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.     

Thomas Hunt Morgan as an Embryologist: The View from Bryn Mawr

Thomas Hunt Morgan taught at Bryn Mawr College from 1891 until1904. During his years there he concentrated his research interestson embryology; he included regeneration as an integral partof development. This article maintains that Morgan did not abandonhis interest in embryology when he became a geneticist at Columbia,but it deals mainly with his teaching and research while atBryn Mawr. He worked on the development of a great diversityof organisms, plant and animal, he used widely differing experimentalmethods to investigate them, and he concerned himself with manydifferent general and special problems. He strove to investigateproblems that were directly soluble by experimental intervention,and was highly critical, in the best possible way, of the experimentsand interpretations made by his contemporaries, who regardedhim as a leader. He exerted his influence on developmental biologynot only through his research, but also through a number offine textbooks, and by his teaching. During his Bryn Mawr yearshe encouraged his students, undergraduate and graduate, to carryout independent research. He sometimes published with them asco-author, but dozens of articles by his students were publishedwithout carrying Morgan's name as co-author.     

Common to both academia and industry: the challenge of discovery. An interview with Perry Molinoff

Perry Molinoff recognizes the distinctions between basic and applied science, between academic and industrial research, and between the preclinical and clinical realities of drug development. But he generally discusses these categories in fluid, practical terms, having throughout his career crossed the lines of distinction that have sometimes been rather heavily drawn among pharmacologists. As a third-year medical student at Harvard, he decided "to take a year off" to conduct laboratory research. After receiving his MD and pursuing further clinical and postdoctoral work, he enjoyed an academic career that included fourteen years as the A.N. Richards Professor and Chair of Pharmacology at the University of Pennsylvania School of Medicine. He has just completed six years as Vice President of Neuroscience and Genitourinary Drug Discovery for Bristol-Myers Squibb and will soon return to teaching, in the Departments of Psychiatry and Pharmacology at Yale University. Referring to himself as either pharmacologist or neuroscientist, depending on context, he has made fundamental discoveries in receptor biology, has overseen the discovery and development of drugs and their subsequent clinical trials, and has mentored a host of pharmacologists and neuroscientists who themselves have established careers in industry and academia. The pursuit of discovery as its own reward emerges as a theme that has marked his professional life (and is perhaps reflected also in the images displayed in his office of the Himalayan mountains, photographed by Molinoff himself from the Everest base camp last year).     

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.     

Q & A. [interview

George Oster is Professor of Biophysics, University of California, Berkeley. He received his B.S. at the U.S. Merchant Marine Academy and his Ph.D. at Columbia University. He began his career in biophysics as a postdoc at the Weizmann Institute under Aharon Katchalsky, where his research involved membrane biophysics and irreversible thermodynamics. His concern for environmental issues led him into population biology, which shaded into evolutionary biology and thence to developmental biology, cell biology and, most recently, protein motors and bacterial motility and pattern formation. His tools are mathematics, physics and computer simulation. He is currently a faculty member in the Departments of Molecular and Cellular Biology and the College of Natural Resources at Berkeley.     

