Countdown to iblastoids

By Elizabeth Finkel

Human embryos cloned from skin cells, mouse fetuses grown in incubators, human-monkey embryos… It’s not a line-up from the latest Netflix sci-fi series. This was the stuff of news headlines in March and April.

“These really are big steps,” says Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland, Ohio. Hyun sits on the ethics committee of the International Society for Stem Cell Research (ISSCR), which advises researchers and policymakers. “Taken together they might make some people nervous,” acknowledges University of Melbourne bioethicist Megan Munsie, the committee’s chair.

At a time when it appears ethical lines in the sand are being erased, there’s a call to erase one more: the fourdecade-long restraint that forbids researchers from growing human embryos in the lab for more than 14 days.

Neither ethicist is losing sleep over the possibility. They believe that, as technology and values evolve, society needs to revise where ethical lines should be drawn. “We need to talk,” Munsie says.

In March, two labs reported in Nature magazine that they had created a “complete” model of a human embryo. At the University of Texas Southwestern Medical Center, a research group led by stem cell biologist Jun Wu used pluripotent human stem cells (cells that can form many of the tissues that make up the body) as the starting material and dubbed them “blastoids”, because they resemble five-day-old embryos known as blastocysts. In another major breakthrough, stem cell biologist Jose Polo’s group at Monash University created similar embryos starting from skin cells. They were dubbed “iblastoids”. In theory, these developments mean an embryo could be cloned from a person’s own skin cells – no egg or sperm required. In papers yet to be peer-reviewed, two other groups, one at the California Institute of Technology, the other at Peking University Third Hospital, have also reported making complete embryos.

These reports are groundbreaking. Until now it has only been possible for researchers to produce incomplete embryo models. These lacked the cells that give rise to life-support tissues: the yolk sac that nourishes the embryo till about 12 weeks, and the placenta that then takes over. The new “complete” embryo models have it all, looking and acting like blastocysts. So, are they in fact human embryos and deserving of the protections that follow? Australia’s National Health and Medical Research Council (NHMRC) has decided that they are. That means, among other things, they are subject to the 14-day limit, established by a British committee in 1984 and adopted by many countries, that restricts the study of a human embryo to those first 14 days of its development, at which point it becomes philosophically considered a single entity because it can no longer split into a twin.

Developmental biologist Jacob Hanna’s lab, at the Weizmann Institute of Science in Israel, pushed back another technological boundary in March by taking a mouse embryo halfway through development in an artificial womb, generating a tiny fetus with a clearly beating heart, equivalent to the stage of a five- to sixweek-old human fetus. Published in Nature magazine, their paper documented how fetuses were suspended in liquid nutrient–filled rotating bottles and were monitored by sensors that made continuous adjustments to oxygen levels.

Then, in April, came the publication of another boundary-breaking experiment: a monkey-human hybrid embryo made by a collaboration between scientists at California’s Salk Institute and China’s Kunming University of Science and Technology. The researchers inserted 25 human pluripotent stem cells into long-tailed macaque monkey embryos, allowing them to live for about 20 days, during which time both the human and monkey cells multiplied. The experiment was carried out in China; while not illegal in the United States, it would have been difficult there because researchers are banned from using government funds or facilities.

What’s driving these researchers? Not human hatcheries or human-ish monkeys. “It makes great sci-fi, but it’s not what the science is about,” says Hanna.

These researchers all converge on a common mission to decode human development, and they are also compelled by the power their science has to alleviate human suffering. Many are deluged by pleas from people who have been injured in accidents or afflicted by disease. Everyone’s hopes have been raised; how could decoding the instructions to build body parts from stem cells not deliver?

What Polo’s Monash team has created are models, the most complete yet, for the stage of development just before an embryo attaches to the wall of the uterus at around eight days. But Polo has no doubt they are non-viable. Similar models in mice shrivel up after being implanted into a mouse uterus. Moreover, the human iblastoids have glitches. They lack an outer shell called the zona pellucida, and unlike natural blastocysts, which move through their developmental steps with chorusline precision, many of the iblastoids falter.

So, Polo’s embryos are imperfect, but useful, models. While human fetuses have been studied from about eight weeks in aborted material, the earlier stages are hidden from researchers. Embryo models may shed light on why the success rate of in-vitro fertilisation is only about 30 per cent per cycle. For women over 35, one in 10 babies are conceived this way, so improving the odds would reduce the considerable financial and emotional burden.

