The origins of bone marrow as the seedbed of our blood: from antiquity to the time of Osler.

T he marrow is currently well defi ned as the seedbed of our blood, producing 200 billion red cells, 10 billion white cells, and 400 billion platelets on a daily basis. Yet, the role of the marrow was unknown in antiquity and only fi rst experimentally defi ned during the latter 19th century. Hippocrates (460–375 bc), who used observation and reasoning rather than mysticism to reach his conclusions, considered the marrow the nutrient source for bone, an opinion shared by Galen (130–200). Aristotle (384–322 bc) took the opposite view and considered the marrow to be an osseous waste product (excrementum ossium) (1). Impressed by the vascularity of the marrow, anatomists in the 18th century also expounded Hippocrates’ view and considered the marrow the vascular component of bone. Yet, it was noted in 1700 by the French anatomist Duverney that many bones, like those of the middle ear, have no marrow, and hence it would be unlikely that the marrow was essential for the nutrition of bone (2). It was also noted by Charles Robin in 1872 that in the course of development, the marrow was formed after the bone, again suggesting the unlikelihood that it was a source of bone nutrition (1). Literature through the ages often alluded to marrow as the essence or central part, considered rich and nutritious as a food source, possessing warmth, energy, and inner heat, as well as being the seat of vitality and manliness. Th e Greek playwright Euripides (480–406 bc) noted: “Love must not touch the marrow of the soul. Our aff ections must be breakable chains that we can cast them off or tighten them.” A quote from Shakespeare’s Macbeth: “Avaunt! And quit my sight! Let the earth hide thee! Th y bone is marrowless. Th y blood is cold; thou hast no speculation in those eyes which thou dost glare with.” Yet, in his chapter entitled “Bone Marrow: the Seedbed of Blood” in Wintrobe’s Blood: Pure and Eloquent published in 1980, Tavassoli noted: “For centuries, poets, healers, and philosophers saw and described the close link between blood and life. Not so the marrow. Its role as the seed bed of blood lay hidden, like a seed in the soil” (3). While red cells were fi rst described in the 17th century, it was not until the 19th century that a search for their origin could begin. Th e concept of red cell production could not be formulated until cell theory was postulated in 1838 by Schleiden and Schwann, identifying the cell as the fundamental unit of life (4, 5). Schleiden proposed that cells were formed by a process analogous to crystal formation with confl uence of granules. He did not conclude that living cells were necessary for the formation of new cells. Scholars of this period also were not cognizant that blood formation was a continuous process. Th ere was no recognition of a fi nite life span for red cells necessitating continuous replenishment. Th e focus was on embryonic life, with the assumption that blood cells, once formed in the embryo, remained in the body throughout life. Neumann and Bizzozero, both contemporaries of Osler, are credited with making the initial observations leading to the recognition of the marrow as the seat of blood formation. Ernst Neumann (1834–1918) was a lifelong citizen of Konigsberg, capital of former eastern Prussia, where he was appointed professor of pathology in 1866 (Figure 1). He had done postgraduate studies in Prague and trained with Virchow in Berlin. In his report published in October 1868, Neumann described the presence of nucleated red blood cells in the bone marrow sap of humans and rabbits by squeezing bone (6). He was the fi rst to conclude that during postembryonic life, erythropoiesis was taking place in the marrow. Translation from this text is as follows: