The article selected for this assignment is “Targeted Gene Correction of α1-antitrypsin Deficiency in Induced Pluripotent Stem Cells”, by Kosuke Yusa, et al., and was published as a Nature Letter on October 20th, 2011.1 This is a proof-of-principle study for a new technology developed by the authors for eventual application in cell replacement therapy. The authors used a novel combination of zinc finger nuclease and piggy-Bac methodology in human induced-pluripotent stem cells (iPSCs) to correct a single point mutation in the α1-antitrypsin gene that is known to be responsible for α1-antitrypsin deficiency in humans. After successfully correcting the point mutation in several patient iPSC lines, the authors were able to differentiate the lines into fully hepatocyte-like cells in both structure and function. After in vivo transplantation into mouse livers, the hepatocyte-like cells distributed throughout the lobes of the liver and appeared to be functioning normally. The authors assert that their work is the first proof of principle for combining a genetic correction and human iPSCs in a way that is clinically applicable for cell therapies in which a patient’s own cells are isolated, subjected to corrective gene therapy, and then returned to the patient.
I selected this article for the midterm assignment because I was interested in learning more about research with human induced pluripotent stem cells and cell replacement therapy after the class session and paper discussion with Dr. Melissa Wong about intestinal stem cells. In addition to introducing a new method aimed at iPSC replacement therapy, the authors also test their method against several potential problems that could prevent it from being clinically applicable. Overall,...
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References
1. Yusa, K. et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391–394 (2011).
2. Fairchild, P. J. The challenge of immunogenicity in the quest for induced pluripotency. Nat. Rev. Immunol. 10, 868–875 (2010).
3. Lu, X. & Zhao, T. Clinical Therapy Using iPSCs: Hopes and Challenges. Genomics Proteomics Bioinformatics 11, 294–298 (2013).
4. Kim, A. & Pyykko, I. Size matters: versatile use of PiggyBac transposons as a genetic manipulation tool. Mol. Cell. Biochem. 354, 301–309 (2011).
5. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).
6. Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S. & Gregory, P. D. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646 (2010).
The cells unique nature has scientists intrigued to do research with the focus of finding a way that these cells can be used to replace patients’ injured or diseased tissues. Advancement is made to all the three types of stem cells namely embryonic stem cells, adult stem cells in addition to induced pluripotent cells. Embryonic cells are the building blocks of an embryo that is developing, and can develop into almost all body cell types. Somatic cells are found in the body tissues. They renew and regenerate in healthy bodies. The third type which is induced pluripotent is genetically modified embryo cells from skin cells.2 Research on these cells are geared towards saving humanity; a noble course.
Pluripotent stem cells were first induced using other model organisms such as Xenopus and Mus, but the methods were still considered controversial because they still included the use of an embryonic stem cell (such as cell fusion, nuclear injection) . In 2006, a new method of inducing pluripotency that did not utilize an embryonic stem cell was generated by manipulating the four reprogramming factors Oct3/4, Sox2, Klf4, and c-Myc. They were integrated into the genome of mice fibroblast cells using retroviral vectors, which yielded cells capable of in vitro and in vivo differentiation into various cells of all three g...
Stem cell research began in 1956 when Dr. E Donnall Thomas performed the first bone marrow transplant (“Adult stem cells are not more promising,” 2007). Since that time, research has evolved into obtaining cells from a variety of tissues. According to stem cell research professors, Ariff Bongso and Eng Hin Lee (2005), “Stem cells are unspecialized cells in the human body that are capable of becoming cells, each with new specialized functions” (p. 2). Stem cells are in various adult tissues, such as bone marrow, the liver, the epidermis layer of skin, the central nervous system, and eyes. They are also in other sources, such as fetuses, umbilical cords, placentas, embryos, and induced pluripotent stem cells (iPSCs), which are cells from adult tissues that have been reprogrammed to pluripotency. Most stem cells offer multipotent cells, which are sparse...
