Xenotransplantation is a scientific method that entails the transfer of organs into humans from a non-animal human source which may be animals (www.fda.gov). The process of Xenotransplantation has gained momentum because of the increasing need for human organs for clinical purposes that has become an uncontrollable issue (www.fda.gov). In connection with xenotransplantation, there is a need to know about other scientific terms like zoonosis/zoonoses, and endogenous vs exogenous. Zoonosis is a disease spread from a vertebrate animal to human beings. Generally, the individuals become susceptible to exposure to zoonoses due to occupation. For example, Psittacosis which is considered a chlamydial infection of birds had infected nearly 88% of individuals in the US due to a hobby in keeping birds as pets (Michele, 1982). The infection to humans is acquired when the droppings of a bird get inhaled which would result in disease with headache, coughness, altered bowel habits and anorexia (Michele, 1982). Similarly, other infections specific to Toxoplasmosis, Yersinia enterocolitica, Giardia lamblia and Campylobacter play important role in transmitting diseases of varying degrees (Michele, 1982). This has strongly indicated that zoonoses are acquired by humans from animal either directly or indirectly by various zoonotic agents (Michele, 1982). Zoonoses may be of two types.
These are endogenous and exogenous. Endogenous zoonoses are transmitted by zoonotic agents which are excreta from infected cattle (ww.milkproduction.com). These zoonoses are infectious irrespective of their disease-inducing properties in cattle (ww.milkproduction.com). On the other hand, the agents that originate from different sources, like the environment, are termed exogenous zoonoses (ww.milkproduction.com). These have contaminating properties and could spoil milk. This may indicate that endogenous zonooses most likely contact individuals who occupationally work in dairy farms. Endogenous zoonoses may have a great chance to enter the food chain Exogenous zoonoses were more probably spread by environmental agents like the infrastructure and the unhygienic conditions of buildings, the methodology involved in the sewage-disposal (www.milkproduction.com). Pigs are chosen and considered better for Xenotransplantation as tend to mature early generate litters in high quantity and possess organs that could be analogous to human organs in terms of morphology and function in early development and adult stages (www.bio.org). In addition, pigs could be selected for breeding in order to meet standard health criteria under stringent microbiological conditions (www.bio.org).
However, there are barriers to xenotransplantation. This could be because that the utility of xenotransplantation products harbors spontaneous and anticipated hazards of transferring infectious agents (http://emedicine.medscape.com). This risk even exceeds the limit imposed by the agents that have a link with a process of allotransplantation, which is an adverse outcome of immunosuppression(http://emedicine.medscape.com). Generally, this problem gets initiated from the strong ability of xenotransplantation to transfer the infection to human beings from animals (http://emedicine.medscape.com). To mention, Severe acute respiratory syndrome, Ebola virus outbreaks, Creutzfeldt-Jakob disease, and HIV pandemic have raised potential issues with regard to the spread of familiar and unfamiliar infectious agents to the hosts, their contact sources, occupational workers in the profession of health care has turned into a common health debate (http://emedicine.medscape.com). Next, for the purpose of xenotransplantation, the appropriate animals, like pigs, have to be prepared. This is accomplished through a process of genetic modification and animals that are produced by this technology are known as transgenic animals (http://genome.wellcome.ac.uk). This was first done in 1995 were pigs were manipulated for organ transplantation (http://genome.wellcome.ac.uk). The preparation involves the expression of the protein, human decay-accelerating factor (DAF), that binds to the cell membrane and prevents the action of complement (http://genome.wellcome.ac.uk).
In view of these concerns, there were certain regulations that have come to light. Countries like US, UK and Spain have a common opinion about the issues surrounding xenotransplantation (www.bio.org).
These countries have set their own criteria in regulating the process of Xenotransplantation. In the year 1999, FDA’s Center for Biologics Evaluation and Research has released certain official principles (www.bio.org). These were devised keeping in view of public opinion, prolonged monitoring of individuals who receive the transplant and setting up of a repository to store patient profiles and samples of donors (www.bio.org). Therefore, several authoritative bodies of the U.S. Department of Health and Human Services, FDA, Center for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), have promoted regulations in the form of open dialogue with regard to xenotransplantation by organizing campaigns (www.bio.org). Likewise, stringent regulations have also been imposed in Spain and UK before the initiation of a clinical trial (www.bio.org). Xenotransplantation has also turned into a questionable debate due to various ethical considerations which need to be answered. They are with regard to the benefit, justice person’s respect and Animal Related Ethics (http://emedicine.medscape.com).
