ABSTRACT:
Stem cells are found in the human body during various stages of life. Due to their undifferentiated nature and unique characteristics, stem cells are viable therapies for a large number of chronic illnesses. The field of stem cell genomics is coming into prominence as a means of making stem cells as effective as possible. Leukaemia, a type of blood cancer, is a chronic illness; patients with this disease could greatly benefit from the novel treatments that stem cells provide. This paper discusses stem cells and the field of stem cell genomics, along with the applications of stem cells, current and future literature, and suggestions for future research.
KEYWORDS:
Stem cells, genetics, genomics, leukaemia.
INTRODUCTION:
It is important to begin this paper by defining certain key terms. Stem cells are unspecialised cells, often collected from sources such as the umbilical cord. They are becoming more prevalent in modern science because of their ability to help the body fight against malignant and non-malignant diseases.[1] Genomics is the study of the human genome and its relations to the environment.[2] STEM cell technology is a new field that combines the study of cells and stem cells with the study of genetics and its applications in the real world.[3] STEM cell genomics is a field that studies the genetics behind stem cells.
Because stem cells are unspecialised (meaning that they are not formed to perform a particular function) and because they are able to quickly and effectively divide to replace lost or carcinogenic cells, they are an emergent therapy for cancers like leukaemia.[4] Leukaemia is often named one of the deadliest cancers and causes hundreds of thousands of deaths each year. It affects the bone marrow and blood cells, can spread extremely quickly, and can end up affecting multiple organs because it does not concentrate or originate in any particular area. This also makes treatment for leukaemia more difficult than other cancers; since it is not necessarily contained, it is difficult to perform targeted treatments. Additionally, large amounts of radiation or chemotherapy drugs aimed at killing all leukaemia cells can greatly damage the bone marrow, leading to a decreased production of healthy blood cells and dangerous complications due to a shortage of blood cells.[5]
Due to complications with other therapies, stem cell transplants are becoming a more prevalent treatment for leukaemias. The transplant occurs in the bone marrow, which allows for the replacement of cancerous cells with healthy bone marrow cells that can produce healthy blood cells and help reverse the adverse effects of leukaemia on the body.[4] Allogeneic stem cell transplants are made possible by donors (often close family members) that have bone marrow tissues similar enough to the patient’s, such that they will not cause a negative reaction. [6]Alternatively, a portion of the patient’s healthy stem cells can be harvested and frozen, then re-infused into the body after chemotherapy and a ‘purge’ of leukaemia cells. This is called an autologous transplant and is usually a last resort when a donor cannot be found.[7]
The connection between leukaemia, stem cells, and genetics is stronger than one may think. Most predispositions to cancers are genetic, and the field of genetics is used to determine which patients are at a higher risk for leukaemia in general, or for a more malignant form of cancer. There are many different types of stem cells, and they all have differing properties. Researchers have been able to create stem cells in the lab, and the genomics of stem cells have greatly affected the process. Testing the genetic properties of stem cells is important because they are unspecialised and are more prone to genetic abnormalities[8], which can cause issues when they are used as therapies against diseases. Checking the genomic health of stem cells allows researchers to avoid such issues and to ensure their ideal performance in a clinical setting.
Stem cell genomics can have applications in future, such as more effective treatments against leukaemias. This paper will explore the currently available treatments, future innovations, and the process that will allow stem cell research and the field of genomics to fuel extensive research into an emergent, effective, and crucial new cure for leukaemia.
DISCUSSION- THE CURRENT SITUATION:
Currently, there are limitations regarding what we can do with stem cells due to the lack of knowledge and research. However, significant strides have been made. There are multiple different types of stem cells. Adult stem cells are stem cells that are already differentiated (meaning that they carry out a function specific to where they are located in the body) and are able to renew damaged tissue when transplanted. These cells are also often called somatic stem cells. On the other hand, embryonic stem cells are cells taken from the blastocyst and are the result of in vitro fertilisation. They are able to become almost any type of cell in the body, as they are harvested at a very early stage of development. Lastly, induced pluripotent stem cells are cells that are created by researchers in a lab setting, created by introducing embryonic genes to an adult stem cell and essentially changing the cell from a differentiated adult cell back to a stem cell that can be used to regenerate tissue.
