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Health and Disease

“Saviour Siblings”: Taking a look at PTT

“Saviour siblings” have conjured up a controversial debate between scientists, with many critical of its potential. In this article, I explore this technology and whether it should be considered using.

By Asmita Anand

Published 2:05 EST, Sun October 3rd, 2021

What are Saviour Siblings?

A saviour sibling can be best described as a child created using IVF and genetic diagnostics. They will provide an organ or cell transplant for a sibling who is critically ill and suffering from a fatal disease.

For certain diseases, a human leukocyte antigens identical stem cell transplant can be the only treatment. While stem cell therapy is a very attractive option, finding a donor can be a challenge.

The Technology Behind Saviour Siblings

Preimplantation tissue typing (PTT) is a technology that allows us to test and select embryos in order to treat children in need of stem cell transplants. PTT is also sometimes called HLA tissue typing. Preimplantation HLA typing is a great solution for children requiring stem cell transplants. It is a common treatment used to treat blood diseases such as thalassemia, sickle cell anaemia, and malignant diseases such as leukaemia and lymphoma. [1]

PTT or PGD-HLA was first introduced clinically in 2001 to treat Fanconi Anaemia (FA), a rare but serious genetic disorder that mainly affects the bone marrow. [2] For conditions such as Fanconi anemia, the only treatment option is bone marrow transplantation, which will restore hematopoiesis. Due to the high rate of transplant-related mortality, using HLA identical cord blood transplantation is increasingly attractive. It will help avoid complications and produce a better outcome. PTT provides realistic hope as a radical treatment option for those suffering from congenital and acquired bone marrow failures. FA is the first disorder in which cord blood stem cell transplantation has been performed.

The Procedure

By selecting embryos for the new sibling, we can ensure that the new sibling can provide an exactly matched tissue donation to the child suffering from the life-limiting disease, and hence act as a saviour. Apart from serving as a donor of pluripotent haematopoietic stem cells, the new sibling will also be screened for the same disease through preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) is used when either one or both parents carry a known genetic mutation and seek to transfer a non-affected embryo. [3] It involves the analysis of artificially fertilised embryos in order to find one with the desired genotype. [4] Preimplantation genetic testing for monogenic disorders (PGT-M) combines both in vitro fertilisation (IVF) in conjunction with PTT.

PGT-M is a standard biopsy procedure performed on cells from a blastocyst embryo. It will also determine whether the embryo has the same inherited genetic mutation that has caused the life-limiting disease in the older child. It is done by testing for the single gene mutation associated with the disease.

The first step would be to create an embryo through IVF treatment. IVF involves the following steps: ovarian stimulation, oocyte retrieval, sperm retrieval, and fertilisation. During IVF, the egg retrieved from the uterus will be fertilised with sperm in a laboratory to produce a zygote. After IVF, the embryo biopsy will be prepared by removing a small number of trophectoderm cells (layer of cells on the outer edge of the blastocyst). While testing occurs for any abnormalities, the embryos will be frozen and preserved for implantation.

Once you find out the results of the biopsied cells, you can then select an embryo free from the same life-limiting genetic disease and simultaneously also a tissue match. This is vital so that the umbilical cord blood of the new sibling can provide stem cells to treat the existing sibling who has the disease.

These unaffected embryos will then be assessed for their HLA compatibility with the sick sibling to find a tissue match. Then, the unaffected and tissue-matched embryo will be ready to be transferred to the woman’s uterus. Once the new sibling has been born as a viable donor, the umbilical cord blood will be taken and used for hematopoietic stem cell transplantation. Umbilical cord blood is a great source of hematopoietic stem cells(HSCs) and has a higher concentration of HSCs than adult blood. These multipotent HSCs will then be used to treat the existing sibling.

Should it be used? Ethical considerations, benefits, and risks

PGT-M is a technically demanding procedure and involves the use of highly specialized molecular biology techniques. [5] Many arguments favouring and condemning PTT are based on the welfare and commodification of the donor sibling. [6]

Many who are against PGD may view it as selective breeding and “reproductive discrimination.” However, it is important to note that PGT-M currently cannot be used to select embryos for ‘designer babies’ as we are still not capable of scientifically determining certain characteristics. It is only used to test for a single genetic mutation.

Another common protest is that the donor baby may not be born for the right reasons and is used as a “medical commodity.” It’s vital to consider the reasons and intention of the parents to have another child. For some, this new baby may not act as a burden as they genuinely wish to have more children. But for others, the same cannot always be said as it’s difficult to gauge the parent’s true motives.

It is also reasonable to question whether individuals should be able to select an embryo simply on the basis that the child born may be the source of life-saving therapies for a sibling.

PGT-M also can be considered ethically problematic, considering affected embryos will be discarded. For some, this is not an issue as they are discarded at a very early stage of development and aren’t as severe as terminating a pregnancy at a later stage. PGD provides the advantage that difficult decisions to terminate a fetus are removed since only tissue-matched embryos will be implanted in the mother’s uterus.

