Theodor Boveri Research Articles

Genetics of congenital solid tumors.

When we discuss the genetics of tumors, we cannot fail to remember that in the second decade of the twentieth century, more precisely in 1914, Theodore Boveri defined for the first time the chromosomal bases of cancer. In the last 30 years, progresses in genetics have only confirmed Boveri’s remarkable predictions made more than 80 years ago. Before the cloning of the retinoblastoma 1 (RB1) gene, the existence of a genetic component in most, if not all, solid childhood tumors were well known. The existence of familial tumor aggregations has been found much more frequently than researchers expected to find at random. Sometimes, the demonstration of this family predisposition was very difficult, because the survival of children diagnosed as having a certain tumor, up to an age at which reproduction and procreation is possible, was very rare. In recent years, advances in the diagnosis and treatment of these diseases have made it possible for these children to survive until the age when they were able to start their own families, including the ability to procreate. Four distinct groups of so-called cancer genes have been identified: oncogenes, which promote tumor cell proliferation; tumor suppressor genes, which inhibit this growth/proliferation; anti-mutational genes, with a role in deoxyribonucleic acid (DNA) stability; and micro-ribonucleic acid (miRNA) genes, with a role in the posttranscriptional process.

A Brief History of Xenopus in Biology.

Xenopus is one of the premier model systems to study cell and developmental biology in vivo in vertebrates. Here we briefly review how this South African frog came to be favored by a large community of scientists after the explosive growth of molecular biology and examine some of the original discoveries arising from this sturdy frog. Experimental embryology started in Rana but developed in newt embryos for historical reasons. A long lineage of mentorship, starting with Theodor Boveri, Hans Spemann, Fritz Baltzer, Ernst Hadorn, and Michail Fischberg, used newt embryos. In Oxford, Fischberg made the transition to Xenopus laevis because it was widely available for human pregnancy tests and laid eggs year-round, and he fortuitously isolated a one-nucleolus mutant. This mutant allowed nuclear transfer experiments showing that genetic information is not lost during cell differentiation and the demonstration that the nucleolus is the locus of transcription of the large ribosomal RNAs. With the advent of DNA cloning, the great equalizer among all fields of biology, microinjected Xenopus oocytes became an indispensable tool, providing the first living-cell mRNA translation, polymerase II and III transcription, and coupled transcription-translation systems in eukaryotes. Xenopus embryos provide abundant material to study the earliest signaling events during vertebrate development and have been subjected to saturating molecular screens in the genomic era. Many novel principles of development and cell biology owe their origins to this remarkably resilient frog.

“… the marvelous freedom to research what one finds interesting”: Theodor Boveri at the Naples Zoological Station

In January 1888, shortly after his Habilitation (Nov. 1887), Theodor Boveri came for the first time as guest investigator to the Naples Zoological Station. The last of his eight research stays took place in spring 1914, the year before his untimely death in 1915. The Naples Station was therefore a constant presence in all his scientific life. At least 20 of his publications are based on research done at Naples.In this paper, I will try to outline the unique working conditions that Boveri found at Naples. By 1888, the Naples Station was already an expanding, smoothly functioning organism. Excellent animal supply and research equipment, the constant presence of an international scientific community and the beauties of Mediterranean nature and European culture fostered a creative atmosphere that gave particular relevance to a research stay at Naples. In 1910, Boveri defined the Naples Station a “permanent international congress of zoologists”. Boveri's “Naples experience” will be described and some light will also be shed on Boveri's role in keeping the memory of Anton Dohrn alive.

Risks of aneuploidy induction from chemical exposure: Twenty years of collaborative research in Europe from basic science to regulatory implications.

Although Theodor Boveri linked abnormal chromosome numbers and disease more than a century ago, an in-depth understanding of the impact of mitotic and meiotic chromosome segregation errors on cell proliferation and diseases is still lacking. This review reflects on the efforts and results of a large European research network that, from the 1980's until 2004, focused on protection against aneuploidy-inducing factors and tackled the following problems: 1) the origin and consequences of chromosome imbalance in somatic and germ cells; 2) aneuploidy as a result of environmental factors; 3) dose-effect relationships; 4) the need for validated assays to identify aneugenic factors and classify them according to their modes of action; 5) the need for reliable, quantitative data suitable for regulating exposure and preventing aneuploidy induction; 6) the need for mechanistic insight into the consequences of aneuploidy for human health. This activity brought together a consortium of experts from basic science and applied genetic toxicology to prepare the basis for defining guidelines and to encourage regulatory activities for the prevention of induced aneuploidy. Major strengths of the EU research programmes on aneuploidy were having a valuable scientific approach based on well-selected compounds and accurate methods that allow the determination of precise dose-effect relationships, reproducibility and inter-laboratory comparisons. The work was conducted by experienced scientists stimulated by a fascination with the complex scientific issues surrounding aneuploidy; a key strength was asking the right questions at the right time. The strength of the data permitted evaluation at the regulatory level. Finally, the entire enterprise benefited from a solid partnership under the lead of an inspired and stimulating coordinator. The research programme elucidated the major modes of action of aneugens, developed scientifically sound assays to assess aneugens in different tissues, and achieved the international validation of relevant assays with the goal of protecting human populations from aneugenic chemicals. The role of aneuploidy in tumorigenesis will require additional research, and the study of effects of exposure to multiple agents should become a priority. It is hoped that these reflections will stimulate the implementation of aneuploidy testing in national and OECD guidelines.