Stem cell research encompasses stem cell therapy, drug discovery, and the modelling of diseases. Stem cells have been used in multiple clinical trials to replenish damaged tissue in spinal cord injuries, macular degeneration, and more. In 2015, AST-OPC1 cells were tested in a clinical trial against spinal cord injuries. [1] The cells were given to patients with neurologically damaging spinal cord injuries, in increasing doses, to test their efficacy against such injuries. The cells were deemed effective enough to become an FDA-approved treatment for cervical spinal cord injuries. Similarly, hESC and hiPSC were used in clinical trials to test stem cell efficacy against macular degeneration[9], a (currently) incurable eye disease often beginning in old age and caused by the deterioration of the retina, resulting in progressively worsening vision loss. The idea behind the trial was to use stem cells to ‘rebuild’ the eye tissue that was destroyed by the disease. Although we do not have clear results from the study as of yet, results look promising.
Stem cells are also being used to combat large-scale diseases that plague hundreds of thousands of patients, such as heart disease and diabetes. In terms of diabetes research, hESC and iPSCs are being used to develop insulin-producing cells and to provide biological vehicles to deliver diabetes drugs into the body. In type 1 diabetes, islet cells that produce insulin (found in the pancreas) are attacked by the body, leading to a reliance on insulin injections to stay healthy. Cell replacement therapy, made possible by stem cells, allows for a potential therapy for type-1 diabetes without a lifelong reliance on often expensive insulin injections.[9] Human pluripotent stem cells are able to regenerate and create different types of cells. They are currently being used to create glucose-responsive beta cells that are similar enough to those found in the human body to replace them altogether in patients with diabetes.[9] Stem cell-derived biological markers are being transplanted into the human body to help increase progress for patients with heart failure. Additionally, hESC are being used in emergent cancer ‘vaccinations’ in clinical trials aimed at combating lung cancer.[9]
In the field of stem cell genomics, researchers are analysing the genomes of stem cells to collect data for future applications in gene editing and gene therapy.[10] This will make the process of stem cell transplants easier and will help facilitate the increased prevalence of stem cells in a clinical setting, particularly relating to chronic illnesses such as leukaemia.[10] Haematopoietic stem cells (HSCs) are being used in stem cell transplants for leukaemias, and scientists are looking into other applications and approaches for stem cells as treatments, with the goal of increasing patient immunity to promote safety and reduce vulnerability during and after a transplant.[10]
Because patients are often immunocompromised as a result of chemotherapy or radiation therapy before a stem cell transplant, they are in a very critical and vulnerable stage just before, during, and shortly after the transplant. They will be extremely weak and unable to fight potential illnesses or infections. During this stage, a common cold can quickly become deadly. Thus, immune cells and cells that replenish the red and white blood cell count are being studied. If the patient and the donor cells have a genetic difference, even if it is minute, it can be deadly and cause a reaction within the patient. Thus, the genomics of stem cells are becoming more prevalent, and genetic engineers and scientists are looking into the possibility of altering the genomes of stem cells to ensure safety in transplants and widen their applications.
DISCUSSION- CURRENT GAPS IN UNDERSTANDING/SUGGESTIONS FOR FUTURE RESEARCH:
The scope of research in stem cell genomics has been expanding rapidly in recent years. Researchers have discovered genetic mutations in adult stem cells that could potentially counteract their positive effects after transplants. These are extremely rare deletion and substitution mutations that can multiply quickly due to the intensive radiation and chemotherapy transplant recipients undergo. Sequencing cultures derived from organ cells can help researchers look into the factors surrounding these mutations, and clonal organoid cultures have been sequenced for the small intestines, colons, and livers of patients. [11] However, there is a knowledge gap regarding the specifics of certain mutations—seemingly random amino acid deletion mutations in stem cells, the approximate locations of specific mutations, and the severity of specific mutations—particularly regarding mutations that arise in cancer illness and treatment.[12]
Although it can be extremely helpful for researchers, understanding the factors behind mutations does not help eradicate them. Future research must look into the possibility of eradicating or reducing the severity of mutations through cell engineering and, for specific cases, reamination of deaminated purines or pyrimidines in stem cells. Studies have shown that mitochondrial DNA mutations play a large role in stem cell mutations. Thus, the gene editing of DNA polymerase to prevent the clonal expansion of mitochondrial DNA mutations must be explored. The underlying mechanisms of mutations among stem cells in uninvestigated vital organs are also a necessity for future research. Mutation mechanisms include metabolite-induced aneuploidies on chromosomes 7,8, and 9, as well as metabolite-induced translocations of chromosomes 8 and 21 [12]. These mechanisms, along with the others behind point mutations in clonal stem cells in the liver, must be investigated; this will help reduce the instances of ineffective liver stem cells, making widespread treatment for liver diseases using stem cells possible.
