Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

CHAPTER 23 VOLITIONAL EVOLUTION

In 2007, Anne Morriss and her partner decided to start a family. The two women went to a sperm bank and chose a donor based on a few criteria (“sporty” was high on the list). Sperm banks typically only screen donors for a couple of genetic diseases—cystic fibrosis and spinal muscular atrophy—but Morriss had no reason to be alarmed. However, a few days after giving birth to a baby boy, she received a distressing phone call from a Massachusetts public health employee.

“Is your son okay? Is he still alive?”

A stricken Morriss stammered, “Yes, I think so. I just put him down for a nap.”

“Can you go and check?”

After birth, Morriss’s son Alec had received the standard Guthrie heel-stick test, in which a drop of the baby’s blood is screened for a few dozen serious genetic disorders. Against all odds, Morriss and the anonymous sperm donor were both carriers of a rare recessive genetic trait—MCAD deficiency, which affects about 1 in 17,000 people. This gene encodes an enzyme called medium-chain acyl-CoA dehydrogenase that helps the body convert fats into energy. Morriss and her partner immediately modified Alec’s diet before any serious problems ensued. A fortuitous phone call had saved their son’s life, but hospital bags remain packed by the Morriss front door in case of an emergency.

A motivated Morriss teamed up with Princeton University geneticist Lee Silver (author of Remaking Eden) to launch a next-gen diagnostics company called GenePeeks. Using Silver’s “Matchright” algorithm, GenePeeks created “digital babies” by virtually matching the DNA of the client with potential sperm donors. The client could then see which donors were predicted to have an increased risk of creating an embryo with one of hundreds of genetic disorders. These individuals could then be excluded from the donor pool, without selecting or freezing spare human embryos.

Silver and Morriss were featured in a story on 60 Minutes, almost literally their fifteen minutes of fame. In the future, Silver predicted “people will not use sex to reproduce” because it was too dangerous to leave inheritance to chance. I published my first story on GenePeeks in January 2013, the same week as the first demonstrations of CRISPR editing in mammalian cells.¹ Silver and Morriss weren’t attempting genome editing, but in their own way were looking to skew the odds in the otherwise random genetic assortment that underlies conception. “Our mission was to empower parents with insight and information that could protect their future children from devastating diseases,” Morriss told me. Several hundred couples used GenePeeks’s pre-fertilization matchmaking service before the company ran out of money and dissolved. Evidently the world wasn’t ready for digital babies. But is it ready for #CRISPRbabies?

We probably won’t hear about another gene-edited baby for several years given the widespread support for a moratorium, but this state of affairs won’t last forever. The next time someone tries this, whether government approved or secretly in some offshore CRISPR clinic, they will probably succeed. And so we should ask: under what circumstances, if any, might germline editing be justified?

Despite evidence that gene editing in human embryos using CRISPR-Cas9 poses risks of “on target” DNA rearrangements, the pace of research suggests that in a few years, we will have the technical ability to safely perform precision DNA surgery in a human embryo.^I Fyodor Urnov suggests a thought experiment: Let’s say we are part of a group that has raised $1 billion and can draft a biotech dream team, the Avengers of genome engineering. Can we imagine that embryo editing reaches the stage where we can finesse the editing so there are no rearrangements, no off-target effects, no mosaicism? “We could get there quickly,” Urnov surmises. “But the $64,000 challenge is: What are we going to do?”²

We’ve been wrestling with this dilemma for decades, since before the recombinant DNA revolution. But there is a renewed urgency since the first reports of human embryo editing. Eric Lander addressed this issue head-on at the first international genome editing conference in 2015. In preimplantation genetic testing (PGT), we already have a method, he argued, to reduce the transmission of disease genes. “The truth is, if we really care about avoiding cases of genetic disease, germline editing is not the first, second, third, or fourth thing we should be thinking about,” he said.³

The use of PGT has exploded since its development in 1990 by Alan Handyside, Robert Winston, and colleagues in London.⁴ Many clinics offer couples the chance to screen their IVF embryos, taking a cellular biopsy after the embryos are about five days old (about 250 cells). Embryologists carefully remove two or three cells from the blastocyst bundle, then amplify and sequence the target gene. This allows them to designate each embryo as being healthy or carrying one or two copies of the mutant gene. Following this scorecard, the couple can choose which embryos to implant and which to put into deep freeze (or perhaps donate for research purposes). For couples who carry a recessive disease gene, there is a one-in-four chance of a child inheriting the disorder. PGT can theoretically eliminate that risk by analyzing the embryos after IVF to identify the healthy embryos for implantation. For dominantly inherited disorders such as Huntington’s disease, half of the IVF embryos conceived by a Huntington’s patient would on average possess the disease gene. Over the past two decades, PGT has been performed about 1 million times; about a tenth of those cases are to test for a monogenic disorder.⁵

