A selected history and future of immunoassay development and applications in clinical chemistry

BACKGROUND: The first immunoassay was described by Berson and Yalow in 1959. Their work resulted in their receipt of the Nobel Prize in Medicine in 1977. Since this introduction, immunoassays have evolved considerably. METHODS: There have been several milestones that have led to the proliferation of modern immunoassays. The development of monoclonal antibodies from mouse hydridoma cells by Millstein and Kohler (Nobel Prize in 1984) enabled the production of high quantities of antibodies with well characterized epitope specificity. The first homogenous immunoassay (no separation step required) was the Enzyme Multiplied Immunoassay Technique (EMIT), which enabled adaptation of this assay onto automated chemistry platforms. EMIT was also one of the first immunoassay that made use of non-isotopic labels. Other non-isotopic labels became available such as chemiluminescence to improve the analytical sensitivity of immunoassays. The advantages of high-sensitivity immunoassays have created expanded diagnostic roles for some existing assays such as thyroid stimulating hormone for hyperthyroidism, C-reactive protein for cardiovascular risk assessment, and other applications. The development of instrumentation capable of automated heterogeneous immunoassays (separation step to improve sensitivity) has enabled movement of this technology from the "special chemistry" sections of a clinical laboratory into the "core" laboratory with other high-volume testing. CONCLUSION: Today, immunoassays play a prominent role in the analysis of many clinical laboratory analytes such as proteins, hormones, drugs, and nucleic acids. The future involves development of assays with higher sensitivities which will enable the discovery of new biomarkers for disease diagnosis, and technology that will enable simultaneous multimarker analysis of tests whose needs are naturally grouped together (e.g., cytokines and allergens).     

Update on parathyroid hormone: new tests and new challenges for external quality assessment

It is now 43 years since Berson and Yalow published the first radio-immunoassay (RIA) for parathyroid hormone (PTH) [S.A. Berson, R.S. Yalow, G.D. Aurbach, J.T. Potts, Immunoassay of bovine and human parathyroid hormone. Proc Natl Acad Sci U S A 49 (1963) 613-617] [1]. Since then, there have been marked advances in our understanding of this peptide hormone, its mechanism of action and biological regulation [J.T. Potts, Parathyroid hormone: past and present. J. Endocrinol. 187 (2005) 311-325] [2]. PTH has become a routine assay in tertiary care hospitals and is an essential element in the management of chronic kidney disease, parathyroid disorders and the investigation of abnormalities in calcium homeostasis. Despite continuing technological advances in PTH measurement, analyte heterogeneity remains a problem, while improved turnaround time and better precision are constantly escalating clinical demands. This mini-review begins with a brief update of current knowledge on PTH, followed by a summary of a recent Ontario-wide External Quality Assurance (EQA) survey, and concludes with comments on utilization trends, current and future.     

Bibliometric analysis of Nobelists’ awards and landmark papers in physiology or medicine during 1983–2012

Abstract

Aim. This study's purpose was to determine if there was a relationship between Nobel Laureates’ awards and landmark papers and winning the Nobel Prize in Physiology or Medicine during 1983–2012.

Methods. The 66 Nobelists’ awards and landmark papers in the period 1983–2012 were analyzed.

Results. The results showed that the most Nobelists had won Gairdner, Lasker, Howitz or Wolf Award before they won Nobel Prize, indicating that Gairdner Award may be considered as a Nobel Prize’s wind vane. A small number of landmark papers were indeed published in low impact factor journals (10.5% below impact factor 5.0) and some of their citation were low (23.2% below 400 times). There were 61 of 76 landmark papers published in the journals of JCR partition 1, reaching 80%, but 2 of 76 landmark papers were even outside of JCR partition, demonstrating that JCR partition acts as a reciprocal supplement with impact factor and citation times. The test period of Nobel Prize was substantially between 10 to 30 years. There were 5 persons whose landmark papers were cited all above 6000 times to get Nobel Prize within the test period of ten years, suggesting that there is a trend of certain inverse ratio between the citation and the test period of Nobel Prize.

Conclusion. These findings provide a new insight into the relationship among Nobel Laureates’ awards, landmark papers and Nobel Prize in Physiology or Medicine.     

Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine

In 1951, Max Theiler of the Rockefeller Foundation received the Nobel Prize in Physiology or Medicine for his discovery of an effective vaccine against yellow fever—a discovery first reported in the JEM 70 years ago. This was the first, and so far the only, Nobel Prize given for the development of a virus vaccine. Recently released Nobel archives now reveal how the advances in the yellow fever vaccine field were evaluated more than 50 years ago, and how this led to a prize for Max Theiler.     

