Highlights in BioScience ISSN:2682-4043 DOI:10.36462/H.BioSci.202205 Review Open Access 1 Department of Animal Hygiene and Zoonoses, Faculty of Veterinary Medicine, University of Sadat City, Egypt. 2 Faculty of Veterinary Medicine, Cairo Univer- sity, Egypt. 3 Department of Biophysics, Faculty of Science, Cairo University, Egypt. 4 Biotechnology Program, Faculty of Science, Cairo University, Egypt. 5 Department Zoology and Chemistry, Faculty of Science, Cairo University, Egypt. 6 Department of Bacteriology, Mycology and Immunology, Faculty of Veterinary Medicine, University of Sadat City, Egypt. * To whom correspondence should be addressed: vet_noura@yahoo.com Editor: Hatem Zayed, College of Health and Sciences, Qatar University, Doha, Qatar. Reviewer(s): Santosh K Maurya, Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India. Amira M. Elsherbini, Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35116, Egypt. Received: September 7, 2022 Accepted: December 15, 2022 Published: December 29, 2022 Citation: Eissa N, Badrkhan SM, Mohamed MA, Shaban JY, Shahban RS, Dawoud M. Xenotransplantation: past, present, and future directions. 2022 Dec 29;5:bs202205 Copyright: © 2022 Eissa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and supplementary materials. Funding: The authors have no support or funding to report. Competing interests: The authors declare that they have no competing interests. Xenotransplantation: past, present, and future directions Nourhan Eissa*1 >< , Salma M. Badrkhan2 >< , Maha A. Mohamed3 >< , Joumana Y. Shaban4 >< , Rahma S. Shahban5 >< , Mai Dawoud6 >< Abstract Xenotransplantation, in its broadest sense, is the transplantation, implantation, or in- fusion of cells, tissues, or organs from one species to another. While there is a high demand for human tissues, cells, and organs for use in clinical transplantation, they are often in short supply. Recent scientific and biotechnological advancements, coupled with the scarcity of human allografts, have led to renewed interest in developing exploratory treatment strategies that use xenotransplantation products in human recipients. However, despite its potential benefits, the use of xenotransplantation is still limited due to various considerations, as discussed in this review of the past, present, and future directions of xenotransplantation. One of the key ethical concerns surrounding xenotransplantation is the potential impact on the animals from which the cells, tissues, or organs are obtained. As with genetic modification to fix genetic defects or prevent disease, the ideal outcome for these animals is that they will be better off as a result of the change. However, unless there are major changes in the way science is taught to incorporate ethics into recognized scientific theory and practice, these concerns will not be adequately addressed. Keywords: Donor animals, Ethical issues, Immunological barriers, Religious considerations, Xenotransplantation Introduction Despite the fact that there are over 135,000 transplants carried out annually throughout the world, this still only accounts for less than 10% of the true global needs for failing organs (such as kidneys, skin, testicles, hearts, livers, lungs, bones, small bowels, and pancreas, etc.) due to a lack of donors. This is true even though living donor transplants have been performed since the 1960s [1]. This fact has prompted medical professionals and researchers worldwide to develop a "bridge the gap" technique called xenotransplantation (cross-species transplantation, implantation or even infusion of live cells, tissues or even organs, especially from pigs and nonhuman primates to humans) in order to provide an immediate and limitless supply of transplantable organs that could aid in the treatment of many disorders [1; 2]. While an in-depth discussion of the history of numerous successful clinical attempts at xeno- transplantation is impractical for the current review paper, it is important to highlight the key con- tributions that helped the field get to where it is nowa shining example of the power of science and medicine working together for the greater good. The cultural backdrop of xenotransplantation, religious beliefs, ethical considerations, desirable qualities of donor animals, challenges that the xenotransplantation procedure faces, and the influence of xenotransplantation on zoonotic risk are all briefly reviewed in this study. Another important consideration is the potential for the spread of diseases from animals to hu- mans. Because the cells, tissues, or organs used in xenotransplantation come from another species, there is a risk that they may carry diseases that are not present in humans. This could potentially lead to the spread of new diseases or the exacerbation of existing ones. To minimize this risk, it is impor- tant to carefully screen the cells, tissues, or organs before they are used in xenotransplantation, and to implement strict protocols to prevent the spread of disease. Despite these challenges, researchers are continuing to explore the potential of xenotransplantation as a way to overcome the shortage of human allografts. Highlights in BioScience Page 1 of 15 December 2022|Volume 5 https://doi.org/10.36462/H.BioSci.202205 https://creativecommons.org/licenses/by/4.0/ vet_noura@yahoo.com https://orcid.org/0000-0002-3622-6023 shamms951@gmail.com https://orcid.org/0000-0002-0407-1151 Mhmohamed2013@gmail.com jomanayousef12@gmail.com https://orcid.org/0000-0002-5038-0270 rrsaid315@gmail.com https://orcid.org/0000-0002-2082-7692 Mai_dawoud30@yahoo.com http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions In the future, it is likely that advances in science and tech- nology will make it possible to overcome many of the challenges currently facing xenotransplantation , paving the way for its wide– spread use in clinical transplantation. Chimeras in folklore Historically, Folklore had long contained accounts of chi- maeras (i.e. monstrous creatures composed of parts of multi- pleăspecies) before the technique of xenotransplantation was even considered. People were sporadically shown in prehistoric cave paintings, but the sole example of a human is a man with a bird’s head in the Lascaux cave in France (about 15,000 BC), which is where the stories of vampires and werewolves (half man, half beast) originated. The Great Sphinx of Giza (about 2500 BC) features a lion body with a human head in contrast to the gods of Ancient Egypt (Anubis), who were commonly depicted with a human body and an animal (jackal) head. Additionally, a San- skrit document from the 12th century BC has the first account of xenotransplantation in Indian mythology, which describes Gane- sha, a huge infant with an elephant-like head (a son of two Indian gods, Shiva and Parvati). In addition, xenotransplantation was depicted in Greek mythology through the likes of the Minotaur (a man with a bull head), Esfinge (a winged lion with a woman head), and Centaurs (horses with a man’s head and trunk), as well as in Homer’s Odyssey, which featured chimaeras that were half-swine, half-man (about 750 BC) [3; 4; 5; 6]. History of clinical experiences with xenotransplanta- tion The idea of human xenotransplantation attempts actually got started in the 17th century with the first attempt to transfuse sheep blood into people in 1667 (Figure ??)