There are rare cases where PGT won’t be helpful. If both members of a couple have a recessive disease such as cystic fibrosis or the deafness gene that Rebrikov is contemplating, one could potentially CRISPR the embryos to fix one or both copies of that gene, restoring it to the healthy (wild type) version. There are also rare situations where a patient has inherited two copies of a dominant disease gene. PGT would be redundant as the patient is guaranteed to pass on the disease to his or her progeny. Only germline editing (fixing both copies of the broken gene) could produce a healthy biological child.

“It’s not a very big need, but it’s not nothing,” Lander observed. “If we truly care about preventing needless genetic disease, we should be empowering genetic diagnostics for families, not editing embryos.” Researchers at a fertility clinic in Los Angeles took a stab at estimating what “not nothing” actually entails.⁶ The numbers of cases were few and far between, perhaps a few dozen a year in the United States. But IVF is not a trivial procedure: it is expensive, painful, and frequently unsuccessful, producing insufficient healthy embryos to ensure a healthy pregnancy.

As we survey the human genome and identify more of the genetic variants and pathways that underlie more common diseases, the menu of PGT services will inevitably expand, straying beyond the merely medical. In fact, it’s already happening. The Ferny Fertility Clinic in New York offers couples a cosmetic gene test to select embryos for a particular eye color. “As has been happening from the beginning of humankind, only mom and dad can ‘make’ the eye color by combining their own unique genetics into the new child,” says the clinic’s founder, Jeffrey Steinberg.⁷ For a while, the Ferny clinic even offered a discount for people with blue, green, or hazel eyes.

In the future, there may be a way to circumvent editing embryos completely. An alternative approach that is gaining interest is to edit the eggs or sperm prior to fertilization. For example, at the Weill Cornell Medical Center in New York, embryologist Gianpiero Palermo is literally zapping sperm (excess material donated for research) to target the BRCA2 gene using CRISPR.⁸ To coax the CRISPR molecules into the sperm heads, technician June Wang pulses the sperm with a quick electric shock. She places the vial containing 50 million sperm in an electroporation machine and turns it up to 11—1,100 volts, that is. The pulse loosens up the densely packed DNA in the head of the sperm to give Cas9 access to its intended target.

“Before 2020, germ-line engineering to cure severe genetic disease in human embryos will be an established therapeutic option.”⁹ Lawyer and author Philip Reilly made that prediction in 2000, and while it hasn’t quite materialized the way he anticipated, he was correct in believing we would cross the germline threshold, reaching into the genetic fabric in a human embryo to rewrite the book of life. Designing humans—editing humanity—does not seem quite so far-fetched now our species has dared to cross the germline. As evolutionary biologist Mark Pagel wrote before the JK debacle: “The first truly and thoroughly designed humans are more than just the subjects of science fiction: they are on our doorsteps, waiting to be allowed in.”¹⁰ Reilly predicts that by 2050, germline editing would be as routine as cosmetic surgery.

At this point, I’m contractually obliged to bring up Brave New World, the classic novel published in 1932. As we’ve seen, discussion of embryo selection, genetic modification, and designer babies inevitably conjures up a reference to Huxley’s dystopian vision. It’s been that way for decades in discussions about medical involvement in procreation and eugenics, test-tube babies, and Dolly the sheep. As Leon Kass wrote in 2001, “Huxley saw it coming.”¹¹

But as Derek So has pointed out, Brave New World was never intended to be a warning about technologies such as genome editing.¹² Huxley doesn’t describe any form of genetic engineering or testing. The upper castes in Brave New World were smarter than the remainder not because they were enhanced but because the lower castes were deliberately subjected to impairment. Nor is the novel a good example of parents selecting designer babies. Huxley himself was much more worried about totalitarianism than new reproductive selection technologies. Huxley, like his brother Julian, was a member of the Eugenics Education Society and believed England should enforce mandatory sterilization lest the country devolve into a nation of half-wits.