Risk and Benefit
Here, the researchers should look for minimum harm or risk to the patient or society while anticipating the benefit (http://emedicine.medscape.com). For this purpose, they need to appropriately consider data specific of pre-clinical and non-human primates (http://emedicine.medscape.com). The animals to be employed should be bred in stringent sterile conditions to enable them free of human-specific pathogens (http://emedicine.medscape.com). Reassurance is required with regard to the handling of porcine materials, recipients who receive porcine-specific insulin, and skin grafts (http://emedicine.medscape.com).
Xenotransplantation also carries the risk of infection to even distant geographic locations if it is not carefully monitored by an international surveillance system (http://emedicine.medscape.com). This could be due to frequent air travel by the tourists. Hence, this issue which can be considered as an ethical principle of justice demands that every country need to take up the job of controlling the threats of infectious sources (http://emedicine.medscape.com).
Next, obtaining informed consent from the patients is an emerging challenge. This could be because the patients need to comply with the monitoring process throughout life (http://emedicine.medscape.com). This would later prevent him or her to give up participation during any stage of clinical trials. The recipient should also prevent donating blood. Any contact with a recipient from the caregiver should be informed as it may carry the risk of infection (http://emedicine.medscape.com). But this would violate the confidentiality rules of xenotransplantation (http://emedicine.medscape.com). Hence, the government agencies should carefully honor the patient’s promises and see that the spread of infection is low (http://emedicine.medscape.com).
Animal activists oppose xenotransplantation and stress that humans do not possess the right to use animals for experimentation. In addition, some argue that animals used for this purpose need to be fairly treated provided there is approval from institutions. Hence, ethical considerations should be given paramount importance.
The viruses that are considered most common to pigs are that of porcine endogenous retroviruses (http://emedicine.medscape.com). The viruses could be eliminated by assessing the threats connected to the spread of infections to human beings from pigs after porcine tissue transplantation. This is accomplished through the development of Qualified Pathogen-Free pig production and animal testing essential to prove that the elimination criteria were met. A sampling strategy has been devised by the private firm Imutran that enables the animals in large groups to be qualified for routine testing. This could possibly eliminate the infectious animal and subsequently make it amenable for xenotransplantation. The major difference in eradicating the exogenous and endogenous viruses would be that exogenous viruses need stringent environmental regulations. As mentioned earlier they rely on the infrastructure and the unhygienic conditions of buildings, the methodology involved in the sewage disposal.
As such, the strategies like Qualified Pathogen-Free pig production and sampling method developed by Imutran would be affected by external sources. On the other hand, endogenous viruses would not affect the strategies as they rely on the spread of infection from the infected pigs (www.milkproduction.com). This is because pigs suspected of infection would be screened for risk assessment by Qualified Pathogen-Free pig production and appropriate sampling strategies. The transplantation of organs from pigs to humans induces health problems related to specific viruses which are considered a public health risk. These are reported to be the Torque teno virus. Porcine herpesviruses, Anellovirus, and Porcine herpesviruses (Scobie and Takeuchi, 2009). It was revealed that these viruses get transmitted to humans via allotransplantation (Scobie and Takeuchi, 2009). This in turn may induce adverse health consequences that could lead to various illnesses (Scobie and Takeuchi, 2009).
Further, it was reported that PERVs could infect humans by invading several human primary cells. Uninfected cells when subjected to serial passaging of PERVs have become infectious and the cell lines derived from those cells indicate that PERV’s have the potential to harbor the infectious cells. PERVs could also induce murine leukemia virus (MuLV) that makes the human host become infected with tumors. This might enhance the chances of developing a defective immune system. The risk of transferring PERV to humans is well connected due to the threat of transfer of zoonotic microorganisms. This is because PERV’s have their genome integrated into the pigs (Denner, 2008). As such, types PERV-A and PERV-B in pigs could infect humans (Denner, 2008). This was revealed when attempts were made to show that individuals who receive xenotransplantation could develop infections (Denner, 2008). There were failures when the administration of immunosuppressed small animals and non-human primates did not produce anticipated PERV infection.