[7]. In reality, sci- entists and doctors are unable to create true human-animal chi- maeras followed by an opacified human cornea was replaced with a transparent porcine cornea [8] and a kidney xenotrans- plantation from a rabbit occurred in 1905 [9; 10], the clear pig cornea was then used to replace an opaque human cornea, and in the early 1970s, successful corneal xenotransplantations from fish and gibbons were performed [10; 11]. Additionally, a clin- ical study of kidney xenotransplantation from a chimpanzee to humans was conducted between 1963 and 1964 [12]. This was followed by the first attempts at heart xenotransplantation from chimpanzee and baboon donors in 1964 [13] and 1984 [14], re- spectively. Using baboon donors, the first successful liver xeno- transplantation procedure was carried out in 1992 [15]. Clin- ical xenotransplantation experiments have not been conducted in the United States or the majority of European nations since the 1990s because of certain xenozoonoses, immunological con- cerns, surgical effectiveness, and other regulatory concerns [16]. But according to reported reports, between 2013 and 2017 China and Russia used xenotransplantation to cure diabetes patients us- ing transplanted neonatal pig islets [17]. Figure 1. Historical recorded trials concerning xenotransplantation in different organs. Blood xenotransfusion If we delve beyond myth and folklore, we find Jean Bap- tiste Denis started the therapeutic practise of transfusing animal blood into humans [18; 19]. Results were conflicting and not sur- prising. Consequently, xenotransfusion was outlawed in France for a while. A strong case could be made for using pigs as a source of blood cells and blood products (if they are maintained in ideal "clean" conditions and are periodically checked to en- sure no infectious agent is being passed) given the current threat of infectious pathogens being transferred and the need for future human blood transfusions [19]. In actuality, this method has been reevaluated by a number of studies [20]. Blood vessel anastomosis More scientific developments had to wait until the 20th cen- tury, when French experimental surgeon Alexis Carrel devised surgical methods for anastomosing blood arteries, enabling the first successful organ transplant to occur. Carrel worked first in France and subsequently in North America [21]. Skin xenotransplantation Various animal species and humans began using skin grafts in the 19th century when either pedicle or free skin grafts were used as the skin transplants. The donor, which may be a sheep, a rabbit, a dog, a cat, a rat, a chicken, or a pigeon, had to stay immobile while connected to the patient for a period of days so that the recipient could reportedly vascularize the graft. The perfect transplant would have looked like it was taken from a frog since they occasionally had "skinned alive" skin. When used to cover skin ulcers, it’s likely that some of these grafts were "successful" in the sense that they provided protection, at least for a few days, as the ulcer healed below them. But it’s likely that none of the grafts turned out to be long-lasting [22; 23]. Corneal xenotransplantation Corneal xenotransplantation, the process of transplanting corneas from one species to another, has a long and fascinating history. Highlights in BioScience Page 2 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions The first recorded corneal xenotransplantation was actually per- formed from a human to a dog in 1838 by Dr. Samuel D. Gross [24]. However, it wasn’t until 1905 that the first corneal allograft, a transplant from a person to a pig, was successfully completed [10; 25]. Since then, the field of corneal xenotransplantation has made significant progress, with various animal species, including pigs, rabbits, and monkeys, being used as potential donors [26]. De- spite these advances, the use of animal-derived corneal grafts in humans remains controversial, with concerns surrounding the potential transmission of diseases, the ethical implications of us- ing animals as organ donors, and the potential immunological reactions of the recipient [27]. Despite these challenges, research into corneal xenotrans- plantation continues, with the hope of eventually finding a reli- able and safe alternative to human corneal transplantation, which is currently limited by the shortage of donor tissue [28]. Cell xenotransplantation Serge Voronoff, a Russian immigrant who settled in Paris, had the concept of transplanting cells that produced a hormone that the recipient lacked. Given the small number of human pan- creases that become available each year, there is tremendous interest in utilising pig islets for this. But for older guys who had lost their "zest for life," Voronoff’s main goal was to slow down ageing. He implanted chimpanzee or baboon testicles into a sizable number of male human patients [29; 30]. His method involved cutting the animal testicle into slices and inserting the pieces into the testicles of the recipients. On both sides of the Atlantic, the treatment gained popularity, and several hundred of these surgeries were carried out. It is improbable that any of them had any positive effects besides psychological ones, yet there have been tales of extraordinary "rejuvenation" in men who have undergone surgery and reported having considerably more energy. Because donor testicle slices may have necrosed and cre- ated infectious or inflammatory problems occasionally, the surg- eries must have had significant complications. Furthermore, the first kidney allotransplant was carried on 1933 [31] John Brink- ley maintained the concept of transplanting goat glandular tissue to produce hormones that the recipient would benefit from in the United States [32]. Nevertheless, the development of several clinics, particularly in Europe, where patients get injections of animal tissue or serum to treat a variety of disorders