Introduction
In 2012, John B. Gurdon and Shinya Yamanaka jointly received the Nobel Prize in Physiology or Medicine. Their discovery lies in the fact that mature cells can turn back into their stem cell form and then become a different kind of tissue than they were initially. Stem cells are considered highly valuable in medicine, as they can develop into any kind of cell in the body and potentially repair tissue damage.
Additionally, by returning cells that are afflicted with some conditions to an immature state, researchers may be able to determine the reason why they developed an abnormality. Overall, the potential presented by the discovery is tremendous, though the specific applications are still mostly under development. This essay will examine the history of the discovery, the methods used in the studies, and its impact on humanity’s science.
John B. Gurdon’s Discovery
Humanity has known about how cells mature and how they may be manipulated to develop in a particular cell type for over half a century. However, researchers had assumed that once a cell settled upon being of a particular type, it would lose the information necessary for development into any other type. According to Gurdon (1962), the reason was that it was difficult to conduct studies with fully differentiated cells, as their nuclei were “susceptible to damage through exposure to saline medium” (p. 622). As such, with the methods available at the time, it would take a significant amount of time and effort to obtain any meaningful results.
Many researchers preferred to pursue different topics that would have more direct implications on medicine and cellular biology, seeing the idea of nuclei transplants with differentiated cells as impractical.
John B. Gurdon decided to undertake the endeavor and try to determine whether the nuclei of mature cells would produce any unusual effects when transplanted into undeveloped ones. At the time, he worked in Oxford, beginning with the classics but eventually switching to zoology after becoming interested in it. At the time, he was working on a Doctor of Philosophy degree, being particularly interested in zoology and cell transplants.
Before the study, he successfully cloned a frog, becoming a pioneer in that area, as well. His interest in the topic likely arose during these studies, as he wondered if he could achieve the same results with a developed organism as he could with an embryo. As such, he had considerable experience with nuclei transplants, which he could apply to achieve excellent results in his chosen area of research.
The researcher decided to use the subspecies Xenopus laevis laevis, also known as the African clawed frog, for the experiment. Gurdon (1962) notes that he took intestinal epithelium cells from tadpoles and transplanted them into eggs of the same species, using the standard process with a slight modification (Figure 1). He did the same for blastula and gastrula nuclei as a control group. A total of six experiments was carried out, concluding in a total of 726 total intestine cell transplants and 279 control group procedures. Ten attempts from the first group produced normal tadpoles, while the others displayed some type of abnormality.
Gurdon (1962) found that specific imperfections in the transplantation technique could explain many of these oddities. Regardless, the study proved his hypothesis that mature cells’ nuclei retained the capability to develop into any other kind of cell.
The work contributed to the development of more advanced nuclei transplant methods by identifying weaknesses in the process and methods that could be used to address them. It also created interest in the topic, in general, as scientists saw the implications of the finding. At first, scholars would try to check the finding and confirm or disprove it, eventually succeeding at the former. Then, they became interested in the reason for this ability’s existence and began studying stem cells and cellular nuclei in general with considerably more attention.
Organisms that developed after a nucleus of a differentiated cell were transplanted into an embryo, and their properties were also an area of considerable attention. However, the method still had a low success rate and many issues, and nuclei transplantation techniques would develop slowly and become more mature throughout the next half-century.
Gurdon proceeded to expand upon his initial finding once studies by other researchers confirmed the results of the original paper. In the article by Gurdon, Laskey, and Reeves (1975), he concludes that “cell specialization does not involve any loss, irreversible inactivation or permanent change in chromosomal genes required for development” (p. 93). Additionally, the transplantation of a cell from an organism to an egg was found to create an animal that is genetically identical to the source. Eventually, the idea of transplanting the nucleus of an organism into the egg of another organism became known as cloning.
Research into this approach is still ongoing, with few successes on a significant scale, such as Dolly the sheep. Gurdon is now known as the originator of the technique and continues studying nuclear transplantation and cell differentiation to this day.
Shinya Yamanaka’s Discovery
Medicine kept advancing after Gurdon’s initial study, though his finding applied more to topics such as cloning than the development of new cures. People recognized the usefulness of stem cells, but treatments that used them were mostly in the early stages of development. According to Takahashi and Yamanaka (2006), the reasons were that human embryos had to be used to obtain stem cells, which created ethical difficulties, and that patients would sometimes reject the new tissue.
Neither problem would arise if the cells used for the transplantation were sourced from the patient. Shinya Yamanaka began considering the potential of Gurdon’s research and the later developments that resulted from it, which proved that differentiated cells could be reprogrammed into a pluripotent state. If a reliable and effective method to do emerged, stem cell-based treatments would advance considerably.
The primary limitations of the nuclei transplant method are that it is slow and inefficient while also requiring some external source of undifferentiated cells. The process is expensive and has no guarantee of succeeding for the reasons described above. It also works on an individual cell basis, and it can take a long time to obtain an adequate number of cells to achieve any medical purpose. Yamanaka tried to create a method that would fix both of these issues by using cells that were procured from the person into whom they would later be implanted and translating them into a pluripotent state en masse. However, Gurdon’s experiments and similar techniques could not be used for this method because they all required embryonic cells. As such, Yamanaka had to consider different approaches and develop a new method that would be more suitable for medical uses.