Fifty years of development in the endocrinology laboratory

The hormone assay laboratory has seen incredible changes over the last 50 years. In this historical review, we describe how the evolution of fundamental concepts in endocrinology and in hormone assay technology have faceted the laboratory as we know it today. The discovery of neurohormones, hormone receptors and the evolution of the concept of free hormones had a very significant impact on our understanding of the mechanisms of hormone action in health and disease and therefore on how physicians currently prescribe endocrine tests. In the analytical field, modern hormone assays rapidly replaced crude colorimetric methods and bioassays. Starting with the pioneering work of Yalow and Berson, hormone assays have gradually evolved through improvements in all aspects of assay design. This is best exemplified by the evolution of thyroid and parathyroid hormone assays. After reviewing some of the limitations of actual hormone immunoassays, we present some reflections on what the future of the hormone laboratory may look like considering all the developments in automation, point-of-care testing, molecular biology and array technologies.     

Brenner,the worm and the prize

The recent award of a Nobel Prize to Sydney Brenner crowns an astonishingly distinguished scientific career. He must have come very close to winning it several times in the past. A colleague described him as 'a visionary who sees further into the future than anyone'. This is borne out by his decision--made 40 years ago--to study a one-millimetre long worm in detail to define the biochemical and genetic control of its development and differentiation. The impact of these studies has been so profound, with a significant bearing on human physiology and disease, that over 400 laboratories worldwide have now adopted the worm as a research tool. In this article, a brief outline is given of his work on the worm and of some of the highlights of his brilliant career.     

Bárány's discovery and its reception by his contemporaries

Bárány's main achievement is that he unified known, but apparently contradictory facts into one perspective. The concept of a method for examining each ear individually by means of the caloric test fundamentally advanced diagnostics. In 1914 he was honoured with the Nobel Prize, but in his home town of Vienna he was denied the title of professor. Many debates took place about this. In 1917 he moved to Uppsala where he eventually became head of the laryngology department. Two reasons justify the fact that we may call Bárány an Austrian Nobel Prize Winner, firstly that he kept his loyalty to Vienna, his birth place and, secondly, that all his work for which he was awarded the Nobel Prize was done in the Vienna General Hospital.     

Artemisinin-derived antimalarial endoperoxides from bench-side to bed-side: Chronological advancements and future challenges

According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite-resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 “Nobel Prize in Physiology or Medicine” was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as “Nobel medicine.” The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971-2019) in the medicinal chemistry of ART-derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.     

Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease

The biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract. Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio-pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.     

An appreciation of Ralph Marvin Steinman (1943–2011)

Ralph Steinman, an editor at the Journal of Experimental Medicine since 1978, shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of dendritic cells (DCs) and their role in immunity. Ralph never knew. He died of pancreatic cancer on September 30, 3 days before the Nobel announcement. Unaware of his death at the time of their announcement, the Nobel Committee made the unprecedented decision that his award would stand. Ralph was the consummate physician-scientist to the end. After his diagnosis, he actively participated in his 4.5 years of treatments, creating experimental therapies using his own DCs in conjunction with the therapies devised by his physicians, all the while traveling, lecturing, and most of all pursuing new investigations in his laboratory. For 38 years—from his discovery of DCs to his Nobel Prize—Ralph pioneered the criteria and methods used to identify, isolate, grow, and study DCs. He and his colleagues demonstrated that DCs are initiators of immunity and regulators of tolerance. In his most recent studies, Ralph was harnessing the specialized features of DCs to design improved vaccines. The following synopsis describes some of his seminal discoveries.     

How does Cell Machinery Sense and Deal with Hypoxia? The 2019 Nobel Prize for Medicine

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - The Nobel Prize in Physiology or Medicine for the year 2019 has been awarded to three scientists, namely...     

Histamine: new thoughts about a familiar mediator

Any health-care provider knows that the sneezing, wheezing, and itching that are commonplace most often involve a small molecule, namely, histamine. In addition to its inherent physiologic role, this seemingly small "actor" is of profound historical and fiscal significance. This is evidenced in part by the awarding of the 1936 Nobel Prize in physiology or Medicine to Sir Henry Hallett Dale and Dr Otto Loewi who discovered the actions of histamine and the 1957 Nobel Prize in physiology or medicine to pharmacologist Dr Daniel Bovet who discovered the first antihistamine, pyrilamine (neoantergan)(1). (see Supplementary Data for full reference).     

