Scientists at the Port Stephens Fisheries Institute in Australia successfully bring to term six healthy shark pups — in an artificial womb. This uterus is no cozy dark place: it is a series of fluid exchange tubes and life support equipment, and takes up as much room as a good-sized refrigerator. Nevertheless, in many ways, these pups are much luckier than some of their natural-birth cousins: had they been grey nurse shark fetuses reared in a real uterus, only one of them would have made it out alive.

The research, appearing in the journal "Zoo Biology" on September 8, 2011, is inspired by the efforts to save the grey nurse shark from extinction (fewer than 1,000 are thought to be left in their habitats near Australia). Their lengthy gestation period as well as bizarre method of in-utero development has made the populations of these shark species particularly sensitive to unintentional trapping and to fishing accidents, landing them a spot on the IUCN Red List.

The grey nurse female has a pair of uteri, each holding about 20 fertilized eggs. Surviving the gestation period of nearly a year during which a baby is expected to grow to a whopping length of 3 feet is no small feat. After about two months, the internal food supply (the yolk) runs out. Pressed for food, the babies begin to devour each other, turning each uterus into a gladiator arena. At birth, only two babies emerge — the strongest and fiercest of each womb.

The artificial uterus, designed to bypass the cannibalistic phase, aims to bring more babies to term than the natural mother. The device was tested on a related, non-endangered shark species, the wobbegong shark. Replicating the fine chemical balance of the uterine fluid has proven to be the bottleneck of the study. As of now, the uterus is capable of bringing to term surgically removed fetuses for their final 18 cannibalistic days before birth. However, with more work, the ectogestation period can be expanded to include the earlier stages of pregnancy. The uterine fluid composition undergoes many changes throughout the stages of pregnancy, and replicating it completely from start to finish would be, according to primary investigator Nick Otway, a “difficult but feasible challenge.”

While the shark is no human, it, similarly to us, gives birth to live young. The research is intimately relevant to human reproductive health as well. Such a device would enable doctors to revive preterm babies younger than 24 weeks, the cutoff age for the most state-of-the art baby incubators. It would also aid women suffering from reproductive system disorders or frequent miscarriages. One could also look at more controversial applications of such technology, such as a method to settle the abortion issue or an unintentional step towards a Brave New World-like future.

Redesigning the uterus

For almost two decades, researchers have made steps to redesign the uterus. A successful artificial uterus seemed imminent in the 1990s and early 2000s, with pioneering studies demonstrating fetuses that survived into the late stages of gestation and the filing of patents for tissue-engineered and mechanical uterus replacements. Some researchers focused on early gestational stages, while others attempted to bring developed fetuses to term. Several groups claimed to be on the brink of successfully supporting embryos through an entire term; however, the claims always fell short of reality: the womb has proven tricky to replicate.

In the 1990s, Japanese researchers lead by Yosinori Kuwubara began a series of experiments with a mechanical artificial womb. The uterus, somewhat similar to that utilized to gestate baby sharks, brought goat fetuses to term for their last three weeks of gestation. Some of the embryos made it to term and were “born.” However, they all had striking deformities and died soon after birth.

At Cornell University, a research group led by Hung-Ching Liu took a different approach, focusing on tissue engineering and emulation of the early stages of pregnancy. In the early 2000s, Liu grew a uterus-like structure with scaffolded endometrial cells bathed in hormones and growth factors. Trials that showed any success were ones where the mouse embryos were reimplanted into and spent at least a week in a natural womb. To mimic these unknown essential conditions, the whole engineered uterus was reimplanted into the body cavity of a mouse. However, blood vessels failed to develop properly, launching the group's research into genetic modification of vessel-forming genes. All-in-all, this biomimetic approach proved more successful than Kuwubara's mechanical uterus, with several mice surviving for weeks, and at least one surviving almost to a full term in the artificial uterus in 2003. That mouse was able to move and breathe on its own; however, ultimately, it also died.

What now?

Now, scientists have taken one step back, embracing the womb's complexity. Latest research demonstrates the intricacy of the mother-fetus relationship — on the molecular level. A 2009 study showed that maternal immune cells may "train" the budding immune system of the developing baby [1], while even the most miniscule hormonal fluctuations due to stress levels of the mother may have profound developmental effects on her fetus [2].

Various groups are taking a more thorough look at the process of gestation and its various key players (the amniotic fluid, placenta, uterine sac, hormonal fluctuations and mother-fetus molecular signaling). The preferred approach has become a biomimetic one, with the goal of mimicking the uterine environment using high-tech material science and tissue engineering. Some interesting results utilize electro-spun spider silk as scaffolding for tissue cultivation. This biomaterial had previously shown success for bone grafts and brain implants. In 2010, it was successfully used to grow an artificial cervix. A 2009 study was able to engineer a womb containing all three uterine layers [3], while in a separate 2008 study, researchers were able to place tissue culture molds into the peritoneal area of rats and rabbits (the area between the skin and membrane surrounding the abdominal cavity). Once tissue had grown in the molds, the artificially grown uteri were harvested. They were then swapped with their real counterparts and actually supported pregnancy for up to late gestation stages [4]. Lastly, a 2011 review reported some progress on tissue engineering, with a focus on proper vascularization as well [5].

All in all, with baby steps, researchers hope to mimic and reconstruct the uterine environment and gestational process. Perhaps the recent shark success may prove to be a back-to-the-basics result that nevertheless paves the way for mammalian, and ultimately human, artificial uterus research.

photo credit: chem7