Chimeras—Growing Human Organs Inside Pigs

Shinjini Bandopadhyay, Amity University Kolkata

In Greek mythology, chimeras were hybrid creatures; part lion, part goat, part snake. Now chimeras can be simply defined as animals made up of cells of two separate zygotes. Chimeric animals have more than one set of parents. 

Chimeras can be built in two ways; the first is to introduce the organs of one animal into another—for instance, some labs have used pig lungs to filter human blood. However, there is a risk because the host’s immune system may reject the transplanted organ.

The second method is to begin at the embryonic level by introducing one animal’s cells into the embryo of another and allowing them to grow together into a hybrid.

These hybrids can be intra-specific in which case two embryos of the same species fuse at early stages to make a single embryo, or they are inter-specific like in human/non-human animal chimeras.

The latter involves combining human stem cells with a non-human species for various purposes: 

• studying the resultant animal as disease models 
• researching the proliferation potential of human stem cells 
• providing a platform for clinical drug testing 
• establishing a new method of producing human donor organs

Pluripotent stem cell (PSC) research has relied upon chimeras to examine all these but the most exciting discovery has been building human organs inside non-human animals. This deals with inter-specific chimeras.  

How Are Inter-Specific Chimeras Born?

Pluripotent stem cells can differentiate into all cell types; introducing human PSCs inside the early blastocyst of a developing non-human embryo allows these stem cells to now incorporate themselves into the growing blastocyst and divide alongside the host cells.

Successful integration of human cells into host embryos leads to the formation of a chimeric animal with cells from two different species. 

Previous studies have described a phenomenon called the ‘blastocyst complementation approach’ in which the host embryo has a mutation in a key regulatory gene important for directing the development of the desired organ.

Without scientists intervening, the animal would most probably die due to the absence of that organ. However, studies showed that human PSCs added at the blastocyst stage could somehow sense this deficiency and be directed to form the missing organ and produce a completely functional organ.

This was first discovered in mouse/rat chimeras where a mutation of the pancreas-determining Pdx1 gene was observed in a rat host. A fully functional rat-sized pancreas was seen to form from mouse PSCs inside the host, indicating that signals from the rat were able to determine organ size and function. The mouse pancreases grown inside rats also successfully treated diabetes when parts of the healthy organs were transplanted into diseased mice.

Scope for Human Organ Transplants

The most promising potential of the use of human PSC/non-human animal chimeras is the future possibilities of generating entire human organs that can grow and survive inside the host animal. Human organs are in short supply and there is a great demand for new sources of transplantations.

To build a human-sized organ, a larger host is required and recent studies show chimera formations with human PSCs are placed inside pig or cattle blastocysts. 

A team of scientists at Salk Institute’s Gene Expression Laboratory discovered that pigs had notable similarities to humans; their organs looked a lot like human ones although pigs have a longer gestation period.

Slightly developed human PSCs were injected into the pig embryos and the embryos survived. They were then transferred into adult pigs which carried the embryos between 3-4 weeks before they were removed.

In total, the team created 186 late-stage chimeric embryos that all survived.

There has been great progress in using human PSCs to start working towards building human organs in other species, most commonly in pigs. However, several ethical issues are surrounding the creation of chimeric animals and they may halt the possibilities of drastic experimentation with chimeric transplants in the near future. 

Also read: FGFR1-targeted kinase inhibitors can now help in treating breast cancer

Reference(s):

The Contribution Of Human/Non-Human Animal Chimeras To Stem Cell Research, Sonya Levine, Laura Grabel, 2017 Sept 14, Stem Cell Research Volume 24 Pages 128-134 DOI https://doi.org/10.1016/j.scr.2017.09.005

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