has ensured that the concept of cell xenotransplantation has endured to the current day. Controversy has been created by the results [33]. Xenotransplantation of the kidney By the 1960s, Keith Reemtsma of Tulane University in Loui- siana had proposed that transplanting human recipients with non- human monkey kidneys might successfully treat renal insuffi- ciency. At that time, French and American surgeons had spent a lot of effort on the concept of kidney transplantation, but there were not enough deceased person kidneys accessible, and chronic dialysis had not yet been invented. So long as organs from non- human animals couldn’t be procured, Reemtsma thought the pa- tient had no alternative but to pass away. He decided to get the organs from chimpanzees because of their close evolutionary re- lationship to humans. He carried out 13 of these transplants, each of which included giving the patient both kidneys from a chimpanzee (which generally weighs considerably less than an adult human) [12]. During autopsy, the chimpanzee kidneys showed no abnormalities or signs of acute or enduring rejection. The notion of employing non-human primates as kidney donors was pioneered by several surgeons, most notably by Tom Starzl who used baboons as donors in Colorado [34], and his findings were comparable to those of Reemtsma. Others had insignificant contacts in the US and France [35]. Xenotransplantation of the heart When James Hardy visited Reemtsma in 1963 and conducted the first human lung allotransplant, he was struck by the recip- ients of chimpanzee kidney transplants who were all in good condition. Hardy decided to buy some chimpanzees as possi- ble "donors" in 1964 in order to execute the first clinical heart transplant in the event that he was unable to find a deceased hu- man donor. He had a less-than-ideal patient who would not be allowed for heart transplantation today due to his patient’s sig- nificant atheromatous vascular disease, for which he had both of his legs amputated, and the fact that he was semicomatose at the time the surgery was carried out. However, the patient’s rapid de- cline prompted Hardy to perform a chimpanzee heart transplant [21]. Because the chimpanzee heart was too tiny to maintain the circulation, it failed within a short period of time. Contrary to the attempted lung allotransplantation, the heart xenotransplan- tation received a negative response from the public and medical community, which deterred Hardy and his colleagues from try- ing again. The heart allotransplantation procedure was later de- veloped by Barnard and his collaborators in 1967 [21]. Later, they carried out two heart xenotransplantations [36]. Lung xenotransplantation Only the Maryland team has lately engaged in active lung xenotransplantation research. Platelet sequestration and activa- tion during GTKO was discovered by [37]. The hCD46 pig lung perfusion by human blood was mostly caused by GPIb, GPIIb/IIIa, and von Willebrand factor. GTKO is reduced by transgenic expression of the human leukocyte antigen (HLA-E). The hCD46 pigs with xenograft pulmonary injury. Ex vivo hu- man blood perfusion models of the lungs of genetically altered pigs with drugs that suppress complement activation, coagula- tion, and inflammation dramatically improved lung xenograft survival in vivo [38]. Liver xenotransplantation Tom Starzl, one of the most important pioneers in the area of kidney and liver allotransplantation, tried a few liver transplanta- tions on young patients and nonhuman primates in Colorado in Highlights in BioScience Page 3 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions the 1960s without long-term success [39; 40; 41]. In the 1990s, he and his Pittsburgh team performed two liver transplants from baboons in adult patients, with one patient enduring 70 days of survival after tacrolimus was added to the immunosuppressive arsenal [15]. The results, however, were not convincing enough to warrant continuing this exploratory clinical trial. The pig [42] and other nonprimate mammals have been used in a few efforts, but they haven’t been very effective. Most early attempts at therapeutic organ xenotransplantation obtained their organs from nonhuman primate species [35]. The first islet xenotransplantation An estimated 2 to 3 million persons in the United States alone have type 1 diabetes. Since pig insulin varies from human insulin by just one amino acid and has been used successfully to treat diabetic patients for decades before recombinant human in- sulin became available, it is reasonable to anticipate that normo- glycemia will result from a successful pig islet transplant. The first effort at pig islet transplantation in diabetic patients was un- dertaken in 1993 by a Swedish team under the direction of Carl Groth [43]. Features of the perfect donor animal include When we analyse the ideal qualities of animals suitable as or- gan donors for humans, a large list forms. The animal’s anatomy and physiology must first be compatible with humans for the desired organ to work well in them. The risk of an infection from one species (i.e., an animal) to another should also be elim- inated. Even human viral infections would not be able to pass through an excellent animal donor organ. This animal species should also be inexpensive to feed and produce because to its short gestation periods and frequent births each litter to achieve economies of scale. Additionally, no immunologic obstacles to transplanting into humans should be present in such an animal. Finally, there shouldn’t be much ethical debate about using this animal in this way. There is no animal species that satisfies all of the aforementioned requirements. Apes and monkeys are nonhu- man primates that resemble humans the most anatomically and physiologically. They might also be resistant to some human dis- eases. In reality, because of their hepatitis B and HIV resistance, baboon liver xenografts have been used in research [15]. But the xenotransplant community appears to have given up on the idea of utilising nonhuman primates as xenograft donors, mainly due to the hazards of infection for human patients and those who come in contact with them. Some monkey viruses, like herpes 8, can kill people in a couple of days [44]. It is thought that raising pathogen-free herds in sufficient numbers to satisfy ther- apeutic demand would be prohibitively costly. Last but not least, using nonhuman primates as human organ donors has serious ethical problems [45; 46]. Due to its large litter sizes (up to 10 littermates), short gestation periods (4 months), anatomical and physiological similarities to humans, widespread