Improvements in IVF mean the procedure could—in theory—become the default means of human reproductionby Philip Ball / January 2, 2018 / Leave a comment
While babies have been born by in vitro fertilisation (IVF) for four decades now, this form of assisted reproduction is still in its infancy. Give it several decades more and things could look very different indeed.
At present, it remains a difficult, uncomfortable and uncertain process. A woman’s egg production must be stimulated artificially with hormones, while other drugs are needed to suppress the menstrual cycle. Egg collection is painfully invasive, and fertilisation by sperm “in a test tube” doesn’t guarantee good-quality (or indeed any) embryos. One or two embryos (in general) are then transferred to the womb in another surgical intervention, where hopefully they will implant and develop. The success rate, in terms of live births, for women under 35 is around 40 per cent, but it drops rather quickly with age.
But some commentators think that making eggs and embryos may eventually become so easy—and control of embryo characteristics so routine and dependable—that IVF will become the default means of human reproduction. We could be looking at “the end of sex.”
Speaking at a recent London meeting on the future of human reproduction, organised by the Progress Educational Trust (PET), philosopher Anna Smajdor of the University of Oslo used that arresting phrase, though she admitted that it was more of a rhetorical provocation than a prediction. Certainly there’s no reason to suppose that non-reproductive sex will go out of fashion. But in his 2016 book of that same title, law professor Henry Greely of Stanford University in California, a specialist on developments in assisted reproductive technology (ART) and their legal context, outlined a scenario in which it might indeed become the default option to make babies the “artificial” way, via IVF.
What is that scenario, and just how plausible is it? According to Greely, two technologies in particular could promote such an outcome (he neither advocates nor deplores the possibility in itself). The first would enable us to ditch the current, troublesome method for accessing eggs. That in itself wouldn’t obviously make IVF any more attractive than the traditional means of conceiving a child, when that’s an option. But what if IVF embryos could be quickly and cheaply screened to produce a predictive profile of their genetic inheritance? Then you could not only avoid embryos with susceptibilities to genetic disease but pick out those with genetic advantages. To go even further, what if such defects or enhancements could be edited out of or into the respective genomes?
Put these types of technology together and the thought becomes clear. It’s the “designer baby” scenario par excellence. At least, depending on your point of view.
The ingredients of Greely’s vision were among the topics aired at the meeting. One way to ensure an egg supply could involve taking a “slice” of ovarian tissue in a once-only operation and then freezing the many eggs it contains for future use. But a still more dramatic option, discussed by developmental biologist Azim Surani of Cambridge University, is to make eggs artificially from other cells, such as skin cells harvested in a very simple and painless procedure, by “reprogramming” them using a cocktail of genes so that they are returned to a stem-cell state from which any other tissue type can be produced. The resultant eggs could then be used for IVF.
“Is infertility a medical condition akin to disease, warranting a cure?”
At present, such cell reprogramming for reproduction is not legal in the UK. Mice have been conceived and born from eggs made this way, but is simply not known what the health risks might be for humans, or whether it would be possible at all. But it’s conceivable that such methods could be eventually used for IVF. The notion of children “grown” from a piece of arm might sound bizarre, repugnant and even impious to some. But it is far from obvious why there should be any logical ethical objections if the procedure was shown to be as safe as any reasonable assessment might allow.
At the same time, however, the whole concept of infertility is more complicated than it sometimes seems, as Smajdor pointed out. Definitions are often tortuous and tautological. Is it a medical condition akin to disease, warranting a “cure”? Not obviously. Such confusions are reflected in debates about whether IVF should be a state-funded medical treatment—indeed, a “right”—and whether the desire for a biologically related child is just a form of narcissism. There’s no doubt, though, that difficulties in conceiving a child are often immensely distressing and continue to be stigmatised in some cultures.
If we’re already confused about what infertility means, artificial gametes will complicate matters much more. Smajdor suggested that they “could blow away the biological barriers of reproduction”—for example, making it possible for post-menopausal women and prepubescent children. That was a deliberately provocative claim, her point being not that we should rush to embrace such options but that we are going to have to grapple with some hard questions about what we mean by fertility—and its absence.
The second pillar of Greely’s “end of sex” argument is equally contentious. The technique called pre-implantation genetic diagnosis (PGD) is now routinely used for couples who are both carriers of gene mutations linked to a serious genetic disease. It can identify embryos produced by IVF that are free from the genetic defect in question. In the UK it is permitted by the Human Fertilisation and Embryology Authority (HFEA) to screen for around 400 such diseases. The screening is done by taking a cell from a very early-stage embryo for genetic testing.
As genetic testing becomes ever cheaper, quicker and more routine, it will be possible in principle to screen for a wider range of genetic conditions—and not just for diseases, but for genes linked to other traits, most controversially things such as height, athleticism and intelligence.
This picture is now complicated further by the advent of genome editing: the availability of biotechnological tools to change a cell’s or organism’s genetic code by removing one piece of DNA, targeted with great precision by enzymes, and replacing it with another. That’s been possible to some extent for many years, but the recent discovery of a piece of bacterial enzyme machinery called CRISPR (pronounced “crisper”) has revolutionised the field, making the editing more accurate and reliable. Genome editing using CRISPR has already been done in human embryos. In 2015, researchers in China examined the feasibility of the idea (in work that was rejected for publication by leading journals on ethical grounds), and it has now been carried out elsewhere too, including in the UK and US. Kathy Niakan of the Francis Crick Institute in London received HFEA authorisation to use the technique on very early-stage human embryos (which were not even in principle viable for implantation in the womb) to study the genetics of embryo growth. The initial results were recently published, and Niakan hopes they will offer insights into the factors that lead to the early loss of embryos, perhaps ultimately helping to reduce rates of miscarriage.
