New definition of a human embryo proposed amid rapid scientific advances

When someone says the word embryo, what do you think of? Probably that picture you’ve seen a thousand times on a thousand different news articles: a translucent orb swelling with cytoplasm being prodded by a microinjection needle under the light of a microscope. The mainstreaming of IVF, or in vitro fertilization, has familiarized new generations of people with what the earliest stages of human development entails.

But earlier this summer, when scientists revealed they’re now able to create blobs of stem cells in the lab that self-organize into the same sorts of structures embryos themselves build during those first few weeks, it blasted wide open whatever ideas of the embryo we used to have. Were these structures embryo models, as some scientists named them, or something approaching actual embryos? How would anyone know when that line had been crossed?

“The definition of the human embryo is far from being engrained, it’s constantly evolving with scientific advances,” said Nicolas Rivron, a developmental biologist at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna. In a perspective published Thursday in Cell, he and an international group of leading luminaries in the fast-moving field of synthetic embryology — or “stembryology,” as it’s sometimes called — argue that these latest scientific advances justify a new definition for the human embryo that’s rooted not in how it was made, but in what it can become.

“Because of this new path, we think it becomes more and more important to think about the embryo not in terms of how it was formed but about the potential it has to generate something,” Rivron told STAT.

He and his co-authors proposed that embryos be defined as “a group of human cells supported by elements fulfilling extra-embryonic and uterine functions that, combined, have the potential to form a fetus.”

In other words, embryo models could be considered embryos if they have the potential to survive to the equivalent of eight weeks into a pregnancy — a stance at odds with a statement issued earlier this year by an international group of stem cell scientists.

The first known usage of the word in the English language dates back to the 14th century, coming from the Greek embryon for “that which grows.” It wasn’t until the 1870s, when a scientific consensus began to emerge on the roles of eggs and sperm, that embryos began to be defined by the process of fertilization. Throughout most of the 20th century, legal definitions of the embryo referred to a group of cells resulting from fertilization and covered this developing mass until it had transformed into something with a heart and brain and other organs, at which point (about 56 days later) it became a fetus.

But in 1997, that definition became obsolete. The birth of Dolly the Sheep showed the world that you didn’t need an egg and a sperm to make a living, breathing mammal. You could drop the DNA from any cell into an empty oocyte and produce a clone, bypassing fertilization altogether. It opened the possibility that the technique, called somatic cell nuclear transfer, could one day be applied to humans.

As far as we know, that never happened. But the possibility that it might spurred a number of nations to change their legal definitions of the embryo. Japan and Australia added language about stages of development. The Netherlands, Belgium, and Germany, among others, did away with the fertilization language, opting instead for the idea of potentiality — that an embryo was defined by its capacity to generate a human being.

But those definitions have often been both broad and vague. The result is a complicated global patchwork of laws that leave a lot of ambiguity about what it means to be an embryo, said Hank Greely, director of the Stanford Center for Law and the Biosciences. “There really is a need for more clarity on what the laws say.”

It’s into this legal vacuum that stembryology has arrived — the marriage of stem cell biology with bioengineering to produce self-organizing embryo-like blobs that can be cultured in a dish, grown in great numbers, and poked, prodded, tracked, and quantified in real time. Scientists believe they will prove to be an incredibly powerful tool for prying back the lid on the black box of early human development, yielding new insights into infertility, miscarriage, and genetic diseases. They also may provide a more flexible and ethical alternative to the study of human embryos, which has been historically limited by regulations and the willingness of IVF donors.

As researchers like Rivron push the field forward, they worry that the lack of legal clarity around embryos — and therefore when an embryo model might become one — could jeopardize funding, lead to public backlash, or even unintentionally land scientists in jail. Their proposal is an attempt to avoid those outcomes, while still recognizing the radical new possibilities these scientific advances represent.

“Right now, these structures we can form in the lab, these embryo models, we know they are not embryos because they are incapable of forming a neonate,” Rivron said. “But if in the future they tip over and prove capable of doing so, then for us there’s no reason to set them apart. We will have to raise our ethical standards regarding their use for research.”

To establish potentiality, the authors also propose a developmental Turing test — a means for determining if a human embryo model is capable of becoming a living, breathing person. The ultimate test, of course, would be to start a pregnancy with one. But existing bans on human reproductive cloning in at least 45 countries would likely prevent such a test from being conducted on models formed from stem cells. (Guidelines issued by the influential International Society for Stem Cell Research, or ISSCR, also prohibit the transfer of any human embryo model to the uterus of a human or an animal.)

