Four decades of discovery in breast cancer research and treatment--an interview with V. Craig Jordan. Interview by Marc Poirot

V. Craig Jordan is a pioneer in the molecular pharmacology and therapeutics of breast cancer. As a teenager, he wanted to develop drugs to treat cancer, but at the time in the 1960s, this was unfashionable. Nevertheless, he saw an opportunity and through his mentors, trained himself to re-invent a failed "morning-after pill" to become tamoxifen, the gold standard for the treatment and prevention of breast cancer. It is estimated that at least a million women worldwide are alive today because of the clinical application of Jordan's laboratory research. Throughout his career, he has always looked at "the good, the bad and the ugly" of tamoxifen. He was the first to raise concerns about the possibility of tamoxifen increasing endometrial cancer. He described selective estrogen receptor modulation (SERM) and he was the first to describe both the bone protective effects and the breast chemopreventive effects of raloxifene. Raloxifene did not increase endometrial cancer and is now used to prevent breast cancer and osteoporosis.The scientific strategy he introduced of using long term therapy for treatment and prevention caused him to study acquired drug resistance to SERMs. He made the paradoxical discovery that physiological estrogen can be used to treat and to prevent breast cancer once exhaustive anti-hormone resistance develops. His philosophy for his four decades of discovery has been to use the conversation between the laboratory and the clinic to improve women's health.     

An interview with Dr. Heiko Hermeking on his highly cited paper published in Cell Cycle

Heiko Hermeking holds a professorship for Experimental and Molecular Pathology at the Pathology Institute of the Ludwig-Maximilians University Munich in Germany. He also received his Ph.D. from this university, working in Dirk Eick’s laboratory, where he discovered that p53 mediates c-MYC-induced apoptosis. He then carried out four years of postdoctoral studies in Bert Vogelstein and Ken Kinzler’s laboratory at the Johns Hopkins Medical School in Baltimore, MD, where he used the SAGE technique, which had just been developed in this laboratory, to identify important p53 (14-3-3 ) and c-MYC (CDK4) target genes. Then he was an independent group leader at the Max-Planck-Institute of Biochemistry in Martinsried near Munich. His current work focuses on the analysis of genes, microRNAs and pathways that are regulated by c-MYC or p53.     

Q & A

Gregory A. Petsko is Gyula and Katica Tauber Professor of Biochemistry and Chemistry and Director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University. He did his undergraduate work at Princeton and his graduate work as a Rhodes Scholar at Oxford University. He held faculty positions at Wayne State University School of Medicine and MIT before moving to Brandeis in 1990. A structural biologist, he is best known for his work, together with his colleague Dagmar Ringe, on the structural basis of enzyme catalytic power and the role of protein dynamics in protein function. He writes a regular opinion column for the journal Genome Biology.     

Jordan Raff

Jordan Raff is a Cancer Research UK funded group leader at the Wellcome/CR-UK Gurdon Institute in Cambridge, England. He obtained his PhD from the Department of Biochemistry at Imperial College, London, and he worked as a Post-doctoral fellow at the Department of Biophysics and Biochemistry, University of California, San Francisco. He is currently a Director of the Company of Biologists, and on the committee of the British Society of Cell Biology. He has studied centrosomes and cell division in fruit flies throughout his scientific career.     

Contribution of late Professor T. C. Tung to the experimental embryology of Amphioxus

Professor T. C. Tung (Fig. 1) was a prominent experimental embryologist in China. He was born in Jin County, Zhejiang Province, China in 1902. After he obtained his Bachelor's degree from the Department of Biology, Fudan University, Shanghai in 1927, he was appointed as a teaching assistant in that department until he moved to Belgium in 1930. He studied as a graduate student in Professors A. Brachet and A. M. Dalcq's laboratory at the Universite Libre de Bruxelles, Belgium and obtained his Doctor of Science degree there in 1934. During that period, he made two short working visits to the Institute of Marine Biology in France and took one training course at Cambridge University (UK). In 1934, he was invited to return to China as a Full Professor to teach at several Chinese universities, (Shandong University in Qingdao, Shandong Province; the National University in Nanjing; and Fudan University in Shanghai). He spent 1 year at Yale University (USA) between 1948 and 1949 as an invited scientist in a joint research project and finally returned to China in 1949. He was Chairman of the Department of Zoology, Shandong University in Qingdao (1949-1952), Vice-President of Shandong University (1952-1960), Director of the Marine Biological Institute, the Chinese Academy of Sciences (CAS) in Qingdao (1949-1958), Director of the Institute of Oceanology (CAS) in Qingdao (1959-1966), Director of the Institute of Zoology (CAS) in Beijing (1960-1962), member of CAS since 1955, Vice-Chairman of the Biological and Geographical Division of CAS (1955-1958), Chairman of the Biological Division of CAS (1959-1979) and Vice-President of CAS in Beijing (1978-1979). In spite of his administrative duties, he spent most of his life conducting bench work in his laboratories at the Institutes of Oceanology and Zoology, CAS, respectively, until he passed away in March 1979. Professor Tung's main research interest was with classic experimental studies on the determination of the egg axis and symmetry planes of fertilized eggs, early differentiation and organizing substances of egg cytoplasm, induction between embryonic cells and cytoplasm in embryogenesis, immunological studies on nuclear transplanted eggs, and cell fusion etc., in several types of animals. He conducted his experiments on a number of invertebrates (ascidians and Amphioxus) and vertebrates (fish and amphibians) by means of very skillful microsurgical operations and the nuclear transplantation method. Among these topics, his studies on the organization and developmental potency of Amphioxus eggs were unique. His important contribution to this research field involved not only establishing a practical method for collecting and using this rare animal for experimental purposes, but also clarifying controversy about the nature and early development of its eggs. He also provided conclusive evidence to determine its evolutionary position between invertebrates and vertebrates. The present article briefly reviews the main results obtained by Professor Tung and his colleagues on Amphioxus. Although their original articles were written both in Chinese and English, many international readers may not even know those original works because they were only published in scientific journals inside China from the 1950s. Comments and discussion on the experimental results of Amphioxus research by Tung's group and those from other earlier authors are also included.     

