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Authors: Aarathi Prasad

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For the survival of babies born prematurely, the incubator is a triumph of bioengineering. Yet what can be achieved with
incubators is still very limited.
One of the paediatric consultants on the Hackney ward described how, although modern incubators look sleek and efficient, the way they function and what they can provide has essentially not changed
in decades. While the incubators can provide warmth and humidity, they still cannot give any of the nutrients necessary for growth. Instead, a premature baby must have all those tubes inserted into
his or her body to deliver ‘parenteral nutrition’, that is, the complete nutrition provided intravenously, via needle-like catheters inserted directly into the veins and bypassing the
digestive system altogether. Yet more tubes passed through the nose and threaded to the stomach will give the child milk, if tests show its digestive system is able to take it. This care is
incredibly challenging due to the extreme immaturity of the baby’s gut. In a mother’s womb, the stomach and gut will not digest food at such an early stage of gestation, but once out of
the womb, a small amount of the mother’s breast milk will be used to acclimatize the baby’s stomach to its new environment. The baby will also be sedated, at least some of the time, to
stop him or her from pulling the tubes out, and to decrease or prevent any discomfort or pain. Moreover, infection around the tubes is a serious threat, and can lead to severe problems for the
child’s future health, should he or she survive. However you look at it, the incubators we have today are still a poor substitute for the relative security provided by the mother’s
womb.

Over those same decades, doctors have been attempting to secure the viability of ever-more premature babies. To succeed, they will have to invent an incubator that is more womblike –
something almost like the womb itself. One unlikely source of data into how a womblike incubator might work has come from studies of miscarriages that have occurred at the very earliest stages of
pregnancy. By looking at pregnancies that have failed, researchers have been better able to understand how embryos
implant into the womb. Some day, with this information,
embryos might not only be created in the laboratory, through in vitro fertilization, but even be attached to an artificial placenta in an artificial womb and gestate there until they are ready to
be born. Still, it’s one thing to cultivate sharks successfully in a man-made environment; it’s another to nurture humans in one.

Scientists in Japan and the United States are experimenting to find out if an artificial womb for humans might be feasible, using cells both in Petri dishes and in living animals to copy the
inner workings of mammals. With all mammals, it is vital that newborns are able to discard the placenta when they leave the natural womb. The placenta, after all, is the life-support mechanism that
allows a fertilized egg to develop into an embryo; it is also the frontline of development in protecting the foetus from infection and in providing nourishment. For this reason, when in the 1960s
researchers first began to toil towards creating a machine that would stand in for the essential placenta, they faced many of the problems that intensive care doctors face when human babies are
born prematurely. These problems proved especially challenging with their chosen subjects – goat foetuses.

During a further series of experiments in the 1980s, a team led by the late Professor Yoshinori Kuwabara encountered several serious setbacks. In particular, the goat foetuses moved, as all
babies in the womb do – and some quite vigorously. During incubation, and especially once their condition was stable, the goat foetuses showed a variety of movements that would have been
absolutely normal behaviour had they been in their mothers’ wombs. They rolled their eyes, moved their mouths, swallowed, breathed, twitched, wriggled, rolled, stretched, and moved their
limbs. One even tried to stand up and run!

Although these movements were a positive sign, demonstrating that the foetuses in those primitive systems were active
and seemingly stable, they caused malfunctions in the
system; tubes got pulled out with all that wriggling. In fact, for the foetus that tried to stand up and run, the movements cost it its life. The animal sustained massive blood loss through the
umbilical blood vessels, from which it had inadvertently pulled out its tubes. Other foetuses perished in the same way.

Swallowing also proved a problem. The foetuses did not drink out of thirst, but rather to help train the muscles of the throat and the digestive system during development – movements that
are crucial for survival after birth. (Indeed, swallowing fluid inside the womb is the definition of redundant: a foetus’s body-water balance is maintained by the placenta.) In the
environment of the artificial womb – a clear plastic tank about the size of a home aquarium filled with yellow liquid – the goat foetuses drank up their surroundings without any care
for how much they ingested – and they ingested a lot. Several days after their incubation began, they had accumulated enough excessive fluids that their lungs became swollen. The fluid load
also affected their developing cardiovascular system. The scientists were only able to continue the experiment by delivering sedatives and muscle relaxants to the goats, something that most human
parents would be reluctant to see prescribed for their own child in an artificial womb, given the potential for life-long addiction.

In the 1980s, researchers in Tokyo were garnering the first promising results in experiments with goats and artificial placentas. Then in 2002, Kuwabara’s group developed an incubator
consisting of a plastic tank filled with artificial amniotic fluid and a complete artificial placental system to provide oxygen into the blood directly, instead of via tubes into the veins. Unlike
previous attempts, which only kept goat foetuses alive for about two days, the scientists reported that the foetuses placed in their fluid-filled plastic boxes stayed alive for three weeks. Like
the wobbegongs, they too survived a trial birth.
The artificial womb was becoming a reality.

An aquatic environment, an artificial womb, a synthetic placenta: these can surely keep premature babies alive. But could they be used to craft the future of all
pregnancies?

