In 2018, He Jiankui, a Chinese scientist, claimed to have created the world’s first gene-edited babies. He modified the DNA of human embryos during in vitro fertilization by disabling a gene called CCR5, which could potentially make the babies resistant to infection with HIV.1
The babies, twin girls known as Lulu and Nana, were born in 2018,2 and a third baby with an edited CCR5 gene is due to be born in 2019.3 He’s team received major backlash from the highly controversial move, as while the technology to genetically edit human babies has existed for some time, ethical considerations had stopped researchers from tinkering with the human germline.
In the case of editing germline cells, such as embryos, eggs and sperm, changes made to the genome will be inherited by future generations, potentially altering the course of evolution. What’s more, it’s becoming increasingly clear that altering even a single gene can lead to a cascade of unexpected changes.
Such is the case with the CCR5 gene, as new research published in Nature Medicine revealed that knocking out that gene may lead to negative effects on life expectancy, potentially shortening the gene-edited babies’ life spans before they were even born.4
World’s first gene-edited babies may die early
University of California Berkeley used genotyping and death register information of 409,693 individuals of British ancestry to determine the effects of mutations to the CCR5 gene, similar to what He’s team altered in the “designer” babies. While they did, indeed, find that such individuals may have higher immunity against HIV, they also had a 21% increase in all-cause mortality rate.
In other words, those with CCR5 mutations were about 21% less likely to live to be 76 years. Study author Rasmus Nielsen, a professor of integrative biology at the University of California, Berkeley, told NPR, “This is a cautionary tale … What we found is that they had significantly increased mortality … It’s rather substantial. We were quite surprised the effect was this large.”5
Nielsen and colleagues believe altering the CCR5 gene may weaken immunity against other viruses, such as acquiring a fatal case of influenza.6 So a gene alteration that may be considered to be protective can quickly turn out to actually be harmful. Nielsen continued to The Telegraph:7
“Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do. In this case, it is probably not a mutation that most people would want to have. You are actually, on average, worse off having it.”
What is CRISPR and CRISPR-cas 9?
CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeat, allows scientists to modify an organism’s DNA, leading to possibilities that were unheard of generations ago not only in the medical field but also in agriculture and manufacturing. By tweaking genetics, researchers could theoretically help prevent inheritable diseases or create hardier, more nutritious plants, for instance.
Whereas gene editing was once a very imprecise and expensive process, scientists can now go into your DNA and essentially cut and paste it at specified places. The technology can be traced back to bacteria, which protect themselves by cutting out invading virus’ DNA and inserting it into their own, then replicating the new sequences to prevent future viral invasions.8
In 2012, researchers refined the system and revealed that any DNA (not just bacteria) has this ability — and the process works in humans.9 With CRISPR-Cas 9, the technology was said to be even more precise, acting as a pair of scissors to “snip” DNA at specific locations. As explained by the U.S. National Institutes of Health:10
“CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to ‘remember’ the viruses (or closely related ones).
If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.
… Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell’s own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.”
Why the world has resisted the creation of CRISPR babies
While the U.S. National Institutes of Health does not provide funding for studies on gene-editing technologies in human embryos, CRISPR technology has already been used to edit human embryos made from sperm from men carrying inherited disease mutations. The researchers successfully altered the DNA in a way that would eliminate or correct the genes causing the inherited disease.11,12
Unlike in the Chinese study, the gene-edited embryos were only allowed to develop for a few days.13 There was no intention to implant them into a womb to develop into babies, but had this been done, the gene edits would have been passed on to future generations as well.
This is a large part of the controversy surrounding He’s gene-edited babies. William Hurlbut, a scientist and bioethicist at Stanford, told NPR, “I think we’re facing a very serious issue as a species here … This is not like other technologies. It’s not like you’re just dealing with an individual patient. You’re now dealing with the entire human gene pool.”14
Also problematic, He’s genetic editing disabled CCR5 in an attempt to replicate the effect of a CCR5 variant called delta 32, which occurs naturally in about 10 percent of northern Europeans,15 but much less often in Chinese people.16
However, while it approximated the natural CCR5 mutation, it did not duplicate it exactly, leading some experts, like professor Robin Lovell-Badge, from the Francis Crick Institute, to call the study “foolish” and question whether it would work to prevent HIV in the babies:17
“It is impossible to predict if the mutations carried by the twin girls will have any effect … [the study] shows once more that He Jiankui was foolish to choose CCR5 to mutate.”