Instead, Rivron and his colleagues propose a combination of proxy measures, laying out a sort of road map of experiments scientists might undertake to understand just how likely it is that embryo models could ever have the potential to become more than just a few cells in a dish. They include creating embryo models of large animals like pigs and monkeys and implanting them into those species to see if they can develop normally and go on to produce fertile offspring of their own.

“I really appreciate that they are open to the possibility that some embryo models might actually deserve to be treated as embryos some day,” Greely said. “Because the general reaction in the field has been to make a hex sign and say, ‘these are not embryos.’”

That was the message sent by ISSCR earlier this summer. In a statement released in June, the organization reiterated its support for research using embryo models and decried the use of the term “synthetic embryo” to describe them. “Integrated embryo models are neither synthetic nor embryos,” the statement said. “While these models can replicate aspects of the early-stage development of human embryos, they cannot and will not develop to the equivalent of postnatal stage humans.”

Rivron said he is in discussions with the ISSCR to set up a formal working group to tackle this issue. He hopes the paper will be a first step toward raising awareness among policymakers, scientific societies, and ethics committees.

“There is definitely a lot at stake here,” said Insoo Hyun, a bioethics affiliate at Harvard Medical School who sits on the ISSCR’s ethics committee and is also director of life sciences and public learning at the Museum of Science in Boston. “These definitional matters aren’t trivial because it really does matter for things like funding or even for criminality.”

It matters especially in places where there are funding or legal restrictions on what kinds of things you can do with embryos. In Canada, for example, scientists can conduct experiments on donated embryos but can’t create embryos specifically for research. In the U.S., there are no laws that explicitly regulate embryo research. But a rider called the Dickey-Wicker Amendment bars the federal government from funding any research that creates, destroys, or knowingly harms human embryos.

That provision establishes a legal definition of the term “human embryo” that governs how the National Institutes of Health can dole out research dollars. It considers embryos to be any organism not already protected by human subject research regulations “that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes (sperm or egg) or human diploid cells.”

Hyun said it’s possible that some embryo models might fall under that definition, depending how you interpret what an “organism” is. “We know that NIH has been kind of puzzling over this,” Hyun said. “They’re still very gun-shy because there’s a lot of confusion about what to do with these models.”

Lyric Jorgenson, acting director of the Office of Science Policy at the NIH, said in a statement to STAT that the institutes don’t anticipate changes to the Dickey-Wicker Amendment definition or to NIH policies. But she applauded Rivron’s team’s efforts to construct a definition for non-NIH funded research “that is reflective of the current state of the science.”

“It will be critical that we collectively continue to assess these definitions as our technologies evolve to ensure our policies keep pace with the knowledge gained at the frontiers of human biology,” Jorgenson said.

Sarah Franklin, director of the Reproductive Sociology Research Group at the University of Cambridge in the U.K., welcomed the work Rivron and his colleagues are doing to bring these issues into the wider conversation. “They’ve done a service to their profession by putting a lot of work into answering a really important question: Do we need a new definition of an embryo?” she said. “But I’m not sure that way of asking the question is the best way of getting to where we need to be. It’s not a question that fits particularly easily with efforts to create policy.”

Rather than focusing on the ontological conundrum of what an embryo is, she’d like to see social scientists study how the public feels about permissible versus impermissible uses for them. Franklin pointed to how little current data there are on public views about embryo research, let alone the science of stem cell-based embryo models.

“I think that we should be careful not to assume that we know what the kind of hot-button issues around this are going to be,” she said. “That’s the big missing piece of the puzzle right now.” But that’s the piece that she believes might better help governments create clear, logical regulations that reflect the values of the societies where they exist.

For Hyun and Greely, they also have concerns that in some ways, the new definition raises more questions than it answers. The balls of cells that IVF clinics transfer into the uteruses don’t yet have the “elements fulfilling extra-embryonic and uterine functions” described by Rivron and colleagues. Those develop only after implantation. Does that mean that such entities, which are currently referred to as embryos, would cease to be embryos under this definition? What about an embryo that has implanted but has a fatal genetic condition like trisomy 8, meaning it has no chance of surviving past 20 weeks. Is that an embryo?

Echoing the views of Mary Warnock, who led the U.K.’s early policy development in this area, Franklin suggested that we might not be able to come up with a definition of embryo that is right — biologically, ethically, legally. “But if we have one that is alright to enough people, we will get some legislation rather than none,” Franklin said. “And what we want to avoid is being in a situation where there are no limits. That’s something most people really don’t want.”