Ian Humphery-Smith on current challenges in proteomics

Ian Humphery-Smith is Professor of Pharmaceutical Proteomics at Utrecht University, The Netherlands, and until recently was a Managing Director and Chief Scientific Officer of Glaucus Proteomics. After a PhD in Parasitology at the University of Queensland, he studied virology and bacteriology in France as a post-doc, before returning to Australia as Course-Coordinator in Medical Microbiology and Immunology at the University of Sydney. During this time, Humphery-Smith took up the posts of Executive Director of Australia's second largest DNA sequencing facility and Director of the Center for Proteomic Research and Gene-Product Mapping, which later became the world's first center to focus on studying the proteome. Humphery-Smith has devoted ten years of research to analyzing proteins in health and disease, and it was his work that originally coined the term ‘proteomics’. He was the first to publish the most complete analysis of an entire proteome in 2000, that of the bacterium Mycoplasma genitalium. He currently serves as a council member of the Human Proteome Organization (HUPO) and has been a prime mover in efforts to have the Human Proteome Project become a formally-ratified international initiative to follow-on from the Human Genome Project.     

An interview with Dr. Frank Slack on his highly cited paper published in Cell Cycle

Frank Slack received his B.Sc from the University of Cape Town in South Africa, before completing his Ph.D in molecular biology at Tufts University School of Medicine. He started work on microRNAs as a postdoctoral fellow in Gary Ruvkun’s laboratory at Harvard Medical School, where he co-discovered the second known microRNA, let-7. He is currently an Associate Professor in the Department of Molecular, Cellular and Developmental Biology at Yale University. The Slack laboratory studies the roles of microRNAs and their targets in development, disease and aging.     

Philip Cohen

Philip Cohen trained at University College London and, after postdoctoral research at the University of Washington, joined the University of Dundee Scotland, in 1971, where he has worked ever since. He is a Royal Society Research Professor and Director of the Medical Research Council Protein Phosphorylation Unit. His main contributions have been in the area of protein phosphorylation and its role in cell regulation and human disease. In 1998, he was knighted for his contributions to biochemistry and the development of Life Sciences at Dundee.     

In defense of the somatic mutation theory of cancer

According to the somatic mutation theory (SMT), cancer begins with a genetic change in a single cell that passes it on to its progeny, thereby generating a clone of malignant cells. It is strongly supported by observations of leukemias that bear specific chromosome translocations, such as Burkitt's lymphoma, in which a translocation activates the c-myc gene, and chronic myeloid leukemia (CML), in which the Philadelphia chromosome causes production of the BCR-ABL oncoprotein. Although the SMT has been modified and extended to encompass tumor suppressor genes, epigenetic inheritance, and tumor progression through accumulation of further mutations, perhaps the strongest validation comes from the successful treatment of certain malignancies with drugs that directly target the product of the mutant gene.     

