Ethan Weiss, a physician-scientist at University of California San Francisco, and his wife nicknamed their daughter “Billy Idol” for her fluorescent blond hair. Doctors eventually diagnosed Ruthie with albinism, caused by a mutation in the OCA2 gene. “I did imagine that genetic engineering could someday help kids who were diagnosed right after birth,” Weiss wrote. “But I focused instead on just loving and supporting the child I had, and not the one I wished I had.”60 Tempting though technologies like germline editing might sound, their usage raises concerns that “the world will be less kind, less compassionate, less patient, when or if there are no more children like Ruthie.” Weiss insisted that he and his wife were better parents for raising their daughter, but more importantly, “we believe the world is a better place for having kids like Ruthie in it, and we want the world to think hard about whether it really wants to go down a path of engineering a world where there are no Ruthies.”
Discussions about whether we dare to place our own designs on the human genetic code inevitably paint a picture of a slippery slope. “Slopes are only slippery if they catch us unaware and we have strayed on to them inadequately equipped,” wrote the British philosopher John Harris.61
Since the first inkling of gene therapy in the early ’70s, we have tended to regard somatic gene therapy as noble and idealistic, life-saving, whereas germline therapy (or editing) is dangerous and immoral. Those who wanted to push for enhancement did so under the banner of eugenics, looking to perfect the human species. But for the past fifty years, as we look down on the proverbial slippery slope, it is as if there is a giant wall halfway down the hill with no back door or underground tunnel. That barrier prevents us sliding to a dystopian “fully synthesized natural world where nothing exists outside human intentionality.” So says John Evans, a sociologist at the University of California San Diego, who argues that the somatic/germline distinction is on its last legs. The mid-slope barrier worked well in a 20th-century era where attempts to cure monogenic genetic diseases were in stark contrast to eugenic fantasies of an Aryan race. But that barrier has dissolved as the new genomic century has produced a much deeper understanding of genes and diseases. The debate has evolved from changing the species to changing an individual.
Evans contemplates several other types of barrier as we contemplate our descent. One is a safety barrier, which is essentially in the same position as the germline barrier. This is actually more of a speed bump, which slides down the slope as our skill and precision improves. Another is the biological reality barrier, which says that it will be impossible to edit for perfect pitch or higher intelligence because the genetics are too complex. “This is a loser move,” Evans says. In the early ’80s, the eminent geneticist Arno Motulsky waved off discussions of germline editing because he insisted it would not be possible for fifty to three hundred years. Finally, Evans says there is the Boundary of Humanity barrier, which demarcates any natural human gene variant from a novel mutation that no human has ever had.
The ethical debate about germline editing will rage on for years if not decades. The reports from august committees convened by the National Academy of Sciences and the WHO will be valuable, but by no means the last word. I’m not pushing germline editing, nor am I unequivocally opposed on moral, religious, or scientific grounds. I suspect there will come a time when the pros will outweigh the cons, at least in some situations.
Meanwhile, other areas of medicine and surgery are advancing relentlessly. In 2005, a French woman named Isabelle Dinoire who was disfigured when she was bitten by Tanya, her golden retriever, became the first person to undergo a face transplant (the donor had committed suicide). Despite the medical and ethical controversies, dozens of facial transplants have been performed subsequently. Surgeons can correct birth defects such as spina bifida in utero, while the fetus is still in the womb. DNA surgery seems to be the next logical frontier.
Clinical geneticist Helen O’Neill, at University College London, concludes: “No technology is perfect—not IVF nor genome editing—but when combining these and applying them to the most flawed of systems, human biology, we may ask ourselves ‘When will good ever be good enough?’ ”62
I. Studies first reported in June 2020 by three eminent groups (one in the UK, two in the US) showed damaging “on target” DNA rearrangements in a fraction of human embryos edited in the lab using CRISPR-Cas9. There is still much we do not fully understand about DNA repair and recombination in embryogenesis.
II. From Game of Thrones—unsullied as in resistant to pain, not eunuchs.
III. Patients who inherit mutations in p53 have Li-Fraumeni syndrome, and are at risk of developing a variety of different cancers, indicating p53’s critical role in governing cell growth in many different tissues and cell types.
IV. I was a decent singer until my voice broke. At age twelve, I sang at Covent Garden in Carmen as a member of the troop of street urchins belting out “Avec la garde montante” in front of the Queen Mother. I would then try and wrestle a melon off Placido Domingo in Act IV.
V. Genome-wide association studies are performed by surveying a million SNPs on hundreds of thousands of patients and controls. The associations are graphed on an end-to-end map of human chromosomes known as a Manhattan plot for its resemblance to the jagged Big Apple skyline. The tallest peaks indicate the location of the strongest associations.
CHAPTER 24 BASES LOADED
CRISPR genome editing is not yet a decade old but, as I’ve tried to show in this book, it is poised to transform myriad areas of science, medicine, and agriculture. But there are many scientific, regulatory, and ethical challenges ahead. One setback in a clinical trial could precipitate another decade in the dark ages, as happened to gene therapy. Tim Hunt, Editas’s former head of corporate affairs, is refreshingly honest about the business challenges ahead for “cash-eating machines” like Editas commercializing somatic genome editing. “We’ve raised $500–600 million. We’ll need $1–1.5 billion before we have a product on the market,” he said in early 2020. “CRISPR is often described as fast, cheap, and easy. But making a medicine is not fast, not cheap, and not easy. It’s a long journey.”1
From building a company, managing preclinical research and clinical trials, bankrolling manufacture, enhancing delivery, and navigating regulatory red tape, the road to commercial success is tortuous. And in some cases, genome editing is targeting a very niche market. The numbers of patients receiving some therapies, such as those with orphan diseases, are very small. All of these factors drive up the price of potentially life-saving drugs. Ross Wilson and Dana Carroll exhorted genome editing companies and regulators “to accept the challenge to make genome editing therapeutics affordable and accessible, which would represent a massive contribution to global health justice.”2
There may come a time when it makes sense to perform germline editing, but not now, not yet. Maybe in a decade or two, we might consider heritable genome editing to be technically safe, ethically sound, medically justified, and publicly supported. I believe that day will come eventually. Perhaps by 2032, the centennial of Brave New World. Or 2053, the one hundredth anniversary of the double helix. Or 2078, when Louise Brown turns one hundred. Or 2100, a century since we first cracked the sequence of the human genome.