Carlo M. Croce: Seeking Truth and Beauty

Believe it or not, as a boy Carlo Croce liked to hang out in art museums, to his mother’s chagrin. There are a lot of art museums in Italy, so his mother started dropping him off and going off to the coffee bar to find more interesting company. He bought his first painting, an old master, at age 12 and that used all his savings. He didn't resume his old master collection until he was in his 30s and had saved some money from his job at the Wistar Institute in Philadelphia. He now has an exciting and growing collection.In the meantime, he received his MD degree from the University of Rome “La Sapienza” while reading textbooks and journals in English to supplement the old style medical education. He planned to join Karl Habel at Scripps Clinic in 1970 for a research fellowship just as Dr. Habel was struck in his prime by a monkey B virus infection, so Carlo was diverted from California to Philadelphia to join Hilary Koprowski's internationally known Wistar Institute of Anatomy and Biology. I was a Ph.D. student at Wistar at the time and witnessed the arrival of the quiet 25 yr. old Italian who was too shy to try out his textbook English.He began his work in somatic cell genetics and virology in a large laboratory where a number of us worked on related projects, including Barbara Knowles (now Associate Director for Research at Jackson Laboratory) and Davor Solter (now Director of Developmental Biology, Max Planck Institute, Freiburg, Germany).One of his first accomplishments was to map the very first viral integration site on chromosome 7q in an SV40 transformed fibroblast cell line, using human-mouse somatic cell hybrids that retained human chromosome 7, the SV40 T-antigen and the SV40 genome. Very recently, one of his hybrid clones was used by others to clone the SV40 genome integration site and to show that the SV40 genome had integrated into a common fragile site.Still using somatic cell hybrids, Carlo Croce and his laboratory began in the late 70s and early 80s to map genes important in cancer, such as the immunoglobulin genes that are rearranged in lymphomas, along with the MYC and BCL2 genes among others. These experiments took advantage of the leukemia/lymphoma specific translocation to walk from immunoglobulin loci, and later TCR loci, into the oncogene loci juxtaposed by translocation, the beginning of positional cloning of translocation breakpoints. These studies involved collaborations with valued colleagues, including Peter Nowell, the co-discoverer with David Hungerford, of the Philadelphia chromosome, the first reported cancer specific chromosome alteration. In the exciting decode of the 1980s, the Croce laboratory published 23 reports in Science, including the discovery of the BCL2 gene with Yoshiide Tsujimoto (now University of Osaka). They also observed that mistakes by immunoglobulin family rearrangement/recombination machinery was responsible for the type of chromosome translocations that involved the IG and TCR genes.Carlo Croce has been not only an outstanding laboratory scientist with numerous important discoveries to his credit; he has also been the Director of an NCI designated Cancer Center, first at the Fels Institute for Cancer Research, where he built a first class basic cancer research faculty from the ground up. In 1991, he moved his cancer research faculty to Jefferson Medical College, where it took the name of its benefactor, Sidney Kimmel, and became the Kimmel Cancer Center. At KCI the Croce laboratory continued to find and study genes involved in cancer development: oncogenes activated by translocation such as ALL1, involved in biphenotypic leukemias, discovered with another important collaborator, Eli Canaani and TCL1 (with Gianni Russo’s lab) activated by translocation to the TCRa locus in lymphomas of ataxia telangiectasia patients; or tumor suppressor genes, lost usually through deletions in epithelial cancers, such as FEZ1/LZTS1 at 8p22 lost in prostate, breast and other cancers and the FHIT gene at the 3p14.2 common fragile site (discovered in a collaboration with my laboratory), confirming a long held hypothesis that genes at chromosome fragile sites could contribute to cancer development through frequent chromosomal rearrangements. At the same time, Carlo Croce was living the nearly always tumultuous life of a Director of a Cancer Center, involving recruitment of faculty, constant bargaining with Deans, department chairman, University administrators, but he still manages to fit in a few skiing meetings, gossip sessions with colleagues like Web Cavenee, visits for good coffee, good food and TV appearances in his beloved Italy and most of all, he still manages to study, examine, buy, transport, restore, reframe and admire his old master paintings. I think he loves it as much as science because discovering a beautiful but misattributed painting at an obscure or even well known auction house, buying it and then proving that it is actually a painting by a Gentileschi or a Cavallino is as thrilling and elegant as discovering the connection between a specific gene alteration and its cancer.     

How serendipity shaped a life; an interview with John W. Saunders,Jr. by John F. Fallon

John W. Saunders Jr. is an outstanding contributor to the field of Developmental Biology. His analyses of the apical ectodermal ridge, discovery and study of the zone of polarizing activity, insights into cell death in development, and analytical studies of feather patterns are part of a legacy to developmental biology. The body of his published work remains central to the understanding of limb development and is a major reason for the premiere place that the developmental biology of limbs holds in our research and teaching today. Beyond these things known to nearly everyone, there is John's role as teacher that is equally impressive. His one-on-one style, in small groups or from the podium is engaging, encompassing, and above all else, enthusiastic about the study of the development of living things. His love of developmental biology comes through to students of all ages and is inspirational. And, of course, inimitable charm accompanies the substance of any interaction with John. He still teaches in the Embryology Course at MBL Woods Hole. Recent students say that hearing his lectures and his involvement in the laboratory are highlights of the course. His continued knowledge of science and delight in new advances is a model for students to follow and they recognize it. John Saunders is a scientist and educator par excellence. His contributions have stood the test of time. His personal interactions with colleagues and students have enriched their lives in innumerable ways, large and small. His is a lifetime of outstanding achievements. In this interview, he reflects on his six--going on seven--decades in science and his personal enjoyment of recent advances in Developmental Biology.     