From the laboratory to the patient and back--an interview with Marc Mareel. Interview by Marc E. Bracke

The career of Marc Mareel is a synthesis of scientific research and clinical activity. During his medical studies, he already made his first enthusiastic steps in research via experimental work on avian developmental biology. Later, during his training as a radiotherapist, he founded his own laboratory for experimental cancer research. There he built up his international reputation as a pioneer in invasion research. Although invasion is the hallmark of tumor malignancy, he also kept an open mind about invasion in non-cancer conditions, such as in placental behavior, developmental biology, immunology and parasitology. His contribution to our understanding of invasion mechanisms has been both technical and conceptual. A number of assays have been developed in his lab, such as the embryonic chick heart and collagen gel invasion models, that have been (and still are) useful for many other research teams. He also contributed to the discovery of a number of key elements in the process of invasion, such as the stromal influence (including its extracellular matrix) and the cadherin family of cell-cell adhesion molecules. Concerning metastasis formation, he developed the original concept that a number of interacting eco-systems are implicated, such as the primary tumor, regional lymph nodes, the bone marrow and the (pre)metastatic niches in distant organs. Since his retirement, Marc Mareel has continued to integrate clinical practice with research creativity. He favours the idea of translational research bringing the results of laboratory findings to medical applications, and exploiting the feedback to the laboratory. The team in the Laboratory of Experimental Cancer Research at Ghent University currently consists of about 25 collaborators, who continue to appreciate his inspiring ideas and suggestions.     

Evidence that chromosome band 22q12 is concerned with cell proliferation in chronic myeloid leukaemia

Summary A man and two of his three children carried an abnormally short chromosome 22 resembling the Philadelphia chromosome (Ph¹). Giemsa banding showed that the abnormal chromosome resulted from a translocation t(11;22) (q25;q13). The breakpoint on chromosome 22 was at the q12/q13 band interface compared with the breakpoint of Ph¹ at the q11/q12 band interface. The absence of leukaemia or haematological disorder in members of this family suggests that the critical genetic site on chromosome 22 concerned with abnormal myeloid cell proliferation in human leukaemia is contained in the 22q12 band.     

Jonathon Howard.

Jonathon 'Joe' Howard (Fig. 1) is Group Leader and Director at the Max Planck Institute of Molecular Cell Biology and Genetics; he and his research group moved to Dresden, Germany, in July 2001. Howard received his PhD in neurobiology in 1983 from the Australian National University in Canberra. He did postdoctoral research there and also at the University of Bristol, UK, and at the University of California, San Francisco. In 1989, he joined the faculty at the University of Washington. His book "Mechanics of Motor Proteins and the Cytoskeleton" was published earlier this year. [interview by Mari N. Jensen]     

The manzanar project: Towards a solution to poverty, hunger, environmental pollution, and global warming through sea water aquaculture and silviculture in deserts

Summary Dr. Gordon Sato is a former Editor-in-Chief of In Vitro Cellular and Developmental Biology, President of the Tissue Culture Association (now Society for In Vitro Biology), and Director of the W. Alton Jones Cell Science Center (now Adirondack Biomedical Center). He began pilot experiments on the Manzanar Project at test sites in the Salton Sea while a Professor of Biology at the University of California, San Diego and continued the project in the laboratory at the Cell Center in Lake Placid, NY and at Eritrean test sites during their war of independence. Since 1994, he spends up to 10 mo. per yr in Eritrea where he directs the Manzanar Project and trains young Eritrean scientists in the field in the area of what he refers to as “low-tech biotech.” The name of the Manzanar Project was inspired by the camp in California where Dr. Sato and his family were interned during World War II.—The Editor     

Reconstitution of an operon from overlapping fragments: use of the lambda SV2 integrative cloning system

We have used the lambda SV2 system [Howard and Gottesman. In Gluzman (Ed.), Eukaryotic Viral Vectors. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1982, pp. 211-216; in Inouye, M. (Ed.) Experimental Manipulations of Gene Expression. Academic Press, New York, 1983, pp. 137-153] to reconstitute the Salmonella typhimurium his operon from overlapping fragments. lambda SV2 can be propagated as an autonomously replicating plasmid or as a prophage integrated in the Escherichia coli chromosome at the lambda attachment site; our reconstitution was accomplished in the integrated state. We first inserted a portion of the his operon into lambda SV2 and integrated the resulting plasmid by site-specific recombination into the E. coli chromosome. This was achieved by brief induction of a resident prophage. The lysogen was then transformed with DNA from a lambda SV2 clone carrying the remainder of the his operon on an overlapping DNA fragment. The second plasmid was forced to integrate into the first by homologous recombination. When this recombination occurs at the his overlap, a lysogen carrying two lambda SV2 prophages is produced. One prophage carries the entire his operon and the other carries the his overlap region. The latter is removed by site-specific recombination, permitting further contiguous sequences to be sequentially added to the remaining prophage. This method should be applicable for the reconstitution and maintenance of large genes or gene clusters in the E. coli genome.     

ROBERT TEMPLE: an eye for data. Interview

Robert Temple has spent more than thirty years of his career at the Food and Drug Administration-and he still likes it! After medical school, internship, and residency, Temple pursued endocrinology research at the NIH before deciding, in the early 70s, to apply his interests in science to consumer advocacy at the FDA. The FDA was undergoing enormous changes at that time, and Temple enjoyed the challenges associated with improving drug development and patient safety. Always relying on a critical evaluation of data, he is comfortable discussing mechanisms of drug action, experimental design, and regulatory policies, as well as the social implications of direct-to-consumer advertising of drugs. Currently, Temple is Director of one of the six Offices of Drug Evaluation and also serves as the Associate Director for Medical Policy.     