Stem cells can help cure diseases, repair damaged organs, and replace the need for organ donors. Stem cells may play a major role in cancer research, treatment, and maybe even a cure. Using stem cells in better treatments for diseases can give economic gains for society. According to the Mayo Clinic, over 100 million suffer from diseases that eventually may be treated more effectively or even cured with embryonic stem cell research (“Stem Cell Transplant”). This may be the greatest opportunity to alleviate the suffering of humans. Stem cell research has a lot of potential; there is a long list of diseases and other conditions that stem cells may be able to treat and possibly one day
There are many different types of stem cells that are being looked at for research. These include embryonic stem cells, adult stem cells, and induced pluripotent cells. Embryonic stem cells are cells that have the potential to produce many different cells in the body. They are cells that are tak...
Gene therapy is a relatively new concept owing mainly to our current knowledge of the human body and the relatively modern understanding of genetic coding and process. We now are able to better identify and understand the genetic causes of human ailments, and are just beginning to understand how to fix, replace, or eradicate the chromosomal basis for these issues; this is the concept of gene therapy. However logistically dealing with the small structure of genes, chromosomes, and DNA is not as easy as repairing a cracked wall or damaged water pipe, we are dealing with complex and microscopic materials that ordinary tools cannot deal with. Manufacturing such tools to deliver corrective DNA into affected cells within the body is just one of the obstacles that scientists and researchers are facing.
Lopez, Gerald Gabriel. "Gene Therapy: the Scientific vs. the Societal" The Resource. Jan. 1998. 10 Apr. 2001. .
The scientific process of genetic engineering is very complex and much more difficult than it would seem. First, an organism with the desired trait is located and selected. Cellular DNA is extracted from this organism to transplant the desired trait into the new organism. Gene cloning follows, with the locating and copying of the desired trait. The new gene(s), called a transgene is delivered into cells of the recipient organism, or trans...
Although humans have altered the genomes of species for thousands of years through artificial selection and other non-scientific means, the field of genetic engineering as we now know it did not begin until 1944 when DNA was first identified as the carrier of genetic information by Oswald Avery Colin McLeod and Maclyn McCarty (Stem Cell Research). In the following decades two more important discoveries occurred, first the 1953 discovery of the structure of DNA, by Watson and Crick, and next the 1973 discovery by Cohen and Boyer of a recombinant DNA technique which allowed the successful transfer of DNA into another organism. A year later Rudolf Jaenisch created the world’s first transgenic animal by introducing foreign DNA into a mouse embryo, an experiment that would set the stage for modern genetic engineering (Stem Cell Research). The commercialization of genetic engineering began largely in 1976 wh...
Induced pluripotent stem cells (iPSCs) have the capacity to have a widespread impact on biomedical research and therapeutic approaches to an array of diseases and disorders. These stem cells are of extreme potency because they can self-renew in culture while maintaining the capability to become virtually any cell type (Zhu and Huangfu, 2013). While there are many ethical concerns regarding embryonic stem cells, induced pluripotent stem cells arise from adult somatic cells that can be reprogrammed to enter the pluripotent state and have similar characteristics of embryonic stem cells such as having normal karyotypes, expression of telomerase activity, cell surface markers and genes, as well as mature and differentiate into advanced derivatives of the primary germ layers (Yu et al., 2007). These features are of great utility because they give insight to developmental biology and are extremely useful in the emerging field of regenerative medicine. This paper discusses the methods of which human somatic cells are reprogrammed allowing the generation of disease-specific and patient-specific pluripotent cell lines that can provide immense promise in regenerative medicine.
“Top Ten Things to Know About Stem Cell Treatments.” Www.closerlookatstemcells.org ISSCR. Web 1 November 2013
Because the best system for the study of disease is humans, a new technology called induced-pluripotent stem cells has been discovered, offering the opportunity to study disease relevant human tissue that is specific to an individual.
It is a possible and likely treatment to several diseases, through the use of iPSCs. It can also heal injuries and even restore or create new organs by harnessing the untapped power of the stem cell. Finally, despite the major debate regarding cloning concerns how moral it is, due to the past use of embryonic stem cells, novel and more ethical methods have been made. Therapeutic cloning, through these ways and perhaps more, could change all of the ways patients are medically treated. Even more, in the near future therapeutic cloning could revolutionize the entire medical world.
Park, I, Arora, N, Huo, H, Maherali, N, Ahfeldt, T, Shimamura, A, Lensch, M, Cowan, C, Hochedlinger, K, & Daley, G, 2008. Disease-Specific Induced Pluripotent Stem Cells. Cell, 134, 877-886.