Scientists from the Guangzhou Institute of Biomedicine and Health, in China, together with the Spanish doctor Miguel Ángel Esteban, have managed to obtain for the first time a rudiment of a human organ in an animal (chimeras), according to the prestigious scientific journal Cell Stem Cell.
Specifically, a type of rudimentary kidney has been generated, an intermediate phase of the renal system called mesonephros. To do this, researchers have used human induced pluripotent (iPS) cells. These cells are obtained by reprogramming adult human cells in the laboratory to a state similar to the embryonic one, so that they regain the ability to form different types of tissues and organs.
Human iPS cells have been introduced into pig embryos that are just a few days old. To ensure that human cells direct their efforts to generate a kidney, and not another organ, genetically modified pig embryos have been used to inactivate two genes relevant to the formation of the porcine kidney (SIX1 and SALL1). Thus, the pig cells were incapable of developing a kidney, leaving a niche that human cells have occupied relatively effectively. The embryos have been gestated in sows for up to 28 days, a quarter of the pregnancy time in pigs, after which they have been extracted for analysis.
Spanish researcher Juan Carlos Izpisua, who carried out pioneering research in this field, considers that “It goes a step further and shows that cells can be organized in space and give rise to organized tissue structures.” “It has not yet been possible to develop mature humanized organs in pigs, but this study brings us one step closer.” (Source: El País)
Previous research, such as Izpisua’s outstanding paper published in 2017, only achieved a small percentage of human cells in animal embryos. The novelty of the current publication is that the closest thing to the generation of a human organ in an animal has been achieved to date. However, as the authors of the work point out, there is still a long way to go to resolve a series of obstacles.
Thus, many pig embryos do not survive the chimerization process, and it remains to be determined whether this is related in part to chimerism itself, which involves a mixture of cell lineages from different species with the difficulties of coexistence that this implies, or to any other aspect of the developed procedure.
Furthermore, it is important to consider that organs are made up of multiple types of cells, including vascular cells, which are essential for normal functioning and when performing a transplant could cause immunological rejection in the recipient if any were of porcine origin.
Therefore, it is necessary to continue advancing until the simultaneous suppression of the development of different tissues (for example, kidney and endothelium) in pigs is achieved and the different “niches” are occupied by human cells.
The results obtained in the new research indicate that in the future it could be possible to generate a functional human kidney in pigs, offering an alternative to try to solve the shortage of human organs for transplants. In this regard, as recently published, xenotransplantation to humans of porcine organs, genetically modified to reduce antigenicity, has shown significant advances in the short term, but it has not yet been possible to completely avoid immune rejection.
Furthermore, physiological differences between humans and pigs can cause organ dysfunction after transplantation. Therefore, progress in the field of human-animal chimeras is very promising from a medical point of view.
However, development in this field raises different ethical problems of notable seriousness, including the use of embryonic stem cells in experiments and the possibility of chimeric animals developing human-like qualities, particularly in the face of possible proliferation of human cells in the animal brain.
In this sense, the study we are discussing does not use embryonic stem cells, but rather iPS, which is an ethical advantage over other similar research. As for the human contribution to the animal brain, the study shows that very few human cells were dispersed throughout the brain and spinal cord of the pig embryos. ““To eliminate any kind of ethical problem, we are further modifying the human cells so that they cannot go to the pig’s central nervous system in any way”says Esteban.
The nephrologist Rafael Matesanz, founder and former director of the National Transplant Organization, was one of the members of the committee that authorized Izpisua’s experiments in Murcia. In his opinion, it is “doubtful” that a trial like the one now carried out in Guangzhou would be approved in Spain, due to the possibility that some human cells colonize the brain of the pig embryo, as has actually happened. “The major risk is for the cells to go to the central nervous system and produce a human-pig. Or for them to go to the reproductive system, [which poses the same risk],” he warns. “[These experiments are geared] toward China, which has much laxer legislation than [Europe] and the United States,” says Matesanz.
Lucía Gómez Tatay
Bioethics Observatory – Institute of Life Sciences
Catholic University of Valencia