A conceptual history of the “regulatory genome”: From Theodor Boveri to Eric Davidson

The formalization of the idea of “Regulatory Genome” is a recent one. However, it stems from a long tradition in the study of how the genetic information is transferred between generations. Theodore Boveri suggested for the first time that the whole genome participates in the shaping of individuals. Through a long lineage of researchers, we have learned how this whole-genome activity is regulated, in space and time. It is, however, due to the insights and experimental approaches taken by different researchers, among them Eric Davidson and associates, that we understand the mechanistic basis of this regulation. Whole batteries of regulatory genes interact through their cis-regulatory modules, generating a precise pattern of cross-controlled gene activity (Gene Regulatory Networks). How these genes are deployed in development and evolution has become an area of vibrant research. Here we revisit the history of this intellectual endeavour, taking as key defining points along this historical trajectory the contributions of Theodor Boveri and Eric Davidson.

Mechanistic philosophies of development: Theodor Boveri and Eric H. Davidson

Theodor Boveri’s (1862-1915) and Eric Davidson’s (1937-2015) achievements represent thoroughly two quite distant time frames in the history of the mechanistic approaches to development, that Jane Maienschein (2014) has characterized respectively as the era of the “experimental embryo” and of the “computed embryo”. Nonetheless, Davidson’s special bond to Boveri is meant to emphasize the genealogical continuity of an embryological tradition of mechanistic philosophy that, differently from molecular biology, is committed to an explanation of the hereditary transmission of organization. Davidson’s genealogical claim is reconsidered through a contextualized analysis of the function of machine-like models and of the role of experiment in the making of their respective mechanistic philosophies. This analysis may help to shed light on resilience and change in the understanding of a mechanistic approach to development.

Revisiting Centrioles in Nematodes-Historic Findings and Current Topics.

Theodor Boveri is considered as the “father” of centrosome biology. Boveri’s fundamental findings have laid the groundwork for decades of research on centrosomes. Here, we briefly review his early work on centrosomes and his first description of the centriole. Mainly focusing on centriole structure, duplication, and centriole assembly factors in C. elegans, we will highlight the role of this model in studying germ line centrosomes in nematodes. Last but not least, we will point to future directions of the C. elegans centrosome field.

Mary Jane Hogue (1883–1962): A pioneer in human brain tissue culture

ABSTRACTThe ability to maintain human brain explants in tissue culture was a critical step in the use of these cells for the study of central nervous system disorders. Ross G. Harrison (1870–1959) was the first to successfully maintain frog medullary tissue in culture in 1907, but it took another 38 years before successful culture of human brain tissue was accomplished. One of the pioneers in this achievement was Mary Jane Hogue (1883–1962). Hogue was born into a Quaker family in 1883 in West Chester, Pennsylvania, and received her undergraduate degree from Goucher College in Baltimore, Maryland. Research with the developmental biologist Theodor Boveri (1862–1915) in Würzburg, Germany, resulted in her Ph.D. (1909). Hogue transitioned from studying protozoa to the culture of human brain tissue in the 1940s and 1950s, when she was one of the first to culture cells from human fetal, infant, and adult brain explants. We review Hogue’s pioneering contributions to the study of human brain cells in culture, her putative identification of progenitor neuroblast and/or glioblast cells, and her use of the cultures to study the cytopathogenic effects of poliovirus. We also put Hogue’s work in perspective by discussing how other women pioneers in tissue culture influenced Hogue and her research.

Singling Out Chromosome Gains in Tumor Evolution

In this issue of Cancer Cell, Sheltzer etal. shed new light on Theodor Boveri's century-old hypothesis by demonstrating that aneuploidy characterized by single-chromosome gains acts to suppress tumorigenesis and that aneuploidy itself is a nidus for genomic instability.

