Other genes that would be prime candidates for future genetic modification are those that govern risk for obesity and cardiovascular disease, diabetes, and hypertension. We know humans will go to extremes to address body weight and heart health, from liposuction and gastric bypass surgery to billions of dollars spent annually on statins and other drugs. While obesity and heart disease are complex traits influenced by the interaction of multiple genes and environmental factors, some rare mutations with a profound influence on body weight and heart health are known.
In the mid-1990s, Helen Hobbs, a geneticist at the University of Texas Southwestern Medical Center, set out to identify individuals with rare mutations that might offer protection against heart disease. One of the women she screened was an African American yoga instructor who possessed an enviable cholesterol leveclass="underline" just 14 mg/deciliter, compared to the average of 100 mg/dl. The woman inherited two faulty copies of the gene that encodes PCSK9, a regulator of the LDL receptor. Knocking out PCSK9 increases the number of LDL receptors in the liver that mop up “bad” cholesterol. “Of all the intriguing DNA sequences spat out by the Human Genome Project and its ancillary studies, perhaps none is a more promising candidate to have a rapid, large-scale impact on human health than PCSK9,” wrote Stephen Hall.19
Sure enough, two PCSK9 inhibitors, Praluent and Repatha, were approved by the FDA in 2015. Cardiologists Sekar Kathiresan and Kiran Musunuru (as noted in the previous chapter) cofounded Verve Therapeutics to develop gene-editing approaches to treat patients at high risk of heart disease by mimicking the rare, naturally occurring protective variants seen in genes like PCSK9 and ANGPTL3. Just to be clear, the company adds a disclaimer: “We will not edit embryos, sperm cells, or egg cells.”
Another coveted trait is the ability to thrive on just a few hours of sleep. In 2009, Ying-Hui Fu, a geneticist who studies circadian rhythms at the University of California, San Francisco, reported the discovery of a private mutation in DEC2 in a mother and her daughter, both “natural short sleepers” who need only six hours of sleep a night (with no evident downsides). They awake each morning around 4:30 A.M. alert and ready to start the day. The mutation appears to release the brake on production of a hormone called orexin that is linked to wakefulness.
Earlier we met some rare genetic mutants who carry the scars and injuries that accompany a pain-free existence. No doctor would recommend eliminating pain sensitivity, but such concerns wouldn’t deter some hawkish politicians from fantasizing about an elite force of gene-edited unsullied.II This notion has already been raised in Congress, during one of the first hearings on CRISPR. In 2015, Jennifer Doudna was the star witness in a briefing convened by the Research & Technology subcommittee. Brad Sherman, a Democrat congressman from California, remarked that it took just six years from the development of atomic energy to the dropping of the atomic bomb. It might be unethical, he said, but some countries would jump at the chance to create “super soldiers” with enhanced courage, stamina, and strength. He asked the experts if anyone would like to suggest a timeframe to produce such super soldiers? Doudna and her fellow panelists tittered nervously, unsure how to answer an apparently serious question.20
Ameliorating pain would have one medical benefit in the context of late-stage cancer. But would it ever be feasible or sensible to edit embryos to provide some sort of cancer vaccination? We give teenagers an HPV vaccine to reduce their risk of cervical and other virally-caused cancers, but could that and more be engineered from birth? One intriguing idea for a genome inoculation is amplifying the number of copies of an essential tumor suppressor gene—p53, the so-called “guardian of the genome.” Elephants never forget, so the saying goes; apparently, they never get cancer, either. This makes little sense, for if cancer risk is proportionate to the number of cells (and cell divisions) in an animal, then elephants should be at extreme risk. Yet across the animal kingdom, the odds of developing cancer show no link to body size—a conundrum known as Peto’s paradox, first posed by British epidemiologist, Richard Peto.
In 2012, Vincent Lynch at the University of Chicago discovered surprisingly that the elephant genome carries a whopping twenty copies of p53,21 which happens to be the most frequently mutated gene in cancer.III I’ve heard speculative proposals that adding a p53 cassette (say five to ten additional copies) could provide lifelong protection against cancer. Researchers are studying the idea of boosting p53 levels as a form of genetic protection against radiation. America’s new Space Force—Maybe your purpose on this planet isn’t on this planet—won’t go far unless scientists can devise a mechanism to protect astronauts from excessive, dangerous amounts of radiation (as would be endured on say a voyage to Mars). Urnov’s team at IGI has received funding from the Defense Advanced Research Projects Agency (DARPA) to conduct CRISPR screens to identify gene variants that could help soldiers survive radiation exposure by giving them, in Urnov’s words, “a molecular coat of armor.”22
But who is to say that other genes and fanciful ideas won’t prove more realistic, perhaps a suicide mechanism for cancer cells? Is that such a bad genetic modification? “Some people will want to never allow germline genome editing because they think it’s bad for humanity,” said Robin Lovell-Badge, a vocal critic of He Jiankui’s actions. But what he says next might surprise some. “That scares me. I don’t like closing and locking doors. Take global warming—we might need to modify ourselves.”23
Gene cassettes might be normal genes or they could be custom DNA sequences. There is growing excitement around synthetic biology, in which molecular engineers design custom gene circuits that can be tested in our favorite model organisms, yeast or fruit flies or mice. Before the end of this century, we could be installing next-gen DNA circuits in the genomes of the next generation. But before we get too carried away, there’s a problem. “Imagine two generations from now: Harry meets Sally,” says Lander. “Harry has inherited one circuit. Sally has inherited another clever circuit. No one has a clue what will happen when they coexist in their offspring… It’s complicated.”24
Most discussions about designer babies quickly descend into debates about intelligence and other supposedly desirable physical and behavioral traits. But these utopian fantasies overlook the daunting genetic complexity and heterogeneity of these complex traits. Although Church and others have demonstrated impressive technical virtuosity to edit hundreds of genes simultaneously, the prospect of precisely sculpting scores of specific genes in a human embryo—and achieving the desired outcome—is not feasible at present. But it won’t stay that way forever. Before we can answer the question of whether we should contemplate such interventions, we first need to identify the genes required to alter human behavior or personality or cognition. That’s by no means straightforward.
What if, in our brave new genetic future, CRISPR clinics decide to add height or mathematical ability or skin color or even intelligence to the menu? This is still the domain of science fiction. These are highly polygenic traits, shaped not by the large effects of solitary genes but by the combined influence of hundreds of genes. Height is a classic example: it is one of the most polygenic traits known, with variants in hundreds of genes associated with a person’s stature.