Technical Considerations in the Pig-To-Human Kidney Xenotransplant: A Historical Perspective.

As the limited supply of human donor organs remains the greatest barrier to renal transplantation, porcine renal xenografts have the potential to reduce the organ shortage. Recent attempts at using genetically engineered porcine renal xenografts have met with technical and functional problems. It is theorized that if transplantation of the en bloc kidneys had been performed: (1) the double nephron mass would provide normal renal function, (2) the procedure would be easier and safer by using the larger and thicker donor aorta and vena cava instead of the smaller and thinner-wall renal vessels, and (3) the operative procedure would be less time consuming because there are only 2 anastomoses to perform instead of a minimum of 4. The literature review on the use of en bloc renal xenografts is performed, as well as the application on the long-term use of small pediatric kidneys in humans.

The rise and fall of heterologous transfusion.

Now a routine lifesaving treatment, blood transfusion between humans became a safe procedure only after many early therapeutic disasters. Performed between different species, heterologous transfusions actually succeeded homologous transfusions, those performed between members of the same species. In the early history of transfusion, both homologous and heterologous transfusions were performed in many clinical settings. Early clinicians were unable to distinguish between deaths caused by baseline illness and those resulting from transfusions. This report examines both early experiments with homologous transfusion between animals and later efforts investigating and finally abandoning heterologous transfusion. Topics explored include: 1) contributions and lessons learned from key individuals, 2) how these researchers suggested, performed, advocated, or challenged the practice of heterologous transfusion, and 3) why heterologous transfusions were even considered as a mode of therapy.

Leo Fabian: A Life of Accomplishment.

Leo Fabian played a role in many anesthesia firsts: the first halothane anesthetics in the United States, the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. As was common for men of his generation, Fabian's first taste of medicine came during World War II, as a pharmacist's mate aboard the U.S.S. Bountiful. Afterward, he pursued his medical education before joining Dr. C. Ronald Stephen and the anesthesiology department at Duke. There he helped to create one of the first inhalers for halothane, the Fabian Newton Stephen (F-N-S) Fluothane Vaporizer. Fabian left Duke for the University of Mississippi Medical Center, where he consistently worked with the chair of surgery, Dr. James Hardy. Together they performed the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. By the end of his time at Mississippi, Fabian and Hardy had several philosophical disagreements, and Fabian ultimately left for Washington University in St. Louis, where he rejoined Dr. Stephen. He served as Stephen's right-hand man and would oversee the department when Stephen was away. Fabian spent the final years of his career as chair of the department before his own health forced him to step down.

Ideal xenograft or a perfect bone substitute?-A retrospective review and analysis of the historical concept of ivory implants in orthopaedics.

PURPOSE: Surgical treatment of fractures has evolved with the development of anaesthesia in 1846. Experiments with different implants both organic and non-organic had led to introduction of sometimes extremely peculiar materials coming from different species like ox bone or elephant's ivory. The aim of this article is to present not widely known concept of ivory use in bone surgery that set its foot in the history of orthopaedics and laid foundations for orthobiologic reconstructions. METHODS: Retrospective analysis of articles and books published between 1846 and 2017 that describe various examples of ivory application in the treatment of fresh fractures, non-unions and reconstruction of joints. RESULTS: Our research shows that ivory to the surgical world was introduced by Friedrich Dieffenbach, founder of the modern plastic surgery. It was also used with different rate of success by many of the famous surgeons of the nineteenth and twentieth century to include Trendelenburg, Billroth, Volkmann, Paget and Hey Groves. Ivory was immensely popular in bone surgery and became material of choice demonstrating amazing biological properties and very low rate of infections. CONCLUSION: Ivory has served well in successful treatment of various orthopaedic conditions for over 100 years. In this article, we are using history as a stepping stone to examine material that is not rejected by the body and promotes bony healing without increased infection or other complications. It is worth considering further analysis of historically acquired specimens for further development of materials for further orthopaedic fracture and reconstructive techniques.

200 Years After Frankenstein.

Mary Shelley's Frankenstein is 200 years old and remains relevant to 21st-century scientific experimentation. Molecular biologists today have become especially bold in their attempts to cure diseases while remaining mindful of the real dangers of their research. Scientists presumably share an abiding concern about producing uncontrollable mutations in people, animals, and the wider environment, yet a sense of urgency appears to inform the current scientific willingness to take risks, especially in the realm of embryology and germ-line modification. This willingness to go more boldly than before could be influenced by the unprecedented ability of such gene-cutting technologies as CRISPR to make immediate and lasting improvements to persons suffering from certain diseases and other physical malignancies, but also by an acculturated sense that such persons deserve to participate more fully in broader society.

Renal xenotransplantation: experimental progress and clinical prospects.

