Abstract
The number of people being affected by various diseases that require them to have organ transplants increases every day. Meanwhile, the amount of donated organs is extremely insufficient to meet the high demand. There is also the problem of finding a donor match for a recipient and the need to take strong medications that suppress the immune system of the recipient so that the transplanted organ is not rejected. A solution to these problems has been and is still being developed, with laboratory-grown organs holding much promise. These organs can be tailor-made using the patient’s own cells or other cell sources, so there is no risk of rejection, and immunosuppressant drugs become unnecessary. Lab-grown organs, as they are being called in various news reports, are a result of various tissue engineering and regenerative medicine (TERM) studies. There is much controversy with this technology because many aspects of it, especially the use of and researches involving stem cells, fall in the gray area of ethics and morality. However, the controversy TERM finds itself in is not very new to the public, because any new technology (especially in the field of medicine or medical research) is bombarded with a lot of questions on their being ethical or not. The technological advancements in TERM have allowed successful growth of various tissues and organs within the laboratory. Moreover, transplantation of simpler organs has spawned a number of success stories. The future for TERM is bright and still very much full of promise.
Keywords: tissue engineering, regenerative medicine, lab-grown organs, organ transplant
Introduction
- How do laboratory grown organs differ from traditional transplant organs?
- Why are laboratory grown organs controversial?
- What does the future hold for laboratory-grown organs?
Research was primarily done through a review and analysis of published documents (scientific journal articles) and news reports. An interview was also conducted with a medical professional adept in the field of internal medicine, Dr. Katherine Asadi. The interview was conducted through e-mail correspondence from October 6th to 7th of the year 2014. The interviewee is a medical doctor with 20-year experience in both private and public practice of internal medicine. The interview comprised of questions regarding the background and experience of the interviewee in the field of medicine, if the interviewee had any experience with patients needing transplants, and what the interviewee thought of laboratory-grown organs. For a full transcript of the interview, see Appendix A.
Results and Discussion
How do laboratory grown organs differ from traditional transplant organs?
Lab-grown organs vs. Traditional transplantation
Traditional transplantation refers to the transplant of organs from a donor to a recipient. It is the usual treatment for end-state organ failure. However, there are limiting factors that impede the use of organ and tissue transplants from donors. The most apparent and most critical of these factors is the shortage of organs that are suitable for transplantation. Second is the complex issue of immunology which often requires the use of medications to suppress the immune system so that the organ will not be rejected. The use of immunosuppressant medication increases the chance of infection that could be fatal to the patient and complexes the healing procedure at post-operation. Indeed, Dr. Asadi states that “The most difficult part [of organ transplantation] is taking the medication to suppress the rejection and prevent infections” (personal communication, October 2014). Also, not every organ is suitable for transplantation--for example, components of the nervous system are virtually impossible to transplant. Last is the limited lifetime of transplanted organs, which implies that patients would need further transplants in the future (Llames et al., 2012; Badylak et al., 2012). Thus, the use of laboratory-grown organs is a promising alternative to donor-based transplantation and may successfully bridge the wide gap between supply and demand.
Tissue engineering and Regenerative Medicine (TERM) and lab-grown organs
The science behind these so called lab-grown organs is called tissue engineering and its implementation in the medical field is called regenerative medicine. Tissue engineering is defined as "an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve tissue or organ function" (Langer and Vacanti, 1993). Regenerative medicine is a more recent term that is harder to succinctly define but basically utilizes tissue engineering to create "living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects" (Hunziker, 2010; Meyer, 2009). These two terms are often used together and compounded as tissue engineering and regenerative medicine (TERM).
The synthesis of tissues and organs in the laboratory is based on three types of structure: cells, scaffolds, and a suitable culture environment. Tissues and organs are made up of cells that are fixed to a three-dimensional structure that is the extracellular matrix (ECM). They are connected to the blood supply through vascularization, and this allows the tissues to receive nutrition and oxygen and also removes wastes. Also, the tissues also need to be innervated or connected to the nervous system (Mikos et al., 2006; Llames et al., 2012).
Growing an Organ in the Laboratory: Cells
The cells used in TERM must be easily accessible, can proliferate to a significant degree, and is able to differentiate into the required cell type, in instances that the cell source used is different from the tissue or organ to be fixed. There are many sources of cells to be used.