Patial trisomy 1 due to 1/17 translocation in Ph'-Positive chronic myelocytic leukemia

Summary A patient with chronic myelocytic leukaemia (CML) had the Philadelphia chromosome from the standard 9/22 translocation, a partial trisomy 1 secondary to an unbalanced 1/17 translocation, and a more recent clone with the addition of trisomy 22. This is the third case of partial trisomy 1 associated with the Philadelphia chromosome. Trisomy 1 in haematological disorders is discussed with reference to its clinical significance in CML, the segment of chromosome no. 1 involved, and the mechanisms of origin of the partial trisomies. Anomalies of chromosome 1, although not specific to any of them, seem to be important in the development of myeloproliferative disorders and of neoplasms in general.     

Paul Ehrlich: Pathfinder in Cell Biology 1. Chronicle of His Life and Accomplishments in Immunology,Cancer Research,and Chemotherapy1: Paul Ehrlich's Recipe for Success: “Patience,Ability, Money and Luck”

The paper reviews the life of Paul Ehrlich and his biomedical accomplishments in immunology, cancer research, and chemotherapy. Ehrlich achieved renown as an organic chemist, histologist, hematologist, immunologist, and pharmacologist. He disliked the formality of school but managed to excel in Latin and mathematics. His role model was an older cousin, Carl Welgert, who became a lifelong friend. Ehrlich studied medicine at Breslau, Strasbourg, Freiburg, and Leipzig, coming under the influence of Wilhelm Waldeyer, Julius Cohnheim, Rudolf Heidenhein, and Ferdinand Cohn. As a medical student, Ehrlich was captivated by structural organic chemistry and dyes. When he was 23, his first paper was published on selective staining. His doctoral thesis, “Contribution to the Theory and Practice of Histological Staining” contained most of the germinal ideas that would guide his future career. Most of his early work was centered in Berlin at Charité Hospital, where he did pioneering studies on blood and intravital staining, and at Robert Koch's Institute for Infectious Diseases, where he undertook important investigations in Immunology. Ehrlich became an authority on antitoxin standardization and developed the “side-chain theory” of antibody formation for which he was later awarded the Nobel Prize. He became director of an Institute for Experimental Therapy in Frankfurt where he continued research in immunology and carried out routine serum testing. He developed new lines of investigation in cancer research and originated the field of chemotherapy. Using principles developed in his early work with dyes, he successfully treated certain experimental trypanosomal infections with azo dyes. His crowning accomplishment was discovering that the compound Salvarsan could control human syphilis. Ehrlich's legacy in immunology and chemotherapy is discussed and an intimate portrait is drawn of Ehrlich the person.     

Reciprocal translocation and the Philadelphia chromosome

Summary We examined metaphases from three patients with chronic myeloid leukaemia and a typical Philadelphia chromosome with one chromosome 9 as the recipient to determine whether the 9q+ 22q- translocation is reciprocal. Good quality G-banded photographs of the chromosomes concerned were subjected to light absorption density analysis. This provided enlarged tracings corresponding to the relevant chromosome regions and so facilitated accurate measurement. This technique has unambiguously shown that the typical Philadelphia chromosome results from a reciprocal translocation and that probably no material is gained or lost in the exchange. Furthermore, in a total of six patients for whom sequential G and C banding was performed, the chromosome 9 with the largest block of centromeric heterochromatin received the translocated material. We offer tentative explanations for this curious observation.     

Sergei Winogradsky: a founder of modern microbiology and the first microbial ecologist

Sergei Winogradsky, was born in Russia in 1856 and was to become a founder of modern microbiology. After his Master's degree work on the nutrition and growth physiology of the yeast Mycoderma vini at the University of St. Petersburg, he joined the laboratory of Anton DeBary in Strassburg. There he carried out his studies on the sulfur-oxidizing bacterium Beggiatoa which resulted in his formulation of the theory of chemolithotrophy. He then joined the Swiss Polytechnic Institute in Zurich where he did his monumental work on bacterial nitrification. He isolated the first pure cultures of the nitrifying bacteria and confirmed that they carried out the separate steps of the conversion of ammonia to nitrite and of nitrite to nitrate. This led directly to the concept of the cycles of sulfur and nitrogen in Nature. He returned to Russia and there was the first to isolate a free-living dinitrogen-fixing bacterium. In the flush of success, he retired from science and spent 15?years on his familial estate in the Ukraine. The Russian revolution forced him to flee Russia. He joined the Pasteur Institute in Paris where he spent his remaining 24?years initiating and developing the field of microbial ecology. He died in 1953.