We wish to suggest a structure for the salt of deoxyribonucleic acid (DNA). This structure has novel features which are of considerable biological interest.8
Word traveled slowly in those days. It took the New York Times six weeks before it saw fit to print a front-page story on the double helix. Watson and Crick published a follow-up paper in which they proposed that “the precise sequence of the bases is the code which carries the genetical information.” For the next decade, the smartest minds in life sciences set about deciphering the code and figuring out how it was broken in genetic diseases. Only then could they contemplate how to fix it.
Watson has been justifiably criticized for his sexist portrayal of Franklin (“terrible Rosie”) in The Double Helix, which was published over Crick’s objections in 1968. In subsequent editions and other venues, he has acknowledged the importance of her scientific contributions. But Maddox, Franklin’s biographer, defended Watson. “If it weren’t for Watson, no one would have heard of Rosalind Franklin. He is deservedly in the top rank of writers of the 20th century.”9 Franklin died of ovarian cancer in 1958, denying her a thoroughly deserved share of the Nobel Prize. Today her contributions are widely recognized. In the 2015 West End production of the play Photograph 51, Nicole Kidman starred as Franklin.
Six months after Crick and Watson picked up their Nobel Prizes, Salvador Luria declared: “If knowledge is power, the science of genetics has placed in the hands of man an impressive amount of power in the last few decades.”10 But a new question loomed large: “Does the new knowledge of the genetic material and of its function open the door for a more direct attack on human heredity?”11 Drawing an analogy with the physicists who split the atom and developed the atomic bomb, Luria was certain that geneticists would soon gain the power to contemplate “a direct attack on the human germ plasm.”
A big name in bacterial circles, Rollin Hotchkiss was one of the first scientists to articulate concerns about the dangers of human genetic engineering. After excelling in high school in the 1920s and completing his PhD at Yale in organic chemistry in just three years, Hotchkiss turned to microbiology, discovering antibiotics and the first chemical modification to DNA.12 Hotchkiss thought it was natural to feel “instinctive revulsion” at the thought of meddling with human nature but it would surely be done. “The pathway will, like that leading to all of man’s enterprise and mischief, be built from a combination of altruism, private profit, and ignorance,” he said.13 Humans have long sought to improve on nature—seeking shelter, foraging for food, and defeating disease, whether modifying the diet of a baby diagnosed with phenylketonuria or administering chemotherapy to interfere with DNA replication in a cancer patient. Human genetic manipulation was on the horizon, Hotchkiss warned, and “we are going to yield when the opportunity presents itself.” It was not too soon “to diminish the dangers to which this course will expose us.”
Robert Sinsheimer, who passed away in 2018, is known as one of the architects of the Human Genome Project. In May 1985, while chancellor of the University of California Santa Cruz, he hosted a workshop to discuss a “big science” initiative to sequence the human genome (and put Santa Cruz on the map).II Sinsheimer’s role in catalyzing the inception of the genome project crowned more than four decades in molecular biology. In 1953, he embarked on a six-month visit to Delbrück’s lab to learn about phages. (Ironically, the greatest minds of the era were studying phages and bacteria, but oblivious to CRISPR.)
Sinsheimer studied a phage named ΦX174, the smallest phage known. His work helped lay the foundation for the sequencing of the very first complete genome, by Fred Sanger in Cambridge in 1977. Along the way, Sinsheimer demonstrated that the viral genome was merely a single strand of DNA, a stunning result that overturned six years of double helix dogma, like “finding a unicorn in the ruminant section of the zoo,” Sinsheimer said. He followed that with another heretical result: the ΦX174 DNA wasn’t even a linear molecule, but a ring. The enzyme that closed the loop—DNA ligase—proved to be the missing link in the ability to replicate the virus in a test tube. In 1967, Sinsheimer collaborated with Nobel laureate Arthur Kornberg to successfully replicate ΦX174 that could infect bacteria. The result was even picked up by President Lyndon Johnson, who said on television, “Some geniuses at Stanford University have created life in the test tube!”
By this time, Sinsheimer was thinking hard about far-reaching implications of genetic advancement. The year before, he delivered a talk on the future of molecular biology at an event to celebrate the 75th anniversary of Caltech. He spent months preparing his lecture, mulling over the ramifications of humanity acquiring the keys to its own inheritance. On October 26, 1966, sporting a bow tie, Sinsheimer walked to the podium to warm applause, and addressed his “fellow prophets” in the audience. The title of his lecture was “The End of the Beginning.”
He began by recalling his travels through the breathtaking canyons and landscapes of Arizona and Utah, where the sands of time formed layers of rock visible in cross section along the river gorges, revealing a billion years of geologic history. “On that immense scale,” Sinsheimer said, “a foot represents the passage of perhaps 100,000 years. All of man’s recorded history took place as an inch was deposited. All of organized science a millimeter. All we know of genetics, a few tens of microns. If we remember that timescale, then what vision can seem too long?”14 Then he said this:
The dramatic advances of the past few decades have led to the discovery of DNA and to the decipherment of the universal hereditary code, the age-old language of the living cell. And with this understanding will come control of processes that have known only the mindless discipline of natural selection for two billion years. And now the impact of science will strike straight home, for the biological world includes us. We will surely come to the time when man will have the power to alter—specifically and consciously—his very genes. This will be a new event in the universe. The prospect is to me awesome in its potential for deliverance or equally, for disaster.
Sinsheimer’s mesmerizing words envisioning a future of human genetic modification predated the recombinant DNA revolution and genetic engineering, let alone the invention of DNA sequencing and the Human Genome Project. How might we change our genes, he asked rhetorically? Might we “alter the uneasy balance of our emotions. Could we be less warlike, more self-confident, more serene?” After two billion years, he said, “this is, in a sense, the end of the beginning.”
Sinsheimer followed his speech with a powerful essay in American Scientist on “The Prospect of Designed Genetic Change.”15 “There is much talk about the possibility of human genetic modification—of designed genetic change,” he wrote. “A new eugenics” was potentially “one of the most important concepts to arise in the history of mankind. I can think of none with greater long-range implications for the future of our species.” Star Trek had just debuted on television in 1966, but no fancy hyperdrives or teleports were needed to conjure up visions of mankind boldly going where no one had gone before.
One hopeful idea was to treat diabetes by reanimating the insulin gene that, except for a few specialized cells in the pancreas, lies dormant in the human body. Viruses could be used to deliver the insulin gene to the necessary cells once scientists had sequenced and resynthesized it. Sinsheimer wasn’t advocating for a utopian super race but for equality of opportunity. He wasn’t pushing for Galtonian state-sponsored coercion but rather a voluntary improvement of the cognitively disadvantaged, such as 50 million Americans with an IQ of 90 or less. Should we “continue to accept the innumerable, individual tragedies inherent in the outcome of this mindless, age-old throw of dice,” or instead “shoulder the responsibility for intelligent genetic intervention”? The stakes, Sinsheimer argued, were little short of astronomicaclass="underline"