Portal de Periódicos da CAPES

Rosa Beddington

2001; Cell Press; Volume: 105; Issue: 6 Linguagem: Inglês

10.1016/s0092-8674(01)00393-2

1097-4172

Peter Rigby,

Reproductive Biology and Fertility

Rosa Beddington died on May 18th, 2001; she was just 45. Rosa was an embryologist of the greatest distinction; she had extraordinary technical skills, a piercing intelligence, and an artist's intuitive view of the problem she worked on. Combined with the ability to meld together the approaches of classical embryology and modern molecular genetics, these qualities allowed her to make many significant contributions during her career. She also had a profound influence on the work of others. