The University of Southampton

Author: Abigail Whitehead

Organ Factories: human-animal chimera donors

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Mentioning chimeras tends to evoke images of the mythical monster, part lion, part goat, part snake. When human chimeras – someone whose cells are derived from two or more zygotes – were introduced at the beginning of the lecture series I wondered, given the difficulty we have preventing organ rejection after transplants, how do chimeras avoid it? Simply put, the immune system develops recognizing both sets of antigens as self but while looking for an answer I came across this:

“fetus bodies as living factories for organ generation”

It was a jarring turn of phrase in a section talking about the potential of growing humanized organs in surrogate animals. As an idea I knew very little about it seemed like a promising concept but my own alarm at that phrasing prompted further reading. A brief outline of the process is given the diagram.

Making human organs in interspecies chimeras using blastocyst complementation. Human cells (teal) are added to edited pig (purple) blastocysts. These are genetically modified to be incapable or growing a particular organ. The human pluripotent cells can integrate into the modified pig blastocyst to make the missing organ. The blastocyst is then implanted into a surrogate. When mature the organ produced in the chimeric animal can be transplanted into the human cell donor (patient).
Image from Brown et al A Technological and Regulatory Review on Human–Animal Chimera Research Creative Commons Attribution Non Commercial 4.0 License

Why do we need to grow organs?

Before I go further into chimeric organs and the concerns raised by them, the problem this technique aims to solve should be described. This March there was around 8000 people waiting for organ donation in the UK. Between 1 April 2021 and 31 March 2022, 429 people died while on the transplant waiting list. Medical care and safety systems are improving which may reduce the number of donors (who are usually deceased). Other methods for reducing this shortage –therefore other competitors for funding – include expanding the donor pool and increasing the utilisation of less ideal donors but this can reduce the success of transplants.

So humanised organs from chimeras could bridge this gap and hold the potential to solve the problem that brought my attention to chimeras in the first place: immune rejection. Anti-body mediated rejection can cause organ transplants to fail when the recipient’s immune system detects the donor organ as a foreign body and attacks it. In chimera donors the organ is grown from induced pluripotent stem cells of the patient so should possess the same antibodies and not be rejected. Sounds good so far…

But whereas human donors (or their relatives) make an informed decision on whether to donate, chimera donors would involve creating, growing and killing animals to produce human organs. A multitude of animals are already raised and slaughtered for the food industry though this is not without contention.

Ethical issues

Concerns raised include issues surrounding identity, transspecies infection, economic considerations and the allocation of pig vs. human organs. The latter is a fascinating conundrum whose shape will depend on comparative efficacy and cost of the two methods. Will chimera organs be the cheap second tier option or the premium and should either scenario be allowed? There is also concern that giving pigs human cells could confer enhanced cognitive abilities that allow pigs human-like thought.

The technology is not ready yet so will require further time and funding that could be allocated to, for example, preventative treatments. A heart xenotransplant has been attempted that used a pig edited with human genes -not whole human stem cells- that aimed to reduce the immune response inserted but the heart was rejected.

Conclusion

Chimeric organ donation has the potential to alleviate human suffering but at the cost of animal welfare, sparking debate. Emotional responses against chimeras may be rooted in the monstrous associations of the name itself and expressed as going against nature. From a consequentialist view the benefit to humans could outweigh the exploitation of animals but developing the technology will involve considerable risks to people. While researching this my opinion has swung between for and against but settled on cautious support for chimeric organs.

3D Bioprinting

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Press a button, print an organ. Perhaps the idea is not as Sci-Fi as it sounds. 3D bioprinting is an advancing field that uses layer-by-layer positioning of cells and biomaterials to produce living scaffolds for a variety of uses.

Depending on the qualities needed in the final product, techniques and materials vary. All start with a digital 3D model produced using computer aided design (CAD) software. One powerful feature of this is that CT and MRI scan data from patient can be used to tailor, for an example a tracheal graft, to personalised dimensions.

Next, the structure can be bioprinted using a bioink. Things to consider when choosing a bioink are the cells, biomaterial and growth factors included. Biomaterials such as alginate and polyvinyl-alcohol provide a structural scaffold for new cells to grow on. The ideal biomaterial must be biocompatible (not trigger an immune response) and biodegrade at the same rate as the new tissue grows.                                     

Cells and growth factors goes hand in hand, to print a bone graft you would use mesenchymal stem cells and a corresponding growth factor or chemical that encourages the pathway of differentiation looked for. The bioink used can dictate the printing method. Three popular approaches include inkjet-based, laser assisted and extrusion-based bioprinting. Each has their own set of opportunities and challenges.

Inkjet bioprinting uses the bioink droplets deposited by a piezoelectric actuator. Laser-assisted uses an a donor layer than absorbs energy from laser stimulation with a bioink layer underneath it and a collecting layer to form the tissue constructs. Extrusion uses mechanical force to deposit a continuous cylindrical stream of bioink.
Mechanisms of 3D bioprinting: Adapted from an image by Loai et al, licenced under Creative Commons Attribution 4.0 International License from https://doi.org/10.20900/rmf20190004

Inkjet

Droplets of bioink, generated either through heating or a piezoelectric effect, are deposited on the substrate. High throughput, high resolution, low expense and strong cell viability count in favour of this technique. The key drawback is the need for low viscosity bioink to pass through the fine nozzle which results in low structural quality.

Extrusion

If a strong structure is a priority then extrusion printing comes to the fore. It relies on pneumatic or mechanical force to print uninterrupted lines of a far more viscous bioink. However, the increased shear stress involved reduces cell viability. High viscosity bioinks tends to result in lower resolution and the process is much slower.

Laser assisted

This uses a laser induced forward transfer technique (LIFT) which means that a laser is used to force material from a thin donor layer of bioink onto the substrate being printed onto. Advantages of this include high cell viability as there is no direct contact between the bioink and the dispenser so no stress forces and that the technique is compatible with a wide range of bioink of varying viscosities. Unfortunately, the complexity of this method results in high equipment cost.

Potential Uses

  • Organ replacement
  • Tissue grafts such as skin, bone muscle and cartilage
  • Organs on a chip – used for drug and vaccination screening
  • Drug delivery scaffolds
  • Building disease models

Moving Forward

Printing organs for those currently awaiting a donor remains science fiction for now but great progress is being made towards that goal. However, even this is just the start as ethical considerations need to be made.

Integral to the whole process are stem cells and their source. The ethics of stem cells use are hotly debated but the alternative, induced pluripotent stem cells, are associated with more unpredictable behaviour.

Safety and quality control of bioprinted organs need to be considered, and this is made harder personalisation of treatment which reduces replicability of results. Arguably, for a terminally ill patient the benefits of an untested treatment outweigh the risk, but can this then be applied to non-life-threatening cases?