that controls for how she might identify psychologically. And she could exhibit many of the behavioural traits of a woman, despite being anatomically male. Mukherjee reminds us of the critical distinction, that gender can be genetically determined separate from sex. Such individuals may recognize themselves as “psychologically female, [...] neither male or female, or [they] imagine [themselves] belonging to a third gender altogether.” To turn gender and sex into universal archetypal categories is to ignore such outliers.

Women with Swyer syndrome are physically, anatomically, and psychologically female. And yet, they are chromosomally male. They are not “women trapped in men’s bodies.” They are “women trapped in women’s bodies that are chromosomally male.” They have the male Y chromosome, but because of a mutation in the SRY gene, their male features are not switched on. These women feel no “disjunction” with their bodies.

Image of Merogenomics article quote on gender genetics

Gender, Mukherjee explains, is genetically determined by the SRY gene. If the SRY gene is turned on, you are anatomically and physically male. Turn it off and “you are anatomically and physically female.” A cascade of genetic switches are turned on or off, amplified or diminished, and instructions are carried out for male or female characteristics. But, while the SRY gene might be a binary switch, variability within each gender is infinite. There are “continuous curves of behaviour, identity, and physiology.” And genes “integrate input” from environment too, including “cultural role-playing.” And while much is made of gender differences, the genetic overlap between genders, Mukherjee points out, is 99.68%. The distributions are mostly overlapping; you should treat people as individuals.

If racists have an essentialist view of the “races,” this essentialist view starts to fall apart when you take into account how small the human species is. Chimpanzees, Mukherjee points out, are a much larger species than humans, even if they have a much smaller population. They are a larger species in the sense that they are more genetically diverse. Humans have little genetic variety. Our common ancestor lived only some two hundred thousand years ago--a blip in the grand scale of evolution. As a result, intraracial differences are 85 to 90 percent, while interracial differences are only seven percent. So, the sweeping majority of genetic variation occurs within so-called races, not between. “The racist,” Mukherjee writes, “comes home empty handed.”

Image of Merogenomics article quote on human genetic diversity

A recurring motif throughout the book is that many people who made significant contributions to our understanding of the gene had learning disabilities of some sort. Mendel failed his oral exam to become a teacher twice. Herb Boyer—who helped jumpstart the field of genetic engineering—got a D in metaphysics and didn’t get accepted into med school. Craig Venter—who invented the shotgun sequencing technique, and pioneered the creation of synthetic organisms—was “a reluctant student with middling grades,” and (not mentioned in this book) was later diagnosed with ADHD.

At a conference, Mukherjee describes meeting a 15 year old girl, who he calls Erika. A teenager with not one, but two rare mutations that cause her to suffer a severe, degenerative condition. While confined to a wheelchair, and plagued by chronic tremors, Mukherjee describes Erika as “utterly charming—modest, thoughtful, sober, mordantly funny. She seemed to carry the wisdom of a bone that has broken, repaired itself, and become stronger. She had written a book and was working on another. She maintained a blog, helped raise millions of dollars for research, and was, by far, among the most articulate, introspective teenagers that [Mukherjee had] ever encountered.”

The heritability of intelligence is a hotly debated issue, and I particularly like how Mukherjee handles the topic. The entirety of the book illustrates the coming together of various minds across time and space to solve problems, with various perspectives contributing. Francis Crick and James Watson discovered the shape and structure of DNA after Rosalind Franklin provided sharp criticism of their earlier models, and made breakthroughs in X-ray diffraction photography, with the eureka-inducing Photo 51 coming out of her lab. Responding to studies searching for differences in IQ between races, Mukherjee points out the completely uneven playing field on which we measure such differences. Poverty, it turns out, affects genetic expression. And even asking a black participant in a study to identify his race can affect his score on an IQ test.

Image of Merogenomics article quote on ethnic genetic diversity

 

Contradictions: human nature and our genes

The multiple intelligences theory discussed by Mukherjee is part of a broader point he effectively makes in The Gene: that the ambiguity of gene expression currently makes the genetic improvement of our species a minefield to traverse. On one hand there are simple straightforward monogenic diseases like Tay-Sachs, and cystic fibrosis. Correct for one genetic mutation, and an embryo won’t grow up with the disease. But then, with polygenic mental illnesses, like schizophrenia or bipolar syndrome, we don’t know the full role each gene plays. The genes that cause bipolar syndrome might also cause creative effervescence. Would you want to prevent genes of someone like Virginia Woolf or van Gogh from existing?