Figure 1. A stem cell gains a mutation, becoming a cancer cell.[19]
The technology available to engineer stem cells is limited, costly, and cumbersome for most researchers. Stem cell reprogramming kits are a key example of expensive stem cell technology; a single sendai particle kit used for the generation of pluripotent stem cells can cost almost 3000 USD. Additionally, the process of stem cell generation involves generational screening, molecular characterization, and multiple differentiation procedures (typically, progenitor cells must be differentiated from pluripotent cells, followed by multiple other differentiation processes and ending with a maturation protocol). Future research must incorporate potential methods to streamline the multi-step and difficult process of stem cell production using technological developments and new non-technological options, such as proteins. Currently, a major player in stem cell production technology is CRISPR/Cas-9 (Clustered Regularly Interspaced Short Palindromic Repeats), the novel system used for gene editing. A recent advancement in CRISPR, namely extracellular vesicles as a means of delivery/transportation for Cas-9, has large implications in stem cell technology. Successful testing of this method could lead to substantially increased efficiency and cost-effectiveness when producing stem cells, leading to a wider availability of stem cells for research and clinical treatment.[14] These vesicles have other implications as well; they have the potential to be used as transportation for stem cells around the human body. Future research must investigate this possibility using protein ‘reprogramming’ (the remodeling of epigenetic markers in proteins using lipid nanoparticles and similar means). Although it sounds viable in theory, in reality, this type of research will require much testing work. However, this major discovery, if proved viable, could greatly decrease the frequency of time-consuming and painful stem cell therapies by replacing them with a safer and far simpler option.
Figure 2. The use of differentiation and stem cells in disease modeling and drug development[15].
Scientists are currently looking into the possibility of new stem cell-based medical procedures that could potentially replace today’s common surgeries with safer options. For example, advancements in regenerative medicine, such as the RECLAIM (recycled cartilage auto/allo implantation), once perfected and in common use, will allow physicians to repair cartilage and collagen in bones using mesenchymal and autologous stem cells. This will also allow for novel alternatives to bone or joint surgeries—hip arthroplasties, knee replacements, and shoulder replacements—and has the potential to increase the longevity of even compromised bones. This breakthrough is a major one for older adults, who often suffer from complications and lengthy recovery times after these types of surgeries.
Cartilage implantation using mesenchymal and autologous stem cells also has the potential to become a standard treatment method for one of the most common types of surgery in the world: broken bone repair [16]. Currently, metal screws, plates, and implants are used to repair broken bones in surgery. However, the use of the RECLAIM procedure and stem cells can make this procedure less painful, more efficient, and more effective. This has enormous applications for spine and collarbone fractures; breaking these bones is extremely dangerous, and surgery or bone replacement on the spine in particular can cause irreparable damage to the central nervous system. Using stem cells to rebuild the cartilage and collagen in these bones would allow for a more streamlined recovery, reducing the hassle of metal detectors and the potential for infections and follow-up surgery. Thus, this must be researched further.
Stem cells can be incorporated into therapies for hormone-based disorders, such as congenital adrenal hyperplasia, if incorporated into a treatment plan. Research on the potential of using stem cell transplants to regenerate hormone-producing cells has occurred. This new type of stem cell transplant will involve the use of haematopoietic stem cells to essentially rebuild patient immunity by regenerating white blood cells, which has huge implications for the future of autoimmune disorders. Such transplants will be life-changing for patients for whom hormone therapy is no longer functional for any reason (formulation or dosage issues, increased complications in the endocrine system, etc). Researchers have begun looking into the use of stem cells to create organs for use in transplantation. Stem cells could similarly be used to treat or replace damaged glands of the endocrine system because of their applications in the creation of hormone-producing cells. Some scientists believe that the creation of organs and glands with stem cells is too expensive and that complications with compatibility and organ rejection make the process dangerous. However, organ rejection is already an important consideration in organ transplantation. Additionally, with the enormous positive implications of such research (constant availability of organs for transplantation, the potential demise of the organ harvesting industry, decreased side effects from hormone replacement therapy, etc), it is worth the cost. Although the construction of stem cell organs and glands will be a definite challenge, it must be investigated further.