After giving a talk recently about CRISPR at my children’s former high school in Lexington, Massachusetts, a student stumped me by asking if I’d read Margaret Atwood’s MaddAddam trilogy, set in a hyper-capitalistic late 21st century. In the first book of the trilogy, Oryx and Crake, a brilliant geneticist named Crake usurps natural selection to conceive and create a superspecies adapted to thrive in a post-pandemic society, on a planet ravaged by climate change. They replaced socially normal mating customs with features beneficial to procreation and survival. The Crakers had beautiful skin of many colors resistant to sun damage and able to repel insect bites and infection. They also boasted bovine-like digestive systems requiring only nutrients provided by ubiquitous weeds.

The ability to eat weeds isn’t high on anyone’s wish list (yet) but some of us do possess extraordinary “superhuman” traits. Take seventy-year-old Jo Cameron, who lives near Loch Ness in Scotland. Her life has been free of pain and anxiety—she barely felt any discomfort giving birth, although has suffered plenty of serious bruises and burns. She didn’t appreciate her superpower until undergoing hip surgery in her sixties, managing the pain with just a small dose of acetaminophen. In 2019, researchers found a variant in one of Cameron’s genes called FAAH-OUT, which raises levels of anandamide, an endogenous cannabinoid, and makes her almost unable to feel pain.

The first example of a pain-resistance mutation was described in 2006 in members of a consanguineous (inbred) Pakistani family, incriminating a gene that codes for a sodium ion channel called NaV1.7, involved in the propagation of nerve signals.¹³ One boy in particular was a well-known street artist, painlessly walking on hot coals or stabbing his arms with knives. On his fourteenth birthday, he jumped off a house roof and fell to his death. Pain has its purpose enabling humans to comprehend and internalize risk. The English team that made that gene discovery learned about another extraordinary family from Siena, Italy, featuring people who cannot feel extreme pain or temperature. For example, Letizia Marsili shrugged off a nasty crash while skiing, only to discover that evening that she’d sustained a broken shoulder.¹⁴ The Marsilis carry a mutation in a gene called ZFHX2, and now have a syndrome named after them. This discovery could eventually turn into a powerful nonaddictive pain reliever.

Marvel creator Stan Lee made an entire television series devoted to real superhuman genetic outliers—echolocation, extreme endurance, temperature resistance, mathematical wizards, and people with eidetic or photographic memory.¹⁵ The actor Marilu Henner is the most famous person (although all told there are only a dozen) with total memory recall, a condition called hyperthymesia or highly superior autobiographical memory (HSAM). Scientists are eagerly trying to untangle the neural basis of this extraordinary ability and its possible genetic underpinnings.

Julian Savulescu, a philosopher at Oxford University, can reel off a list of traits he’d like to see engineered into humans that would have made Stan Lee blush. Bat sonar. Hawklike vision. Enhanced memory. Radical life extension. Increased IQ to the point that we become a separate species. Humans have been seeking to enhance the quality of life for years. We add iodine to salt and vitamin D to milk, and calcium to orange juice. We take Ritalin to improve concentration, hormones to improve vitality, and undergo Lasik surgery to dispense with spectacles. We perform IVF, prenatal diagnosis, and PGT, what some term liberal eugenics. “Parents should be allowed [to undertake embryo editing] provided they don’t harm their children or other people,” Savulescu suggests.

George Church is somewhat agnostic about germline editing but supports using the protective effects of known gene variants to aid human health and longevity. The ends are more important than the means. For years, Church has compiled a set of gene variants that offer potential physical, medical, or behavioral advantages—some call it the transhumanist wish list (see table on the next page). Some of these gene discoveries are already fueling drug discovery advances. But if germline editing was ever offered in the future, these would be some of the first genes on the clinic menu.

CCR5 was on this list long before the JK scandal, as resistance to viral infection is in principle a highly desirable trait. That was true even before the COVID-19 pandemic began.¹⁶ We don’t yet know of a gene variant that confers resistance to SARS-CoV-2, but such protective polymorphisms likely exist. The FUT2 receptor is the cellular foothold for the norovirus, which afflicts hospitals and cruise ships with regularity. Immunity to the winter vomiting bug would be nice but knocking out FUT2 appears to increase risk of Crohn’s disease and colon cancer. There are few free lunches in the human gene pool.

