A Deep and Intimate Inquiry of Genes

If you were to write your first book and get a Pulitzer Prize, you might think about resting on your laurels, to quit while you’re ahead. But not Siddhartha Mukherjee, who felt compelled, after his Emperor of All Maladies definitive biography of cancer, to take on the big, highly ambitious project of telling the story of the gene—a story that had been previously told in many pieces but not from Pythagoras (530 BC) to the present, no less the “future of the future.”View Large Image | View Hi-Res Image | Download PowerPoint SlideMukherjee frames the discovery of the gene—the particulate unit of heredity—as a puzzle that took many decades to solve, getting off to a serious start with Darwin and Mendel in the mid-1800s. He connects the two: “both clergymen, both gardeners, both obsessive observers of the natural world” and that their work complemented one another—“heredity was the yin to evolution’s yang.” Their classic work with finches and peas, respectively, was not appreciated when presented. Darwin’s was described that it had “not yielded any particularly noteworthy discoveries” and Mendel’s 44-page paper was cited only 4 times between 1866–1900. Talk about sleeping beauty scientific publications. The problem was that the gene was conceptual and only abstract, a “ghost lurking in the biological machine,” even when the term genetics was coined by Bateson in 1905 and gene in 1909 by Johannsen.A break occurred in 1911, when Sturtevant, an undergraduate student in the Morgan lab studying Drosophila genetics, produced the first linear genetic map. Yet the value of such a linkage framework to map the human genome took almost seven more decades before Botstein, Davis, and Skolnick published their paper in 1980 that ultimately led to the Human Genome Project (Am. J. Hum. Genet. 32, 314–331). That paper is described in typical Mukherjee style: “festooned with statistical data and mathematical equations, reminiscent of Mendel’s classic paper.” It took the concrete discovery of DNA’s structure by Watson, Crick, and Franklin and the ability to sequence the genome by pioneering efforts of Sanger, Gilbert, and others to eventually realize that mapping the human genome could indeed be accomplished.Mukherjee is one the most talented doctor-authors of our era, who has a remarkable way with words, exemplified by many passages throughout the book, as he takes on the role of master explainer. For epigenetic marks, he turns to margin notes written in a book that change the context without changing the words. He likens the CRISPR/Cas9 genome editing system of “seeker” and “hitman” to Bonnie and Clyde. The Y chromosome is a “victim of planned obsolescence, destined to a male-only convalescence home where it can vanish, puffing its last cigar, into oblivion.” Human embryogenesis is described: “A dormant spaceship comes to life…genes that coordinate metabolism, motility, cell fate, and identity fire ‘on.’ The boiler room warms up. The lights flicker on in the corridors. The intercom crackles alive.” Besides the frequent use of metaphors, he bends our minds by quoting an eclectic group of people ranging from Snoop Dogg to Shakespeare.The dark side of genetics occupies a significant portion of the book. Ironically, Darwin’s cousin, Francis Galton, a pioneer of the eugenics movement in the late 1800s, initially takes us there. The horrific story of Carrie Buck, born in 1906, sterilized and institutionalized despite being normal, is an exemplar; the book is co-dedicated to her for experiencing the perils of eugenics. For Mukherjee acknowledges that the “gene,” “the fundamental unit of heredity, and the basic unit of all biological information” is “one of the most powerful and dangerous ideas in the history of science.” The deep dive into eugenics characterizes Nazism’s “applied biology” and “racial hygiene,” the Sterilization Law that led to about 400,000 sterilizations between 1933 and 1943, and ultimately the systematic genocidal extermination of millions of people. The depiction of how eugenics scorched the earth includes the Soviet collectivization and later in the book the “ghastly distinction falls on India and China, where more than 10 million female children are missing from adulthood because of infanticide, abortion, and neglect of female children.”Mukherjee doesn’t shy away from other ominous directions in genetics, including several chapters that debunk gender, race, sexual orientation, intelligence, and the politics of identity. He exudes compassion when describing children with Down’s syndrome having “an extraordinary sweetness of temperament, as if in inheriting an extra chromosome they had acquired a concomitant loss of cruelty and malice.” Regarding a teenager with profound neurologic impairment but intact cognitive ability, he points out: “To fail to acknowledge the depth of Erika’s anguish is to reveal a flaw in our empathy. But to refuse to