The researchers tried to find a method that would enable them to reprogram colonies of cells, as opposed to individual ones. Takahashi and Yamanaka (2006) introduced 24 different genes into various colonies, individually and together, through retroviral transduction and measured their resistance to the G418 drug, which is known as an indicator of pluripotency (Figure 2). They were able to determine combinations of 10 and 4 genes that could induce the creation of colonies that matched the necessary criteria.
When grown in culture dishes, they would form embryoid bodies that would eventually begin differentiating, indicating that they were initially both undifferentiated and pluripotent. Additionally, upon transplantation into nude mice, the colonies would form differentiated tumors. Overall, the scientists were able to confirm that it was possible to source undifferentiated pluripotent cells from a mature organism.
The discovery has significant implications for the treatment of many conditions, particularly those that leave the person affected with permanent damage. For example, Hayashi et al. (2016) consider the usage of pluripotent cells, shortened to iPS by Yamanaka, to treat people’s eyes, which are notoriously complex and challenging to heal. Part of the reason is that the eye is a highly complex organ that consists of a high number of different tissues, each of which is critical to its operation. However, iPS cells can help regrow each of these parts at once due to their ability to differentiate after introduction to the eye.
Similar considerations can be applied to many other body parts, both complex and simple. As such, the initial research has been essential for medicine and warrants the Nobel Prize received by both of the scientists responsible for the discovery.
Effects on Theory and Practice
The studies conducted by Gordon and Yamanaka have changed humanity’s perspective regarding cellular development. In particular, the two have shown that genetic changes in cells can be reversed, which is a remarkable discovery. It changed science’s view on how organisms develop and created the question of why cells would retain this information. In the future, the ability to revert the state of a cell or tissue may lead to the creation of various innovative treatments.
However, so far, the technologies used to do so are not advanced enough to enable complicated practices, and development mostly focuses on refining them. While the technique holds more promise than typical embryo-based methods, it is in its early stages and has low efficiency. Before implementations are medically and commercially viable, they should increase the rate of success and address limitations.
In addition to the issues that surround the development of pluripotent cells from mature ones, the usage of successfully created tissues creates another set of complications. According to Takahashi and Yamanaka (2006), while the implantations into the mice used in the experiment were not rejected, they developed into tumors and killed their hosts in every case. While it is possible to obtain stem cells, making them fulfill the purposes set for them by the medical professional is a separate and significant challenge.
As such, research into both the applications of iPS cells and their safety is actively ongoing, and they are not used in medical applications at this time. While there are many potential issues, the potential offered by the discovery is significant enough that it warrants a significant investment of money and effort, with the most significant ideas described below.
One use of the ability to control the development of cells is to analyze those afflicted by some currently underexplored conditions. Scientists can look at the development of a cell taken from a patient and compare it to the same process for a healthy alternative.
As a result, they can better understand why the condition happens and experiment with various treatments. Additionally, by working with a specific person’s cells, medical professionals can develop personalized treatments that will be more effective for that patient. Overall, reprogramming offers a variety of new possibilities for the personalization and general improvement of treatments, both on a large scale and in specific cases. This practice is most likely to be developed in the near future, as it does not necessarily require the introduction of stem cells into the patient’s body and can be accomplished using current tools.
The second possibility is the repair of damage caused by various conditions, both genetic and caused by other factors. The study by Hayashi et al. (2016) serves as an example of the application of this approach to possibly cure eye conditions up to and including blindness. iPS cells can help the person heal formerly irreparable damage with little to no lasting consequences. However, the considerations about controllability and possible development of tumors apply strongly here. It can be challenging to access the cells to address any issues that result from the practice, as the tumor may be deep in the patient’s body and will have merged with their original and likely damaged tissues. Much of the current research and testing, including that done in the original study, try to refine this method and make it viable.
The third and final significant application of iPS cells can be seen as an extension of the prior approach. It is the creation of replacement organs for transplants to supplant the current practices of finding donors. Such an organ would essentially be taken from the person themselves and, thus, have no risk of rejection. However, making an organ is challenging due to its complexity and requires advanced manipulation of cell development.
As such, this practice is currently mostly theoretical and requires extensive testing and development before it can be considered for human applications. Regardless, it may not replace donor transplants because some such operations will be urgent and not give medical professionals time to grow a replacement. Still, the development is promising and can make a dangerous practice safer for patients with severe issues.
Conclusion
Gurdon and Yamanaka made their discoveries fifty years apart but received a shared Nobel Prize for their discovery. The studies that they have conducted have led to the creation of several prominent fields that can revolutionize medicine. They enable new treatments for conditions and issues that were impossible to address before, and the award is entirely warranted. However, currently, the fields derived from their work are still in an early stage of development. While the methods have a high potential, they are too ineffective and unsafe and need considerable refinement. As such, the work of numerous scientists who try to make the possibilities enabled by the two pioneers into reality should also be acknowledged and respected.
References
Gurdon, J. B. (1962). The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Journal of Embryology and Experimental Morphology, 10(4), 622-640.
Gurdon, J. B., Laskey, R. A., & Reeves, O. R. (1975). The developmental capacity of nuclei transplanted from keratinized skin cells of adult frogs. Journal of Embryology and Experimental Morphology, 34(1), 93-112.
Hayashi, R., Ishikawa, Y., Sasamoto, Y., Katori, R., Nomura, N., Ichikawa, T.,… & Quantock, A. J. (2016). Co-ordinated ocular development from human iPS cells and recovery of corneal function. Nature, 531, 376-380.
Karlén, M. (2012). The Nobel Prize in Physiology or Medicine 2012. Web.
Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676. Web.