Table: A list of gene variants that offer potential medical or other advantages

GENE

MUTATION

EFFECT

CCR5

-/-

HIV resistance

FUT2

-/-

Norovirus resistance

PCSK9, ANGPTL3

-/-

Low coronary disease

APP

A673T/+

Low Alzheimer’s

GHR, GH

-/-

Low cancer

SLC30A8

-/+

Low T2 Diabetes

IFIH1

E627X/+

Low T1 Diabetes

LRP5

G171V/+

Extra-strong bones

MSTN

-/-

Lean muscles

SCN9A, FAAH-OUT, ZFXH2

-/-

Insensitivity to pain

ABCC11

-/-

Low odor production

DEC2

-/-

Reduced sleep

What about protection against dementia or premature aging? We’ve already seen how one version of the apolipoprotein E (APOE) gene on chromosome 19—APOE4—is associated with a roughly tenfold increased risk of developing Alzheimer’s. Editing the E4 variant to the E2 or E3 form might lower disease risk and is worth exploring. In Colombia, a huge extended family suffers from a rare hereditary form of early-onset Alzheimer’s caused by a mutation in the gene for presenilin. About 1,200 family members harboring this mutation are affected—except one.¹⁷ It turns out this seventy-three-year-old woman carries another mutation in the APOE gene called APOE-Christchurch, originally discovered in the 1980s by a team in Christchurch, New Zealand.¹⁸ This variant codes for a protective nonstick version of the normal protein, reducing the prevalence of protein aggregates in the brain.

There is also evidence that elevated levels of a protein called Klotho, sometimes dubbed the longevity gene, can improve cognition and protect against Alzheimer’s—at least in mice. A Japanese group named the gene after Clotho, daughter of Zeus, and one of the three Fates in Greek mythology. Several biotechnology companies—seemingly driven by Silicon Valley billionaires contemplating their own mortality—are desperately seeking genes that might slow down the aging process.

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 level: 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.

Before the Human Genome Project, we naïvely thought that variants in single genes could account for major mental illnesses and complex behavioral traits. It was a classic case of looking for your lost car keys only under the lamppost. In 1988, Nature published a British claim for the mapping of a schizophrenia gene that didn’t hold up. Science trumped that by publishing evidence for a “gay gene” on the X chromosome. The evidence was perilously thin, collected from fewer than fifty gay couples, and never replicated.

A quarter century later, Benjamin Neale’s team at the Broad Institute performed a state-of-the-art genome-wide analysis involving 1 million DNA markers on a database of nearly 500,000 people. The results painted a vastly more complex picture of same-sex behavior, one in which gene variants explained less than half the variance in the trait. The top five gene “hits” made up less than 1 percent of the variance. Nevertheless, even highly polygenic diseases and traits may have simple genetic switches. “Just because it is polygenic doesn’t mean it doesn’t have a monogenetic solution,” Church says. For example, stature is a very polygenic trait, but many patients with short stature can be treated with human growth hormone.

Would a musician want to ensure their child had the mysterious gift of perfect (or absolute) pitch? My father had perfect pitch, which propelled him to a successful career in the West End as musical director of hit shows including Cabaret and Fiddler on the Roof. As a boy, I’d be ushered backstage after a Saturday matinee to meet a young Judi Dench or Topol. If there’s a gene for perfect pitch, I didn’t inherit it.^IV My former colleague Alissa Poh recounted her daily experience living with absolute pitch: her car horn hovers between an E and F, her cell phone rings in A minor, while her refrigerator hums in B-flat.²⁵ Studies by Jane Gitschier among others support a nature and nurture model—the trait is manifest by inheriting an as yet unidentified gene along with early musical training.²⁶ But perfect pitch doesn’t make a musician, nor are all great musicians born with perfect pitch.

In the next fifty to one hundred years, it might become possible to apply genome surgery on artistic or mathematical behavior. And, as Church predicts, once we can do it for a single gene, we will develop safe methods to extend this in parallel, multiplexing edits at multiple genes simultaneously.

In early 2019, I was invited to attend an unusual conference at the Ditchley Estate, a quintessential English stately home reminiscent of Downton Abbey just outside Oxford, ostensibly to discuss the intersection of gene editing and artificial intelligence (AI). During World War II, Winston Churchill spent weekends there (Checkers, the official retreat of the prime minister, was too recognizable for the Luftwaffe). After a welcoming reception with tea and biscuits, forty of us took our seats at a long boardroom table in the old library. The first speaker to be introduced was Stephen Hsu, a theoretical physicist at Michigan State University. This seemed like a peculiar choice—until Hsu started talking.

