The Coming Age of Genetic Modification, Part I
Last week, Dr. Shoukhrat Mitalipov and a team of researchers at Oregon Health and Science University announced they had successfully altered human embryos with a mutation of the MYBPC3 gene—a defect that causes hypertrophic cardiomyopathy in 1 out of every 500 people, and is among the leading causes of sudden death for young athletes. If true (the research is still pending publication), this could be a revolutionary development in the field of genetics. It would mark the first time such a modification was conducted using the CRISPR gene editing technology, demonstrating the technology’s ability to both safely and effectively excise abnormalities in an embryonic genome.
The thorny ethical debates probably won’t be far behind, but we shouldn’t be talking about “designer babies” just yet. Rather, Mitalipov’s experiment shines a light on a more nuanced subset of the genetic modification debate: the ethical difference between editing somatic cells versus germ cells.
Before we go further, a quick refresher on biology is in order. Germ cells develop into gametes. Gametes then fuse together during sexual reproduction to create zygotes, which in turn become the cells that make up an embryo. The germline refers to the entire collection of cells in the body that can pass on genetic traits through sexual reproduction. In contrast, somatic cells are essentially any cell in a mammalian organism that are not gametes or germ cells—that is, any cell not involved in the reproductive process and which does not pass down inherited genetic traits to subsequent generations. So, for example, your skin, bones, heart, liver, lungs, blood, and muscles are all composed of somatic cells.
One of the major concerns in germline editing has been a fear that off-target edits (that is, unintended changes that occur to other genes) could result in unforeseeable, and potentially costly, consequences for future generations carrying those genetic alterations. The concerns have been so pronounced that many nations have instituted blanket bans on germline editing. The 1997 Oviedo Convention of the Council of Europe, for example, states unequivocally that: “An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.” Prohibitions in Europe and the United States, however, have not prevented research and testing elsewhere in the world.
In 2015, for example, Chinese scientists were the first to use CRISPR to edit the genomes of human embryos. Only a fraction of the surviving embryos were successfully “spliced”—meaning the targeted genes were excised from the genetic sequence—and only a fraction of those contained the intended replacement genetic material. Even more unfortunate, the CRISPR technology produced a high number of off-target mutations, fueling skepticism over the technology’s safety. That same year, the International Summit on Human Gene Editing released a statement in which they declared those concerns explicitly:
It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application.
If indeed Mitalipov’s experiment succeeded where the Chinese failed, and can prove that “the relevant safety and efficacy issues“ of germline editing in human cells “have been resolved,” or at least considerably diminished, then things could get very interesting. Of course, the risk of off-target editing can vary widely between targeted genes, and there’s no evidence—yet—to suggest the experiment would be generalizable across the human genome. Nevertheless, it’s an important and exciting development for future advances in genetics.
Notwithstanding the safety and efficacy issues, there remain a number of criticisms to germline editing. Two of the most oft-cited are that it is dangerous (because the changes could permanently alter the human genetic sequence) and immoral (because the future child cannot consent to the genetic procedure it will have to live with for the rest of its life). However, in a 2015 article for Nature, Dr. George Church, one of the world’s foremost molecular geneticists and the father of synthetic biology, argued against both of those points:
Human-germline editing is not special with respect to permanence or consent. Replacing deleterious versions of genes with common ones is unlikely to lead to unforeseen effects and is probably reversible. Even if the editing was difficult to reverse, this would not be especially unsafe compared with other commonly inherited risks. Offspring do not consent to their parents’ intentional exposure to mutagenic sources that alter the germ line, including chemotherapy, high altitude and alcohol—nor to decisions that reduce the prospects for future generations, such as misdirected economic investment and environmental mismanagement.