Now, with increasing precision, non-invasive prenatal testing can reliably screen for genetic abnormalities that predict traits with high degrees of penetrance. Pregnant women can act on that information and choose to terminate a pregnancy. The critical ethical element is that women have choice, unlike in forced sterilization programs of the early Twentieth Century.

What makes questions of genetic selection so provocative today is that the technology to create germline (sperm and egg) genetically modified humans exists. Actually. Mukherjee walks us through the steps: “(a) the derivation of a true human embryonic stem cell (capable of forming sperm and eggs); (b) a method to create reliable, intentional genetic modifications in that cell line; (c) the directed conversion of that gene-modified stem cell into human sperm and eggs; (d) the production of human embryos from these modified sperm and eggs by in vitro fertilization.” And that is how you “rather effortlessly” create a genetically modified human.

Image of Merogenomics article quote on current genome manipulation capabilities

Our ability to perform each of those steps, as described by Mukherjee, already exists. Despite a moratorium by the NIH and in most countries on such germline genetic modification, China started experimenting with this technology in early 2015, making genetically modified fetuses, none of which were carried to term. Chinese medical ethicists cite Confucian philosophy which suggests that “someone becomes a human after they are born.”

Mukherjee discusses at great length many of the inherent limitations of ranking our genes from good to bad. Some genes perform more than one function, and we don’t know all the functions of the gene. We currently only know what a small fraction of the human genome does. But, as Mukherjee discusses in his epilogue, our knowledge is growing, and the genome is knowable.

He describes a hypothetical experiment, where you sequence the genomes of 100,000 children and follow their lives. You could cross reference “virtual genetic twins” and effectively create the world’s largest twin study. You could cross reference the variety of genotypes with all phenotypes (genetically expressed traits), and make a “fate map.” This could measure not just illnesses, but anything you wish to measure, ranging from “coming out, [or] an impulsive marriage,” to “a cataract in the left eye.” According to Mukherjee, such an undertaking is now conceivable, due to technological breakthroughs in computing, data storage, and genome sequencing. Such an experiment would offer a vastly rich dataset with which to better understand the contradictions of the human genome.

Image of Merogenomics article quote on human genome

With breakthroughs in our understanding of the genome, Mukherjee alludes to personalized medications. If many genes are only pathological with regards to certain environments, then you can simply change the environments of individuals. To name just a few examples mentioned: “A child with a predilection toward a genetic form of obesity, for instance, might be monitored for changes in body mass, treated with an alternative diet, or metabolically “reprogrammed” using hormones, drugs, or genetic therapies in childhood. A child with a tendency for an attention-deficit or hyperactivity syndrome might undergo behavioral therapy or be placed in an enriched classroom.” With genetically complex diseases, like cancer, genetic diagnostics can reveal mutations, which “are used to identify culprit pathways that fuel the growth of cells and to devise exquisitely targeted therapies to kill malignant cells and spare normal cells.”

Mukherjee is a brilliant science writer because he uses simple English, evocative analogies, and he holds you by the hand. He is patient and yet he conveys a sense of urgency. He spends most of The Gene illustrating the history of its discovery, which is both awe-inspiring and concerning. This history serves as a useful prelude to the questions bioethicists and humanity now face.

The Gene is not a comprehensive summary of the topic, and this review is far from a comprehensive summary of the book. We have a limited caring capacity, so what’s the call to action? For one thing, general genetic literacy. DNA is simply a code that can be rewritten. There are consequences to using this technology. But there are consequences to not using it too. We need to measure and balance risks with rewards. When we begin to “re-write our selves, ourselves,” questions remain about the dangers of such an undertaking, as we move into unknown territory. But for our genome, as the unknowable becomes knowable, and then known, its “stewardship may be the ultimate test of knowledge and discernment for our species.”

 

This article has been produced by Michael Mulligan. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

 

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