Hsu’s interest in genetics traces back to his childhood, avidly watching Star Trek and pondering Kirk, Khan, and the Eugenics Wars. “If I get to be one of the scientists who makes real some amazing trope from science fiction, that would be the most awesome thing in the world,” Hsu told Radiolab.²⁷ Although he gravitated toward physics, Hsu remained fascinated by the link between genetics and intelligence. He was formerly an advisor to BGI’s controversial Cognitive Genomics project, since aborted. Now he believes he can apply AI to the prediction of complex polygenic traits including cognitive ability. Once, when asked to give his view of a superior human intelligence, Hsu offered as an example John von Neumann, the 20th-century polymath, developer of game theory, and computer science, who was capable of total recall and a photographic memory. “In my opinion,” Hsu says, “genotypes exist that correspond to phenotypes as far beyond von Neumann as he was beyond a normal human.”

Hsu cofounded a PGT clinic called Genomic Prediction, located in an unremarkable office park off the New Jersey Turnpike, a short drive from Manhattan. Dressed in a T-shirt and torn genes, Nathan Treff, the company’s chief medical officer, met me in his small office decorated with framed posters of Pearl Jam and Iron Man.²⁸ Genomic Prediction offers the usual menu of PGT services—tests for chromosomal abnormalities and genetic diseases such as CF, Tay-Sachs, and Huntington’s disease. But Genomic Prediction goes further, offering couples tests for polygenic conditions including heart disease, obesity, diabetes, and short stature. Also on the menu: low cognitive ability.

Since a landmark paper from researchers at the Wellcome Trust Sanger Institute in 2007, researchers have identified thousands of gene variants that influence our risk for hundreds of complex traits.^V We can’t point to a solitary genetic risk factor for type 2 diabetes or obesity, but we can confidently circle dozens or hundreds of specific DNA variants that influence our susceptibility to these and other disorders.

More recently, government-funded databases such as the UK Biobank have made available full genomic and medical data on some 500,000 (mostly European) volunteers. This allows researchers to run machine learning programs to “train” on the data, looking for genetic predictors for medical and behavioral traits. Kathiresan’s group at Harvard Medical School developed polygenic risk scores (PRS) for five complex diseases including heart disease, type 2 diabetes, and breast cancer.²⁹ Hsu’s team extended this work, but he doesn’t stop at merely medical disorders. By identifying some 20,000 DNA variants that influence height, Hsu claims he can build an algorithm to calculate a PRS and predict someone’s height to plus or minus one inch.³⁰

Whereas most investigators are studying PRS in patients, Hsu is courting controversy by insisting he can calculate a PRS before birth in an individual embryo. Hence Genomic Prediction’s menu of available polygenic risks includes short stature and low cognitive ability. Hsu scornfully dismisses criticisms, shocked that human geneticists have virtually no idea what their colleagues in livestock or corn breeding are doing.

The genetics of intelligence is a controversial and fraught issue. A recent Canadian study examined the effect of DNA deletions or insertions (copy number variants) in more than 24,000 people. The authors concluded that the number of genes that influenced intelligence was around 10,000—fully half the genes in the human genome.³¹ But that hasn’t deterred Hsu. Projects like the UK Biobank haven’t been conducting IQ tests but have asked volunteers to list their level of education. Using that as a proxy for IQ, Hsu’s team mined these data for DNA markers associated with cognitive ability. He says he can predict cognitive ability with a correlation of about 30–40 percent. In the same way that a college dean would look askance at a student who had underperformed on the SAT, Hsu says, “parents may deserve a warning if we find that an embryo has super elevated risk of intellectual disability.”³²

Championing couples’ “reproductive liberty,” Treff’s team has already reported IVF embryo screenings for breast cancer and type 1 diabetes.³³ Hsu says they can go further to predict which embryo would develop with low cognitive ability—that is, it carries an excess of DNA variants that are predicted to depress IQ below a clinical threshold. The company is not offering clients the option to select for an extra-intelligent embryo—not because the technology isn’t there, Hsu says, just that society isn’t ready for it. Suppose you want to start a family and you learn that embryo #4 was predicted to be in the top percentile of cognitive ability. What would you do? Would you rather rely on the embryologist judging the health of each embryo by shape and morphology (as happens now) or by analysis of its DNA?