Michael Akam and the rise of evolutionary developmental biology

Michael Akam has been awarded the 2007 Kowalevsky medal for his many research accomplishments in the area of evolutionary developmental biology. We highlight three tributaries of Michael’s contribution to evolutionary developmental biology. First, he has made major contributions to our understanding of development of the fruit fly, Drosophila melanogaster. Second, he has maintained a consistent focus on several key problems in evolutionary developmental biology, including the evolving role of Hox genes in arthropods and, more recently, the evolution of segmentation mechanisms. Third, Michael has written a series of influential reviews that have integrated progress in developmental biology into an evolutionary perspective. Michael has also made a large impact on the field through his effective mentorship style, his selfless promotion of younger colleagues, and his leadership of the University Museum of Zoology at Cambridge and the European community of evolutionary developmental biologist.     

Howard A. Schneiderman--Planetary Patriot

SYNOPSIS. This symposium on arthropod development is dedicatedto the memory of Howard A. Schneiderman, who died on December5, 1990. Howard devoted much of his professional life to researchon arthropods and was the author of numerous publications onthe developmental biology of moths and flies. At Case-WesternReserve University and at the University of California-Irvinehe founded research institutes devoted to developmental biologyon arthropods as well as other organisms. Howard Schneidermanchampioned the use of insect growth regulators, which derivedfrom his research on the chemistry and physiology of juvenilehormone, as environmentally innocuous methods of controllinginsect pests of our food and fiber. In recent years he was aproponent of the use of molecular biology to alter the plantgenome so that insect-resistant crops might be grown and therebyreduce the use of insecticides. His global perspective was evidentin his understanding of how biotechnology could be applied toworld agriculture. Moreover, he quickly achieved prominencein promoting industry-university relations in his capacity asSenior Vice President for Research and Development at the MonsantoCompany. The cooperation among academic and industrial institutionsthat he fostered stands as a model for such relationships. HowardSchneiderman's influence on science and its applications, andon the universityindustry interface was profound and will befelt for many years to come.     

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.     

The sea spider's contribution to T.H. Morgan's (1866-1945) development

Over a century ago, T.H. Morgan helped found The Journal of Experimental Zo?logy, a series devoted to emerging investigations in development and evolution, variation and heredity, adaptation and ecology. T.H. Morgan initially encountered these topics in his graduate research on the ontogeny and phylogeny of the sea spiders. His Ph.D. thesis, written in 1891, reflects in interesting ways the conceptual shifts in evolutionary biology in the late 1800s. Embryology had become a major criterion in using morphological similarity to speculate on phylogenetic relationships. Yet, when Morgan studied the development of sea spiders to draw conclusions about their relatedness, he struggled with the incompleteness of knowledge about the role of inheritance and variation of ontogenetic processes. This can best be seen in his discussions of the properties of conservation during embryonic cleavage, varied development of supposedly homologous appendages, and the evolvability of larval stages. After his dissertation, Morgan never returned to phylogenetic analysis. He had been dissatisfied with the plethora of untestable phylogenetic hypotheses based on comparing complicated embryological phenomenon, and joined an experimental movement in which systems were explicitly chosen and constructed to test hypotheses about developmental processes.     

Proteomics data mining

Marc Wilkins completed his undergraduate and doctoral studies at Macquarie University, Sydney, Australia. During his doctoral studies, he defined the concept of the proteome and coined the term. After postdoctoral studies in Geneva, Switzerland, during which he co-edited the first book on proteomics, he returned to Australia, where he cofounded the company Proteome Systems. More recently, Marc took a position as Professor of Systems Biology at the University of New South Wales. He has established and directs the NSW Systems Biology Initiative, and is currently researching the role that protein post-translational modifications play in the regulation of protein-interaction networks.     

Classic limb patterning models and the work of Dennis Summerbell

Dennis Summerbell was a leading contributor to our understanding of limb patterning prior to the advent of molecular biology. He published several groundbreaking papers, including one that developed a key model for patterning the limb from the shoulder to the fingertips and another that presented the co-discovery of the effect of retinoids on limb morphogenesis. He brought detailed quantitative analyses to bear on these studies, as highlighted in two of his insightful papers published in the Journal of Embryology and Experimental Morphology, in which he provided elegant models that, today, remain relevant to limb patterning, as well as to many disciplines of developmental biology.     

The Tragedy of a priori Selectionism: Dennett and Gould on Adaptationism

In his recent book on Darwinism, Daniel Dennett has offered up a species of a priori selectionism that he calls algorithmic. He used this view to challenge a number of positions advocated by Stephen J. Gould. I examine his algorithmic conception, review his unqualified enthusiasm for the a priori selectionist position, challenge Dennett's main metaphors (cranes vs. skyhooks and a design space), examine ways in which his position has lead him to misunderstand or misrepresent Gould (spandrels, exaptation, punctuated equilibrium, contingency and disparity), and discuss recent results in developmental biology that suggest that an a priori position does not fill the demands of an evolutionary biology. I conclude by insisting that evolutionary biology is many leveled, complicated, and is carried on an ever shifting and expanding empirical base that when disregarded results in caricature.     

