Stem Cell Therapy: Retinoblastoma and Acute Lymphoblastic Leukemia

Stem cell therapy (SCT) is the use of stem cells to prevent or treat a condition or disease. This is
possible due to their unique properties; stem cells have the ability to self-renew, referring to the ability for a cell
to undergo mitotic division while maintaining the same undifferentiated state as its parent cell (Lin et al., 2013).
Stem cells are also able to differentiate into different cell types, having potency, derived from the Latin term
meaning “have power”. They are categorized in hierarchical order based on their degree of potency: totipotent
(able to differentiate into all tissue types, stemming from the human embryonic stem cell (hESCs)), pluripotent
(can differentiate into cell types in an adult), and multipotent (restricted differentiation into certain lineages of
adult tissues) (Lin et al., 2013). hESCs are totipotent, which are often used in various forms of SCT. Stem cells
in bone marrow are an example of pluripotent stem cells, differentiating into the different components of blood
(Lin et al., 2013). Examples of multipotent stem cells include hematopoietic or blood-forming stem cells
(HSCs), neural stem cells (NSCs), and epithelial stem cells (EpSCs), characterized by their anatomical location.
Hence, SCT can be used to treat and study conditions like Retinoblastoma (Rb) using totipotent hESCs and
Acute Lymphoblastic Leukemia (ALL) using pluripotent bone marrow stem cells.

Retinoblastoma (Rb) is a congenital malignant tumor of the retina. Common in young children, the
earliest evidence of the tumor is a white reflex in the pupil (leukokoria) and strabismus, or misaligned eyes. It is
presumed to arise from photoreceptor elements in the retina (Wong & Dornan, 1982). The incidence rate of Rb
is 1 per 17,000-24,000 live births, and is often treated with high-dose chemotherapy (HDCT) followed by SCT.
This has a high efficacy, with 67.5% of patients having no evidence of disease after treatment (Clarissa et al.,
2021). HDCT is used because Rb is chemosensitive, however it HDCT exacerbates bone marrow suppression,
so SCT using hESCs and bone marrow rich in HSCs is used to compensate (Clarissa et al., 2021). Rb treatments
involving stem cells have also been developed to be genetically engineered. Scientists at Wenzhou Medical
University developed a way to use genetically engineered hESCs to develop retinal organoids (Liu et al., 2020),
contrasting the more common forms of SCT; in this case, they can investigate the biallelic mutation of the RB1
gene causing Rb, developing stem cell treatments and technology for those with the gene (Liu et al., 2020).
ALL is a rare, hematological malignancy of bone marrow caused by blocked precursor lymphoblasts during
early cell differentiation (Katz et al., 2015). These lymphoblasts proliferate and impede hematopoietic cells,
causing symptoms like bleeding and shortness of breath. The incidence of ALL peaks in children around 1-4
years old (Katz et al., 2015). A bone marrow transplant is a form of SCT used to treat the disease, replacing
infected tissue with healthy donor tissue (Antman, 1996). Stem cells are collected from the patient and a
genetically compatible donor, often a sibling. After cancer treatment, these donor pluripotent HSCs are injected
into the bloodstream, settling in bony cavities to replenish bone marrow (Antman, 1996). This is referred to as
an “allogeneic transplantation”, accounting for the majority of ALL treatments with SCT (Antman, 1996).
HSCs are also sometimes derived from the placenta and umbilical cord of a newborn baby who is a match,
referred to as “cord blood transplants” (Antman, 1996).

The main criticism of the use of embryonic stem cells for treatments, like those used for Rb and ALL are
the ethical issues. Many critics question the morality of using human embryos for research, like in the
development of organoids to Rb, as well as the laboratory fertilization of embryos for the sole purpose of
destruction, both for research and transplantation (Solbakk & Holm, 2008). Like in ALL treatments, hESCs are
often used. They are derived from blastocyst stage embryos, 5-7 days after fertilization, posing a moral dilemma
when contemplating whether the destruction of embryos is ethical even for lifesaving purposes (McLaren,
2007). These issues are relevant on an international scale. Many European countries have completely banned
ESC research, and scientists in these countries must import ESCs from other countries where derivation is legal.
Scientists, doctors, and the media are often criticized for using an arguably unethical method to derive these
cells, and also criticized for eliciting false hope in victims of disease, as many clinical trials, like Rb trials, take
time and sometimes do not yield effective results. This reiterates the moral conflict of performing “unethical”
experiments, especially considering they may be unsuccessful (McLaren, 2007).
 References

Antman, K. (1996). When Are Bone Marrow Transplants Considered? Scientific American, 275(3), 124–125.

Clarissa, A., Sutandi, N., Abdul Fath, A. (2021). Stem-Cell Therapy Following High-Dose Chemotherapy in
Advanced Retinoblastoma: A Systematic Review. Asia-Pacific Journal of Ophthalmology, 10(4),
297-407.

Katz, A. J., Chia, V. M., Schoonen, W. M., & Kelsh, M. A. (2015). Acute lymphoblastic leukemia: an
assessment of international incidence, survival, and disease burden. Cancer Causes & Control, 26(11),
1627–1642.

Lin, H.-T., Otsu, M., & Nakauchi, H. (2013). Stem cell therapy: an exercise in patience and prudence.
Philosophical Transactions: Biological Sciences, 368(1609), 1–14.

Liu, H., Zhang, Y., Zhang, Y.-Y., Li, Y.-P., Hua, Z.-Q., Zhang, C.-J., Wu, K.-C., Yu, F., Zhang, Y., Su, J., & Jin,
Z.-B. (2020). Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin.
Proceedings of the National Academy of Sciences of the United States of America, 117(52),
33628–33638.

McLaren, A. (2007). Science and ethics of stem cell research. Current Science, 92(4), 424-425.

Solbakk, J.H. & Holm, S. (2008). The Ethics of Stem Cell Research: Can the Disagreements Be Resolved?
Journal of Medical Ethics, 34(12), 831-832.

Wong, D. L., & Dornan, L. R. (1982). Retinoblastoma. The American Journal of Nursing, 82(3), 425–431.