Organ Transplantation

In 2022-2023 it was estimated that 4600 transplants were completed thanks to thousands of donors in the UK. However, it is also estimated that 7000 people were on the waiting list, almost 1.5x the number of transplants completed. Tragically, from this, 430 died waiting for an organ last year. This is a huge issue in modern medicine that needs to be tackled immediately. The NHS are advertising the importance of being an organ donor, in May 2022 the UK introduced an opt-out system. Each country in the UK has similar legal implications surrounding this subject; which states if you are over 18 and have not opted-out and aren’t in an excluded group, you are deemed authorised for organ donation. Scotland differs a little bit whereby you are deemed authorised at 16 and assume consent if not opted-out. This has increased the donor rate by 50% in 5 years and is hoping to double in 10.

When Death Turns Into Life…

I was first interested in this subject after reading Merzrich’s When Death Turns Into Life, which discusses dilemmas of transplant surgeons as well as their breakthroughs. Reading the trials regarding xenotransplantation pricked my interest and prompted me to research further. The efforts of Keith Reemsta, a risk-taker determined to transplant primate organs into humans was particularly fascinating. One case was that of 43-year-old Jeffery Davis, who was in heart failure and end stage renal disease and could not live on short-term dialysis. Reemsta transplanted both kidneys still connected to the vena cava and aorta and treated with the available immunosuppression medication available in 1963. Davis sadly died a month and a half later from pneumonia and not rejection. Reemsta continued transplanting a further 13 patients who enjoyed 9-60 days of extended life. I respect how driven Reemsta was to move forward his research, though in 1965 this halted when chronic dialysis became available.

Primates vs Pigs?

There is evidence now that attempting to transplant chimpanzee organs is unsustainable as they are endangered, difficult to breed, have one offspring at a time, expensive to care for and exposes humans to xenoviruses due to the homology in genetics between the species. There is also an ethical debate regarding whether these animals are too much like humans, which we would raise purely to harvest organs from, where do we draw the line?

Alternatively, pigs could be used, which have more reason to be use instead, such as easy breeding, big litters, appropriate size, fair genetic homology, cheap and more socially acceptable. This is in the sense that pigs are already harvested for pork products, why could we not harvest their organs as well to help the global shortage of organs. I think this would be a major breakthrough in research. However, using pigs could cause debates from a religious standpoint, in Islamism this would be seen as a betrayal of their religion. One of the biggest issues with using pigs is the presence of alpha-gal epitope, a protein non-primate mammals possess which could lead to rejection. Since the discovery of CRISPR/Cas9, George Church has successfully generated pigs with inactivated PERV elements, causing the threat of xenoviruses to be diminished, but is still yet to get FDA-approved.

In the book there was a lovely phrase, which I believe sums up the research in xenotransplantation perfectly:

‘Xenotransplantation is just around the corner, but it may be a very long corner’ – Sir Roy Calne 1995

Below is an interesting video about why pigs should be used for future organ donation, exploring how we may be able to genetically-modify them to prevent rejection through Chimeras.

Acknowledgements

Mezrich, Joshua D. When Death Becomes Life : Notes from a Transplant Surgeon. New York, Ny, Harper, An Imprint Of Harpercollinspublishers, 2019.

NHS. “Organ Donation and Transplantation.” NHS Blood and Transplant, 2022, www.nhsbt.nhs.uk/what-we-do/transplantation-services/organ-donation-and-transplantation/.

“Organ Donation Laws.” NHS Organ Donation, 2016, www.organdonation.nhs.uk/helping-you-to-decide/organ-donation-laws/.

“Improved System of Organ Use to Save Lives.” GOV.UK, www.gov.uk/government/news/improved-system-of-organ-use-to-save-lives#:~:text=The%20opt%2Dout%20change%20to.