As a result of the rogue study that many believe violated ethical rules, He was fired from his university position and criticized by Guangdong’s health ministry.18 Yet, according to Hurlbut, at least one fertility clinic in Dubai has already contacted He to ask if he would teach the technology to his clinic. “You can see from this that there will be immediate uptake for application of this,” Hurlbut said.19
Xinzhu Wei, another author of the study that found CCR5 mutations may shorten life span, added: “Because one gene could affect multiple traits, and because, depending on the environment, the effects of a mutation could be quite different, I think there can be many uncertainties and unknown effects in any germline editing.”20
She also told BBC News, “The Crispr technology is far too dangerous to use right now for germ-line editing.”21
CRISPR leads to unexpected off-target mutations
Warning bells have been sounded before when it comes to CRISPR, as the technology leads to unexpected mutations — even in the case of the “more precise” CRISPR-Cas 9. One study used a different method to search for unintended mutations, based on a separate study that used CRISPR-Cas9 to restore sight in blind mice by correcting a genetic mutation.
The researchers sequenced the entire genome of the CRISPR-edited mice to search for mutations. In addition to the intended genetic edit, they found more than 100 additional deletions and insertions along with more than 1,500 single-nucleotide mutations, raising concerns that testing CRISPR in humans may be premature, even with CRISPR-Cas 9.22
Study author Dr. Stephen Tsang of Columbia University Medical Center said that even a single change to a nucleotide could have a “huge impact.”23 Indeed, in animals, gene editing has led to unexpected side effects, including enlarged tongues and extra vertebrate.24,25
Does CRISPR carry cancer concerns?
Off-target mutations that occur as the result of gene editing include rearranging chromosomes, inactivating essential genes or improperly activating others, such as cancer-causing genes.26
For instance, CRISPR-Cas 9 leads to the activation of the p53 gene, which works to either repair the DNA break or kill off the CRISPR-edited cell.27 CRISPR actually has a low efficacy rate for this reason, and CRISPR-edited cells that survive are able to do so because of a dysfunctional p53.
Unfortunately, p53 dysfunction is also linked to cancer (including close to half of ovarian and colorectal cancers and a sizable portion of lung, pancreatic, stomach, breast and liver cancers as well).28
In one study, researchers were able to boost average insertion or deletion efficiency to greater than 80 percent, but that was because of a dysfunctional p53 gene,29 which would mean the cells could be predisposed to cancer. Tinkering with genetics is an exciting field and one that holds great allure to scientists looking for fame and fortune, but the fact is there’s a great number of unknowns when it comes to altering genetics.
It’s quite possible, for instance, that using CRISPR to cure one chronic or terminal disease could come at the “cost” of a shortened life span or an increased cancer risk later.30 And if that’s the case, do the benefits still outweigh the risks? Hurlbut told CNBC, “We want to be very careful, nature is a profound balance and if we intervene in a way that is not profound we can upset things.”31
Is caution also warranted for gene-edited food?
The evidence is in favor of using extreme caution when proceeding with genetic tinkering of human germlines — if it should be done at all. Some scientists have called for a global moratorium on CRISPR babies,32 even as another area of gene editing — that of your food — is moving full-steam ahead.
A gene-edited soybean oil created by biotech company Calyxt, contains two inactivated genes, resulting in an oil with no trans fats, increased heart-healthy oleic acid and a longer shelf life — but with unknown effects on human health.
Although they’re genetically engineered, gene-edited foods are not marketed as GMOs, nor are they labeled as such.33 What’s more, Calyxt’s gene-edited soybean oil is already on the market and being served at restaurants, so you could be eating it without even knowing.
As for gene-editing on embryos, it raises an even more profound question about informed consent — is it ethical for parents to alter their children’s genetics without their consent? Questions such as these will only continue to mount as CRISPR and other gene-editing technologies race forward at an unprecedented pace.