In a quest for novel forms of longevity medicine, an Israeli biotech company intends creating embryo-stage versions of humans to harvest tissues for use in transplant treatments – and to possibly solve fertility, genetic issues and those related to old-age.
The company, Renewal Bio, is pursuing recent advances in stem-cell technology and artificial wombs demonstrated by Jacob Hanna, a biologist at the Weizmann Institute of Science in Rehovot.
Recently, Hanna showed that starting with mouse stem cells, his lab could form realistic-looking mouse embryos and keep them growing in a mechanical womb for several days until they developed beating hearts, flowing blood and cranial folds.
It’s the first time such an advanced embryo has been mimicked without sperm, eggs, or even a uterus. His report was published in the journal Cell.
He told MIT Technology Review he was already working to replicate the technology, starting with human cells, and hopes to eventually produce artificial models of human embryos equivalent to those of a 40- to 50-day-old pregnancy. At that stage basic organs are formed, as well as tiny limbs and fingers.
“We view the embryo as the best 3D bio printer,” says Hanna. “It’s the best entity to make organs and proper tissue.”
Researchers can already print or grow simple tissues, like cartilage or bone, but making more complex cell types and organs has proved difficult. An embryo, however, starts building the body naturally.
“Our company’s view is, ‘Can we use these organised embryo entities that have early organs to get cells usable for transplantation?’”
They want, he added, to use this science for organ tissue transplants that could solve infertility, genetic diseases, and issues related to old age. For example, blood cells from the embryo could potentially be used to help boost immunocompromised systems.
Renewal Bio believes some of the world's most pressing problems are “declining birth rates and fast ageing populations”.
Embryonic blood cells might be collected, multiplied and transferred to an elderly person to reboot the immune system. Another concept is to grow embryonic copies of women with age-related infertility. Researchers could then collect the model embryo’s gonads, which could be further matured, either in the lab or via transplant into the woman’s body, to produce youthful eggs.
Mechanical womb
To create the succession of breakthroughs, Hanna’s lab has been combining advanced stem-cell science with new types of bioreactors.
A year ago, the stem-cell specialist first showed off a “mechanical womb” in which he managed to grow natural mouse embryos outside a female mouse for several days. The system involves spinning jars that keep the embryos bathed in nutritious blood serum and oxygen.
In the latest research, Hanna used the same mechanical womb, but this time to grow look-alike embryos created from stem cells.
Remarkably, when stem cells are grown together in specially shaped containers, they will spontaneously join and try to assemble an embryo, producing structures called embryoids, blastoids, or synthetic embryo models. Many researchers insist that despite appearances, these structures have limited relation to real embryos and zero potential to develop completely.
By adding these synthetic mouse embryos to his mechanical womb, however, Hanna managed to grow them further than ever before, to the point where hearts started beating, blood began moving, and there was the start of a brain and a tail.
“The embryos really look great,” says Hanna, “and similar to natural embryos.”
Mini-Me
In a next set of experiments, Hanna is using his own blood or skin cells (and those of a few other volunteers) as the starting point for making synthetic human embryos. It means his lab could soon be swimming in hundreds or thousands of tiny mini-mes, all genetic clones of himself.
He views these as entities without a future. They’re probably not viable, he says. Plus, right now there is no way to graduate from jar life to real life. Without a placenta and an umbilical cord connected to a mother, no synthetic embryo could survive if transplanted to a uterus.
“We are not trying to make human beings. That is not what we are trying to do.” says Hanna. “To call a day-40 embryo a mini-me is just not true.”
Although Hanna doesn’t think an artificial embryo made from stem cells and kept in a lab will ever count as a human being, he has a contingency plan to remove confusion. It’s possible, for instance, to genetically engineer the starting cells so the resulting model embryo never develops a head. Restricting its potential could help avoid ethical dilemmas.
“We think this is important and have invested a lot in this,” he says. Genetic changes can be made that lead to “no lungs, no heart, or no brain”.
The same week this paper appeared in Cell, the University of Cambridge-based laboratory of Prof Magdalena Zernicka-Goetz published two papers on a preprint server outlining how they had observed similar organ structures start to form in their own research using embryo models.
