A few years back I attended the annual conference of the British Society for Developmental Biology. There was a discussion session towards the end of the day concerning future developments and directions in our field of research, namely how one goes from the early embryo to, ultimately, the adult human (or other organism). Into a lull in the conversation, my then-boss, who was heavily pregnant with twins and very uncomfortable, interjected the following question: “I only want to know one thing right now: when are we going to be able to grow babies in artificial wombs?” Good question…

This is something that’s surfaced in the news again recently, with the publication of a study trialing a system that was able to keep premature lambs alive to full-term. You can read the full study here (it’s open-access). I have to say that the reporting on this was mostly fairly accurate, correctly pointing out that this was a breakthrough that might lead to an improved system for incubating premature babies. Though of course there were the odd few opinion pieces worrying about women of the not-too-distant future dispensing with all that yucky pregnancy business and growing their babies in tanks for the whole process. Perhaps they were thinking too much of one of the more famous science fiction examples of this, Huxley’s Brave New World, or cloned armies in Star Wars. (Artificial uteruses are frequently linked with clones in SF, interestingly).

The leading cause of death of newborn infants in developed countries is premature birth (and a significant one in developing countries, which generally have higher levels of premature birth). It’s also a significant cause of long-term disabilities such as cerebral palsy. The limits of viability – i.e., the gestational age at which it is possible for a premature baby to survive – is currently around 22-23 weeks, and that is unlikely to change much anytime soon. An infant at this age is extremely small, with very under-developed organs. If they are born after 28 weeks, the chances are fairly good for both survival and long-term health. In fact, the number of people with long-term disabilities resulting from premature birth has actually risen because the limits of viability have been increased: more survive, but with more problems. So that 23-28 week window is a real target for intervention: to try and improve the chances of these extremely premature babies both surviving and reduce the likelihood of long-term disability. The biggest problem relates to the fact that the lungs are very under-developed: artificial intubation has limited success because they are just not mature enough to perform proper gas exchange, and this will often cause damage to the delicate lung tissue. In the uterus, the lungs are surrounded by fluid and gas exchange is via the placenta and umbilical cord.

The authors state themselves that:

Our goal is not to extend the current limits of viability, but rather to offer the potential for improved outcomes for those infants who are already being routinely resuscitated and cared for in neonatal intensive care units.

What they did was take lamb fetuses (by caesarian section) at 106-113 days of gestation, which is biological equivalent to a 23-24 week human fetus in terms of lung development, and kept them alive until they were near-full term in their artificial incubator, the “Biobag.” In fact, “incubator” isn’t a very accurate description, because the real breakthrough is that the system is performing, in part, as an artificial placenta. Here’s their figure below:

Lamb bio incubator

(a) Circuit and system components consisting of a pumpless, low-resistance oxygenator circuit, a closed fluid environment with continuous fluid exchange and an umbilical vascular interface. (b) Representative lamb cannulated at 107 days of gestation and on day 4 of support. (c) The same lamb on day 28 of support illustrating somatic growth and maturation.

From Nature Communications, 2017

They were able to keep the lambs alive and developing normally for up to 4 weeks, until they were mature enough to survive. Lung and brain development was normal. There are a lot of technical problems to overcome doing this: for a start, they invented a pumpless system. If you have pumped fluid, the changes in pressure tend to cause bleeding on the brain and other damage. There are additional problems to manage regarding the correct gas mixture in the artifical amniotic fluid (something a placenta can continually adjust to the fetus’ demands), and making sure infection doesn’t set in. Looking at their data, one of the most common complications they encountered was bacterial infection setting in, but most animals did well.

So this is a really important step forward. Bear in mind though, that one of the key interventions introduced in the care of premature babies, the use of steroids to accelerate lung growth, took years to go from research data to clinical use, so we won’t be seeing Biobags for humans for a while yet.

Could we, ultimately, gestate a human from embryo to birth-equivalent, all artificially? That’s something that will remain in the realm of science fiction for quite some time. I don’t think it’s impossible: I do think that our technology and our understanding of human development would have to be greatly advanced compared to our current knowledge. You would essentially need an “intelligent” placenta and uterus system that would change the input to the fetus as it develops and respond to physiological changes adaptively and in real time.

Technicalities aside, the fundamental question it boils down to is really this: how much of the embryo’s normal development is dependent on input from the mother? We know that the fertilised egg contains all the genetic information (and signals laid down in the egg by the mother) to develop into an adult. We also know that factors such as maternal food and alcohol intake, and smoking, can both affect the development of the embryo and lead to heritable changes in the activity of genes (epigenetics) that can be inherited by that embryo’s offspring when it reaches adulthood. It’s strongly likely that there needs to be a significant sensory input into the developing brain in order for it to develop normally; probably more so for a human than any other animal. That would be hard to replicate. The authors themselves also note that the lamb brain matures earlier than the human one, so their system is not suitable for assessing the risks of intracranial haemorrhage and other brain problems. It will, however allow for more study into the placenta because you are removing the maternal dimension:

Long-term physiologic maintenance of a fetus amputated from the maternal–placental axis has now been achieved, making it possible to study the relative contribution of this organ to fetal maturation.

It should be noted that I am fairly certain that our ability to genetically engineer a human baby will arise before an artificial womb does – so the whole “designer baby” question raises its head in an entirely new way.  There are a lot of complex ethical questions to consider, of course, but one approach that should not be taken is to forbid such technology just because it’s not natural, and there’s a whole slew of patriarchal assumptions about women and motherhood usually shoved in there too. This is reflected in the science fiction too: often, the gestating of a human in an artificial uterus is symptomatic of a society that is ethically flawed. Apart from our clone armies, we have, for example, Solaria in Asimov’s The Naked Sun, a warped society in which humans live such isolated lives they cannot bear to touch each other. And I was put right off reading Bujold’s Vorkosigan Saga after reading the first (chronological) book, Shards of Honor, in which impregnated rape victims had their fetuses raised in tanks. No. Just no. You don’t get to force women to have their rapist’s children just because they are not actually physically bearing them. Creepy.

If a system existed which could gestate a human just as effectively as a human woman potentially can, then I think it should be allowed in principle. Why? Because pregnancy and childbirth are fundamentally dangerous; both cause long-term morbidity and, particularly in developing countries, significant mortality. Of course, from this perspective, it would be far better to try and improve maternal outcomes than to aim for a conception-to-birth artificial incubator. Nevertheless, there will always be women for whom it is too dangerous, or otherwise impossible.

What we may do sooner than this is re-grow articifial uterus tissue. An exploding area of research, which I have blogged on before, is organoids – growing simplified miniature versions of organs in culture. There have been at least two recent papers reporting the generation of organoids of the endometrium, the lining of the uterus (which is shed during the menstrual cycle and into which the fertilised embryo implants). Indeed, Turco et al succeeded in creating organoids that are responsive to female hormones in a physiologically relevant way:

 These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones….On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy.

Moreover, this system itself can be used to study uterine function and diseases such as endometriosis and uterine cancer.

In the meantime, improving outcomes for the premature babies we have with us today is an important goal.

References

Partridge, EA, et al, 2017: An extra-uterine system to physiologically support the extreme premature lamb. Nature Communications, 8:15112. doi: 10.1038/ncomms15112

Turco, MY, et al, 2017. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.  Nature Cell Biology 19, 568–577. doi:10.1038/ncb3516

 

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