Artificial Wombs Are Getting Closer to Reality for Premature Babies
In 2017, researchers at the Children's Hospital of Philadelphia grew extremely preterm lambs from hairless to fluffy inside a "biobag," a dark, fluid-filled bag designed to mimic a mother's womb.
"There could be quite a lot of infants that would benefit from artificial womb technologies."
This happened over the course of a month, across a delicate period of fetal development that scientists consider the "edge of viability" for survival at birth.
In 2019, Australian and Japanese scientistsrepeated the success of keeping extremely premature lambs inside an artificial womb environment until they were ready to survive on their own. Those researchers are now developing a treatment strategy for infants born at "the hard limit of viability," between 20 and 23 weeks of gestation. At the same time, Dutch researchers are going so far as to replicate the sound of a mother's heartbeat inside a biobag. These developments signal exciting times ahead--with a touch of science fiction--for artificial womb technologies. But is there a catch?
"There could be quite a lot of infants that would benefit from artificial womb technologies," says Josephine Johnston, a bioethicist and lawyer at The Hastings Center, an independent bioethics research institute in New York. "These technologies can decrease morbidity and mortality for infants at the edge of viability and help them survive without significant damage to the lungs or other problems," she says.
It is a viewpoint shared by Frans van de Vosse, leader of the Cardiovascular Biomechanics research group at Eindhoven University of Technology in the Netherlands. He participates in a university project that recently received more than $3 million in funding from the E.U. to produce a prototype artificial womb for preterm babies between 24 and 28 weeks of gestation by 2024.
The Eindhoven design comes with a fluid-based environment, just like that of the natural womb, where the baby receives oxygen and nutrients through an artificial placenta that is connected to the baby's umbilical cord. "With current incubators, when a respiratory device delivers oxygen into the lungs in order for the baby to breathe, you may harm preterm babies because their lungs are not yet mature for that," says van de Vosse. "But when the lungs are under water, then they can develop, they can mature, and the baby will receive the oxygen through the umbilical cord, just like in the natural womb," he says.
His research team is working to achieve the "perfectly natural" artificial womb based on strict mathematical models and calculations, van de Vosse says. They are even employing 3D printing technology to develop the wombs and artificial babies to test in them--the mannequins, as van de Vosse calls them. These mannequins are being outfitted with sensors that can replicate the environment a fetus experiences inside a mother's womb, including the soothing sound of her heartbeat.
"The Dutch study's artificial womb design is slightly different from everything else we have seen as it encourages a gestateling to experience the kind of intimacy that a fetus does in pregnancy," says Elizabeth Chloe Romanis, an assistant professor in biolaw at Durham Law School in the U.K. But what is a "gestateling" anyway? It's a term Romanis has coined to describe neither a fetus nor a newborn, but an in-between artificial stage.
"Because they aren't born, they are not neonates," Romanis explains. "But also, they are not inside a pregnant person's body, so they are not fetuses. In an artificial womb the fetus is still gestating, hence why I call it gestateling."
The terminology is not just a semantic exercise to lend a name to what medical dictionaries haven't yet defined. "Gestatelings might have a slightly different psychology," says Romanis. "A fetus inside a mother's womb interacts with the mother. A neonate has some kind of self-sufficiency in terms of physiology. But the gestateling doesn't do either of those things," she says, urging us to be mindful of the still-obscure effects that experiencing early life as a gestateling might have on future humans. Psychology aside, there are also legal repercussions.
The Universal Declaration of Human Rights proclaims the "inalienable rights which everyone is entitled to as a human being," with "everyone" including neonates. However, such a legal umbrella is absent when it comes to fetuses, which have no rights under the same declaration. "We might need a new legal category for a gestateling," concludes Romanis.
But not everyone agrees. "However well-meaning, a new legal category would almost certainly be used to further erode the legality of abortion in countries like the U.S.," says Johnston.
The "abortion war" in the U.S. has risen to a crescendo since 2019, when states like Missouri, Mississippi, Kentucky, Louisiana and Georgia passed so-called "fetal heartbeat bills," which render an abortion illegal once a fetal heartbeat is detected. The situation is only bound to intensify now that Justice Ruth Bader Ginsburg, one of the Supreme Court's fiercest champions for abortion rights, has passed away. If President Trump appoints Ginsburg's replacement, he will probably grant conservatives on the Court the votes needed to revoke or weaken Roe v. Wade, the milestone decision of 1973 that established women's legal right to an abortion.