acknowledge the price to be paid in this trade-off is to reveal, conversely, a flaw in our humanity.” But it is clear that there is something that really haunts him, perhaps the real motivation for taking on this formidable book project—his family history with two of his father’s brothers and a cousin with schizophrenia.In the prologue, and throughout the book, he refers to these relatives and reveals: “Scarcely a day passes in my adult life when I do not think about inheritance and family.” The book’s subtitle is “An Intimate History” which made me think it is really a double entendre of intimate revelations. But when I read the section on Touched with Fire, the classic study linking creativity and madness, I could not help thinking that the author somehow fits well into the list that includes many of the most accomplished people in history. This continuum of hyper-creativity and mental illness need not occur in the same individual, but manifest itself in a family. As he states, “It does not help that the very definition of illness in one circumstance becomes the definition of exceptional ability in another. Night on one side of the globe is often day, resplendent and glorious, on a different continent.”I found the chapter and sections devoted to “Previvors” especially insightful. This refers to what will be increasingly common scenarios of having a genetic diagnosis, and potentially being consumed by fear of manifesting an illness that is not yet developed. The need for a “forward catalog” or “fate map” (rather than our current rearview mirror, “backward catalog”) is emphasized so that ultimately a person will have an understanding of likelihoods and propensities, a “manual of previvorship.” And this gets personal for the Mukherjees, and their two daughters, as he hopes that the schizophrenia variants, along with most serious medical conditions, will be identified and quantified “by the end of the decade.”Another key part of the book, at various time points, is devoted to engineering the genome. Paul Berg, a mentor for the author, provided leadership in the 1970s for the concerns about recombinant DNA that culminated with the Asilomar Conference. While this historic gathering occurred more than 40 years ago, it is remarkable that more than 10% of the participants were journalists and self-governance was manifest by Berg’s statement that “ignorance that has compelled us to conclude that it would be wise to exercise caution performing this research.” This conference was labeled a “graduation ceremony for the new genetics.”We are taken through the birth of biotechnology and heady days at Genentech and other new companies, and ultimately to the catastrophic story of Jesse Gelsinger who died in an early gene therapy protocol. The discussion between the author and Jesse’s father is illuminating; the author’s quote “the prophets were in for profits” stinging.With genome editing, we now move fast forward to “Asilomar 2” and the prevalent concerns, even a call for a moratorium by many, for using CRISPR/Cas9 to intervene on the human embryo. Such powerful tools to modify our germline could conceivably alter our genetic destiny, leading Mukherjee to express deep concern, differentiating genetic “emancipation” related to hereditary illness from “enhancement”— the potential “to alter our conception of what it means to be ‘human’.”So The Gene is a tour de force, taking us through the history of the gene and medical genetics, cheerleading the many pioneers who brought the field forward but at the same time weighing in on its adverse impact, both in the past and the potential in the future. Is it perfect? Absolutely not, but neither is any human genome. There are some factual errors scattered throughout, which I consider minor. There was a recent Twitter flap about the author’s New Yorker piece on epigenetics that is partly derived from the book (Mukherjee, S., Same but different: how epigenetics can blur the line between nature and nurture. New Yorker May 2, 2016. www.newyorker.com/magazine/2016/05/02/breakthroughs-in-epigenetics). Some of that critique was taken out of context, pointing to the lack of an accurate portrayal of gene regulation without mention of the pivotal role of transcription factors— this is clearly not the case in the book. In this rapidly moving field, some progress has already been made since the book was finished, such as the remarkably heightened specificity of genome editing. But that just accentuates both the excitement and the concern for our unprecedented ability to manipulate and engineer the human genome.The book is big and dense (it is not as easy a read as his book on cancer), just as is the history of the field. It’s great that someone as talented (and likely genetically gifted) as Mukherjee was willing to take it on and that it will lead to a Ken Burns PBS documentary series that will educate the public on human genetics, something that is desperately needed.