A history of diabetes: from antiquity to discovering insulin

This article, the first of a three-part series, gives a historical account of events for diabetes, dating from antiquity and its first recording in the Ebers Papyrus--an Egyptian document circa 1500 BC. This article describes initial thoughts that diabetes was linked to an alimentary complaint, and concludes with the discovery of it being a chronic systemic disease. It highlights the discoveries and also includes details of the failed attempts to locate the cause and identify a solution to the ancient mysterious disease which became known to all as diabetes mellitus. Early remedies and treatments are included. The article tells how for many centuries individuals suffered from the debilitating complaint with very little offered in terms of treatment or relief. Eventually the pancreas was identified as the causative organ and, some time later, animal experimentation resulted in the abstraction of the substance insulin. The article concludes with Frederick Banting and John Macleod being awarded the Nobel Prize in 1923 for their revolutionary discovery of insulin.     

Insulin binding to target cells

Summary Following Yalow and Berson's basic research on the binding of polvpeptide hormones to plasma proteins, an integrated picture of hormone-receptor interaction and biological activity has been proposed for insulin in experimental models and in man. The extracellular interaction of the insulin molecule with the cell membrane structure modifies the intracellular metabolism, and it has been suggested that this occurs through the activation of a second messenger or the trans. duction of an insulin fragment into the cell. The use of monoiodoinsulin has made it possible to perform a series of experiments on cells isolated from the blood (monocytes) or from the tissues (adipocytes) and on plasma membranes prepared by ultracentrifugation. The existence of specific receptor sites for insulin in all cases, both in animals and in man, has been confirmed by mathe matical analysis of the binding curves; their non-linear course as plotted by Scatchard's method, may depend on negative cooperation or on different classes of receptor. From an evaluation of recent studies on human obesity, particularly on adipocytes and circulating monocytes, a new approach to the problem of ‘insulin resistance’ in obesity has been proposed, and this has shown that a reduction in the number of receptors on the target cells may contribute to peripheral insulin insensitivity. This phenomenon, which seems to be characteristic of the static phase of obesity, is reversible during fasting or weight reduction and may be a compensatory mechanism for hyper-insulinaemia. These results are an example of the significance and applicability of the experimental method of detecting insulin binding to target cells, and suggest a wide application in different endocrinological fields.     

Resuscitation great. Willem Einthoven: the development of the human electrocardiogram

The electrocardiogram is one of the most commonly used diagnostic tools in healthcare. This ingenious device was developed and created in the early 1900s by Willem Einthoven, MD, PhD after studying the mechanisms of electromagnetism and Waller's capillary electrometer. Einthoven dedicated most of his research and clinical activities to improve the early versions of the electrical current recording medical devices. Einthoven's most notable invention was the string galvanometer which we now know as the electrocardiogram. Although the idea of using the string galvanometer as a diagnostic tool faced opposition by scientists and physicians of his time, he remained convinced of the potential of his machine to improve patient care. Einthoven's string galvanometer subsequently became the standard diagnostic tool for recognition and differentiation of heart conditions through the interpretation of cardiac waves, and has become standard practice in the field of resuscitation. In 1924, Einthoven received the Nobel Prize in Medicine for his development of the string galvanometer.     

Insulin: discovery and controversy

During the first two decades of the 20th century, several investigators prepared extracts of pancreas that were often successful in lowering blood sugar and reducing glycosuria in test animals. However, they were unable to remove impurities, and toxic reactions prevented its use in humans with diabetes. In the spring of 1921, Frederick G. Banting, a young Ontario orthopedic surgeon, was given laboratory space by J.J.R. Macleod, the head of physiology at the University of Toronto, to investigate the function of the pancreatic islets. A student assistant, Charles Best, and an allotment of dogs were provided to test Banting's hypothesis that ligation of the pancreatic ducts before extraction of the pancreas, destroys the enzyme-secreting parts, whereas the islets of Langerhans, which were believed to produce an internal secretion regulating sugar metabolism, remained intact. He believed that earlier failures were attributable to the destructive action of trypsin. The name "insuline" had been introduced in 1909 for this hypothetic substance. Their experiments produced an extract of pancreas that reduced the hyperglycemia and glycosuria in dogs made diabetic by the removal of their pancreases. They next developed a procedure for extraction from the entire pancreas without the need for duct ligation. This extract, now made from whole beef pancreas, was successful for treating humans with diabetes. Facilitating their success was a development in clinical chemistry that allowed blood sugar to be frequently and accurately determined in small volumes of blood. Success with purification was largely the work of J.B. Collip. Yield and standardization were improved by cooperation with Eli Lilly and Company. When the Nobel Prize was awarded to Banting and Macleod for the discovery of insulin, it aggravated the contentious relationship that had developed between them during the course of the investigation. Banting was outraged that Macleod and not Best had been selected, and he briefly threatened to refuse the award. He immediately announced that he was giving one-half of his share of the prize money to Best and publicly acknowledged Best's contribution to the discovery of insulin. Macleod followed suit and gave one-half of his money award to Collip. Years later, the official history of the Nobel Committee admitted that Best should have been awarded a share of the prize.     