The embryo models are also valuable for testing environmental chemicals, drugs and viruses. For instance, Jianping Fu, a bioengineer at the University of Michigan, made headlines in 2019 with incomplete model embryos that mimic a stage from about 10 to 15 days of development. The US Environmental Protection Agency is collaborating with his lab to test chemicals for toxicity in early pregnancy. Jose Polo’s models, equivalent to about five to 10 days of development, if legalised, may be used for testing for the effects of COVID-19 on early pregnancy. A recent report found that infected women have a higher risk of birth complications.

Another huge medical goal for the boundarybreakers is to provide replacement tissues and, ultimately, replacement organs.

Since 1998, researchers have had access to human embryonic stem cells (HES), which have the potential to form body tissues but not an entire body. They are said to be pluripotent, as opposed to totipotent cells, which can form a complete embryo. Pluripotent HES were sourced from five-day-old IVF embryos, destroying them in the process, a practice that triggered an ethical debate even though these embryos were surplus and destined to be destroyed. Researchers had long

Another huge medical goal is to provide replacement tissues and, ultimately, replacement organs.

suspected that pluripotency was just a matter of how cells were programmed. In 2007, Japanese researchers indeed learnt how to reprogram skin cells to give them the same powers as HES. They were dubbed “induced pluripotent stem cells”, or IPS cells.

These IPS cells freed researchers from the ethical snarls associated with using HES, and research flourished. In the past few years, both HES and IPS cells have delivered retinal tissue to treat macular degeneration, and insulinproducing cells to treat type 1 diabetes. Clinical trials are still ironing out how to deliver these grafts to patients safely and effectively. But even in the dish, facsimiles of tissues and organs (organoids) prove their worth. During the 2016 zika virus epidemic in Brazil, 1600 babies were born with abnormally small heads. Pea-sized brain organoids explained why: zika could infect and destroy developing human brain tissue.

Now researchers are aiming for the next step. Jacob Hanna’s artificial womb is not a proof of concept for human hatcheries but for growing human organs. The growing of an organ, with its multiple interacting cells and complex structure that is fully plumbed by blood vessels, is exceedingly difficult. Hanna believes it will take multiple approaches, including the making of animalhuman hybrid embryos, which his lab is also pursuing. The concept was demonstrated in 2017 when researchers grew a mouse pancreas inside a rat and then grafted it into a diabetic mouse to cure its diabetes. But human cells have been largely rejected when injected into mouse or pig embryos. Hence the human-monkey experiment to test how human cells fare in a more closely related species.

These are all lofty visions. Yet it can’t be denied that it looks to be a matter of time before imperfect blastoids are, indeed, perfected. “It’s hard to deny the potential for these models to possibly develop into human beings,” acknowledges Jianping Fu.

It’s also hard to deny that once a technology arrives, mavericks will attempt to use it. For instance, in the 1970s, the world drew an ethical line in the sand: genetic engineering would never be used to modify a human embryo. It turned out that this line was held not by ethics but the clumsiness of the technology. In the past decade, the CRISPR technique, which edits DNA code with single-letter precision, erased that line. Labs across the world were permitted to edit human embryos, but only in the culture dish. In 2018, Chinese researcher He Jiankui shocked the world by announcing that he had edited and implanted three human embryos into mothers who gave birth under a shroud of secrecy. Jiankui is serving a three-year jail sentence in China.

The vast majority of researchers are not mavericks, of course, and want to work within legal frameworks. Indeed, Polo notified the NHMRC of his newfound ability to create iblastoids a year ago, and has since awaited a licence to continue research.

Nevertheless, the march of technology appears to be erasing ethical lines that have been in place for decades. Is that morally defensible? Do ethics evolve? Absolutely, believes Insoo Hyun. But, he says, this does not mean we are “plunging into a world of pernicious ethical relativism”.

Hyun maintains that the guiding values of research ethics remain constant: the need to uphold rigorous science aimed at improving the human condition, respect for persons, beneficence and social justice.

“Over time, we end up fine-tuning our interpretations of what each of these ethical values mean and what they might call us to do in the name of research ethics. But this occasional recalibration is not an indication that ‘anything goes’ in an ethically relative manner.”

The need for that recalibration is “long overdue”, says Megan Munsie. For many countries, including Australia, current laws are ambiguous about the legality of creating human-animal hybrid embryos and gene editing. Just where the new settings should lie will be addressed by a soon-to-be released set of updated global guidelines from the ISSCR.

No doubt Australia’s NHMRC awaits those guidelines as it ponders whether to grant a licence for iblastoids.

“It’s hard to deny the potential for these models to possibly develop into human beings,” acknowledges Jianping Fu.