Perhaps because of the ethical tangles involved, many scientists working in the field have not disseminated much of their research, or the possible applications of it. That includes scientists
such as Hung-Ching Liu, an internationally respected researcher in reproductive biology who, at a conference in 2001, said that her ‘final goal is having a child in the laboratory’. And
not through old-fashioned childbirth.

By that time, though, Liu had already managed to grow the lining for a human womb, using a sort of scaffolding over which cells, cultured from a woman’s womb, could multiply. This
‘womb’ was only a few sheets of cells in a Petri dish, not an entire organ. But when it was tested using fertilized eggs left over from IVF cycles, the eggs implanted in it at six days,
just as they would in a real womb. Liu believes that this approach would ensure that the whole package – embryo and womb – would not be rejected by the immune system when inserted into
the woman’s body to continue the long process of development.

In the lab, researchers currently are not allowed to grow human foetuses for more than fourteen days, because it is at this point that foetuses develop a neural tube – the precursor of the
brain and nervous system. This meant that Liu’s experiment could not progress beyond eight days after implantation. Still, going ahead even for this scant time gave her an opportunity to
study how the placenta grows, and to see whether she could develop a womb-like device that could remain viable
outside of the mother. The device would need to be hooked up to
a computer, which would regulate the delivery of liquid to nourish the foetus, the removal of waste products, and the control of the team of hormones that are so finely balanced in the real-life
body of an expectant mother. If scientists could achieve this, a baby could conceivably be brought to full term in an artificial womb.

Liu’s vision is not fanciful, in terms of motivation or practicality, when you consider two issues. Women – even young women – without wombs are no small minority. In fact,
‘absolute uterine infertility’, which is defined as a woman’s infertility resulting from defective or absent wombs, affects millions throughout the world. In the United States
alone, around five thousand hysterectomies are performed in women under the age of twenty-four; nearly nine million women of reproductive age have had a hysterectomy due to conditions including
cervical cancer, endometriosis (where uterine cells grow elsewhere in the body, often on the ovaries), and Mayer-Rokitansky-Küster-Hauser syndrome (in which the uterus can be underdeveloped,
shaped more like a cord than a sac, or even absent). Most women with uterine infertility have no chance of becoming a genetic mother, except by the use of another woman as a surrogate, and no
prospect of ever carrying a pregnancy to term. Liu works with infertile women, many of whom have survived cancer but lost their wombs and reproductive potential to the disease. Her hope is to offer
these patients the option of having their own children.

Second, the idea of creating a blood circuit that can serve as a placenta and work alongside an artificial womb and amniotic fluid is complex, seemingly too complex and too dangerous to use in
anything outside of the great works of science fiction. But for premature babies, especially those who have difficulty breathing, the ideal situation would be to maintain them in a
warm liquid bath, like the womb, attached to an artificial placenta rather than a lung-damaging ventilator. If the conditions in that bath could be set to match the environment of a
natural womb, the baby might develop normally, without damage to the lungs and the oxygen-deprived brain. Recently, too, there has been progress in making liquid breathing a reality, through the
development of a fluorocarbon liquid with the capacity to carry a large amount of dissolved oxygen and carbon dioxide. The liquid could be inserted into the lung, so that the lung sacs can expand
at a much lower pressure, creating an intermediate developmental stage between the womb and life in the open air.

Liu and many other researchers in the field are confident that, despite the complications and difficulties, the technological perfection of an artificial womb is achievable. The French biologist
Henri Atlan predicts that, within a hundred years, science will master the complete development of the human foetus from conception. In the meantime, Carlo Bulletti, a professor of reproductive
biotechnology at the University of Bologna, says that
partial ectogenesis
– growing foetuses between fourteen and thirty-five weeks of pregnancy – is already within our reach if
we were to use all of the knowledge and technology at our disposal.

What would it mean if a foetus could be gestated entirely outside of a woman’s body? Ectogenesis is clearly not an ethically easy path for starting or expanding a family. Hand in hand with
the creation of a viable artificial womb, doctors and counsellors would have to create something to analyse a number of genetic defects carried by a fertilized egg or early-stage embryo that may
not yet be recognized through pre-implantation genetic diagnosis. During in vitro fertilization, some embryos may fail to implant in the natural womb because of random or inherited genetic
mutations or those that accumulate with age. With an artificial womb, that process would not work in
the same way; the embryos would likely be attached by doctors to the
synthetic placenta (or other filtration system that might provide nutrition) meaning that implantation would succeed where it would fail in a natural womb. And the embryo with potential
abnormalities might then be able to develop to term in such a highly regulated environment. Would ‘pulling the plug’ on that foetus in an artificial womb be seen as an early-term
abortion or euthanasia?

There is a flip side to that dilemma, of course: it just might be easier to make genetic corrections and modifications to a foetus in a plastic box, which is what an artificial womb is likely to
be, less its sophisticated controls. Not only would it be easier to reach the foetus, it would avoid the need to operate on the mother in order to get into the womb. For both mother and child, this
would make pregnancy a much safer prospect.

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