"A gestateling with intermediate status would almost certainly be considered by some in the U.S. (including some judges) to have at least certain legal rights, likely including right-to-life," says Johnston. This would enable a fetus on the edge of viability to make claims on the mother, and lead either to a shortening of the window in which abortion is legal—or a practice of denying abortion altogether. Instead, Johnston predicts, doctors might offer to transfer the fetus to an artificial womb for external gestation as a new standard of care.
But the legal conundrum does not stop there. The viability threshold is an estimate decided by medical professionals based on the clinical evidence and the technology available. It is anything but static. In the 1970s when Roe v. Wade was decided, for example, a fetus was considered legally viable starting at 28 weeks. Now, with improved technology and medical management, "the hard limit today is probably 20 or 21 weeks," says Matthew Kemp, associate professor at the University of Western Australia and one of the Australian-Japanese artificial womb project's senior researchers.
The changing threshold can result in situations where lots of people invested in the decision disagree. "Those can be hard decisions, but they are case-by-case decisions that families make or parents make with the key providers to determine when to proceed and when to let the infant die. Usually, it's a shared decision where the parents have the final say," says Johnston. But this isn't always the case.
On May 9th 2016, a boy named Alfie Evans was born in Liverpool, UK. Suffering seizures a few months after his birth, Alfie was diagnosed with an unknown neurodegenerative disorder and soon went into a semi-vegetative state, which lasted for more than a year. Alfie's medical team decided to withdraw his ventilation support, suggesting further treatment was unlawful and inhumane, but his parents wanted permission to fly him to a hospital in Rome and attempt to prolong his life there. In the end, the case went all the way up to the Supreme Court, which ruled that doctors could stop providing life support for Alfie, saying that the child required "peace, quiet and privacy." What happened to little Alfie raised huge publicity in the UK and pointedly highlighted the dilemma of whether parents or doctors should have the final say in the fate of a terminally-ill child in life-support treatment.
"In a few years from now, women who cannot get pregnant because of uterine infertility will be able to have a fully functional uterus made from their own tissue."
Alfie was born and, thus had legal rights, yet legal and ethical mayhem arose out of his case. When it comes to gestatelings, the scenarios will be even more complicated, says Romanis. "I think there's a really big question about who has parental rights and who doesn't," she says. "The assisted reproductive technology (ART) law in the U.K. hasn't been updated since 2008....It certainly needs an update when you think about all the things we have done since [then]."
This June, for instance, scientists from the Wake Forest Institute for Regenerative Medicine in North Carolina published research showing that they could take a small sample of tissue from a rabbit's uterus and create a bioengineered uterus, which then supported both fertilization and normal pregnancy like a natural uterus does.
"In [a number of] years from now, women who cannot get pregnant because of uterine infertility will be able to have a fully functional uterus made from their own tissue," says Dr. Anthony Atala, the Institute's director and a pioneer in regenerative medicine. These bioengineered uteri will eventually be covered by insurance, Atala expects. But when it comes to artificial wombs that externally gestate premature infants, will all mothers have equal access?
Medical reports have already shown racial and ethnic disparities in infertility treatments and access to assisted reproductive technologies. Costs on average total $12,400 per cycle of treatment and may require several cycles to achieve a live birth. "There's no indication that artificial wombs would be treated any differently. That's what we see with almost every expensive new medical technology," says Johnston. In a much more dystopian future, there is even a possibility that inequity in healthcare might create disturbing chasms in how women of various class levels bear children. Romanis asks us to picture the following scenario:
We live in a world where artificial wombs have become mainstream. Most women choose to end their pregnancies early and transfer their gestatelings to the care of machines. After a while, insurers deem full-term pregnancy and childbirth a risky non-necessity, and are lobbying to stop covering them altogether. Wealthy white women continue opting out of their third trimesters (at a high cost), since natural pregnancy has become a substandard route for poorer women. Those women are strongly judged for any behaviors that could risk their fetus's health, in contrast with the machine's controlled environment. "Why are you having a coffee during your pregnancy?" critics might ask. "Why are you having a glass of red wine? If you can't be perfect, why don't you have it the artificial way?"
