Enlarge /. A mouse embryo with the nervous system highlighted in blue.
Embryos start out as a single cell and from there have to get to a complicated arrangement of several tissues. For organisms like insects or frogs, this process is fairly easy to study because development takes place in an egg that is released into the environment shortly after fertilization. However, understanding the earliest stages of development is a serious challenge for mammals, in which all development occurs in the reproductive tract. Performing experiments on a developing embryo is extremely difficult and, at some stages, effectively impossible.
However, progress has been made this week in both human and mouse embryos. On the human side, researchers have used induced stem cells to create embryo-like bodies that will take the first important step in development and bring them up to date with the latest in mouse research. On the mouse side, however, a team of researchers made mouse embryos to stay outside of the uterus for almost a week. While this opens up a world of experimentation that was previously impossible, the requirements to get it working make it unlikely to be widespread.
To breed mice, you need rats
The mouse work was a little more technically interesting, so we'll get back to that first. One of the most critical steps in vertebrate development is gastrulation. The process takes some cells that were set aside during the early embryo and turns them into three critical layers that make up the embryo: skin and nerves, intestinal lining, and everything else.
Gastrulation takes place between six and seven days after fertilization, and shortly afterwards many important developmental events take place: the formation of nerve cells and their organization, the development of the ordered structures that make up the vertebrae, and much more. However, given the size of the embryo at this point and its position in the uterus, the process of gastrulation is essentially invisible.
A large team based in Israel decided to figure out how to change this. They first started with embryos that had already gone through the critical stages of gastrulation and figured out how to make them survive. It was'nt easy. First, the embryos had to be incubated in a flask that was constantly rotating to ensure that all the nutrients and oxygen around the embryo were thoroughly mixed, rather than the embryo's energy needs creating a local "dead zone" around it.
The oxygen level had to be controlled by a special internal gas supply system that increased the pressure over time to bring more oxygen into solution. Fresh glucose also had to be regularly infused into the liquid medium.
About this liquid medium. About a quarter of it could be bought from a standard biotech supply catalog. The rest was much harder to buy. Half of this was serum obtained from rat blood. And a quarter was serum made from human umbilical cord blood. None of these are particularly easy to come by. You have tested and you really need human blood; Rat blood alone was nowhere near as good. (How often can I write such a sentence?)
In either case, this was enough for the embryos to develop for four days. This led them from three layers of non-specialized cells to where the spinal cord began to form and limbs budded off the side of the embryo. In terms of development, this includes a number of important events that we are very interested in studying.
By this point, however, the embryo growth circulatory system should have integrated with the placenta to ensure that the entire embryo has been well supplied with nutrients and oxygen. The embryos died in a way that suggested that there was probably no oxygen supply.
While this is an accomplishment, all of this takes place after the gastrulation occurs. So the researchers withdrew a little further and isolated embryos between four and five days after fertilization. The same medium worked, but here the embryos didn't have to be in a rotating bottle to survive. The two incubations could be combined, with the embryos developing outside of the uterus for essentially a full week.
In addition, the team showed that they were able to perform a variety of manipulations on the embryos during this time in culture. This involved inserting DNA into their cells (either using a virus or electrical currents) or adding stem cells to see how they develop. For anyone willing to ingest enough rat and cord blood to make this all work, there is now a lot of developmental research that can now be done on mouse embryos.
The only thing that is obviously inaccessible through this work is the earliest developmental process, during which a cavity opens in the uniform-looking cell ball formed by the first cell divisions of the fertilized egg. This creates the first somewhat specialized cell populations in the embryo (both the outer ones and a cell stain in the cavity). The resulting structure is called a blastocyst.
We have been able to grow a fertilized egg into a blastocyst in culture for mice for years. However, this has not been done with human cells. And to some extent it still hasn't. Instead, two different laboratories started with stem cells, either embryonic stem cells or stem cells induced from adult tissues. In contrast to mouse work, the embryo could be brought this far with commercial ingredients in the media in which the cells were grown.
This opens the earliest stages of human development for study. While the formation of the blastocyst is interesting, much more is going on in the later stages of development. And this is where ethical concerns are likely to limit how far ready we will be to bring human tissue into culture.
The interesting thing is that we can already get mouse embryos to develop into blastocysts, and now we can take in blastocysts well on their way through development. So it's likely that with a little work we can combine the two processes. That would be enough to get from fertilization up to about two-thirds of the way to birth. That's pretty impressive.
But at this point the embryo becomes very three-dimensional, and in order to provide oxygen and nutrients to all of the cells it really requires a functioning blood supply connected to one source for all of the embryo's needs. And it is not clear how exactly we could replace the placenta, which hosts a very sophisticated and specialized exchange between the bloodstreams of the fetus and the mother. In practice, however, these results mean that a whole range of experiments on mice are now possible – provided you are willing to bleed enough rats.
Nature, 2021. DOI: 10.1038 / s41586-021-03416-3, 10.1038 / s41586-021-03372-y, 10.1038 / s41586-021-03356-y (Via DOIs).