However, in order to make sure that these viruses are not risky in the technology of xenotransplantation, methods were devised for the useful clinical needs of porcine xenotransplants (Denner, 2008).
The objective is to minimize the possible hazards of PERV infection to humans. One method is to choose pigs devoid of PERV-C, by eliminating recombination with PERV-A (Denner, 2008). The second method is to choose the animals that harbor small amounts of PERV-A and PERV-B (Denner, 2008). Hence, reliable and sensitive strategies have been adopted to ensure risky free transplantation by associating this with the third strategy of vaccine development that has the potential of conferring resistance against PERV infection (Denner, 2008).
The fourth method is to prevent PERV expression by a process known as RNA interference technology. Here by employing, retroviral vectors and PERV-specific short hairpin RNA (shRNA), PERV expression could be prevented in transgenic pigs and primary pig cells as these were analyzed and shown with low levels of tissue PERV expression (Denner, 2008). Hence, a laborious process is necessary to enhance and unite the methods to lessen the threat of PERV transmission and finally ensure that these viruses are not risky after xenotransplantation (Denner, 2008).
This would greatly accelerate the production of risk-free PERVs in society which could enable a large number of organ transplantations from pigs to humans who are in great concern whether to accept the donor organ or not.
There are accurate methods for detecting these viruses. These include Polymerase Chain Reaction (PCR) method. Here, researchers have developed primers that identify Pig sequences in its genome and control primers that act as complements keeping in view of cytochrome B of mitochondria, a recognized tool for phylogenetic investigations (Blusch, et al., 2000).
In addition, the primer pairs obtained from another region of the PERV genome were cross-bred and determined for their detection strategy when compared to PERV- and pig-specific PCR markers (Blusch, et al., 2000). In another strategy, researchers have devised enzyme-linked immunosorbant assays (ELISA) and Western blot that were made in connection to the crude PERVs generated by human cells and pigs or recombinant viral protein and synthetic peptides (Tacke, et al., 2001). These would respond to PERVs’ transmembrane envelope protein(Tacke, et al., 2001). In another strategy of detection, Porcine kidney cells PK15 harboring PERV and human liver cancer cells SMMC-7721 administered PERV independently into axillary regions of nude mice (Yu, et al., 2008). This animal later expressed PERV-Gag protein, PERV DNA and mRNA, and pig cytochrome oxidase II (COII) gene, PERV DNA, indicating detection of PERV (Yu, et al., 2008). These strategies could eliminate the viruses from society if properly implemented on a large-scale basis.
In view of the above information, it can be concluded that xenotransplantation still needs fine developments in the technology to meet the anticipations of the public who wait eagerly for the donor organs from animals.
Blusch, J,H., Roos, C., Nitschko, H. 2000. A polymerase chain reaction-based protocol for the detection of transmission of pig endogenous retroviruses in pig to human xenotransplantation.
Denner, J. Is porcine endogenous retrovirus (PERV) transmission still relevant? Transplant Proc. 40(2),pp.587-9.
Michele Michaels Ginsberg, Epitomes-Preventive Medicine and Public Health.
Scobie, L., & Takeuchi, Y. 2009. Porcine endogenous retrovirus and other viruses in xenotransplantation. Curr Opin Organ Transplant, 14(2), pp.175-9.
Specke, V., Schuurman, H,J., Plesker, R., Coulibaly, C., Ozel, M., Langford, G., Kurth, R.,Denner, J. (2002). Virus safety in xenotransplantation: first exploratory in vivo studies in small laboratory animals and non-human primates. Transpl Immunol,9(2-4),pp.281-8.
Tacke, S,J., Bodusch, K., Berg, A., Denner. J.2001. Sensitive and specific immunological detection methods for porcine endogenousretroviruses applicable to experimental and clinical xenotransplantation. Xenotransplantation. 8(2),pp.125-35.
William, O., Iverson, Tony Talbot. Definition of a Production Specification for Xenotransplantation: A European Perspective. Annals of New York Academy of Sciences, 862, 121-124.
XENOTRANSPLANTATION: The Benefits and Risks of Special Organ Transplantation. Web.
Yu, P., Zhang, L., Li, S,F., Cheng, J,Q., Lu, Y.R,, Li, Y.P.,Bu, H. 2008. Transmission of porcine endogenous retrovirus to human cells in nude mouse.. Acta Virol. 2008;52(4):257-60.