First, cells may be obtained cells from adult tissue to develop a similar tissue, and is called an autologous culture because the donor is also the recipient. A great advantage of using the patient's own cells is that immunological rejection is avoided. Furthermore, there is minimal risk of transmission of infectious agents. Second, cells can be from human embryonic stem (hES) cells. These cells are multipotent—it means that they have the ability to develop into a lot of different cell types. The third cell source is from adult stem cells (ASC). These cells have the ability to differentiate into a few certain cell types and can obtained from a number of tissues, with the most table being the bone marrow (Mikos et al., 2006; Llames et al., 2012). Another source of cells is relatively new and is called induced pluripotent stem cells (iPSCs). Researchers have managed to reprogram differentiated adult cells back to an "embryonic state" (i.e. a pluripotent state) through the use of certain factors. However, there are immunogenicity issues when attempting to implant cell-derived iPSCs (Llames et al., 2012; Fisher and Mauck, 2013).
Growing an Organ in the Laboratory: The Extracellular Matrix and Scaffolds
In the human body, our cells are embedded in what is called the extracellular matrix (ECM). ECM is a three-dimensional network of fibers and various proteins and it guides the morphological changes, organization and differentiation of cells. The ECM of tissues varies considerably among tissues and should be considered in the production of organs (Llames et al., 2012). To simulate the natural network of our cells, a scaffold, a structure for the cells, is then required in culturing the cells. Biomaterials composed of metals, ceramics, polymers, and composites can be used in the synthesis of the scaffold. The scaffold can also be made using 3D printers combined with image processing software. The most well-known scaffolds are made from native tissues and organs that are decellularized by physical, enzymatic, ionic and chemical means (Badylak et al., 2012; Llames et al., 2012; Milkos et al., 2006). Decellularization simply means that the cells of the organ are removed, thereby leaving behind the ECM. The decellularized matrix can then be repopulated with any of the aforementioned cell sources (Llames et al., 2012; Badylak et al., 2012).
Growing an Organ in the Laboratory: Bioreactors
Within the body, organs are constantly stimulated by mechanical, electrical, biochemical and cellular signals. Tissues and organs fabricated by tissue engineering likewise need these stimuli in order to mature correctly, and this is achieved using bioreactors. Bioreactors maintain the organ or tissue and ensure that the matured tissue will easily integrate into the recipient upon transplantation (Llames et al., 2012). See Figure 1 for the key elements of an organ bioreactor.
Figure 1. Key aspects of an organ bioreactor (Badylak et al., 2012).
Figure 2. Tissue engineering and the production of a human organ (Badylak et al., 2012).
Why are laboratory grown organs controversial?
Controversy surrounding TERM springs from the technologies it uses, which raise a lot of issues on ethics. First and the most widely contested is the use of embryonic stem cells in research. Human embryonic stem cells (hES) come from embryos; creation of new cell lines that risk the destruction of the embryo raises moral and religious concerns (King et al., 2009). The public has long been divided on the morality status of the embryo, usually raising the question: when does life begin? Even when a research study has revealed that cell lines for hES cells can be made from single cells of the embryo called blastomeres without risking the viability of the donor embryos, the debate still goes on (Chung et al., 2008). Thus, the controversy centers on the fact that the source of hES is an embryo.
The second technology in question is the induced pluripotent stem cell (iPSC) and the safety concerns it raises. To achieve the reprogramming of adult cells, introduction of genetic material into the cell is required. This has introduces comparable risks of possible genetic mutations. Furthermore, iPS cells (and also hES cells) have a propensity to form teratoma tumors, thus presenting a risk for therapeutic applications. There are many uncertainties that accompany this technology: its safety, cost and effectiveness have not yet been determined, and much is still unknown (King et al., 2009). Also, use of iPS cells increases the risks of inadvertently producing a clone of the donor due to the cells’ potential to develop into a human embryo (Genetic Science Learning Center, 2014).
Another reason for TERM controversy is its potential reliance on biobanking, which refers to the collection and storage of biological material. Since biobanking systems for stem cells are still in the early stages technologically and policy-wise, practical, ethical and policy issues must be first be sufficiently addressed before such biobanking can be fully realized (King et al., 2009). There is also the problem of risk assessment during clinical trials, but is not quite possible to achieve a simple and general assessment for TERM because its purposes, techniques and application are too variable. Moreover, evaluation for risk assessment is influenced by invasiveness, importance of the substituted function, methodological risks, alternatives, and unexpected risks (Gelhaus, 2012). A comprehensive review and analysis of ethical issues raised by TERM is published and can be used for supplementary reading (de Vries et al., 2008).
What does the future hold for laboratory grown organs?
A professional in the medical field, internal medicine, shares her thoughts on the future of laboratory-grown organs:
I think the future is extremely bright and we will see laboratory organs one day and hopefully during my lifetime. I just read yesterday that a baby was born via a transplanted [woman’s] uterus and if that can be done there is no doubt in my mind that Science can achieve this. (Dr. Katherine Asadi, personal communication, October 2014)
Cardiovascular System
A whole bioartificial heart capable of contracting or beating has been produced from the
decellularized matrix of a whole heart that was seeded with heart muscle cells (cardiomyocytes).
Scientists are still figuring out how to keep the heart beating within a mammal for an extended period of time. However, transplantation into a human recipient may be possible in the foreseeable future (Llames et al., 2012; Maher, 2014).
The technology for heart valves is more advanced than the whole-heart system. There have long been synthetic mechanical valves with excellent clinical outcomes. However, the patient needs to take anticoagulants and are quite susceptible to infections. These mechanical valves can be replaced by biological valves, which may come from animal tissue (either porcine or bovine) or homograft valves from cadavers. Biological valves remove the need for patients to take anticoagulants and patients are less susceptible to infections. However, these must be replaced after a period of time, and their use in children and teenagers is quite problematic as they must be able to adapt to the patient’s growth. TERM clinical studies using decellularized ECM seeded with precursor cells for heart valve transplantations have met with mediocre results (Llames et al., 2012).
Respiratory System
A group of researchers has transplanted a single bioengineered lung into a rat and were able to show that it could support gas exchange. However, this success was short-lived as the airspace was fairly quickly filled with fluids. TE of trachea has seen more success in clinical studies. In 2008, surgeons from Spain successfully transplanted a donated trachea bioengineered to contain the patient’s cell to a 30-year-old female patient whose airways had collapsed due to tuberculosis (Roberts, 2008). In 2011, a fully artificial trachea (i.e. the scaffold was modeled after the patient’s windpipe and no donor was involved) was successfully transplanted to a 36-year-old male cancer patient (Roberts, 2011). There are several other more patients whose lives were saved thanks to these lab-grown tracheas. Scientists over at Harvard are developing a system called Harvard Apparatus Regenerative Technology (HART), which is currently being used to produce patient-custom synthetic tracheas and is foreseen to be possibly adapted for the creation of other organs (Rojahn, 2014).
Hepatic (Liver) Tissue
Bioartificial liver (BAL) support systems are devices that utilize living cells, operate outside the body and replace the liver function. There are a number of examples of BAL support systems, but only a few have gone beyond the first phase of clinical trials. Furthermore, the results obtained with them are variable—they generally improve the patient's metabolic and clinical condition but to do not really improve survival rates for patients suffering from acute liver disease (Llames et al., 2012).
Attempts to construct a whole liver using TERM techniques have been made. The procedure enabled the entire vascular and biliary trees to be preserved. Moreover, it has been demonstrated that after transplantation, the engineered liver is able to take on some of the functions of the mature organ, at least momentarily. This step is an important milestone towards the progress and future creation of whole complex organs (Llames et al., 2012; Uygun et al., 2010).
Renal Tissue (Kidney)
TERM studies on the kidney is currently less advanced than in other tissues due to the existence of other better and more effective clinical alternatives. Nonetheless, whole-organ approaches, such as reseeding of extracellular matrix, have been investigated (Llames et al., 2012). A group of scientists successfully seeded rat renal ECM with mouse embryonic stem cells (ESCs), and showed proliferation and cellular differentiation of the stem cells (Ross et al., 2009). Also, lab-grown kidneys were also successfully transplanted into rats without blood clotting, but did not have the ability to filter urine as well as natural kidneys (Song et al., 2013). Much work is needed to propel kidney TERM studies to clinical trials.
Other tissues and organs have been successfully grown in the laboratory, with some having reaching relative success in clinical trials (O’Brien, 2011). For supplemental reading see Llames et al. (2012).