Hsu offers another chilling scenario: What if the Singapore government, as an example, were to invite his company to alert parents if one of their embryos is likely to be well above average intelligence? Hsu can imagine a situation where “I guess in Singapore it is okay but we don’t feel like Americans are ready for it.”³⁴ If and when Americans decide they are ready for it, I expect Hsu would be happy to oblige. Editing embryos for intelligence remains a fantasy, but ranking embryos via PRS doesn’t look so far away.³⁵

Hsu’s critics argue that selecting embryos based on PRS is risky business, rife with statistical ambiguity, geographic bias, and ethical fragility. “It might be better than a horoscope, but we don’t know—but I don’t think that Genomic Prediction does either,” observes Hank Greely.³⁶ An Israeli study concluded that the gain afforded by PRS calculations—the difference between the “top ranked” embryo from the average—was about 2.5 cm for height and 2.5 IQ points.³⁷ That’s hardly enough to justify the expense and hassle of IVF. “The prediction is not good enough to individually identify an embryo with a certain characteristic,” Kathiresan told me. “There’s not a 1:1 correlation between score and outcome. It’s a probabilistic model. It’s not appropriate in my view to use for embryo selection.”³⁸

Even if you disagree, geneticist Laura Hercher warns that Hsu’s company can’t guarantee giving a couple a child that is not going to get sick and die. “If you are buying into that fantasy, you’re going to be angry. I hope that it is at [Genomic Prediction] and not at your kid,” she says.³⁹

Assuming that CRISPR or base or prime editing is safe (or no worse than the mutation rate caused by background radiation) is there any fundamental reason why it should not be allowed on human embryos for whatever applications we deem to be appropriate? In 1997, at the halfway point of the Human Genome Project, UNESCO declared the human genome to be a priceless heirloom. “The human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity.”⁴⁰

It’s a splendid line, but is the human genome really the heritage of humanity? The sacrosanct property of humankind, to be preserved and protected like a priceless masterpiece? Look but please don’t touch? “It seems the equivalent of The Ark of the Covenant,” Greely declared. And, as anyone who saw the Indiana Jones film Raiders of the Lost Ark knows, “it cannot be allowed to fall into the wrong hands.”⁴¹ The human genome belongs to all of us, argues Françoise Baylis, but there is no pristine genome exhibit we can put on display as the perfect sequence of the genome. What we have instead are 7.5 billion genomes, all iterations of what went before and their future descendants.

What, then, was the Human Genome Project if not the definitive textbook sequence? The fabled reference genome that President Clinton announced in June 2000 was a patchwork quilt with a dozen anonymous contributors. A decade later, major advances in DNA sequencing technologies made it feasible to have your own genome decoded. In 2010, I attended a conference at MIT where the first two dozen genome pioneers gathered under one roof, including Jim Watson, Harvard’s Henry “Skip” Gates, and George Church.⁴² A few notables, including Craig Venter and Black Sabbath’s Ozzy Osbourne, were absent, but I sensed that this would be the last time that (almost) every person sequenced on the planet was in one room. But nobody was proposing to anoint any individual genome to represent the human species. The genome of a Beckham or Beyoncé is littered with mutations just like yours and mine.

While there is nothing sacrosanct about the human genome, there is widespread opposition to the notion of tampering with the germline, knitting by hand a permanent sequence alteration that would be passed on to future generations. But in a practical sense, editing a human embryo is a much safer proposition than treating a child or adult. Church argues that germline editing offers three intrinsic advantages. First, it is more effective than other delivery systems at reaching all cells in the body. Second, after administering the edit, every future child and descendant would receive the edit free rather than costing millions of dollars for their own somatic gene therapy. And third, germline editing goes through a single cell, whereas somatic therapies impact millions of cells—assuming we can sort out delivering genes to the brain or other hard-to-reach organs—any one of which could become cancerous.⁴³ “Somatic gene therapy has been hopeless as a therapy, because you’ve got to get the gene to billions of cells,” says Savulescu.⁴⁴

There is no inviolate reason why we should not contemplate germline editing, and indeed there are arguments in favor from a medical and economic standpoint. But that still doesn’t answer the question of why or when? “Proceed with caution” is a common refrain whenever a new genetics technology looks poised to transform medicine and assisted reproduction. It was the title of Neil Holtzman’s book in the 1980s warning of the potential dangers of prenatal DNA diagnosis. The Lancet editor Richard Horton echoed the phrase shortly before the birth of the CRISPR babies.⁴⁵

