As for HIV, results could have been better. “We didn’t understand enough about the biology. It was not the dramatic cure we hoped for,” Macrae said. “We’re not an HIV company.” More promising data, albeit so far only in mice, suggests that a zinc finger approach can distinguish and shut down the faulty expanded version of the Huntington’s disease gene from the normal counterpart.34 But providing these medicines at an affordable cost to patients will be a challenge for the entire industry. Macrae says a typical Sangamo gene-editing drug costs about $300 million to move from idea to clinical trials to FDA approval.
Sometimes the pioneers are not the ones who reap the rewards. But veteran Ed Rebar, who briefly headed the Sangamo R&D team before joining Sana Biotechnology in 2020, remains a staunch believer in the power of zinc. “For therapeutic applications, ZFNs can do everything we need them to do,” he told a crowd of genome engineers.35 “Precision, any base, high levels of specificity.” CRISPR is a great tool for basic research and has enjoyed widespread adoption. “But therapy is a different type of application.”
Rebar wasn’t exactly preaching to the choir. The answer to most genome editing applications in the clinic is to be found in the New Testament of CRISPR-based therapies. But ultimately, patients and their families won’t care which technology is used if it answers their prayers and delivers a cure.
I. There are about seven hundred genes—3 percent of the total—encoding zinc finger proteins in the human genome.
II. Subsequent studies revealed that some Δ32 homozygotes are infected by a different strain of HIV, which gains entry via the CXCR4 co-receptor.
CHAPTER 9 DELIVERANCE OR DISASTER
The conceptual seeds of genetic engineering date back deep into the 20th century, two decades before the double helix and more than a decade before the demonstration that DNA, not protein, was the genetic material.
In 1932, some five hundred scientists traveled to Ithaca, New York, for the Sixth International Congress of Genetics. The registration fee was $10, a room in a hall of residence $1.75. Delegates could go for a day trip to Niagara Falls, attend a group picnic, or listen to an organ recital in Sage Chapel on the Cornell campus. The scientific program was dominated by the rock stars of the era: Thomas Hunt Morgan and his colleagues—Hermann Muller, A. H. Sturtevant, and Curt Stern—from the famous “fly room” at Columbia University. In a lab that smelled of rotten bananas, Morgan’s group anointed the fruit fly as the ideal model organism to establish the “chromosome theory of heredity.” Morgan’s momentous discoveries were accepted as universal truths: His group built the first genetic maps of chromosomes and demonstrated that X-rays cause gene mutations. Morgan won the Nobel Prize the following year. But the answer to the existential question: “What is the gene?” would only emerge twenty-one years later, courtesy of Crick, Watson, and Rosalind Franklin.
Relegated to a Saturday breakout session, Hubert Goodale, the chief geneticist at the Mount Hope Farm in the northwestern corner of Massachusetts, didn’t have the horsepower of a Morgan; instead of a fly room, he had a “mouse house” and a good story about applying genetic principles to animal breeding. Mount Hope was a leading genetics center in the United States: Goodale kept meticulous breeding records of poultry, cattle, pigs, and other animals, producing marked improvements in egg size, milk, and pork production. The farm’s prize bull was named Satisfaction, but not for the reason you might think: an average Mount Hope cow sired by Satisfaction produced three times as much milk as a typical dairy cow.1 Goodale’s talk, entitled “Genetical Engineering,” was perhaps the first public conceptualization of genetic engineering.2
The year 1932 was also when Aldous Huxley published Brave New World.3 Almost two decades later, genetic engineering made its science fiction debut. In his 1951 novel Dragon’s Island, Jack Williamson wrote:
Man may now become his own maker. He can remove the flaws in his own imperfect species, before the stream of life flows on to leave him stranded on the banks of time with the dinosaurs and trilobites—if he will only accept the new science of genetic engineering.
Written two years before the double helix, Williamson understandably took some pleasure in his foresight—only to learn that the Oxford English Dictionary had unearthed a previous use of the phrase in 1949. “Everybody is famous, if only for fifteen minutes,” he said.4
On March 19, 1953, Francis Crick wrote a long letter to his twelve-year-old son, Michael, at boarding school. As sneak peeks go, it was pretty special. “My dear Michael,” Crick wrote, “Jim Watson and I have made the most remarkable discovery. We have solved the structure of deoxyribosenucleic acid (D.N.A.)…” On the next page, Crick sketched the double helix, showing the pairing of the four bases—C with G, A with T. After several more pages of near textbook detail, Crick invited his son to view the model during his half-term break. He signed off, “Lots of love, daddy.”5 Showing maturity beyond his years, Michael held onto his father’s letter. It was a wise decision: sixty years later, Crick’s letter fetched a world-record price at auction—$6.3 million. Half the proceeds went to the Salk Institute in San Diego, where Crick spent his final years.I
One week earlier, Watson had written a similar letter to one of his scientific idols, Caltech virologist Max Delbrück. Watson shared that he and Crick had fashioned a model of DNA with intertwining strands glued by interlocking base pairs running through its core, and would shortly submit a report to Nature. In a rare moment of humility, Watson conceded that (as had happened before) their model might be wrong. Then again, “If by chance, it is right, then I suspect we may be making a slight dent into the manner in which DNA can reproduce itself.”6
Crick and Watson’s historic success was made possible by data collected by Rosalind Franklin at King’s College London. Franklin, working with her student Raymond Gosling, was a brilliant experimentalist, but uninterested in using her X-ray photographs of DNA crystals in trivial pursuit of building models. Crick was the mathematical brains in the Cambridge partnership, but as the late Brenda Maddox, Franklin’s biographer, observed, he was unlikely “to have reached the goal without the pushing and prodding of the gauche young man from Chicago.”7
In early 1953, Maurice Wilkins showed Watson a pristine, unpublished X-ray image of DNA—photograph 51—taken by Gosling six months earlier. To a trained eye, the trademark “X” pattern visible on “Photograph 51” could only mean that DNA was a helix. Watson pieced the final parts of the puzzle together. Working with cut-out representations of the four constituent bases of DNA, Watson’s pairings—adenine (A) with thymine (T), cytosine (C) with guanine (G)—completed the structure of the molecule of life, two months shy of his twenty-fifth birthday.
A few weeks later, on April 25, 1953, the world—or at least Nature subscribers—got their first glimpse of the double helix. It was a family affair: the eight-hundred-word report was typed up by Watson’s sister Elizabeth, while the double helix was elegantly sketched by Crick’s wife, Odile. The report began with an immortal English understatement: