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.