We all know how human reproduction works: the sperm meets the egg, the fertilized egg begins its journey, transforms into a human embryo, then becomes a fetus, and finally a baby.
But what if boy meets girl isn’t the only way?
Last week, two studies in Nature It torpedoed the classic early life narrative. Two independent teams persuaded normal skin cells to form a living group that resembled a fertilized human egg, and the early stages of a developing human embryo.
To be clear, the teams did not design an artificial embryo that could grow into a viable baby. Rather, they replicated what happens during the first four days after an egg has been fertilized; it turns into a ball of cells called a blastocyst, the first station toward a fully formed baby.
Although they did not go beyond the blastocyst stage, both models are by far the most complete replicas of an early human embryo to date. They not only contain cells that grow into a baby, but also all the supporting structures. In just 10 days inside a jelly-like incubator, the reverse-engineered cells displayed strikingly similar traits to their natural counterparts. For example, the artificial embryos generated cells that make up the placenta, which is essential for a viable embryo that, in theory, could develop further or even until birth.
“It is the first complete model of the early human embryo,” said Dr. Jianping Fu of the University of Michigan, who was not involved in the study but wrote an accompanying perspective paper. “This is an important milestone.”
These studies offer a new window into the early days of pregnancy and can provide insight into previously unexplained infertility or pregnancy loss without experimenting with human embryos.
However, the sophistication of these cells raises concern. For now, because artificial embryos differ from natural ones in several respects, scientists do not expect them to have the ability to develop into full embryos. However, as technologies are further refined, artificial human embryos may develop for longer periods of time, putting the technology on a collision course with debates about the beginning of life.
The unknowns of human development
The first 14 days of the construction of a human being are a mystery.
Scientists know that during a pregnancy, a fertilized egg turns into a blastocyst around day four and then implants around day eight. Around this time, something “magical” happens inside the blastocyst, producing cells that eventually develop into the placenta and others that give rise to a fetus.
The problem? This initial stage is incredibly difficult to study. Until now, scientists have relied on laboratory-discarded human embryos, often from IVF outcasts, which can grow up to 13 days according to ethical guidelines. These tissues are hard to come by, and at this stage, said Dr. Jun Wu of the University of Texas South Medical Center, the proto-embryo is “essentially a black box.”
Scientists have previously tried to replicate the early days of development using mouse embryos. In 2018, a team grew similar blastocysts from mouse stem cells – an admirable effort, but not a perfect model, as mice and humans have different developmental trajectories.
How they did it
The two new studies represent the first time that scientists have been able to create blastocyst-like structures from human cells.
In one study, Dr. José Polo from Monash University started with a previously published recipe. Here, skin cells are gently scraped and bathed in a chemical soup that returns them to a stem-cell-like state, meaning they regain the ability to produce other types of cells. From there, the pseudo stem cells (called iPSCs) are bathed in a nutritious liquid in a Petri dish. The team’s spark of knowledge came when they realized that after three weeks, cells began to branch into a medley of three different cell types found in early human embryos, something that had rarely been seen before. .
Inspired, the team then transferred the cells to a 3D gelatin-like culture system for support. Interestingly, the cells began to self-assemble with a mind of their own. “What was completely surprising is that when you put them together, they self-organize,” Polo said.
The strange “cells assembled” moment led the team to analyze their genetics. To the researchers’ surprise, they found that these early embryo-like structures, called “iBlastoids,” had a similar organization and cellular component to their natural counterpart. One layer, for example, was populated by cells with a genetic signature that designated them as part of a placenta. Others remarkably resembled the cells that eventually develop into a full fetus.
The iBlastoid, in a sense, looked like a normal blastocyst after it was implanted in the uterus, without much investigation by researchers.
In the other article, the team used a mixture of human cells and stem cells to design what they called a “human blastoid.” As in the previous study, the artificial embryos were similar in size and shape to their natural counterparts and had a comparable genetic profile. Using a test that resembles implantation in a uterus but in a culture dish, the blastoids attached and continued to develop, with some reorganization into structures that mimic the next stage of development.
Test tube babies?
Despite their uncanny similarity to reality, for now, the authors emphasize, the blastoids are not real yet. Some of your cell layers don’t seem to form very well, and some have cell types that shouldn’t be there. A 10 percent efficiency rate in successful skin-to-blastoid conversion also makes any scientist wince.
However, all of these problems can be overcome, and experts do not lose sight of the potential of blastoids. Despite the shortcomings, they are the first “human embryo models to be derived from cultured cells” and have “all the founder cells” for growing a fetus, Fu said. For the first time, we may be able to test for possible causes of infertility or pregnancy loss with a much higher yield, which can then be further verified.
“You could use 1,000 or 10,000 iBlastoids to discover something, and then you could go and test that discovery on three blastocysts,” Polo said.
However, as technology is further optimized, the delicate question of a blastoid’s identity cannot be ignored. Since they are similar to the real thing, at what point should they be treated as cloned human embryos? Is it ethical to destroy them? Currently, human embryos can grow in the laboratory for 14 days internationally. Do those rules apply?
Looking ahead, the debate goes even further. Scientists have been working to reprogram skin cells into reproductive cells for years in an effort to help couples who might not otherwise conceive. Healthy mice have already been born from skin cells transformed into ovules. Although they are a long way off, current studies are taking a step in that direction.
A separate study from last week showed that it is possible to grow a mouse fetus halfway through its gestation in an artificial uterus, a record for mammals and that further dissociates reproduction from the ancient story of “sperm meets with the ovum ”. Can we one day clone a human baby using someone’s skin cells and then grow it in an artificial womb with no resemblance to natural reproduction? We should?
Image Credit: Monash University