Marketability of Lab-grown organs
TERM is still in a very early research phase so it would be hard to predict or even estimate costs of each tissue or organ. Traditional transplantation costs can be quite expensive due to the very high demand for and very low supply of organs. Basic economic concepts will tell us that if the low supply is fixed (i.e. supply becomes high) or when the market becomes saturated, prices should relatively decrease. However, even in its infancy, TERM can easily be seen to have great marketability potential since it caters to an expanding market with high demands for various products. Indeed, Dr. Asadi states in an interview:
Economically, I would presume that [lab-grown organs] would be more efficient in many ways. Having [donors] creates so many [obstacles] such as the costs of patient’s time, keeping the patients organs at the appropriate temperature, transferring to the appropriate location, speed of transferring (including transferring them globally at times). (Asadi, personal communication, October 2014)
Summary
Organ transplant waiting lists continue to grow and the number of organs is still at low numbers. Tissue engineering and regenerative medicine (TERM) provides a solution to the low supply and other disadvantages of the traditional whole-organ donor transplantation. While it can be called controversial, it does not seem to evoke novel issues, but shares the controversies associated to any new technology. Technological advancements have reached a point that clinical trials are available and transplantation of some bioengineered simple organs has been successful. TERM is a very promising and fast-growing field of research. With the upward projection of clinical studies and researches, transplantation of bioengineered whole organs can be seen in the near future.
References
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Chung, Y., Klimanskaya, I., Becker, S., Li, T., Maserati, M., Lu, S.J., Zdravkovic, T., Ilic, D., Genbacev, O., Fisher, S., et al. (2008). Human embryonic stem cell lines generated without embryo destruction. Cell Stem Cell 7(2): 113-117.
de Vries, R., Oerlemans, A., Trommelmans, L., Dierickx, K., & Gordijn, B. (2008). Ethical Aspects of Tissue Engineering: A Review. Tissue Engineering: Part B 14(4): 367-375.
Fisher, M., & Mauck, R. (2013). Tissue Engineering and Regenerative Medicine: Recent Innovations and the Transition to Translation. Tissue Engineering: Part B 19(1): 1-13.
Gelhaus P. (2012). Ethical Issues in Tissue Engineering. In U. Meyer, T. Meyer, J. Handschel, & H. Wiesmann (Eds.), Fundamentals of Tissue Engineering and Regenerative Medicine (pp. 23-36). Leipzig, Germany: Springer-Verlag Berlin Heidelberg
Genetic Science Learning Center (2014). The Stem Cell Debate: Is It Over? Learn.Genetics. Retrieved October 02, 2014, from http://learn.genetics.utah.edu/content/stemcells/scissues/
Hunziker, R. (2010). Regenerative Medicine. Retrieved October 3, 2014, from http://report.nih.gov/nihfactsheets/viewfactsheet.aspx?csid=62
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Llames, S., García, E., Hernández, J., & Meana, Á. (2012). Chapter 20: Tissue Bioengineering and Artificial Organs. In C. López‑Larrea, A. López‑Vázquez, & B. Suárez‑Álvarez (Eds.), Stem Cell Transplantation (pp. 314-336). USA: Landes Bioscience and Springer Science Business Media.
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Mikos, A., Herring, S., Ochareon, P., Elisseeff, J., Lu, H., Kandel, R., Schoen, F., Toner, M., Mooney, D., Atala, A., Van Dyke, M., Kaplan, D., & Vunjak-Novakovic, G. (2006). Engineering Complex Tissues. Tissue Engineering 12(12): 3307-3339.
O'Brien, M. (2011). Spare Parts for Humans: Tissue Engineers Aim for Lab-Grown Limbs, Lungs and More [Video file]. Public Broadcasting Service (PBS) News Hour. Retrieved October 2, 2014, from http://www.pbs.org/newshour/bb/science-july-dec11-tissuescience_12-15/
Roberts, M. (2008). Windpipe transplant breakthrough. BBC News. Retrieved October 3, 2014, from http://news.bbc.co.uk/2/hi/health/7735696.stm
Roberts, M. (2011). Surgeons carry out first synthetic windpipe transplant. BBC News. Retrieved October 3, 2014, from http://news.bbc.co.uk/2/hi/health/7735696.stm
Rojahn, S. (2014). Manufacturing Organs: Harvard Bioscience spin-off is stepping up its production of synthetic tracheas to supply clinical trials. MIT Technology Review. Retrieved October 3, 2014, from http://www.technologyreview.com/news/522576/manufacturing-organs/
Ross, E., Williams, M., Hamazaki, T., et al. (2009) Embryonic stem cells proliferate and diff erentiate when seeded into kidney scaffolds. Journal of the American Society of Nephrology 20(11): 2338–2347.
