Therapeutic cloning applications for organ transplantation
Introduction
The fields of regenerative medicine and tissue engineering aim to restore the form and function of damaged tissue and organs that have suffered from disease and injury. Many disorders, such as congenital anomalies, cancer, trauma, infection, inflammation, iatrogenic injuries, and other conditions, can lead to organ damage or loss and to the eventual need for reconstruction. It has been estimated that in the United States, one person in five reaching 65 years of age will receive temporary or permanent organ-replacement therapy during his or her remaining life span [1]. Furthermore, using the kidney as an example, over two million patients are projected to suffer from end-stage renal disease by 2010 and the aggregate health care costs for treating these patients has been estimated to be over $1 trillion dollars [2].
The majority of current reconstructive techniques rely on donor tissue for replacement; however, a shortage of donor tissue may limit these types of reconstruction, and usually significant morbidity is associated with the harvest procedure. Furthermore, the functional aspects of the damaged organ are rarely replaced by these reconstructive procedures, and they may even lead to complications because of the inherently different functional parameters of reconstructed tissue. Other potential sources of tissue include homologous tissues from cadavers, heterologous tissues from animal sources (bovine), and artificial materials (silicone, polyurethane, Teflon). Artificial devices made from these alternative sources were noted to be biocompatible and could provide structural replacement; however, the functional component of the original tissue was usually not recovered. While caution and disease prevention may never completely eradicate the incidence of disease and injury, regenerative medicine physicians and researchers hope to relieve the suffering of their patients from these unfortunate entities, and if possible, to repair or restore the damaged tissue with the hope of regenerating essentially normal body parts.
Organ transplantation was one of the first methods to restore form and function in modern medicine. In 1955, Murray performed the first successful organ transplant (kidney), and in the early 1960s, he performed the first allogeneic kidney transplantation from a genetically dissimilar donor into an unrelated recipient [3]. As one of the first procedures to overcome the immunologic barrier, this revolutionary procedure marked the modern era in which transplantation could be used as means of therapy for diseased and injured organs. Since then, advances in immunosuppressive medications, in the matching of similar donors to recipients, and in the treatment of rejections have resulted in thousands of patients each year undergoing successful transplantation of donor organs. In 2001, over 23 000 patients received a transplanted organ in the United States [4].
However, despite the advances in transplantation over the past 50 years, a severe shortage of donor organs limits the availability of this treatment, such that in 2001, nearly 80 000 patients were awaiting a donor organ, and over 6000 patients were reported to have died while awaiting an organ transplant [4]. This has spawned the search for alternate therapies, such as therapeutic cloning, that can be used in regenerative medicine applications.
Regenerative medicine has the potential to benefit from cloning technology. Cloning techniques are already widely utilized in the modern world, where gardeners perform plant cuttings and commercial companies propagate desirable plant strains and animal breeds [5]. However, since the birth of Dolly as the first animal cloned from an adult somatic cell in 1997, tremendous further interest in cloning has arisen, and cloning has been envisioned as having utility in medical applications as well.
Section snippets
Definition of therapeutic cloning
Nuclear cloning, which has also been called nuclear transplantation and nuclear transfer, involves the introduction of a nucleus from a donor cell into an enucleated oocyte to generate an embryo with a genetic makeup identical to that of the donor.
While there has been tremendous interest in the field of nuclear cloning since the birth of Dolly in 1997, the first successful nuclear transfer was reported over 50 years ago by Briggs and King [6]. Cloned frogs, which were the first vertebrates
Stem cells and therapeutic cloning
Most current strategies for tissue/organ replacement therapy depend upon a sample of autologous cells from the diseased organ of the host. However, for many patients with extensive end-stage organ failure, a tissue biopsy may not yield enough normal cells for expansion and eventual transplantation. In these situations, embryonic stem cells are envisioned as an alternative source of cells from which the desired tissue can be derived. Combining the techniques learned in tissue engineering over
Further improvements in somatic cell nuclear transfer technology
While promising, somatic cell nuclear transfer technology has certain limitations that require further improvements before therapeutic cloning can be applied widely in replacement therapy.
Currently, the efficiency of the overall cloning process is low. The majority of embryos derived from animal cloning do not survive after implantation [38], [39], [40]. In practical terms, multiple nuclear transfers must be performed in order to produce one live offspring for animal cloning applications. The
Tissue engineering principles
After an adequate amount of cells are expanded from a cloned source, tissue engineering will be required to produce transplantable tissue or organs. The field of tissue engineering has emerged over the past 40 years to address the shortcomings of previous replacement therapies. Scientists in this relatively new field aim to combine the principles of cell transplantation, material science, and engineering to construct biological substitutes that will restore and maintain normal function in
Applications of therapeutic cloning
We applied the principles of both tissue engineering and therapeutic cloning in an effort to produce genetically identical renal and cardiac muscle tissue in a large animal model, the cow (Bos taurus) [78]. Unfertilized bovine donor oocytes were retrieved from abbatoir-derived ovaries, and the nuclear material from these eggs was removed by mechanical enucleation 18–22 h after maturation. Complete enucleation of the metaphase plate was confirmed with bisBenzimide dye under fluorescence
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