Erythropoietin.

During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

The value of failure: the discovery of TNF and its natural inhibitor erythropoietin.

The hurtful feelings associated with failing can be devastating especially if the failure occurs after the investment of a considerable effort. The reflection of a lifetime of work in translational medicine has revealed that the study of failures can give birth to new insights that can be explored with important consequences. This article discusses the analysis of two failures that have led to remarkable discoveries. The first led to the discovery of TNF as an important mediator of inflammation that can, if unchecked, cause severe damage in mammals. The second is the identification of erythropoietin as the natural inhibitor of the production and biological activity of TNF. I hope that this paper will help give students the courage to persist in looking for the insights that are the by-products of failure, and to understand the long time lines in the path of discoveries.

Landmark advances in the development of erythropoietin.

This is a Minireview covering landmarks or milestones in the development of erythropoietin (EPO). Thirty-nine landmark advances have been identified, which cover the period 1863-2003. Several reports are included that directly support these original landmark advances. This Minireview also updates some of the advances in EPO research since my last Minireview update on EPO published in this journal in 2003. The areas of EPO research updated are: sites of production; purification, assay and standardization; regulation; action; use in anemias; extraerythropoietic actions; adverse effects; and blood doping. The new reports on the use of EPO in the therapy of myocardial infarction; stroke and other neurological diseases; diabetic retinopathy and other retinal diseases are also covered.

2009: a requiem for rHuEPOs--but should we nail down the coffin in 2010?

The recombinant human erythropoietins and allied proteins (epoetin alfa, attempted copies and biosimilar variants of epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine. This article charts a brief history of their use in clinical medicine, mainly dealing with chronic kidney disease, paying special attention to how these agents were introduced into clinical medicine and what has happened subsequently; in 2009, there were several developments that could be regarded as a "perfect storm" in terms of the long-term use of these compounds in chronic kidney disease and oncology and, likely, elsewhere. We are now very much at a "crossroads," where mature reflection is required, because with the latest trials and meta-analyses, these therapies seem not only expensive but also very much a clinical tradeoff (increased risk of adverse effects versus a small gain in fatigue scores). How we arrived at this crossroads is a useful illustration of how easy it is, without properly designed randomized, controlled trials, to assume that clinical benefit must follow therapeutic interventions.

The meandering 45-year odyssey of a clinical immunologist.

My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.

Recombinant human erythropoietin: 10 years of clinical experience.

The need for a renewable source of erythropoietin to treat the anaemia of chronic renal failure was first recognized in the 1960s, but cloning and expression of the human gene was not achieved until 1983. Clinical testing of recombinant human erythropoietin (r-HuEPO) began in 1985, leading to the first licence as a therapeutic agent in 1988. The first clinical trials showed that an intravenous dose requirement of about 200 IU/kg/week would increase haemoglobin concentrations to 10-12g/dl in >90% of haemodialysis patients. Subcutaneous administration has subsequently been found to be effective, and may allow lower maintenance doses. It is now the route of choice in Europe, but not the USA. The best marker of benefit of the introduction of r-HuEPO is the reduction in need for regular blood transfusions. A marked improvement in anaemia-related symptoms has been clearly demonstrated. The most important factor in optimizing the response to r-HuEPO is iron supply. The marrow should be stimulated slowly, to allow mobilization of iron stores. Functional or absolute iron deficiency should be pre-empted by regular iron supplementation. It is also important to recognize resistant states induced by inflammation and bleeding, and to exclude severe hyperparathyroidism, aluminium overload and other haematological diseases. The most important adverse events associated with r-HuEPO are increased blood pressure and a possible increased risk of access failure. These are, however, challenges to improve practice, not reasons to avoid the use of r-HuEPO.