When stem cells are constructed or used in therapies, they can at times be defective or work slowly, taking up time that a seriously ill patient may not have. The construction of ‘optimum’ stem cells (cells that are suited perfectly for certain procedures, are compatible with the patient’s biochemical state, and are fast-acting) must be an emphasised component of stem cell research. Stem cells can be ‘programmed’ in certain ways using recombinant proteins, and this technology must be utilised and applied to make them more effective and efficient so they become safer and more viable treatments in the medical field. One procedure in this type of programming involves the use of viruses to insert the genes Oct4, Klf4, and the molecule RepSox, which was recently discovered by Harvard researchers.[17] This allows adult stem cells to revert into embryonic stem cells, which can be differentiated into multiple different types of cells that can be constructed (also using recombinant DNA and differentiation procedures) into differentiated stem cells, perfectly suited for a variety of procedures.
‘Programming’ stem cells in this manner could decrease physician and patient reservations regarding the compatibility of stem cells with patients’ bodies after complex surgical procedures, making them a safer option for transplants. Haploidentical haematopoietic stem cell transplantation is a novel procedure used to treat blood cancers. Research into recombinant proteins to construct optimum stem cells for these procedures to ensure compatibility and a more efficient recovery in patients with lymphoma in particular is important. Breakthroughs regarding the creation of optimum lymphocytes with benefits to the patient such as increased humoural immunity are on the horizon.
Figure 3. Diagram illustrating the production of recombinant proteins.[13]
Recombinant proteins can be produced using recombinant DNA. The specialisation of these proteins can be variable, allowing researchers to create recombinant proteins with specific functions, which can have potential benefits in stem cell construction. Increased specialisation in stem cell construction using gene-edited recombinant proteins could allow us to create optimum endothelial, nerve, and muscle cells for implications outside of transplantation—cells that could provide patients with additional benefits, such as increased immunity and more stabilised hormone secretion. Research into these potential applications is important.
Aside from their promise as future cures for various physical disorders, stem cells can potentially also be used as supplemental therapies or treatments for patients who are suffering from mental disorders. This would be a major implication in science and in the treatment of anxiety, depression, schizophrenia, and other mental illnesses. Many mental illnesses can be caused or exacerbated by a hormonal imbalance. For example, depression can intensify because of a lack of enough serotonin in the body. Since stem cells can be specialised using recombinant proteins, they can also potentially become hormone-producing cells that secrete hormones that originate in the brain, such as cortisol, serotonin, oxytocin, and more. This could have huge implications for the treatment of mental illnesses, as it could rebalance hormones in the patient’s body without the need for potentially dangerous medications. Although much research must occur into the transplantation of such cells and the specifics of their creation, this is yet another potential game-changing application of stem cells and stem cell genomics.
CONCLUSION
Stem cells are exciting and new therapy components for illnesses that were previously considered incurable, and the future of research and discovery is bright. Scientists and researchers will continue to study the potential applications of stem cells in order to create a healthier world, and the genomics, genetic mutations, and recombinant genetic material involved with stem cell research will be important considerations as they do so.
References
[1]\”Stem cells: What they are and what they do.\” Mayo Clinic. Accessed November 26,
2021. https://www.mayoclinic.org/tests-procedures/bone-marrow-transplant/
in-depth/stem-cells/art-20048117.
[2]National Human Genome Research Institute. Accessed December 27, 2021.
https://www.genome.gov/about-genomics/fact-sheets/A-Brief-Guide-to-Genomics.
[3]NIH. Accessed December 27, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC1129084/.
[4]American Cancer Society. Accessed December 27, 2021. https://www.cancer.org/
cancer/acute-myeloid-leukemia/treating/bone-marrow-stem-cell-transplant.html.
[5]American Cancer Society. Accessed December 27, 2021. https://www.cancer.org/
cancer/acute-lymphocytic-leukemia/about/what-is-all.html.
[6]Leukemia and Lymphoma Society. Accessed December 27, 2021. https://www.lls.org/
treatment/types-treatment/stem-cell-transplantation/
Allogeneic-stem-cell-transplantation.
[7]Leukemia and Lymphoma Society. Accessed December 27, 2021. https://www.lls.org/
treatment/types-treatment/stem-cell-transplantation/
Autologous-stem-cell-transplantation.
[8] US Government: NIH. \”Dose Escalation Study of AST-OPC1 in Spinal Cord Injury.\” Clinical Trials. Accessed November 26, 2021. https://clinicaltrials.gov/ct2/show/NCT02302157.
[9] Concise Review: Human Embryonic Stem Cells—What Have We Done? What Are We Doing? Where Are We Going? (n.d.). Stem Cells Journals. https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem.2450
[10]Nogrady, Bianca. \”Stem-cell and genetic therapies make a healthy marriage.\”
Nature. Accessed November 26, 2021. https://www.nature.com/articles/
d41586-019-01442-w.