use for hu- man consumption (an estimated 90 million pigs are consumed annually in the USA), and lengthy history of providing medic- Table 1. The benefits and drawbacks of using pigs vs baboons as a source of organs and cells for people, as described by [18]. Comparison Pig Baboon Organ size in adults Sufficient Insufficient Maintenance costs Significantly inferior Elevated Human anatomy similarities Moderately related Very related Human-like physiological similarities Moderately related Very related Accessibility Adequate inadequate Relation with the immune system to humans Distant related Very related Data of tissue typing Significant (in selected herds) Inadequate Age of sexual maturity 4-8 months 3-5 years Breeding potential Good quality Poor quality Pregnancy period 114 ± 2 days 173-193 days Offsprings per time 5-12 1-2 Development Fast (adult human size within 6 months) Sluggish (9 years to reach maximum size) Blood type compatibility with humans Probably insignificant Vital Knowledge of genetic engineering significant None Risk of transfer of infection (xenozoonosis) Low High Availability of specific pathogen-free animals Yes Yes Public opinion More in favor Mixed inals (skin, insulin, cardiac prostheses, and clotting factors) for humans, the pig has emerged as the most likely candidate for consideration as an organ donor. Undoubtedly, considerable hur- dles may arise due to significant discrepancies in the coagulation cascade and other aspects of porcine physiology [47; 48]. Even though they are becoming more recognised, immunologic obsta- cles still need to be overcome. In addition, several diabetes treatments, such as immunosup- pressive regimes and pancreatic islet transplantation procedures, were initially developed using the dog model. Primate models with induced diabetes are being used more frequently as a re- sult of recent developments toward the use of monoclonal an- tibody treatments for immunosuppression in human islet trans- plantation. Researchers in several domains are thinking about using naturally occurring illness models in client-owned pets in addition to induced-disease models in large animals. This article will discuss how naturally existing canine diabetes can be used as a translational model for creating islet transplants for diabetic patients who are humans [49]. Other pharmaceuticals of animal origin In Table 2 we provide a list of various xenotransplantation products and their origins, generic names, product names, and therapeutic class. The table includes products from a variety of animal sources, including horses, pigs, mice, cows, and others. One of the key observations from the table is the wide range of therapeutic applications for xenotransplantation products. These products are used to treat a wide range of conditions, including respiratory problems, anticoagulants, antivenoms, and vaccines. This highlights the potential benefits of xenotransplantation as a way to overcome shortages of human allografts and provide treatments for a variety of medical conditions. Another interesting aspect of the table is the diversity of an- imal sources used in xenotransplantation. The table includes products from horses, pigs, mice, and cows, among others. This Highlights in BioScience Page 4 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions suggests that a wide range of animals can be used as sources for xenotransplantation products, depending on the specific needs of the recipient and the availability of appropriate cells, tissues, or organs. Overall, the table provides a useful overview of the past, present, and future directions of xenotransplantation. It high- lights the potential benefits of using xenotransplantation prod- ucts in clinical transplantation, as well as the ethical considera- tions and technical challenges that need to be addressed in order for it to be widely used. In addition to the observations mentioned above, the table also highlights the potential challenges of xenotransplantation. For example, one of the main challenges is ensuring that the cells, tissues, or organs used in xenotransplantation are compat- ible with the recipient’s immune system. If the transplant is re- jected, it may be necessary to use immunosuppressive drugs to prevent rejection, which can have negative side effects for the recipient. Another challenge is the potential for the spread of diseases from animals to humans. Because the cells, tissues, or organs used in xenotransplantation come from another species, there is a risk that they may carry diseases that are not present in humans. This could potentially lead to the spread of new diseases or the exacerbation of existing ones. To minimize this risk, it is impor- tant to carefully screen the cells, tissues, or organs before they are used in xenotransplantation, and to implement strict proto- cols to prevent the spread of disease. Despite these challenges, the potential benefits of xenotrans- plantation are considerable. In the future, it is likely that ad- vances in science and technology will make it possible to over- come many of the challenges currently facing xenotransplanta- tion, paving the way for its widespread use in clinical transplan- tation. This could help to alleviate the shortage of human allo- grafts and provide new treatment options for a variety of medical conditions. Issues with several xenotransplantation cases Complications include immunological incompatibility, cell death, abnormal cell differentiation and proliferation, virus trans- mission from animals to humans, and ethical concerns hinder the clinical application of xenogeneic stem cell transplantation [50]. Immune rejection Immune rejection is unquestionably the problem with xeno- geneic stem cell transplantation that worries people the most. Immunological rejection is avoided using the following meth- ods: Only a few of the variables that need to be taken into ac- count include the use of cellular desensitisation technology, im- munosuppressive medications, suitable stem cell type selection, gene editing technology, encapsulated cell technology, the use of immunosuppressive drugs, and the regulation of cytokine lev- els. These procedures have increased the success rate of trans- plantations. Selecting stem cells with low immunogenicity, im- munosuppressive, and immunomodulatory traits may help to al- leviate this problem [51]. Injected immunocompetent mice with stem cells obtained from human umbilical cord stroma. The results showed that this kind of human stem cell has immuno- suppressive and immunomodulatory properties [51]. Later re- search showed that xenogeneic stem cells, in particular