Annals of morphology THEODOR BOVERI (1862–1915) To commemorate the centenary of his death and contributions to the Sutton–Boveri hypothesis

One hundred years ago, only 3 days after his 53rd birthday, there died a man who was regarded during his lifetime already such a giant in biology as to rank with Aristotle, von Baer, Darwin, Wallace, Mendel …. Their respective contributions to epigenesis, natural selection, and segregation made it possible to formulate in the late 19th century a science relating “the origin of species” to the origin of the “individual” organisms, their structure and function to that of their parts, their parts to that of their cells, and mitosis to the propagation of their cells. In working out the developmental and cytological details of these processes Boveri achieved his greatness, taking advantage of innate drive, better instrumentation (microscope, microtome), ideal “model” organisms (sea urchin, Ascaris), methods of their study and preservation, and the rediscovery, in 1900, of Mendel's results allowing him to relate mendelism to chromosomal structure and function in what E.B. Wilson subsequently called the Sutton–Boveri hypothesis. When war began in 1914, Boveri married to an American, and father of a 14‐year‐old girl, was already mortally ill, infested with one of his favorite experimental organisms, Ascaris. Given his health problems and attachment to his native Bavaria, Boveri had declined (1913) the directorship of the nascent Kaiser Wilhelm Institute for Biology in Berlin; but two of his recommended appointees there (Warburg, Spemann) became future Nobel Prize winners. Even before the war, Boveri's renown was such that distinguished foreigners, for example, the Americans E.B. Wilson, Marcella O'Grady, Nettie Stevens, Theophilus Painter, a.o., came to the University of Würzburg to work with him, Wilson dedicating all three editions of his rightly celebrated text “The Cell in Development and Heredity” [1896; 3rd Edition, 1925] to Boveri. Boveri's approach to genetics was primarily morphological; however, he was quick to unite mendelian inferences with chromosomal structure, and embryonic development with evolutionary theory. In retrospect, Boveri is perhaps best known for his formulation of a theory relating chromosomal anomalies to malformations, tumor formation and cancer. © 2016 Wiley Periodicals, Inc.

Rudolf Weber (1922-2015): a driving force in the transition of developmental biology into a molecular and cellular science.

Prof. Dr. Rudolf Heinrich Weber passed away on December 23, 2015, at the high age of 93 years. Succeeding Fritz Baltzer and Fritz Erich Lehmann, he became the third in a line of outstanding developmental biologists at the University of Bern, Switzerland. Throughout his career, he helped shape modern developmental biology by introducing and promoting biochemical and molecular techniques. RudolfWeber was born in Basel, Switzerland, on September 27, 1922. He studied biology in Basel and obtained his PhD in 1949 under the supervision of Adolf Portmann. His thesis (Weber 1949) had a developmental topic (Transitory closures of distant sensory organs during the embryonic period in amniotes; translated from German), yet its character was descriptive and comparative, quite in line with Portmann’s tradition of comparative morphology and evolutionary biology. Weber later admitted that he was never quite happy with his thesis, as his main interest had always been to understand the mechanisms that drive development. He was convinced that this could not be achieved solely bymorphological descriptions and comparisons, but that experiments and in particular chemical and biochemical methods had to be used as well. After his graduation, Weber worked and acquired experiences in different fields, countries, and institutions, in particular at the University of Uppsala (Sweden), the Division de Malarialogia in Maracay (Venezuela), the Swiss Tropical Institute in Basel, and the Carlsberg Laboratories in Copenhagen (Denmark). A turning point in his career was 1954, when he accepted an assistant position offered by Fritz Erich Lehmann at the Zoological Institute of the University of Bern. This institution was to remain his academic home until his retirement in 1988. In 1954, Lehmann had just succeeded Fritz Baltzer as institute director, and both of them were world-renowned specialists of developmental physiology (Entwicklungsphysiologie), the term used for the research field of developmental biology at the time. A native of Bern, Baltzer had studied with Theodor Boveri in Wurzburg (Germany) and with Hans Spemann in Freiburg im Breisgau (Germany). These experiences had influenced him, once he was appointed professor in Bern, to study the roles of chromosomal and cytoplasmic determinants in various systems, including sea urchins (Baltzer 1910), the worm Bonellia (Baltzer 1928), and amphibians (newts) (Baltzer 1922; Baltzer 1952). His work was driven by the urge to integrate information from * Daniel Schumperli daniel.schuemperli@izb.unibe.ch

PTEN: History of a Tumor Suppressor.

Starting from the discovery of "inhibitory chromosomes" by Theodor Boveri to the finding by Henry Harris that fusing a normal cell to a cancer cell reduced tumorigenic potential, the notion of tumor suppression was recognized well before any tumor-suppressor genes were discovered. Although not the first to be revealed, PTEN has been demonstrated to be one of the most frequently altered tumor suppressors in cancer. This introductory chapter provides a historical perspective on our current understanding of PTEN including some of the seminal discoveries in the tumor suppressor field, the events leading to PTEN's discovery, and an introduction to some of the most important researchers and their studies which have shed light on PTEN biology and function as we know it today.

Eric Harris Davidson: A systems biologist who studied how genomes function.

The phrase “force of nature” has popped up repeatedly in social media responses to the announcement of Eric Davidson’s death on September 1, 2015. This sobriquet reflects his huge influence on the fields of developmental biology and evolution. His career began about the time Watson and Crick published the structure of DNA, and his contributions continued into the genomic era in which we are now immersed. But his stature wasn’t due to this timing. As Pasteur once said: “Dans les champs de l’observation le hasard ne favorise que les esprits prepares.” (“In the fields of observation chance favors only the prepared mind”). Perhaps Eric’s strong focus on the function of the genome and his great intellect also contributed to this influence. His unwavering focus on how the genome does its job must also play a role. Furthermore, he clearly took genuine delight in confronting complex biological problems, and he erected broad views of the process of nature. This point is documented in his dedication to the third edition of Gene Activity in Early Development, where he credits his father with teaching him about organizing complex perceptions. Eric Davidson was born on April 13, 1937 in New York City, New York. He is the son of Morris and Anne Davidson. His father was a renowned abstract painter of the mid-20th century who maintained a school of painting near Provincetown on Cape Cod, Massachussetts. Eric attended the University of Pennsylvania as an undergraduate, and earned a Ph.D. from Rockefeller University (then Institute). He continued at Rockefeller as a post-doc, and then as assistant professor until 1971. He then moved to the California Institute of Technology, where he remained for the remainder of his career.

The concept of the causal role of chromosomes and genes in heredity and development: opponents from Darwin to Lysenko.

The idea of chromosomes and genes as causal agents in development and heredity originated in late 19th-century cytology, and it was most strongly supported by Theodor Boveri and Edmund B. Wilson. The concept of genes, which was central and most fruitful in classical genetics, appeared, however, unappealing and insufficient to many for explaining complex biological phenomena such as development.Philosophical outlooks, among them "Lamarckian" and holistic predilections, played a significant role in scientists' objection to genes as causal factors. A wide conceptual gap between genetics and developmental biology ensued. The strongest attack on the concept of genes was launched by agronomist and politician Trofim Lysenko in the Soviet Union under Stalin. Brushing aside the "Mendelist-Morganist" methods of classical genetics, Lysenko put forward a holistic concept of heredity that incorporated development and heritable responses to environmental conditions, similar to Darwin's Pangenesis theory, though of course some 60 years later. Recent developments include the role of genes in research on epigenetic marks and in systems approaches based on embryological gene regulatory networks.

Boveri at 100: Theodor Boveri and genetic predisposition to cancer.

One hundred years have passed since the publication of Theodore Boveri's Zur Frage der Entstehung maligner Tumouren [Concerning the Origin of Malignant Tumours]. This prescient publication created the foundations for much of our understanding of the origins of cancer and in particular the genetic basis of some cancers. In his work, Boveri suggested that loss of key cellular attributes, now known as tumour suppressor genes, are a key driver event in the development of cancer and inheritance could play a role in cancer susceptibility. He also predicted that chromosomal (genomic) instability as a key hallmark of cancer. Whilst these key insights that still inform the practice of cancer genetics, they were not the main theme of Boveri's text, which was to describe the role of chromosomal abnormalities in the development of cancer. In making his case he also suggested that genetic information could be contained in distinct packages (genes) that are linearly arranged along chromosomes and that cancers arise from single cells. These remarkably accurate hypotheses add weight to the need to celebrate this landmark publication for its accurate prediction of so much that we take for granted. Here we focus on Boveri's contributions to our understanding of hereditary cancers, which, alongside the astute clinical observations of Paul Broca and Aldred Scott Warthin, were published decades before the field became respectable, yet could still inform anyone studying hereditary cancers.

Boveri at 100: the life and times of Theodor Boveri.

