The Early History of Plasma Cell Tumors in Mice, 1954–1976†

Michael Potter    Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

I Introduction

In the 1950s, a ferment of new theoretical ideas on the cellular and genetic basis of antibody formation electrified the field of immunology and began a new age in experimentation. Two problems dominated the thoughts of scientists during most of this decade—the cellular basis of antibody formation (how did it work?) and the genetic basis of antibody diversity (how could the genes in one individual generate antibodies for the thousands and thousands of antigens?). The period from 1954 to 1976 was one of the most exciting in the history of biology when an explosion of new information unfolded from many fields. This was paced by spectacular technological advances. This was the period when molecular biology emerged and the DNA‐gene‐messenger RNA–translated protein relationship was clarified, when proteins were first sequenced (Sanger, 1959), which led to the deciphering of the genetic code. New insights in the cell biology and genetics of tissue transplantation had a deep impact in the study of hematopoiesis. The use of inbred mice in immunological research greatly expanded. All of these developments in different fields supplied new ideas to each other. The pace of research was remarkable. One bridge between fields such as immunology, cancer research, protein chemistry, and molecular biology was the plasma cell, the antibody‐secreting cell and its neoplastic derivative, the plasma cell tumor (PCT).

II Plasma Cells Before the 1950s: Discovery, Uncertain Origins

Plasma cells were first described in 1890 by the famous histologist Ramon y Cajal who found them in syphilitic condylomas (Cajal, 1906). Since they were unlike any other leukocyte, he thought they might be special embryonic cells [see Michels (1931) for an excellent review of the early plasma cell literature]. Cajal named them “cianophil cells.” His descriptions were published in Spanish in “Manuel de Anatomia Patologica General,” Barcelona, 1890. In 1891, Paul Unna (Unna, 1891), not aware of this work, independently described plasma cells in lupus vulgaris lesions caused by Mycobacterium tuberculosis. He thought they might have originated from fixed connective tissue elements and occurred only under pathological conditions, especially chronic inflammations. Marschalko (1895) found plasma cells in many kinds of normal tissues. Marschalko thought that plasma cells originated from emigrated hemic lymphocytes.

Now hematologists and histologists began debating about their cellular origin and two candidates were proposed—lymphocytes and fixed reticular cells. A voluminous literature was generated. Bloom (1938) who wrote the standard textbook of histology with Alexander Maximov defined reticular cells: “The other constituent of the stroma of the lymphatic tissue is the reticular cell.” He went on to say, “There can be little doubt that lymphocytes may develop from fixed cells of lymphatic tissue.” He could find transition stages between lymphocyte and plasma cell and stated rather emphatically, “The plasma cells are believed by all investigators to develop by individual hypertrophy from various sized lymphocytes.” Others thought the plasma cell originated from a (fixed connective tissue cell) “reticular” cell (Marshall and White, 1950). In the ensuing years, many associations of plasma cells with antibody formation were made, and then Astrid Fagraeus in her elegant and seminal thesis produced evidence that convinced most workers that plasma cells were the source of antibodies: “The capacity of the red pulp (of the spleen) to form antibodies varied with the amount of plasma cells in the tissue and above all with the amount of immature plasma cells,” but she too thought the plasma cell originated from a reticular cell (Fagraeus, 1948). This lack of consensus understanding about the origins of plasma cells in the 1930s carried into the 1950s (Marshall and White, 1950; Sundberg, 1955) and illustrated the lack of a clear understanding of the developmental history of these cells.

III Multiple Myeloma

Multiple myeloma (MM) is a malignant tumor that grows primarily in the bone marrow cavities and spreads from one bone marrow cavity to another. The tumor cells can erode the overlying bone, causing terrible pain and pathological fractures. In 1901, James H. Wright made the important observation that the tumor cells were plasma cells. He obtained them from a patient with MM in which the neoplastic process protruded from the sternum:

IV Abnormal Protein

The feature of MM (mollities ossium or softening of the bones as it was called in 1845) that intrigued physicians beginning in 1845–1848 was its association with abnormalities in protein production. The first patient who was studied very intensively was a London grocer, Mr. Thomas McBean, who besides suffering from the agonies of his bone pain was found to excrete large amounts of protein in his urine [see Kyle (1985) for an exquisite history of MM]. His astute and concerned physicians recognized this was an unusual phenomenon and sent his specimens to Henry Bence Jones, a noted clinical chemist physician in London. Dr. Henry Bence Jones made a detailed analysis of this protein, demonstrating it could be distinguished from albumen (the common pathological urinary protein in renal disease) chiefly because this new protein when precipitated by nitric acid would go into solution when it was boiled (Jones, 1847).

During 1937–1941, serum protein abnormalities in MM were revealed by the analytical ultracentrifuge and moving boundary electrophoresis developed by Theodor Svedberg and Arne Tiselius (Putnam, 1993). These great technological advances paved the way to the analysis of serum proteins. It was discovered that the serum of MM patients contained extraordinary peaks or concentrations of proteins of β and γ electrophoretic mobility (Longsworth et al., 1939). These abnormal proteins were called myeloma proteins or paraproteins, and many regarded them as pathological proteins, a stigma reinforced by Bence Jones proteins that caused renal disease (myeloma kidney). The pathological protein concept prevailed for many years until a better understanding of the genetics of antibody synthesis became known.

V New Ideas About the Cellular Basis of Antibody Formation in the 1950s

Niels Jerne (1955) reawakened the students of antibody formation with his natural selection theory. He proposed that an antigen combines with circulating natural antibodies and the complex is taken up by “a system of cells that can reproduce this antibody.” This idea did not detail how this was done, but it contained fresh thoughts on a subject that had been preoccupied with instructionist theories that were gradually becoming less plausible as more was learned about proteins. Talmage (1957) extended and modified the natural selection idea by suggesting “… one of the multiplying units in the antibody response is the cell itself; according to this hypothesis only those cells are selected for multiplication whose synthesized product had affinity for the antigen injected.” In hindsight, Jerne was in part on the right track, as the “system of cells that can reproduce this antibody” could be the B lymphocyte itself that responds to an antigen‐specific antibody complex. Later in 1957, Frank MacFarlane (Burnet, 1957) began proposing important specifics to the natural selection idea by harnessing the lymphocyte as a player in humoral immunity and linking it to antibody‐secreting plasma cells. It is difficult to imagine in this era of sophisticated T and B cells that in the early 1950s the function of the lymphocyte was not firmly established. Burnet’s hypothesis revealed a...