xeno- geneic MSCs, have low immunogenicity along with immuno- suppressive and immune-modulatory capabilities [52]. Porcine MSCs have been used in xenotransplantation investigations be- cause to their low immunogenicity attributes and immunomodu- latory qualities [53]. Pig umbilical cord MSCs and swine ESC- derived neural progenitors were implanted in non-immunocompr– omised rats [54]. Their investigation revealed similar cell im- munosuppressive effects [53]. The potential of these cells to suppress the immune system and have minimal immunogenic- ity was proven by the transplantation of rabbit umbilical cord MSCs with hyaluronic acid/tricalcium phosphate scaffolds in rats [55]. By co-implanting rat MSCs and pig neuroblasts in immunocompetent rat striata, [52] demonstrated the immuno- suppressive characteristics of these cells. According to study by [56], rat ADSCs can protect themselves from human xenoan- tibodies and complement-mediated lysis. Gal, or galactose-1, 3-galactose, is related with low expression and this capacity is CD59 dependent [56]. Hyperacute rejection Antibodies that are spontaneously generated against blood type antigens are similar to xenoreactive natural antibodies (XNA). The epitope that these antibodies primarily target is the non- reducing trisaccharide group galactosyl a-(1, 3)-galactosyl b-1,4- N-acetyl glucosaminyl, also known as the gal epitope15. Man does not have this epitope because he lacks the enzyme that makes it. Higher primates thus recognise the gal epitope as "non-self" and produce an immune response to it. Numerous microbes16 contain the gal epitope, and humans are exposed to the antigen through their guts, where they develop anti-gal an- tibodies. The key mechanisms by which XNA exerts its effects include natural killer (NK) cells, complement activation, and en- dothelium phenotypic alterations. The goal of research to date has been to lessen the effects of XNA [60; 61]. Acute humoral xenograft rejection (AHXR) The following challenge is delayed xenograft rejection, which is frequently seen. The primary histological features of AHXR are endothelial swelling or disruption, vascular thrombosis with blood extravasation, and interstitial oedema [62]. Within 24 hours of transplantation, this generally develops, gets worse over the next few days, and finally kills the graft. The first response, which is mostly but not solely specific for the gal epitope, is mediated by IgM, and is thereafter followed by an increase in IgG levels [63]. By themselves, these xenograft natural antibod- ies induce a procoagulant state that develops into disseminated intravascular coagulation. Even the best practises for limiting complement activation, lowering T-cell and B-cell driven im- mune responses, and diminishing xenograft natural antibodies Highlights in BioScience Page 5 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions Table 2. Different pharmaceutical products derived from non-human mammalian cells as represented by [57; 58; 59]. Origin Generic name Product name Therapeutic class Equine (Horse) Conjugated oestrogen Premarin Gonadal hormone, Oestrogen Antithymocyte Immuglobulin (ATG) ATGAM Immunosuppressant Snake antivenom Red back spider antivenom Antivenom Tiger snake antivenom Green Pit Viper Antivenin Sea snake antivenin Cobra Antivenin Taipan antivenom King Cobra Antivenin Polyvalent Snake Antivenin Medroxyprogesterone acetate Premia Gonadal hormone Stonefish antivenom Stonefish antivenom Antivenom Porcine (Pig): Coagulation factors II, IX, X, V & VII Prothrombinex-VF Haemostatic agent Heparin sodium Heparinised saline Anticoagulant Amylase, lipase, pancrelipase, protease Panzytrat Digestive supplement Poractant alfa Curosurf Respiratory agent Danaparoid Orgaran Haemostatic agent Human rotavirus live attenuated vaccine Rotarix Vaccine Dalteparin Fragmin Anticoagulant Rotavirus vaccine live oral pentavalent RotaTeq Vaccine Pancrelipase pancreatin Creon Digestive supplements & cholelitholytics Enoxaparin Clexane Anticoagulant, Antithrombotics Zoster virus vaccine live Zostavax Vaccine Vancomycin Hydrochloride Vancomycin HCl Antibiotic, miscellaneous Murine (Mouse) Trastuzumab Herceptin Antineoplastic agent Cetuximab Erbitux Antineoplastic agent Infliximab Remicade Monoclonal antibody Antihemophilic Factor VIII (human) Hemofil M Antihemophlic Agent Bevacizumab Avastin Antineoplastic agent Rituximab MabThera Antineoplastic agent; Monoclonal antibody Golimumab Simponi Antirheumatic agent Abciximab Reopro Anticoagulant Palivizumab Synagis Immunomodifier Somatropin Saizen Pituitary hormone Basiliximab Simulect Immunomodifier Bovine (Cow) Epinephrine Adrenaline Neurotransmitter Sealerprotein solution+ thrombin solution Tisseel VHS/D Solution Haemostatic agent Collagen Zyderm Collagen implants Dermatological preparations Calfactant Infasurf Treatment of premature infant lungs Hepatitis A vaccine Vivaxim Vaccine Allantoin Allantoin Cosmetics, treatment of wounds & ulcers Polygeline Haemaccel Plasma volume expander Varicellazoster vaccine, live Varivax Vaccine Calporo Calporo Herbal daily supplements Insulin Hypurininjection Insulin preparations Bovine colostrums Travelan Anti-diarrhoeal Survanta Beractant Treatment of premature infant lungs Cartilag Cartilag Herbal analgesics & anti-inflammatories Continued on next page Highlights in BioScience Page 6 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions Table 2. – continued from previous page. Origin Generic name Product name Therapeutic class Bovine-manufacture Acitretin Novatretin Antipsoriatic Measles, mumps & rubella vaccine Priorix Vaccine Itraconazole Itrazol Antifungal, azole derivative Inox Mebeverine HCl Mebetin Antispasmodics Amoxycillin Synamox Antibiotic, Penicillin Loperamide Colodium Antidiareal Modim Mycophenolate Mofetil Cellcept Immunosuppressant agent Essential Phospholipids Livovid Cholelitholytics Rabies vaccine Merieux Vaccine Rabipur HepatitisAvaccine Avaxim Vaccine Havrix Hydrocortisone HydrocortisonOrion Corticosteroid Clindamycin HCl Tidact Antibiotic, Lincosamide Recombinant antihaemophilic factor Recombinate Haemostaticagents Nilotinib Tasigna Antineoplastic agent, thyroxine kinase inhibitor Clofazimine Fazim Antibiotics, Leprostatic Ampicillin Sod+ Sulbactam Sod Unasyn Antibiotic, Penicillin Rabies human diploid cell vaccine Verorab Vaccine Hepatitis B vaccine Engerix-B Vaccine Omeprazole Omeprazole Gastric acid secretion inhibitor, proton pump inhibitor Calcitriol Osteocap Vitamin D Analog diphtheria, tetanus & acellular pertussis vaccine Adacel Vaccine Cyclosporin Sandimmun Immunosuppressant, Calcineurin inhibitor Pneumococcal vaccine