[11] Blokzijl, Francis. \”Tissue-specific mutation accumulation in human adult stem cells during life.\” Nature. Accessed November 26, 2021. https://www.nature.com/articles/nature19768.
[12] Perduca, Vittorio. \”Stem cell replication, somatic mutations and role of randomness in the development of cancer.\” European Journal of Epidemiology. Accessed November 26, 2021. https://pubmed.ncbi.nlm.nih.gov/30623292/.
[13]The use of differentiation and stem cells in disease modeling and drug development. Image. Accessed November 26, 2021. https://www.nature.com/articles/s41576-019-0100-z.
[14]\”extracellular vesicles as a means of delivery/transportation for Cas-9.\”
IJMS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200053/.
[15] A stem cell gains a mutation, becoming a cancer cell. Image. Accessed November 26, 2021. https://www.nature.com/articles/s41568-018-0056-x.
[16] Iaquinta, Maria Rosa. \”Adult Stem Cells for Bone Regeneration and Repair.\” Frontiers. Accessed November 26, 2021. https://www.frontiersin.org/articles/10.3389/fcell.2019.00268/full.
[17]\”Stem Cells and Cancer.\” Harvard Stem Cell Institute. Accessed September 3, 2021. http://hsci.harvard.edu/stem-cells-and-cancer.
[18] Nafria, Monica. \”Standing at odds: mutated RAS and hematopoietic stem cells.\” Haematologica. Accessed November 26, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821623/.
[19] Diagram illustrating the production of recombinant proteins. Image. Accessed November 26, 2021. https://www.scielo.br/j/bjm/a/q5VcnRQ9b888WW6XL7X7tTc/?lang=en.
[20] Dulak, J., Szade, K., Szade, A., Nowak, W., & Józkowicz, A. (2015). Adult stem cells: hopes and hypes of regenerative medicine. Acta biochimica Polonica, 62(3), 329–337. https://doi.org/10.18388/abp.2015_1023
[21] \”Hematopoietic Stem Cells.\” Science Direct. Accessed September 3, 2021. https://www.sciencedirect.com/topics/neuroscience/hematopoietic-stem-cells.
[22] Khaddour, Karam. \”Hematopoietic Stem Cell Transplantation.\” Pubmed. Accessed September 3, 2021. https://pubmed.ncbi.nlm.nih.gov/30725636/.
[23] Making insulin producing beta cells from stem cells – how close are we? (n.d.). EuroStemCell. Retrieved July 1, 2021, from https://www.eurostemcell.org/making-insulin-producing-beta-cells-stem-cells-how-close-are-we
[24] Miyajima, A., Tanaka, M., & Itoh, T. (2014). Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell stem cell, 14(5), 561–574. https://doi.org/10.1016/j.stem.2014.04.010
[25] \”Mutations in donors\’ stem cells may cause problems for cancer patients.\” Science Daily. Accessed September 3, 2021. https://www.sciencedaily.com/releases/2020/01/200115191529.htm.
[26] Nowakowski, A., Andrzejewska, A., Janowski, M., Walczak, P., & Lukomska, B. (2013). Genetic engineering of stem cells for enhanced therapy. Acta neurobiologiae experimentalis, 73(1), 1–18.
[27] Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111. https://doi.org/10.1038/35102167
[28] Science Daily. Accessed September 3, 2021. https://www.sciencedaily.com/releases/2016/04/160414143923.htm.
[29] \”Single-cell Sequencing in the Field of Stem Cells.\” US National Library of Medicine. Accessed September 3, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770636/.
[30] \”Stem cell-derived organoids and their application for medical research and patient treatment.\” SpringerLink. Accessed September 3, 2021. https://link.springer.com/article/10.1007/s00109-017-1531-7.
[31] Stem Cell Technology. (n.d.). BMJ.Stem Genomics. (n.d.). Retrieved July 1, 2021, from https://www.stemgenomics.comTypes of Stem Cells. (n.d.). University of Nebraska Medical Center. Retrieved July 1, 2021, from https://www.unmc.edu/stemcells/educational-resources/types.html
[32] Suvà, M. L., & Tirosh, I. (2020). The Glioma Stem Cell Model in the Era of Single-Cell Genomics. Cancer cell, 37(5), 630–636. https://doi.org/10.1016/j.ccell.2020.04.001
[33] Vitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017). DNA Damage in Stem Cells. Molecular cell, 66(3), 306–319. https://doi.org/10.1016/j.molcel.2017.04.006