Mohd Zailani, Muhammad Faiq, et al. “Human–Pig Chimeric Organ in Organ Transplantation from Islamic Bioethics Perspectives.” Asian Bioethics Review, 16 Nov. 2022, https://doi.org/10.1007/s41649-022-00233-2.

The maintenance of stem cell lines

Pluripotent cells (PSC’s) are taken from adult tissue or embryonic cells, these can also be induced, known as iPSC’s. This is when the pluripotent stem cell are genetically modified to be reprogrammed. I undertook some work experience at the Sheffield Institute of Translational Neuroscience Lab, which researches Parkinson’s disease, looking at both drug discovery and how the neurodegenerative disease manifests and progresses. Within the research a big task is maintaining different cell lines for future experiments on fibroblasts, induced neural progenitor cells (iNPC’s), astrocytes and neurons; to complete this, cells must be fed with nutritional media to help them grow and split when their is overcrowding in the dish. A stem cell should have the capability of infinite self renewal and differentiation, however in the lab there was a limit for how many times this could be conducted to prevent stress and harm to that cell line. The number of times the cells are split are called ‘passages,’ there was a rough limit of 15 passages per cell line. To ensure continuation of the line for the future, a spare dish is always kept frozen from the splitting process. Some cells used in the lab are brought in already modified for experimentation but other cells needed to be reprogrammed and grown in the lab, this aspect I got to observe during my visit for neuron cells. This entailed harvesting fibroblasts from the skin of a Parkinson patients and control patients with wild type cells which are exposed to a virus. The virus alters the genetic makeup of this cell to allow for differentiation into iNPC’s and eventually into neurons. This process can take anywhere between 2 weeks and 8 months to occur.

The picture on the LHS shows imaging of a stained Fibroblast, this is how the cells will look at start of the reprogramming process. The picture of the RHS shows a view down the microscope of neuronal cells, this is how they should look once reprogramming is complete, new cell lines can be taken and grown from this. Note: if the neuronal cells are taken from a Parkinsons patient they will be induced dopaminergic neuronal cells.

The legality…

There are legal implications with the use of stem cells in the UK, this varies from country to country, whereby scientists need to obtain permission from the governing body, ‘Human Fertilisation and Embryology Authority’ (HFEA) in order to use them. Lawyers, Clinicians, Scientists and Ethicists will determine if the use of that stem cell line is appropriate or not, if granted, regulations require these cells to be stored in the Stem Cell Bank. This bank enables all cells to be overseen, and allows researchers to use existing stem cells if given approval. Here is a link to the UK Government website explaining in detail the protocols put in place in the UK with regards to stem cells.

Ethical dilemmas…

There are many ethical dilemmas surrounding iPSC’s and the regulation of them. iPSC’s are very powerful having the ability to be taken as a fibroblast from the skin and reprogrammed into any cell type including, an egg or a sperm cell, these have been used to create mouse embryos which can develop into fully grown mice. This raises many questions including the implications of this experiment if it was to be conducted on humans in the future, the ownership of the cells – do they belong to the researcher or the donor? Should iPSC’s be used over embryonic stem cells?  Debates are still occuring to determine answers for these questions and come up with a sytem for monitoring embryonic stem cells and induced pluripotent stem cells looking at the benefits and challenges which come with each.

Accreditation:

Hirai, Takamasa, et al. “Country-Specific Regulation and International Standardization of Cell-Based Therapeutic Products Derived from Pluripotent Stem Cells.” Stem Cell Reports, vol. 18, no. 8, 1 Aug. 2023, pp. 1573–1591, www.ncbi.nlm.nih.gov/pmc/articles/PMC10444560/, https://doi.org/10.1016/j.stemcr.2023.05.003.

“Ethics.” The University of Edinburgh, 2 Aug. 2021, www.ed.ac.uk/regenerative-medicine/about/ethics.

“Sheffield Institute for Translational Neuroscience.” Www.sheffield.ac.uk, 10 May 2023, www.sheffield.ac.uk/sitran. Accessed 8 Mar. 2024.