There are >100,000 patients waiting for kidney transplants in the United States and a vast need worldwide. Xenotransplantation, in the form of the transplantation of kidneys from genetically engineered pigs, offers the possibility of overcoming the chronic shortage of deceased and living human donors. These genetic manipulations can take the form of (i) knockout of pig genes that are responsible for the expression of antigens against which the primate (human or nonhuman primate) has natural "preformed" antibodies that bind and initiate complement-mediated destruction or (ii) the insertion of human transgenes that provide protection against the human complement, coagulation, or inflammatory responses. Between 1989 and 2015, pig kidney graft survival in nonhuman primates increased from 23 days to almost 10 months. There appear to be no clinically significant physiological incompatibilities in renal function between pigs and primates. The organ-source pigs will be housed in a biosecure environment, and thus the risk of transferring an exogenous potentially pathogenic microorganism will be less than that after allotransplantation. Although the risk associated with porcine endogenous retroviruses is considered small, techniques are now available whereby they could potentially be excluded from the pig. The US Food and Drug Administration suggests that xenotransplantation should be restricted to "patients with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available." These might include those with (i) a high degree of allosensitization to human leukocyte antigens or (ii) rapid recurrence of primary disease in previous allografts. The potential psychosocial, regulatory, and legal aspects of clinical xenotransplantation are briefly discussed.

A brief history of clinical xenotransplantation.

Between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century, with grafts from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into elderly men, believing that the hormones produced by the testis would rejuvenate his patients. In 1963-4, when human organs were not available and dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 h. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992 he obtained patient survival for 70 days following a baboon liver transplant. The first clinical pig islet transplant was carried out by Groth in 1993. Today, genetically-modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant.

The long and tortuous history of the discovery of testosterone and its clinical application.

INTRODUCTION: The testis importance in homeostasis was recognized for millennia, but a consistent interest in exploring their endocrine function only goes back to about a century. AIM: The aim of this study is to provide a succinct perspective of the events leading to the discovery of testosterone, the mind-boggling early attempts at therapy and today's situation. METHOD: The literature was reviewed with searches in OvidSP Medline, PubMed, and Google Scholar under the headings of testosterone/androgens history. Due to the explosion of reports between the late 19th and early 20th centuries, a manual review of the collection of the period's journals at the university's library was performed. Pertinent books were consulted for specific biographical details. RESULTS: There is a robust body of literature dealing with testicular function for the period starting in the late 1800s. It is illustrative to learn the painful efforts of many well-intentioned and honest scientists with more conviction and determination than knowledge. Among them, unfortunately, a number of charlatans and profiteers tainted the concept of hypogonadism and its treatment with repercussions lasting until this day. The discovery and synthesis of testosterone represent the effort of brilliant minds (two Nobel Prizes) in various countries and frequently working for the pharmaceutical industry. Shortly after testosterone became available, controversy arose about its application, use, abuse, and potential detrimental effects. Over the decades, the hullabaloo about hypogonadism and its treatment has focused on a variety of issues ranging from absurd efficacy claims to solid studies and from doubts of its existence to convincing proof of a detrimental age-associated deficit in testosterone production. CONCLUSIONS: The history of testosterone discovery, synthesis, and introduction into the therapeutic armamentarium is an outstanding example of human curiosity, ingenuity, greed, and skepticism. Despite the vast progress in the field, many issues remain unresolved, but thoughtful science augurs well for its future.

Voronoff to virion: 1920s testis transplantation and AIDS.

BACKGROUND: We address accusations linking AIDS with testis transplantation performed by a French surgeon, Serge Voronoff (1866-1951), and their implications in the future of animal-to-human organ transplantation. METHODS: Biographical literature on Voronoff and scientific literature on xenotransplantation and the origin of HIV were reviewed. RESULTS: IN the 1920s, Serge Voronoff transplanted testes from primates into humans to revitalize them sexually and physically, making him one of the first surgeons to perform xenotransplantation-transplanting live tissues between species. In recent years, some have postulated that Voronoff's transplants may have caused or contributed to the AIDS epidemic. However, consensus among virologists holds that HIV most likely originated from a chimpanzee virus known as simian immunodeficiency viruses (SIV) which many agree was transmitted to humans during the hunting of primates in the early 1900s. As these accusations have never been addressed, evidence is reviewed which refutes the claims. HIV isolate studies are summarized, which show that SIV was most likely transferred to humans from a chimpanzee species different from those used by Voronoff. Furthermore, literature suggests that Voronoff's experiments were performed in Europe and the United States, not central Africa. CONCLUSIONS: Over 100,000 people await organ transplants, making the prospect of using animal organs to meet demand increasingly favorable. The accusations against Voronoff and others have led to increased concern over cross-species disease transfer. The evidence presented refutes those claims and is used to explain the need for further research into xenotransplantation.