Prevenar Vaccine Doxycycline Xidox Antibiotics, Tetracyclines derivatives Celecoxib Celebrex NSAID, Cyclooxygenase-2 inhibitor Phenytoin sodium Dilantin Anti-epilepsy Dutasteride Avodart 5-alpha-reductase inhibitor Oseltamivir phosphate Fluhalt Antiviral, influenza, neuraminidase inhibitor Diphtheria toxoid ADT Booster Vaccine Boostrix Pancreatin Creon Pancreatic enzyme replacement Danazol Nazo Androgen Oxycodone HCl Oxynorm Opioids analgesic Pregabalin Lyrica Anticonvulsant Didanosine Aurobindo Antiretrovirals Haemophilus B influenzae vaccine Hiberix Vaccine Heparin sodium injection Heparinol Anticoagulant Isotretinoin Acnotin Anti acne, antineoplastic agent Recombinant antihaemophilic factor Recombinate Haemostatic agents Influenza virus vaccine Fluarix Vaccine Tacrolimus Prograf Immunosuppressant agent Fluconazole Fluconazole Antifungals Rivastigmine Rivadem Acethylcholinesterase inhibitor Gem fibrozil Gem fibrozil Dyslipidaemic agents Yellow fever vaccine 17D vaccine Vaccine Continued on next page Highlights in BioScience Page 7 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions Table 2. – continued from previous page. Origin Generic name Product name Therapeutic class Egg/Chicken Measles, mumps and rubella virus vaccine l M-M-R II Vaccine Influenza virus vaccine Agrippal Vaccine Measles, mumps and rubella virus vaccine Priorix Vaccine Measles, mumps, rubella and varicella vaccine Priorix-Tetra & ProQuad Vaccine Rabies vaccine Rabipur Vaccine Coxiella burnetii vaccine Q-Vax & Q-Vax Skin Test Vaccine Influenza virus vaccine Vaxigrip Vaccine Risperidone Rixadone Antipsychotic agent Verteporfin Visudyne ophthalmic medication quadrivalent influenza vaccine Afluria Quad Vaccine Propofol Propofol Sandoz Propofol-Lipuro 1%/2% Provive 1% & Provive MCT-LCT 1% Anaesthetics Yellow Fever Vaccine Stamaril Vaccine Olive oil and soya oil Clin Oleic 20% Parenteral vitamins, minerals and nutrition Sebelipase alfa Kanuma endocrine and metabolic agent Influenza virus vaccine Fluarix Vaccine quadrivalent influenza vaccine Fluad Quad Vaccine Quadrivalent Influenza Vaccine FluQuadri Vaccine Influenza virus vaccine Fluad Vaccine trivalent influenza vaccine Fluzone HighDose Vaccine Clevidipine Cleviprex Antihypertensive agent Influenza virus vaccine Influvac Vaccine Propofol Diprivan Anaesthetics Propofol Fresofol 1% Injection & Fresofol 1% MCT/LCT Anaesthetics Soya oil Intralipid Parenteral vitamins, minerals and nutrition Chinese hamster ovary (CHO) cells Aflibercept Eylea Ophthalmic medication Follitropinalfa Gonal-f Pituitary hormone Erythropoeitin alfa Binocrit Hematopoietic agent Laronidase Aldurazyme Enzyme replacement therapy Abatacept Orencia Immuno-modifier Interferon beta-1a Avonex Immunomodifier Rebif Omalizumab Xolair Other respiratory agent Etanercept Enbrel Tumour necrosis factor inhibitor Panitumumab Vectibix Antineoplastic agents Eptacog alfa NovoSevenRT Haemostatic agent Octocogalfa Advate Haemostatic agent KogenateFS Lenograstim Granocyte Supportive therapy Follitropinbeta Puregon Pituitary hormone Nonacogalfa BeneFIX Haemostatic agent Lutropin alfa Luveris 75 IU Pituitary hormone Imiglucerase Cerezyme Enzyme replacement therapy Dornasealfa Pulmozyme Respiratory agent Continued on next page Highlights in BioScience Page 8 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions Table 2. – continued from previous page. Origin Generic name Product name Therapeutic class Dornasealfa Pulmozyme Respiratory agent Alemtuzumab Mabcampath Antineoplastic agent Trastuzumab Herceptin Antineoplastic agent Choriogonadotropin alfa Ovidrel Pituitary hormone Tenecteplase Metalyse Fibrinolytic agent Darbepoietin Aranesp Haemopoietic agent Recombinate antihaemophilic factor Recombinate Haemostatic agent Agalsidasebeta Fabrazyme Enzyme replacement therapy Epoietin alfa Eprex Haemopoieticagent Rituximab Mabthera Antineoplasticagent Methoxy polyethylene glycol-epoetinbeta Micera Hematopoietic agent Denosumab Prolia Monoclonal antibody Xgeva Moroctocogalfa Xyntha Haemostaticagent Epoetin lambda Novicrit Haemopoieticagent Bevacizumab Avastin Antineoplastic Epoietin beta NeoRecormon Haemopoieticagent Corifollitropin alfa Elonva Pituitary hormones Sheep Box Jellyfish Antivenom Box Jellyfish Antivenom antivenom Digoxin binding antibody Digoxin-specific antibody fragment DigiFab Antidote Fish, Shark and Shell fish house dust mite extract Acarizax Antiallergy preparation Chondroitin Chondroitin Complementary osteoarthritis Inactivated influenza vaccine Fluad Vaccine Glucosamine Glucosamine Complementary osteoarthritis Phleum pratense. Grazax Antiallergy preparation Insulin Human Insulin (rys) & Protaphane Mixtard 30/70. Mixtard 50/50 Insulin preparation Rabbit Funnel web spider antivenom (rabbit) Funnel Web Spider Antivenom antivenom Highlights in BioScience Page 9 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions sometimes fall short of addressing these issues. Diffuse intravas- cular coagulation and thrombotic microangiopathy, which are related to postpone xenotransplant rejection, are caused by un- known processes. AHXR is the least well-known of the early xenograft rejection phases [64]. Cell proliferation, aberrant differentiation, and death Similar to the problems with cell replacement treatment, cell death and abnormal cell differentiation and proliferation directly led to the failure of xenogeneic stem cell transplantation and even injured the recipients. Researchers have shown that the microenvironment of the cell culture affects cell differentiation and death. Several researchers have attempted to change the mi- croenvironment of the cells to prevent cell death and abnormal differentiation. Here, we will discuss two common methods for changing the microenvironments of cell cultures to resemble the in vivo natural growth niche. One tactic is to change the tra- ditional two-dimensional (2D) culture into a three-dimensional (3D) culture. Umbilical cord MSC single-cell derived spheres were produced by [65] using cell chips, a device to restrict cells to specific spatial locations. They combined a 3D culture with a 2D arrayed pattern of single or multiple cells on one patch of the cell chip in order to improve MSC survival and migratory ability and to promote angiogenesis in xenotransplantation [65]. The other technique requires changing the scaffold. Materials used as scaffolds in tissue engineering xenogeneic stem cell trans- plantation may promote cell survival and differentiation. [66] employed a hyaluronic acid-based scaffold that has been cova- lently modified by poly-l-Lysine as a delivery vehicle to deliver hBMSCs to rats with injured spinal cords. Rats