Problem is, even if they want to, they won't be able to afford it.
In a more sanguine version, however, the artificial wombs are only used in cases of prematurity as a life-saving medical intervention rather than as a lifestyle accommodation. The 15 million babies who are born prematurely each year and may face serious respiratory, cardiovascular, visual and hearing problems, as well as learning disabilities, instead continue their normal development in artificial wombs. After lots of deliberation, insurers agree to bear the cost of external wombs because they are cheaper than a lifetime of medical care for a disabled or diseased person. This enables racial and ethnic minority women, who make up the majority of women giving premature birth, to access the technology.
Even extremely premature babies, those babies (far) below the threshold of 28 weeks of gestation, half of which die, could now discover this thing called life. In this scenario, as the Australian researcher Kemp says, we are simply giving a good shot at healthy, long-term survival to those who were unfortunate enough to start too soon.
Swiss researchers have discovered a third type of brain cell that appears to be a hybrid of the two other primary types — and it could lead to new treatments for many brain disorders.
The challenge: Most of the cells in the brain are either neurons or glial cells. While neurons use electrical and chemical signals to send messages to one another across small gaps called synapses, glial cells exist to support and protect neurons.
Astrocytes are a type of glial cell found near synapses. This close proximity to the place where brain signals are sent and received has led researchers to suspect that astrocytes might play an active role in the transmission of information inside the brain — a.k.a. “neurotransmission” — but no one has been able to prove the theory.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.
Martin Taylor was only 32 when he was diagnosed with Parkinson's, a disease that causes tremors, stiff muscles and slow physical movement - symptoms that steadily get worse as time goes on.
“It's horrible having Parkinson's,” says Taylor, a data analyst, now 41. “It limits my ability to be the dad and husband that I want to be in many cruel and debilitating ways.”
Today, more than 10 million people worldwide live with Parkinson's. Most are diagnosed when they're considerably older than Taylor, after age 60. Although recent research has called into question certain aspects of the disease’s origins, Parkinson’s eventually kills the nerve cells in the brain that produce dopamine, a signaling chemical that carries messages around the body to control movement. Many patients have lost 60 to 80 percent of these cells by the time they are diagnosed.
For years, there's been little improvement in the standard treatment. Patients are typically given the drug levodopa, a chemical that's absorbed by the brain’s nerve cells, or neurons, and converted into dopamine. This drug addresses the symptoms but has no impact on the course of the disease as patients continue to lose dopamine producing neurons. Eventually, the treatment stops working effectively.
BlueRock Therapeutics, a cell therapy company based in Massachusetts, is taking a different approach by focusing on the use of stem cells, which can divide into and generate new specialized cells. The company makes the dopamine-producing cells that patients have lost and inserts these cells into patients' brains. “We have a disease with a high unmet need,” says Ahmed Enayetallah, the senior vice president and head of development at BlueRock. “We know [which] cells…are lost to the disease, and we can make them. So it really came together to use stem cells in Parkinson's.”
In a phase 1 research trial announced late last month, patients reported that their symptoms had improved after a year of treatment. Brain scans also showed an increased number of neurons generating dopamine in patients’ brains.
Increases in dopamine signals
The recent phase 1 trial focused on deploying BlueRock’s cell therapy, called bemdaneprocel, to treat 12 patients suffering from Parkinson’s. The team developed the new nerve cells and implanted them into specific locations on each side of the patient's brain through two small holes in the skull made by a neurosurgeon. “We implant cells into the places in the brain where we think they have the potential to reform the neural networks that are lost to Parkinson's disease,” Enayetallah says. The goal is to restore motor function to patients over the long-term.
Five patients were given a relatively low dose of cells while seven got higher doses. Specialized brain scans showed evidence that the transplanted cells had survived, increasing the overall number of dopamine producing cells. The team compared the baseline number of these cells before surgery to the levels one year later. “The scans tell us there is evidence of increased dopamine signals in the part of the brain affected by Parkinson's,” Enayetallah says. “Normally you’d expect the signal to go down in untreated Parkinson’s patients.”
"I think it has a real chance to reverse motor symptoms, essentially replacing a missing part," says Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh.