Q & A. [interview

Joel Rosenbaum was born and grew up in Massena, New York state, on the St Lawrence River border with Ontario, Canada. He received his undergraduate and PhD degrees from Syracuse University, and a Masters Degree in high school biology teaching at St Lawrence University. His PhD work was done with the protozoologist, George Holz Jr, and his post doctoral research on cilia and flagella was at the University Of Chicago with Frank Child and Hewson Swift. He has been at Yale University for 37 years where he has taught Cell Biology. His research has been on the synthesis and assembly of the proteins of cilia and flagella, showing that the flagellar axoneme assembles at the distal tip and that detachment of the flagella upregulates the genes for flagellar proteins. More recently his group has shown that this tip assembly process is facilitated by a rapid kinesin and cytoplasmic dynein-mediated motility underneath the flagellar membrane called ‘intraflagellar transport’. He is a runner with more than 20 marathons under his belt.     

The Claude Bernard Distinguished Lecture. In pursuit of meaningful learning

The Bernard Distinguished Lecturers are individuals who have a history of experience and expertise in teaching that impacts multiple levels of health science education. Dr. Joel Michael more than meets these criteria. Joel earned a BS in biology from CalTech and a PhD in physiology from MIT following which he vigorously pursued his fascination with the mammalian central nervous system under continuous National Institutes of Health funding for a 15-yr period. At the same time, he became increasingly involved in teaching physiology, with the computer being his bridge between laboratory science and classroom teaching. Soon after incorporating computers into his laboratory, he began developing computer-based learning resources for his students. Observing students using these resources to solve problems led to an interest in the learning process itself. This in turn led to a research and development program, funded by the Office of Naval Research (ONR), that applied artificial intelligence to develop smart computer tutors. The impact of problem solving on student learning became the defining theme of National Science Foundation (NSF)-supported research in health science education that gradually moved all of Dr. Michael's academic efforts from neurophysiology to physiology education by the early 1980's. More recently, Joel has been instrumental in developing and maintaining the Physiology Education Research Consortium, a group of physiology teachers from around the nation who collaborate on diverse projects designed to enhance learning of the life sciences. In addition to research in education and learning science, Dr. Michael has devoted much of his time to helping physiology teachers adopt modern approaches to helping students learn. He has organized and presented faculty development workshops at many national and international venues. The topics for these workshops have included computer-based education, active learning, problem-based learning, and the use of general models in teaching physiology.     

Pieter Nieuwkoop's contributions to the understanding of meso-endoderm induction and neural induction in chordate development

Pieter Nieuwkoop, who died September 18, 1996, at age 79 in Utrecht, The Netherlands, is remembered by developmental biologists for his numerous research contributions and integrative hypotheses over the past 50 years, especially in the areas of neural induction, meso-endoderm induction, and germ cell induction in chordates. Most of his experimentation was done on the embryos of amphibia, the preferred vertebrate embryo of the early years of the 20th century. One of his last publications contains a comparison of the experimental advantages and disadvantages of anuran and urodele amphibians (Nieuwkoop, 1996). The significance of his findings and interpretations for developmental biology can be estimated from the fact that researchers of many laboratories worldwide continue to work on the phenomena he first described and to extend the hypotheses he first formulated. The aim of this article is to review Nieuwkoop's main contributions and to cite the recent extensions by others.     

Tumour invasion: effects of cell adhesion and motility

Metastasis is the major cause of failure in cancer therapy. Recent studies of the molecular cell biology of the metastatic process have provided new insights into the mechanisms of cell-cell adhesion, cell-substrate adhesion and cell motility that underly invasion by tumour cells. In this review, Van Roy and Mareel discuss the role of proteins with invasion-promoting and invasion-suppressing functions in metastasis.     

Interventional ultrasound in pregnant macaques: embryonic/fetal applications

Similarities in developmental biology between human and nonhuman primates have resulted in the use of macaque species as models in perinatal research. Studies have frequently included invasive surgical procedures or may have required "blind" injections. Several techniques have been established in human subjects using ultrasound as a guide such as cordocentesis and fetal therapy. These techniques have been applied to the nonhuman primate laboratory setting, which significantly decreases the risk of pregnancy loss due to experimental intervention.