receiving hBM- SCs/hyaluronic acid-poly-l-Lysine showed improved in vivo sur- vival of transplanted hBMSCs, according to [66]. In contrast, when sheep MSCs were injected into immunocompromised rats, a ceramic hyaluronic acid/tricalcium phosphate carrier led to ec- topic osteogenesis, adipogenesis, and hematopoietic-support ac- tivities [67]. The necessity of selecting an adequate substrate for tissue creation while taking into account the anticipated direc- tion of cell differentiation was established by these findings [67]. iPSCs and ESCs may be tumorigenic due to their capacity for cellular growth in cell transplantation and other treatments. This problem was addressed by [68] by implementing optimised di- rected differentiation protocols to generate the desired precursor cell types and by using cellular enrichment techniques to elim- inate unnecessary cells in order to choose only the cells with a restricted proliferation potential for transplantation. Religious restrictions In Table 3 we provide information about the restrictions on xenotransplantation products in different countries based on the religions practiced in those countries. It is important to note that these restrictions are based on the beliefs and practices of individual religions and do not necessarily reflect the views or laws of the countries in which they are practiced. One of the main observations from the table is that many religions place restrictions on the use of certain animal prod- ucts. For example, Islam prohibits the use of porcine products and requires that all animal products be slaughtered in a specific way. Similarly, Judaism prohibits the use of porcine and shell- fish products and has strict rules about the types of land animals, birds, and fish that can be consumed. Hinduism and Sikhism also place restrictions on the use of animal products, with many Hindus abstaining from all animal products and Sikhs prohibit- ing the use of halal sources. Another important aspect of the table is the diversity of reli- gions represented. The table includes information about Islam, Judaism, Seventh Day Adventism, Hinduism, Sikhism, and Je- hovah’s Witnesses, among others. This highlights the fact that religious beliefs and practices can vary widely and may influ- ence the use of xenotransplantation products in different parts of the world. Overall, the table provides useful information about the po- tential restrictions on xenotransplantation products based on the religions practiced in different countries. It is important to con- sider these restrictions when developing and implementing xeno- transplantation treatments in order to respect the beliefs and prac- tices of different religious communities. Ethical concerns Ethics around xenogeneic stem cell transplantation are be- coming more widely accepted. Some people believe that xeno- transplantation consistently transgresses the lines between species and lowers the dignity of humans. Animal welfare organisations also opposed xenotransplantation on the grounds that nonhuman creatures shouldn’t be seen of as re-designable systems [70]. In reality, a wide range of animal products are now used by hu- mans. For instance, bioactive bones from decellularized bovine femoral bone and freeze-dried bone marrow stem cell paracrine factors are widely used in large-sized bone lesions. These suc- cesses are gradually changing people’s opinions and paving the way for xenogeneic stem cell transplantation. However, any ap- plications must consider regional variations in culture, legisla- tion, beliefs, and other factors [71]. Risk of zoonotic infections Potential benefits of xenotransplantation over allotransplan- tation (transplantation between members of the same species) include an almost limitless supply of grafts, animal species resis- tance to certain human infections (baboons, for example, are im- mune to the hepatitis B virus (HBV) and the human immunodefi- ciency virus (HIV)), and the ability to lower the risk of xenograft- associated infections by using specific pathogen-free animals with lifelong controversies, and the ability to reduce the risk of xenograft [72; 73]. However, if the risk to public health arises from introducing novel zoonotic infectious diseases into the hu- man population that aren’t typically present there, the prospect of spreading germs from animals to people via xenotransplanta- tion cannot be completely precluded [74]. The characteristics of Highlights in BioScience Page 10 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions Table 3. Religious restrictions as published by others [59; 69]. Religion Countries where widely practiced Restrictions Islam Indonesia, India, Pakistan, Bangladesh, Egypt, Turkey, Iran, Nigeria, Ethiopia, Afghanistan, Sudan, Iraq, Malaysia, Tanzania, Somalia, Cote dIvoire, Congo, Philippines, Sierra Leone, Thailand, Eritrea, Lebanon Porcine products prohibited All animal products not killed in the prescribed ritualistic way (halal) prohibited Products containing alcohol prohibited Judaism USA, Israel, France, Canada, UK, Russia, Argentina, Ukraine, Brazil and South Africa All porcine and shellfish products prohibited . other rules about animal products that can be ingested: land animals must be mammals which chew their cud and have cloven hooves birds of prey are prohibited . Fish must have scales and fins. Meat and milk (or any other dairy product) cannot be combined; shrimp and other non-fish seafood are forbidden. Observers follow a stringent set of regulations and only eat kosher food. Seventh Day Adventist Australia, USA, South America, some African countries Some abstain from meat, but eggs are permissible. Hinduism India, Nepal, Bangladesh, Indonesia, Pakistan, Sri Lanka, Philippines, Fiji, UK, Mauritius, Bhutan, South Africa, Burma, Singapore For the vast majority of vegetarians, all animal products, including eggs, are forbidden. Bovine and porcine goods continue to be prohibited for persons who are not vegetarians. Sikh India, Pakistan, Malaysia, Singapore, Fiji, New Zealand, USA and UK For some who are vegetarian all animal products including egg prohibited For those who are not vegetarian, restrictions still include bovine and porcine products All animal products from halal sources prohibited Products containing alcohol prohibited. Jehovahs witnesses Australia, USA, Mexico, Brazil and many other countries (240 in total) The use of fractions derived from the primary components of blood is not absolutely prohibited Buddhism Tibet, Bhutan, India, Nepal, Sri Lanka, Burma, Thailand, Laos, Cambodia, Malaysia, Vietnam, China, Bangladesh, Korea, Japan, Singapore, parts of Russia