Historical aspects of human milk oligosaccharides.

This review focuses on important observations regarding infant health around 1900 when breastfeeding was not considered a matter of importance. The discovery of lactobacilli and bifidobacteria and their relevance for health and disease was an important milestone leading to a decrease in infant mortality in the first year of life. At the same time, pediatricians realized that the fecal composition of breast-fed and bottle-fed infants differed. Observations indicated that this difference is linked to milk composition, particularly due to the milk carbohydrate fraction. Circa 1930, a human milk carbohydrate fraction called gynolactose was identified. This was the starting point of research on human milk oligosaccharides (HMO). In the following years, the first HMO were identified and their functions investigated. Studies after 1950 focused on the identification of various HMO as the bifidus factor in human milk. In the following 30 years, a tremendous amount of research was done with regard to the characterization of individual HMO and HMO patterns in milk. In this short introduction to the history of HMO research, which ends circa 1980, some outstanding scientists in pediatrics and chemistry and their pioneering contributions to research in the field of HMO are presented.

Discovery of anticoagulant drugs: a historical perspective.

The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in 1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than 60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based approach, in which specific proteins, or "targets", are chosen on current understandings of pathophysiology, small molecules that inhibit the target's activity may be identified by high-throughput screening and, in selected cases, these new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin, acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins, bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).

A fascination with sugars.

We now recognize that a large number of membrane and soluble proteins contain covalently linked oligosaccharides that exhibit a vast array of structures and participate in a wide variety of biological processes. Nowhere is this better illustrated than the mannose 6-phosphate (Man-6-P) recognition system that mediates the trafficking of newly synthesized acid hydrolases to lysosomes in higher eukaryotes. The Asn-linked high-mannose oligosaccharides of these hydrolases facilitate folding of the nascent proteins in the endoplasmic reticulum via interaction with lectin-type chaperones and after phosphorylation in the Golgi, function as ligands for binding to Man-6-P receptors, a critical step in their transport to lysosomes. Failure to synthesize the Man-6-P recognition marker results in a serious lysosomal storage disease, one of a growing number of genetic conditions, termed congenital disorders of glycosylation, that result from faulty glycan biosynthesis.

Heparin to pentasaccharide and beyond: the end is not in sight.

The 87-year history of heparin began in 1916 when a 26-year-old medical student named Jay McLean startled his mentor William Howell, Professor of Physiology at Johns Hopkins University, by proclaiming that he had discovered "antithrombin." This discovery was so surprising to Howell because he had expected McLean to isolate thromboplastin, a clot-promoting substance from animal tissue. In 1928, Charles Best, M.D., in Toronto, Canada, organized a team of chemists, physiologists, and surgeons to focus on the development of heparin. This group determined which animal tissues were the best source, had performed purification and identification, and had determined pharmacologic properties in vitro. By 1935, they were ready for human trials. By 1941, the group reported a series of 700 patients treated with the glycosaminoglycan called heparin. Meanwhile a critical cofactor, antithrombin, had been discovered at the University of Iowa (Brinkhous, et al). Introduction of newer tests for laboratory monitoring enabled refinement of dosages during the 1960s and 1970s. Its use permitted the development of hemodialysis and cardiopulmonary bypass surgery, and the prophylaxis of deep vein thrombosis in surgical patients. The concept of low-molecular-weight heparin occurred to Dr. Choay and others in France in the late 1970s. During the 1980s and 1990s, the development of low-molecular-weight heparins evolved for both prophylaxis and therapy. The first synthetic product was called the pentasaccharide, named for the five critical sugar units in heparin that bind to antithrombin (1983). Since then, this drug has been studied extensively to prove its clinical efficacy and safety.