Homage to Theodor Boveri (1862–1915): Boveri's theory of cancer as a disease of the chromosomes, and the landscape of genomic imbalances in human carcinomas

During the session on ‘‘Genomic Instability and Cancer’’ at a recent meeting organized by the Center of Excellence in Chromosome Biology (CECB), held at the National Cancer Institute in Bethesda, MD, three of the four speakers referred to or acknowledged Theodor Boveri’s (Fig. 1A) contributions to cancer genetics in one way or the other. This is remarkable because his original, and sole, venture into the cancer problem was published nearly a century ago. Obviously, all of us striving to make significant contributions to science would be very pleased if our own work would be so prominently acknowledged at the beginning of the 22nd century. So the question is justified on why that is so. In trying to provide an answer I will, first, briefly summarize Boveri’s contributions to cancer research and I do hope that I will be able to convey the esthetics of his thoughts and the clarity of the hypotheses of this remarkable cell biologist. Second, I will review what we know today of chromosomes and cancer and relate this knowledge to his previsions. Most of Boveri’s work was derived from analyses of see urchin and Ascaris eggs, for which he traveled to the Stazzione Zoologica in Naples, Italy. These studies resulted in the discovery of the centrosome as the coordinator of cell division. This alone can be considered a milestone, but Boveri also contributed early to the problem of cell polarity and the consequences for cellular differentiation. His student Spemann later received the Nobel Prize for his discovery of the organizer. His meticulous observations of the consequences of an abnormal number of centrosomes on cell division, which he induced by exposure to mechanical stress or through fertilization with two sperms led him to conclude that chromosomes should have both continuity in the interphase nucleus and, importantly, individuality, meaning that the information that one chromosome carries is different from another. These results were summarized in a series of publications during a period ranging from 1887 to 1909. He contributed to the problem of chromosome segregation errors using mathematical models to predict the probability with which different chromosome combinations would occur, and concluded that certain combinations would be incompatible with cell viability (for dedicated literature about his life and work the reader is referred to the following publications: [Stern, 1950; Baltzer, 1967; Cremer, 1985; Moritz and Sauer, 1996; Manchester, 1997; Neumann, 1998; Laubichler and Davidson, 2008; Maderspacher, 2008; Satzinger, 2008]). At the turn of the century, Mendel’s paper, first published in 1866, on the laws of heredity had been rediscovered. It was Boveri’s seminal contribution that he immediately recognized that the postulated individuality of chromosomes could explain Mendel’s laws if chromosomes would carry the genetic information: the chromosome theory of heredity was born (independently, Walter Sutton postulated the same [Sutton, 1903]). Now, what does this have to do with genomic instability and cancer? Boveri was a zoologist, and he recognized that. Hence, his humble apologies for entering the field of cancer research in his beautiful book ‘‘Zur Frage der Entstehung maligner Tumoren’’ which he published in 1914 [Boveri, 1914] (Fig. 1B). The English translation, by his wife and student Marcella Boveri, ‘‘The Origin of Malignant Tumors’’ appeared in 1929 [Boveri, 1929]. A recent, annotated translation by Henry Harris was published by Cold Spring Harbor Laboratory Press in 2008 [Boveri, 2008]. Boveri, however, rarely studied cancer tissues. But he projected his observation of dividing see urchin and Ascaris eggs and their abnormalities on what he perceived to be the genetic basis of malignancy. Others before him, most notably David von Hansemann, who had written ‘‘Über asymmetrische Zellteilung in Epithelkrebsen und