The HFEA does not permit genome editing, by CRISPR or any other means, for human reproduction. Rightly so, because the safety of the method is still in question: even with its reputed precision, the CRISPR system can induce some “off target” edits. But it seems entirely possible that one day CRISPR, or a related technique, might be used to correct genetic defects in IVF embryos. Rather than screening them to find “good” ones (if any), they might all be stripped of disease-causing genetic mutations.
“Biotechnological tools can change an organism’s genetic code by removing one piece of DNA and replacing it with another”
That puts some opponents of such research in a difficult position. Some religious groups in particular, who contest IVF and embryo research in general because it involves the discarding of human embryos, are likely to balk also at the notion of genome editing. But as bioethicist Guido Pennings of Ghent University argued at the PET meeting, editing is in this perspective a morally preferable option, as it means that no embryos—or at least, fewer embryos—subjected to PGD before implantation would need to be thrown away. Pennings believes that genome editing of embryos for reproduction is inevitable at some point.
The widespread objection to such intervention in assisted conception is that it would change the genome of the “germ-line,” with individuals born from “edited” embryos passing the change on to subsequent generations. Some (including one of the discoverers of the CRISPR technique) feel this oversteps an ethical red line. It is one thing to use CRISPR for somatic genome editing, which could correct disease mutations in a specific individual without passing the change on to their offspring; but germ-line editing carries the intervention into the unseeable future.
That concern is worth heeding, particularly while the long-term health risks are unknown. But we shouldn’t make this a bigger deal than it really is. For one thing, no medical intervention or drug would ever be introduced if we insisted it must be known beyond all doubt to be risk-free. Studies on other animals, such as mice, don’t tell us everything about such risks, but neither do they tell us nothing. Bioethicist Philippa Taylor of the Christian Medical Fellowship questioned whether an intervention like this, that anticipates potential diseases in unborn generations, is even medicine at all; but in fact medicine has “cured” future generations for a long time, for example by eradicating the smallpox virus. A vague sense that we should not “tamper with the stuff of life” can become a misanthropic refusal to face biological reality: the gene mutant that causes cystic fibrosis and consigns children to a difficult life followed by early death really has no intrinsic moral virtue, and warrants elimination.
Even more telling was the point made by mouse geneticist Andy Greenfield of the Medical Research Council’s Harwell laboratory that we are conducting de facto germ-line genome editing in humans already. That is precisely what PGD effects. By rejecting IVF embryos that carry a disease-linked genetic mutation, we are removing that mutation from future generations derived from the embryo. As this becomes a more widespread procedure, we are in effect editing the mutation out of the population. We have decided as a society (in the UK and many other countries) that this is acceptable, indeed commendable on medical grounds. Whether we discard the embryo or cut out the defective gene, the effect is the same. Safety issues aside (and they are of course crucial), it makes little logical sense to permit one and not the other: as Greenfield said, “it’s difficult to see a huge ethical distance between them.”
Where things get really sticky is in deciding what to target, whether for PGD today or for genome editing further down the line. Some fear that it will lead to a futile and harmful quest for perfection. Is autism a “disease,” say? And where are the boundaries between corrective medicine and enhancement? (Quick answer: we don’t know. Opinion groups tend to disfavour enhancement but disagree about what it constitutes.)
Already some of these new technologies have opened cans of worms. Sex selection, for example, is permitted in PGD for “family balancing” not just in the largely unregulated IVF climate of the US but also in Sweden and elsewhere. The HFEA currently prohibits it, but one’s instinctive unease (perhaps) is complicated by deeper reflection. Is it really so bad for a family with three girls to select a boy for their fourth child, rather than feigning delight at another girl? One might say that parents’ preferences shouldn’t be indulged—but if a reliable method of intercourse were to be found that enabled sex selection, would we ban it? The havoc wreaked by traditional lopsided gender preferences in some societies is well known, but so far there seems to be no net preference either way in the US or Sweden.
It’s tempting here to get carried away with dystopian, eugenic scenarios. But genetics itself limits the options severely. The idea that all traits and genetic diseases, from muscular dystrophy to intelligence, can be linked neatly and independently to a gene or handful of genes is mistaken. Most of the diseases for which the HFEA permits PGD screening are very rare and associated with (or mostly with) single genes. Many more common diseases with a genetic component, such as heart disease and Type 2 diabetes, seem associated with many genes—perhaps hundreds in some cases. Those genes typically perform other roles, and you won’t be able to tamper with them without having knock-on effects elsewhere. Besides, genes are not destiny: most disease-related mutations are known only statistically to increase a person’s chances of developing the condition. So the information made available in principle by improved PGD of embryos for choices in “designer” IVF could be worse than useless. How will you choose between an embryo that has a 30 per cent higher than average chance of developing heart disease later in life, or one with a 20 per cent increased risk of breast cancer?
It’s possible that market forces and coercive advertising—“Wouldn’t you want to give your child the best possible start in life?”—will nevertheless make “easy IVF” and “easy PGD” the preferred reproductive option, as Greely foresees (and not with relish). But even if the good old-fashioned hit-and-miss methods remain preferable for most of the population, there are challenging questions ahead. We’re in uncharted territory, and the old ethical maps may be of little guidance.