Song, J., Guyette, J., Gilpin, S., Gonzalez, G., Vacanti, J., and Ott, H. (2013). Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nature Medicine 19(5): 646–651.
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Appendix A: Transcript of Interview with Dr. Katherine Asadi
Question 1: What is your background in medicine? (Where did you get your degree, how long have you been a doctor, where have you worked, and with whom?)
Katherine Asadi: I received my degree from 1. University of Maryland College Park - BS Biology with emphasis in genetics. My medical degree is from the Kansas City University of Medicine and Biosciences. I received my Internship from Franklin Square Hospital Center, Baltimore Maryland. I received my Residency training also from the Franklin Square Hospital Center, Baltimore Maryland. I did a Chief Residency also for 1 year at Franklin Square Hospital Center, Baltimore Maryland. I have been practicing Internal Medicine for 20 years. I received a scholarship for medical school through the National Health Service Corp and then served for four years in a rural setting in Clay West Virginia for medical underserved for 1 year.
I transferred to Peoples Community Health Center and served my remaining 3 years of NHSC obligation for the underserved inner city urban population. We did not have the resources to send many of the patients out for consults due to the lack of their health insurance and this is where I gained a tremendous amount of knowledge and experience. I continued my medical experience with running my own private practice for 8 years as a General Internist. I also admitted patients to our local Hospital daily at Greater Baltimore Medical Center in Baltimore Maryland and also admitted and followed patients daily at three Nursing Homes. This is where I gained Administrative Experience on how to run a private practice and medical billing experience. After finishing with private practice, I decided to try the Public Health Service again and served another 3 years at Baltimore Medical Systems in Baltimore Maryland an underserved type population that was mainly involving chronic pain patients, Hepatitis C and a tremendous amount of psychiatric patients such as Bipolar and major depression. After leaving this position, I was asked to accept a position to help build a new practice at Sinai Community Health Center in Baltimore Maryland. I joined this new group in August of 2013 and since built this practice up and we have now added 2 new partners as a result. It is Internal Medicine for mostly middle and upper class type clients , however I have left my panel open to all insurances as I have a strong belief that health care is a right not a privilege and Sinai also holds that strong philosophy. My Public Health service patients continue to see me and have transferred their care to me. I am Board Certified in Internal Medicine
Question 2: Have you had any patients that have been on a transplant organs list? Did they receive said organs or die waiting for them? Katherine Asadi: Yes, I did have a Patient who was on the transplant list and he received a Kidney transplant. Matter of fact, I had several patients who have received transplant organs and watching them go through the stress is very difficult. It is also difficult for the family. The most difficult part is taking the medication to suppress the rejection and prevent infections. I did have one patient die while waiting. He was a very pleasant 47 year old while male with a very young wife and 2 teenage daughters. He had hepatitis C. He was waiting for a new liver. It was very difficult because up until a few days before his death he was very hopeful and optimistic. It actual was one of the most difficult cases of my entire career. I still see his family and it’s really hard. He contracted Hep C via a blood transfusion.
Question 3: What do you think the future will hold for laboratory grown organs versus transplant organs from a donor?
Katherine Asadi: I think the future is extremely bright and we will see laboratory grown organs one day and hopefully during my lifetime. I just read yesterday that a baby was born via a transplanted women's Uterus and if that can be done there is no doubt in my mind that Science can achieve this.
Question 4: Economically, will laboratory grown organs be a feasible alternative to traditional donor organs?
Katherine Asadi: Economically, I would presume that it would be more efficient in many ways. Having Donors creates so many obstacles such as the costs of patient’s time, keeping the patients organs at the appropriate temperature, transferring to the appropriate location, speed of transferring (including transferring them globally at times)
Question 5: What will be the advantages of using lab grown organs?
Katherine Asadi: If Organs are available in the lab then so many of these obstacle are avoided. Not only that there are so many other issues such as graft host rejection. Many times the person receiving the organ will reject the organ and you have the cost of all the medications that must take to suppress all the infections to avoid. With lab grown organs you could possibly avoid that.