Aside from ethics, we need to also consider the practicalities and other effects of the procedure. Down the line, it can potentially cause psychological effects on the saviour sibling as it may have only come into existence to save their older sibling. Furthermore, there can also be an emotional impact on other family members, along with risks imposed on the mother during the ART (Assisted reproductive technology) cycle. [7]

We also need to consider to what extent the saviour sibling is really “saving” their older sibling. Are cells being removed from the umbilical cord and blood, or is bone marrow or an organ being taken? It’s obvious that removing an organ would cause much more damage to the donor sibling, showing that the spectrum the treatment can cover poses its own issues as to whether it can qualify as ethical. Moreover, it opens up the question of how far we will go with this technology. Because it is reassuring that there are existing strict policies and regulatory frameworks for most genetic biotechnology groups, it is unlikely the technology will be misused, and harm to the donor sibling will be minimised.

Lastly, it is also expensive. The procedure itself is costly and can present another limitation, especially if more than one treatment cycle is necessary before a match and the unaffected embryo is found and pregnancy is achieved.

On the other hand, you could also argue that the care and treatment for a disease long-term are costly, and the procedure may end up being less expensive overall, provided that the treatment works. Not only this, but the child will be free of the disease and won’t suffer anymore.

In summary, PGT-M is highly valued when it succeeds despite its complexities and has been described as “a triumph for common sense.” [4]

Conclusion

PGT-M is an evolving technology, which means there are still more improvements that can be made. This ranges from the current protocols in place to databases containing more thorough information on the outcome of the procedure.

At the moment, we are also facing both technical and biological limitations to the PGD-HLA procedure’s success. These include the limited outcome of finding a suitable embryo and the low rates of live births after using IVF and ART. [7] However, we can improve such limitations by rectifying the issues behind this low IVF success rate (e.g., obtaining better-quality oocytes for biopsy and PGD).

Overall, PTT offers the opportunity to save a life and is something which I believe can be an amazing tool, provided there are no indications for it to cause harm to all members involved and that it is used for the right intentions. Personally, if I grew up knowing I’d saved a life, especially my sibling’s, I would be overjoyed the minute I was born!

Asmita Anand Youth Medical Journal 2021

References

[1] Preimplantation Tissue Typing. (2019, February 16). IAKENTRO. https://en.iakentro.com/assisted-reproduction/preimplantation-genetic-control/preimplantation-tissue-typing/

[2] Verlinsky, Y. (2001). Preimplantation Diagnosis for Fanconi Anemia Combined With HLA Matching. JAMA, 285(24), 3130. https://doi.org/10.1001/jama.285.24.3130

[3] Preimplantation Genetic Diagnosis, What is PGD – Testing Services. (2016, May 3). Houston Fertility Institute. https://www.hfi-ivf.com/your-treatment-options/genetic-testing/preimplantation-genetic-diagnosis

[4] Boyle, R. J., & Savulescu, J. (2001). Ethics of using preimplantation genetic diagnosis to select a stem cell donor for an existing person. BMJ, 323(7323), 1240–1243. https://doi.org/10.1136/bmj.323.7323.1240

[5] O. (2019, August 8). Pre-implantation Genetic Diagnosis (PGD) – ORH Fertility Clinic. Overlake Reproductive Health. https://fertileweb.com/reproductive-medicine/pgd/

[6] Liu, C. K. (2007). ‘Saviour Siblings’? The Distinction between PGD with HLA Tissue Typing and Preimplantation HLA Tissue Typing. Journal of Bioethical Inquiry, 4(1), 65–70. https://doi.org/10.1007/s11673-007-9034-9

[7] Traeger-Synodinos, J., Kakourou, G., Destouni, A., & Kanavakis, E. (2013). Eleven years of preimplantation genetic diagnosis for human leukocyte antigen matching: is there room for improvement? Expert Review of Hematology, 6(3), 215–217. https://doi.org/10.1586/ehm.13.29

Pre-implantation tissue typing (PTT) | Human Fertilisation and Embryology Authority. (n.d.). HFEA. Retrieved 7 August 2021, from https://www.hfea.gov.uk/treatments/embryo-testing-and-treatments-for-disease/pre-implantation-tissue-typing-ptt/

I. (2020a, November 25). Embryo Testing: The Difference Between PGT-A and PGT-M. IGENOMIX – With Science on Your Side. https://www.igenomix.com/blog/fertility-challenges/embryo-testing-difference-pgt-and-pgt-m/

Kuliev, A. (2014). Preimplantation HLA typing: Practical tool for stem cell transplantation treatment of congenital disorders. World Journal of Medical Genetics, 4(4), 105. https://doi.org/10.5496/wjmg.v4.i4.105

In vitro fertilization (IVF) – Mayo Clinic. (2019b, June 22). Mayoclinic. https://www.mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716

Kuliev, A., & Rechitsky, S. (2016). Preimplantation HLA typing for stem cell transplantation treatment of congenital and acquired bone marrow failures. Hematology & Medical Oncology, 1(2). https://doi.org/10.15761/hmo.1000108

A. (n.d.). Embryo HLA Typing. British Cyprus Fertility Hospital. Retrieved 7 August 2021, from https://www.cyprusivf.com/embryo-hla-typing/

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