Zernicka-Goetz told MedicalNewsToday their final versions were currently under embargo.
This latest finding builds on the previous work of other laboratories and teams, both those of Zernicka-Goetz and others, said Prof David Glover, her husband.
Glover and Zernicka-Goetz have teams at Cambridge and CalTech, have carried out research together and appear as co-authors on one of the papers due to be published soon.
He told MNT: “I think you have to go back to a paper published in 2017, [whose] senior author was Sarah Harrison, which establishes the principle of being able to make an embryo-like structure using a mixture of extraembryonic cells and embryonic cells.”
Extraembryonic cells include key components forming extraembryonic tissues, crucial to maintaining embryo survival. Extraembryonic tissues include the placenta, yolk sac, and amnion.
Being able to produce embryo models that feature the start of development of these tissues is so important because they help initiate the signalling that helps the embryo model develop and self-assemble much as a naturally developing embryo would, Glover noted.
“Because our own embryos develop inside the womb, they require extraembryonic tissues to develop properly. And those have two functions. They provide, of course, a structural basis, they provide a yolk sac, [and] they provide the placenta.
“But before they get to that stage, they also provide signals to the embryo to tell it how to properly develop. And if you don’t have those signals there, then the embryo doesn’t develop properly,” the researcher added.
These particular models were just one type of embryo model currently being developed, said Glover.
Researchers have also developed other models, such as blastoids, which attempt to recreate the pre-implantation blastocyst stage of the embryo, and gastruloids, which do not have any extraembryonic tissues, and as a result, tend not to have a brain region.
Investigating the pre-implantation stage
Dr Nicholas Rivron’s laboratory at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences, Vienna, has worked on developing embryo models to gain greater insight into the pre-implantation stage.
His group published a 2018 key paper outlining how they developed mouse embryo models using embryonic stem cells and stem cells from the trophoblast layer to create blastoids that could be implanted into the uterus of a mouse for a couple of days.
Then, in December 2021, the same team published another paper outlining how they had created embryo models to the blastocyst stage made from human pluripotent stem cells, which they had induced to become able to differentiate into different types of cells.
Speaking to MNT, Rivron said: “For the next stages of investigation, we need to actually understand how those embryos can be combined with the uterine cells, to understand the processes of implantation into the uterus and how this can develop our knowledge to solve various health challenges of family planning, fertility decline, also the origin of diseases.”
While the embryo models described in the latest paper demonstrated they had self-organised to form some structures that would go on to form the placenta, these embryo models were limited by how much further they could grow without one, said Rivron.
“The limitation is the placenta – the placenta is extremely important,” he said, due to the fact that it provides the nutrients and oxygen to the embryo that are essential for it to grow and develop further.
How far can researchers go?
The latest paper also confirmed that the very first stages of organ development, known as organogenesis, could be observed in these model embryos.
This has typically been difficult to observe, as it typically occurs in the uterus. However, by establishing a process to develop these embryo models in the laboratory, the differentiation of the cells, the genetic control of this differentiation, and the environment needed for typical development can all be studied.
The latest paper used mouse embryonic stem cells to develop the model embryos, which will require ethical approval. By contrast, human embryo research is extensively regulated.
Guidelines for this regulation are released by the International Society for Stem Cell Research (ISSCR) every five years, addressing the existence of stem cell-derived embryo models and the possibility of chimeric embryo models built using cells from different species alongside human cells.
While it may prove technically possible to grow organs using embryo models, Rivron said this may not be necessary or, indeed, ethically desirable.
He pointed instead to the development of organoids, stem cell-derived models of organ tissues that can be used to investigate cellular behaviour, and perhaps the development, of organs too.
Rivron said: “If you want to study organogenesis or create organs, the political principle is that you have to use, morally, the least problematic way of studying these,” and organoids offer a way to do this.”
Both the development of organoids and embryo models have progressed in the past five years, and their basis, new genomic approaches we can use to understand and recreate mammalian structures, are similar.
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