For some vegetarian Buddhists - all animal products prohibited however, no fixed rules. Highlights in BioScience Page 11 of 15 December 2022|Volume 5 http://bioscience.highlightsin.org/ Eissa et al, 2022 Xenotransplantation: past, present, and future directions the particular organism, the amount of the organism transferred, the presence of the necessary equipment (such as receptors and nutrients in the host), and the immunological proficiency of the host all affect the likelihood of contracting a zoonotic infection. Even the wide range of potential clinical signs cannot be pre- dicted for previously undetected animal-derived illnesses in hu- man hosts [75]. Recipients and their contacts should be routinely screened for zoonotic infectious agents, either by direct methods (which depend on detecting the presence of the agent itself or its prod- ucts) or even by indirect methods (which depend on detecting the production of antibodies against specific microbes and anti- gens) [76]. This is to prevent a potential new zoonosis from spreading among humans as a result of xenotransplantation. Conclusion Biotechnology has the power to drastically modify human existence, as we indicated at the beginning of our discussion and as the rise of xenotransplantation amply indicates. Furthermore, according to Gaskell’s research, moral objections to biotechnol- ogy are allegedly more significant to society than even safety objections. Even non-problems, like "violating God’s will" or "going against nature," are elevated to the status of the most se- vere ethical concerns as a result of society’s lack of scientific and ethical understanding, which makes it challenging to come up with reasonable answers. Such an error might restrict the use of biotechnology to save lives and alleviate suffering, as our dis- cussion has shown. This in turn emphasises the critical social illiteracy of science that we mentioned at the beginning of our argument, as well as the urgent need for expanded education of the general public, the scientific community, and society at large on ethics. Although it is relatively easy to see this issue, solving it is much more difficult. We have both taught and pushed for the inclusion of ethical considerations in science education as a necessary precursor to rational solutions to ethical difficulties arising out of scientific findings. We have also seen that such education produces better scientists who have a sense of social responsibility. Additionally, we have argued that it is critical to discuss and elucidate ethical issues while instructing students in science, particularly biological science. This has proven to be considerably more difficult. Obstacles to it include the fact that such an approach is historically uncommon and that the ma- jority of scientists believe research is "value-free in general, and ethics-free in particular," as demonstrated in our debate. The ma- jority of people who teach science do not have formal training in the ethical issues that arise from science or even how to start addressing such obstacles, which creates additional challenges. Determining when and how to begin integrating an ethical com- ponent into scientific instruction might be difficult as a result of these difficulties. The casual attitude of the research community toward the ethical issues associated to animal usage in research, which further distances the scientific community from the gen- eral people, is evident as social concern over the treatment of animals grows dramatically. If, as leaders in the scientific com- munity have repeatedly remarked, scientific growth is entirely dependent upon the use of animals, then it is the responsibility of the scientific community to address social ethical concerns associated to animal exploitation. The development of animal ethics as we have described it is predicated on the notion of an animal, and society seems to concur with this. Furthermore, we brought this up throughout our discussion. The ethical viability of genetic modification, which is readily acknowledged to im- pact both large and small changes in telos, therefore inevitably arises. It is obvious that this is not the place for a comprehen- sive examination of this annoying problem. As long as the telos changes do not negatively affect the animals’ quality of lifethat is, as long as the animals produced through genetic modification are not worse off than their unmodified forebears and, ideally, better offwe have argued that there is no morally wrong with carrying out such genetic modifications. In other words, it’s im- portant to make sure that animal genetic engineering doesn’t do any harm. As with genetic alteration to fix genetic defects or prevent disease, the ideal outcome for animals is that they will be better off as a result of the change. Such problems will not be resolved unless major changes in scientists’ thinking, which can only be made by significantly modifying the way science is taught, are made. At that point, ethics can be incorporated into recognised scientific theory and practise. Reference 1. White S, Hirth R, Mah’illo B, Dom’inguez-Gil B, Del- monico F, Noel L, et al. 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An approach to the control of disease transmission in pig-to-human xenotransplantation. Xeno- transplantation. 2000;7(2):143-55. 75. Fishman J, Scobie L, Takeuchi Y. Xenotransplantation- associated infectious risk: a WHO consultation. Xenotrans- plantation. 2012;19(2):72-81. 76. Food, Administration D. Guidance for industry (final guid- ance): source animal, product, preclinical, and clinical is- sues concerning the use of xenotransplantation products in humans; 2003. Available from: http://www.fda.gov/ cber/gdlns/clinxeno.htm. Highlights in BioScience Page 15 of 15 December 2022|Volume 5 http://www.fda.gov/cber/gdlns/clinxeno.htm http://www.fda.gov/cber/gdlns/clinxeno.htm http://bioscience.highlightsin.org/ Abstract Introduction Chimeras in folklore History of clinical experiences with xenotransplantation Blood xenotransfusion Blood vessel anastomosis Skin xenotransplantation Corneal xenotransplantation Cell xenotransplantation Xenotransplantation of the kidney Xenotransplantation of the heart Lung xenotransplantation Liver xenotransplantation The first islet xenotransplantation Features of the perfect donor animal include Other pharmaceuticals of animal origin Issues with several xenotransplantation cases Immune rejection Hyperacute rejection Acute humoral xenograft rejection (AHXR) Cell proliferation, aberrant differentiation, and death Religious restrictions Ethical concerns Risk of zoonotic infections Conclusion