That’s reasonable, but what if deliberately refusing to alter the human genome affects the future just as if we allow germline intervention? “If it ever became possible to eliminate, say, the gene that causes cystic fibrosis, not then to do so would condemn future generations unnecessarily to suffer from a wretched condition,” writes Kenan Malik. “There is nothing ethically superior in leaving things be if it is possible to change them for the better.”⁴⁶

What if we wanted to correct a devastating gene mutation? Huntington’s disease (HD) only affects 1 in 50,000 people, but it is incurable. Children of HD patients have a 50:50 chance of inheriting the disease gene. In the Ken Burns documentary The Gene, Jenny Allen makes the fraught decision to take a genetic test that will reveal her destiny. Her mother and two of her siblings have HD. As her doctor reveals that she did not inherit the defective gene, Jenny bursts into tears, waves of joy and relief mingled with survivor’s guilt. One day, germline editing could permanently fix this mutation, snipping out the faulty sequence to restore a functioning version of the HD gene. “Why should anyone object if the genome of the 50,000th person is coaxed back to the normal conventional sequence?” Greely asks reasonably.⁴⁷

Savulescu goes further, arguing that parents have a downright obligation to maximize the potential of their children. Eradicating genetic disease is not bad in itself, he says, but our technology won’t stop with reverting to healthy forms of genes. We could introduce novel variations that have not been encountered in our species before.

In the summer of 2015, after the initial furor around CRISPR and human embryos, Harvard professor Steven Pinker wrote a strident op-ed in the Boston Globe. In a world that promised a biomedical bonanza to improve people’s health and longevity, Pinker argued, “the primary moral goal for today’s bioethics can be summarized in a single sentence. Get out of the way.”⁴⁸ While individuals must be protected from harm, a “truly ethical bioethics” should not hold back research in red tape or moratoria, nor should it sow panic about potential future harms or bandy about perverse analogies with Nazi atrocities or science-fiction dystopias like—you guessed it—Brave New World or Andrew Niccol’s sci-fi film Gattaca.

“When science moves faster than moral understanding,” Harvard philosopher Michael Sandel wrote in 2004, “men and women struggle to articulate their own unease.” The genomic revolution has induced “a kind of moral vertigo.”⁴⁹ That unease has been triggered numerous times before and after the genetic engineering revolution—the structure of the double helix, the solution of the genetic code, the recombinant DNA revolution, prenatal genetic diagnosis, embryonic stem cells, and the cloning of Dolly. “Test tube baby” was an epithet in many circles but five million IVF babies are an effective riposte to critics of assisted reproductive technology.

With CRISPR, history is repeating itself, only this time we have the lives of three genetically manipulated human beings weighing on our collective conscience. Lulu, Nana, and the third CRISPR baby did not ask to be genetically modified. “We should all hope and pray that these two little girls are okay,” Francis Collins said. “They did nothing to bring this trouble down upon them. They certainly didn’t give their consent.”⁵⁰ True enough, but then again, no embryo or person has ever given informed consent over the circumstances of their conception or the mash-up of genetic material that accompanied fertilization.

Long before CRISPR babies, some argued that engineering genetic enhancements for cognitive or musical talent or athletic ability would steer such children toward a particular destiny, depriving them of free will. But as Sandel noted, this implies that children are naturally free to choose their fate. “None of us chooses his genetic inheritance,” Sandel wrote. The alternative to a genetically enhanced child “is not one whose future is unbound by particular talents but one at the mercy of the genetic lottery.”⁵¹ Gene editing poses a threat to human dignity. The drive for perfection—mastery of a sport, instrument, or cognitive skill—obscures humanity’s achievements. Sandel says the sin of enhancement would be the evasion of training and hard work. He quotes William May, who said, “to appreciate kids as gifts is to accept them as they come.”