The clinical paradox: Acting in two worlds in parallel

Background : Centred around the thesis that for those engaged in clinical practice there are two worlds present in parallel, this article defines the characteristics of the supposed second, qualitative world. Contrasting these characteristics to those of the world as seen in continuous metric dimensions of space and time, we derive the nature of the qualitative elements and their coherent interaction, as well as the rules governing these dynamic elements' interactions. Results : The second world claimed to exist turns out to be made of individual worlds centred in coherent perspectival interaction. Its polycentric agency enacts individual perspectives and mutual information uptake. This hermeneutical approach conforms with some recent developments in theory, such as that of Nobel Prize winner Elinor Ostrom, or the enactment theory of cognitive science. Conclusions : Following this theoretical process, two practical consequences are drawn. The first consists of an advanced model of biopsychosocial interaction, as extensively published throughout the years. The second presents the concept of quality-oriented self-aid groups open to all exposed to or working in care and healthcare. The corresponding training helps practitioners to consciously and deliberately move, perceive, and perform in the duplicity of worlds, the one the conventional quantifying, metric one, the other the mostly rationally unknown world emerging from qualifying interactive agency.     

Nursing--a new tomorrow

This year's recipient of the prestigious Christiane Reimann Award, the "Nobel Prize of Nursing", was Dame Nita Barrow, Ambassador to the UN from Barbados, who was recognized for her distinguished accomplishments in nursing and health care over decades and continents. She was also the keynote speaker at ICN's 19th Quadrennial Congress in Seoul, Korea, 28 May-2 June 1989, described by Korean Prime Minister Kang Young Hoon in his address at the opening ceremonies as the "festival of peace and friendship for nurses the world over". Below, her keynote address.     

The contributions of Ramon y Cajal and other Spanish authors to hypnosis

The authors review the most important Spanish contributions to hypnosis during the 19th and 20th centuries, with emphasis on the work of Santiago Ramon y Cajal, winner of the 1906 Nobel Prize in medicine. It is widely accepted that he provided a basic foundation for modern neurosciences with his work on neuronal staining and synaptic transmission. What is missing in most accounts of his work is his longstanding interest and work on hypnosis and anomalous phenomena. This article summarizes that lost legacy, discusses other Spanish hypnosis pioneers and gives a brief overview of current hypnosis activities in Spain.     

A brief survey of aquaporins and their implications for renal physiology.

Aquaporins (AQPs) are an important family of proteins that efficiently channel water through the cell membranes. Although water can diffuse across biological membranes at measurable rates, physiologists had long predicted the existence of channels to facilitate rapid reabsorption of water by renal tubular cells. With AQPs present, water can "gush" through the membrane at the extraordinary rate of three billion water molecules per second per aquaporin channel. In their absence, water only trickles across the hydrophobic lipid bilayers of cell membranes. Aquaporins have fascinated researchers over the last decade, culminating in the 2003 Nobel Prize for Chemistry given to their discoverer, Dr. Peter Agre. During the 1990s, scientists identified and characterized members of the mammalian aquaporin family, now designated as AQP0 through AQP10. AQPs are also found in many plant and bacterial species. However, their relevance to the clinical laboratory is only recently emerging. Dr. Agre's Nobel symposium address provides an excellent mini-review of aquaporins in medicine. Our understanding of renal physiology and pathophysiology has advanced greatly as we account for the subtle implications of various AQP systems. For example, nephrogenic diabetes insipidus (NDI), the inability to produce concentrated urine, can result from several different malfunctions in the AQP2 system controlled by anti-diuretic hormone (ADH). Virtually all mammalian cells incorporate aquaporins into their cell membranes, and many cells produce multiple aquaporins, each with a specific function. It is therefore not surprising that malfunctions have important clinical conditions. The present article discusses the implications of aquaporins for renal physiology, while the accompanying article is focused on the clinical aspects of aquaporins.