From Animal Matter to Antibody—a Trail of Research in Cancer

FROM ANIMAL MATTER TO ANTIBODY-A TRAIL OF RESEARCH IN CANCER FRANK W. PUTNAM* Discovery of Bence Iones Protein—Keystone in the Architecture of Antibodies On the first of January 1846, a forty-five-year-old man lay dying at 37 Devonshire Street on Cavendish Square in London just around the corner from Harley Street, then and still the prestige address for British medicine. His was the first recorded case of multiple myeloma [1-3], and the protein he excreted became the hallmark of this disease and the key to the elucidation of antibody structure. For more than a century the patient's name was lost in the archives, but in 1967 his death certificate (fig. 1) was discovered by my former colleague, John Clamp of Bristol, who had undertaken a fascinating search of the records [4]. Note that the cause of death is given as "atrophy from albuminuria certified." This was a remarkable diagnosis for that day, for the term "protein" had only been introduced nine years before in a letter from Berzelius to Mulder, and the word "albumin" originated at about the same time. The discovery of this protein was only one of the many accomplishments of the talented chemical pathologist Henry Bence Jones, who was the physician and friend of Huxley, Darwin, Spencer, and Faraday—and the latter's biographer. The history of Bence Jones and of the protein that bears his name deserves a separate article. Although multiple myeloma accounts for only about two deaths per 100,000 live population per year and comprises only about .50 * Professor of Molecular Biology, Indiana University, Bloomington, Indiana 47401. My investigations have been supported continuously by the National Cancer Institute, National Institutes of Health, since they were initiated at the University of Chicago in 1952. I am indebted to Dr. Charles Huggins of the University of Chicago for encouraging me to undertake the study of Bence Jones proteins when it was unfashionable because they were regarded only as clinical curiosities, and likewise to Dr. Leon Jacobson for inviting me to undertake isotopic studies of patients in the Argonne Cancer Research Hospital. 356 I Frank W. Putnam · Antibodies in Cancer cUTinzD cone or an dokit of death ?J2ÄJ**+t'M iXÉk DEATH in the Sub-district o .» &¿L *A sf"" fu* .-iL M-46**1! CZftTIFIEDIeb(,matspTerMntvhAiCRtaedeBnFerifat)Mroro«aililh«Eto1aitow«e8t]cacd.U11T^ . /f¿A**"V* GfatiMAiCcaMiltKBRiOmcx.laMmllcua,ten(M.MteABSalrfAittldaa«At ATUtKiVt OtOCé^ nt).?ß**_~G-~ "^ Fie. 1,—Death certificate of the first recorded case of Bence Jones proteinuria. (Reproduced with permission of J. R. Clamp, University of Bristol School of Medicine.) percent of all malignancies, there is widespread medical and scientific interest in it because of the characteristic protein abnormalities that affect all patients afflicted with this cancer. This is a tumor of the plasma cells, which are a main site of antibody formation. The protein abnormalities are of three kinds: first, a proteinuria in which the patient secretes in the urine large amounts of the peculiar protein now known as Bence Jones protein—amounts so great that they may equal the individual's daily dietary intake of protein; second, a hyperglobulinemia , in which the patient may have such an enormous increase in a homogeneous kind of immunoglobulin that his total plasma proteins may double; and third, paramyloidosis, an extensive deposition of protein in the heart, intestines, and other organs of the body, leading to death from amyloidosis. A patient may have any one, two, or all three of these symptoms, and the protein he excretes differs in structure from that of every other patient. All of these interrelated symptoms result from a derangement in protein metabolism in the immune system of the body, for multiple myeloma is a tumor of the plasma cells, which normally are involved in antibody biosynthesis. By study of the proteins produced by such patients much has been learned not only about this fatal cancer but also about the structure, biosynthesis, and genetic control of antibodies and about the nature of autoimmune diseases (such as rheumatoid arthritis) and of hereditary deficiencies in the immune system. Not only have these results of basic research on one kind of cancer shed light on other diseases...