In the world of sports, fair play is a forgotten virtue as some professional and aspiring athletes take steroids, growth hormone, testosterone, or erythropoietin to steal an advantage on the competition. Governing bodies can detect traces of chemical doping, but genome editing opens up a Pandora’s box. “There will be others seeking to fill [JK’s’] research shoes and the possibility of hidden funding to attempt to create the perfect athlete,” warned Lord Colin Moynihan, speaking in the House of Lords. “Gene editing clearly has huge benefits, such as relieving the burden of heritable diseases. However, it has no place in the sports arms race if we are to protect the integrity of competitive sport.”⁵²

A bigger concern surrounding genome editing is that it would exacerbate social divisions and inequality. How will access to germline editing be based on need rather than means? The first approved gene therapies are setting record-breaking prices, such as Novartis’s staggering $2 million price for Zolgensma. As companies hike the price of generic drugs, some pharma executives, spouting fiduciary responsibility, seem more interested in putting their shareholders ahead of their patients. Genome editing companies developing somatic therapies aren’t going to give these precious medicines away as they seek to recoup the vast sums invested in R&D and manufacturing. By contrast, a company developing a germline therapy might be able to offer a more affordable procedure, as the CRISPR machinery would only be administered to a single cell (or gamete).

Equal access to 21st-century medicines is a major concern, says Church, who like Lander, thinks the alternative to genetic therapy is actually genetic counseling. With the cost of genome sequencing dropping toward a paltry $100, “everybody could now get their genome sequenced and avoid a huge fraction of these expensive orphan drugs and gene therapies by genetic counseling.”⁵³ The last thing Church wants is a have-and-have-not society. “When people talk about the ethics of CRISPR, 90 percent of it should be, and probably is, about equal distribution of expensive technology.”

In some circles there is a revulsion at the prospect of man-made genetic alterations muddying the gene pool and decreasing human diversity. Would society function better if everyone received an assist on their IQ score? In most countries, high IQ correlates with wealth, health, and overall well-being. But there are ways of addressing that imbalance without resorting to genome surgery in the womb. Why does intelligence, wealth, and job status determine life outcomes so much in the first place? “That is something which should be addressed, rather than reified,” says British philosopher Gulzaar Barn.⁵⁴

Physical attractiveness is rarely a disability in life. A CRISPR clinic offering facial prediction would further the notion that a woman’s value is derived from her appearance, says Barn, accentuating division and privilege in society. In a world with increasing wealth disparity, this procedure would trickle down from the wealthy. Early efforts to predict facial features from DNA by artist Heather Dewey-Hagborg and Craig Venter⁵⁵ met criticism,⁵⁶ but they too will improve. In a fair society, everyone should have access (if they wish) to these sorts of genetic endowments, although that’s a pipe dream. Barn argues we should be addressing societies’ institutions and structures so that life outcomes aren’t so dictated by these factors. “We need to consider whether it is right that a small number of unrepresentative, rich funders and scientists are able to implement technologies that have the ability to radically alter society in unprecedented ways.”

Those opposed to germline editing argue that we would lose diversity, reinforcing the stigma and discrimination faced by those with disabilities or other genetic conditions. “There is value in human fragility that would be lost if disabilities were made to disappear,” says the Lancet’s Horton.⁵⁷ The eugenic concern about “weeding out” disabilities applies more urgently to PGT, where hundreds of thousands of embryos are screened each year, while sub-optimal embryos are consigned to a state of suspended animation. Western countries routinely screen for Down syndrome (trisomy 21) and other trisomies, the incidence of which correlates with increasing maternal age. In Iceland and Denmark, the number of babies born with Down syndrome annually has been reduced to single digits. Columnist George Will, who’s eldest son has Down syndrome, accused Iceland of implementing a “final solution” to the disorder.⁵⁸ Meanwhile, some states in the U.S. have passed laws making it illegal to prevent abortion of fetuses diagnosed with trisomy 21.

Genome editing won’t change society that much in the near future, but the prospect of genetic enhancement would only accentuate societal differences instead of trying to stem such inequalities. As Barn says, we’re all prone to illness and in need of help from others at some point in our lives, which warrants greater investment in public services and support for the less fortunate. “Retaining a more empathetic approach, predicated on the belief that every human life is valuable, is crucial for ensuring a well-functioning society that works for the benefit of all.” Philosopher Mike Parker says the best possible life is not necessarily one in which all goes well. Human flourishing involves aspects of both strength and weakness.

Genome editing stokes fears among many disabled people of “society’s fear of the deviant.” This sense of ableism is “denying us our personhood and our right to exist because we don’t fit society’s ideals,” says Rebecca Cokley, a disability advocate who served in the Obama Administration. Cokley has a form of dwarfism called achondroplasia. She sees her condition as a “rich and diverse culture,” a culture she wants to pass onto her children. “We should have that right,” she wrote in an op-ed in 2017 in the Washington Post. It was titled “Please Don’t Edit Me Out.”⁵⁹

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.