The team also asked patients to use a specific type of home diary to log the times when symptoms were well controlled and when they prevented normal activity. After a year of treatment, patients taking the higher dose reported symptoms were under control for an average of 2.16 hours per day above their baselines. At the smaller dose, these improvements were significantly lower, 0.72 hours per day. The higher-dose patients reported a corresponding decrease in the amount of time when symptoms were uncontrolled, by an average of 1.91 hours, compared to 0.75 hours for the lower dose. The trial was safe, and patients tolerated the year of immunosuppression needed to make sure their bodies could handle the foreign cells.
Claire Bale, the associate director of research at Parkinson's U.K., sees the promise of BlueRock's approach, while noting the need for more research on a possible placebo effect. The trial participants knew they were getting the active treatment, and placebo effects are known to be a potential factor in Parkinson’s research. Even so, “The results indicate that this therapy produces improvements in symptoms for Parkinson's, which is very encouraging,” Bale says.
Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh, also finds the results intriguing. “I think it's excellent,” he says. “I think it has a real chance to reverse motor symptoms, essentially replacing a missing part.” However, it could take time for this therapy to become widely available, Kunath says, and patients in the late stages of the disease may not benefit as much. “Data from cell transplantation with fetal tissue in the 1980s and 90s show that cells did not survive well and release dopamine in these [late-stage] patients.”
Searching for the right approach
There's a long history of using cell therapy as a treatment for Parkinson's. About four decades ago, scientists at the University of Lund in Sweden developed a method in which they transferred parts of fetal brain tissue to patients with Parkinson's so that their nerve cells would produce dopamine. Many benefited, and some were able to stop their medication. However, the use of fetal tissue was highly controversial at that time, and the tissues were difficult to obtain. Later trials in the U.S. showed that people benefited only if a significant amount of the tissue was used, and several patients experienced side effects. Eventually, the work lost momentum.
“Like many in the community, I'm aware of the long history of cell therapy,” says Taylor, the patient living with Parkinson's. “They've long had that cure over the horizon.”
In 2000, Lorenz Studer led a team at the Memorial Sloan Kettering Centre, in New York, to find the chemical signals needed to get stem cells to differentiate into cells that release dopamine. Back then, the team managed to make cells that produced some dopamine, but they led to only limited improvements in animals. About a decade later, in 2011, Studer and his team found the specific signals needed to guide embryonic cells to become the right kind of dopamine producing cells. Their experiments in mice, rats and monkeys showed that their implanted cells had a significant impact, restoring lost movement.
Studer then co-founded BlueRock Therapeutics in 2016. Forming the most effective stem cells has been one of the biggest challenges, says Enayetallah, the BlueRock VP. “It's taken a lot of effort and investment to manufacture and make the cells at the right scale under the right conditions.” The team is now using cells that were first isolated in 1998 at the University of Wisconsin, a major advantage because they’re available in a virtually unlimited supply.
Other efforts underway
In the past several years, University of Lund researchers have begun to collaborate with the University of Cambridge on a project to use embryonic stem cells, similar to BlueRock’s approach. They began clinical trials this year.
A company in Japan called Sumitomo is using a different strategy; instead of stem cells from embryos, they’re reprogramming adults' blood or skin cells into induced pluripotent stem cells - meaning they can turn into any cell type - and then directing them into dopamine producing neurons. Although Sumitomo started clinical trials earlier than BlueRock, they haven’t yet revealed any results.
“It's a rapidly evolving field,” says Emma Lane, a pharmacologist at the University of Cardiff who researches clinical interventions for Parkinson’s. “But BlueRock’s trial is the first full phase 1 trial to report such positive findings with stem cell based therapies.” The company’s upcoming phase 2 research will be critical to show how effectively the therapy can improve disease symptoms, she added.
The cure over the horizon
BlueRock will continue to look at data from patients in the phase 1 trial to monitor the treatment’s effects over a two-year period. Meanwhile, the team is planning the phase 2 trial with more participants, including a placebo group.
For patients with Parkinson’s like Martin Taylor, the therapy offers some hope, though Taylor recognizes that more research is needed.
“Like many in the community, I'm aware of the long history of cell therapy,” he says. “They've long had that cure over the horizon.” His expectations are somewhat guarded, he says, but, “it's certainly positive to see…movement in the field again.”
"If we can demonstrate what we’re seeing today in a more robust study, that would be great,” Enayetallah says. “At the end of the day, we want to address that unmet need in a field that's been waiting for a long time.”