This perspective focuses on the life and personality of TH Boveri, who was one of the leading creative and visionary scientists of the second half of the nineteenth century. Born in Bamberg in 1862, he made his scientific career in Munich and Würzburg, where he produced his prolific and important research, including seminal papers on cytogenetics. Of particular note is his work on chromosomal structures and function, including a theory of meiosis, a field almost new at that time. From these studies he created a theoretical model on oncogenesis, Zur Frage der Entstehung maligner Tumoren, which was originally published in 1914. Boveri's personality was characterized by an active and sometimes turbulent temperament, which nevertheless was controlled by scientific objectivity and doubts about his own abilities, at least with regard to his research. These characteristics made him an outstanding scientist who contributed new knowledge to the world of biology and pathology.

Centrosomes back in the limelight.

Centrosomes and centrioles were ‘born’ towards the end of the nineteenth century when they were first spotted and studied by astute cell and developmental biologists, including Edouard Van Beneden, as well as Theodor Boveri and Walther Fleming, who coined the terms ‘centrosome’ and ‘

The Marine Biological Laboratory (Woods Hole) and the scientific advancement of women in the early 20th century: the example of Mary Jane Hogue (1883-1962).

The Marine Biological Laboratory (MBL) in Woods Hole, MA provided opportunities for women to conduct research in the late 19th and early 20th century at a time when many barriers existed to their pursuit of a scientific career. One woman who benefited from the welcoming environment at the MBL was Mary Jane Hogue. Her remarkable career as an experimental biologist spanned over 55 years. Hogue was born into a Quaker family in 1883 and received her undergraduate degree from Goucher College. She went to Germany to obtain an advanced degree, and her research at the University of Würzburg with Theodor Boveri resulted in her Ph.D. (1909). Although her research interests included experimental embryology, and the use of tissue culture to study a variety of cell types, she is considered foremost a protozoologist. Her extraordinary demonstration of chromidia (multiple fission) in the life history of a new species of Flabellula associated with diseased oyster beds is as important as it is ignored. We discuss Hogue's career path and her science to highlight the importance of an informal network of teachers, research advisors, and other women scientists at the MBL all of whom contributed to her success as a woman scientist.

Cytogenetics of Leukemias: Identifying Genetic Abnormalities with Clinical and Prognostic Significance

Introduction: The importance of cytogenetics in neoplastic processes such as leukemia is known. In 1914, Theodor Boveri suggested that chromosomal abnormalities were cellular alterations that cause the transition from normal to malignant proliferation. Over the course of several decades, different cytogenetic techniques were developed which led to the discovery of an increasingly broad spectrum of chromosomal abnormalities, resulting in a dramatic increase in the knowledge of human cancer. Aim: This article aims to review the role of cytogenetics in leukemia, highlighting its Review Article British Journal of Medicine & Medical Research, 4(12): 2296-2311, 2014 2297 importance for the clinical definition, treatment and prognosis of these neoplasms. Methodology: For this, we carried out a search for scientific articles present in the electronic database PubMed, using the descriptors Cytogenetics, Karyotype, Fluorescent In Situ Hybridization’’, Prognosis, Leukemia, Lymphoid , “Leukemia, Myeloid and Leukemia, Chronic Lymphocytic”. Books and specialized sites were also surveyed. Discussion: Cytogenetic analysis not only helps to confirm a diagnosis but it also aids in obtaining data on prognosis, response to treatment and possibility of relapse. The analysis provides a better understanding of the pathways involved in leukemogenesis processes and the development of new types of therapy. This information is essential for the proper management of patients, underscoring the importance of joint work between the medical oncologist/hematologist and the cytogeneticist.

One hundred years of somatic mutation theory of carcinogenesis: Is it time to switch?

During this current year of 2014 biologists and cancer researchers will commemorate the centenary of the publication of Zur Frage der Entstehung maligner Tumoren (On the Origin of Malignant Tumors, Williams & Wilkins. Philadelphia, PA, USA) by the German zoologist Theodor Boveri, a book that directly and indirectly impacted both the biological sciences at large and cancer research in particular. Before 1914, Boveri made important contributions in the fields of Mendelian inheritance, cellular and developmental biology: among others, the Sutton– Boveri theory of chromosomal inheritance; the individuality of chromosomes and the concept that the assortment of chromosomes rather than their number was necessary for development; the finding that comparable sets of chromosomes are contributed by the oocyte and the sperm. Boveri also paved the way for the discovery of the “organizer” by Spemann and Mangold [1]. These contributions were the fruit of his great observational skills, experimental ingenuity and dexterity, and his theorizing acuity. Finally, he wrote the aforementioned book, widely acknowledged to be seminal in cancer pathogenesis.