Even so, some will argue that there are better ways to treat genetic ailments. Current techniques like pre-implantation genetic diagnosis (PGD) for in vitro fertilization (IVF) can help prevent hereditary genetic mutations and diseases from passing down to subsequent generations. Unfortunately, they do so by preventing would-be-children with those inherited traits from ever coming into existence at all (through the option of discarding genetically defective embryos during PGS). As the University of Oxford’s Practical Ethics blog points out:
Some couples will only produce a single embryo through IVF, and so selection is not an option. Even when multiple embryos are produced, the number is small (typically around 7 per cycle). This places tight constraints on the number of health related traits that can be targeted simultaneously. All of us have hundreds of genetic limitations or dispositions to disease that make it more likely we will get cancer, heart disease, dementia etc. If a couple want to use PGD to select for 20 different desirable genes in an embryo, they would need to create around 10,000 embryos to make it sufficiently likely that one will have the right combination at all 20 loci. This is not possible with current IVF technologies. Gene editing provides a way to iron out all of our genetic wrinkles. All could live much longer and healthier in a world of effective gene editing.
Not everyone is as optimistic about that potential future. Critics such as Françoise Baylis point to the need for “broad societal consensus” in the application and use of germline editing technology—the second prong of the International Summit on Human Gene Editing’s 2015 statement. In a recent article from Motherboard, Baylis takes these arguments further, and “stressed that it isn’t up to ‘individual governments’ to decide what happens with CRISPR and with the human genome.” Rather, she argues, “[w]e the people have a right to say what should happen to the human germline.”
But how would that work in practice? Is a consensus to be achieved through a national plebiscite, or do existing statutes serve to communicate that intent? If the decisions aren’t the purview of “individual governments,” than does the referendum need to be global in scale? Do the decisions of scientists and researchers weigh more heavily than average voters? Do the concerns of parents wishing to avoid passing along degenerative hereditary mutations to their children matter more than the religious convictions of those with a fervent belief that these practices constitute playing God?
These aren’t easy issues to address. Democratizing decisions related to technological progress, however, probably won’t suffice to remedy the ethical concerns associated with these developments. Even if a global referendum was possible, there’s no guarantee that we wouldn’t let the genie out of the bottle anyway. As the Motherboard article pointedly concludes:
The [United States] can bar clinical trials, but that doesn’t mean they won’t happen elsewhere—nor will it stop the technology from being taken up in other places including, eventually, for-profit fertility clinics attracting medical tourists from abroad.
This is global innovation arbitrage in a nutshell: what is prohibited by statute or regulations in one country won’t be prohibited in another. Capital investment, research and development, and ultimately the benefits of innovations will ultimately flow along the path of least resistance. Indeed, Mitalipov himself noted that if the United States wouldn’t permit clinical trials of germline edited embryos—that is, actually transplanting the embryos with the intention of establishing a pregnancy—he “would be supportive of moving this technology to different countries.” It wouldn’t be the first time Mitalipov had taken advantage of global innovation arbitrage. He was previously a pioneer in mitochondrial replacement therapy, which aims to prevent diseased mitochondria from being transmitted to future generations. Unfortunately, the procedure was banned in the United States, so Mitalipov conducted his clinical trials, which yielded “extremely valuable” insights and “useful information,” in Mexico.
And of course, for those more unscrupulous researchers, there’s no need to turn to China or Mexico if you’re just willing to embrace the black market. This is a key concern for Dr. Church, who argues that perpetuating these bans won’t just drive the best medical innovation overseas; it will drive what remains underground:
Banning human-germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism, which are fraught with much greater risk and misapplication. Instead, the generally high safety and efficacy standards of regulatory agencies should be encouraged rather than saddled with pessimistic assumptions about the trajectory of promising approaches.
Some governments may ban these procedures, but others will surely permit them, just as some researchers will call for moratoriums, while others charge ahead at breakneck speed. We stand on the cusp of possessing the technology and know-how to change humanity’s genetic makeup forever, but there will not be an international plebiscite to guide that future. No referendum has ever dictated the terms of human evolution; we did not vote on whether to crawl out of the primordial seas or descend from the treetops. And for better or worse, we will not collectively decide the future of our species’ genetic code at the ballot box.
In a subsequent blog, I’ll discuss the current regulatory landscape for gene therapy procedures and germline editing here in the United States, and offer some thoughts on how we can best prepare ourselves for the coming age of genetic modification.
Ryan Hagemann is the Director of Technology Policy at the Niskanen Center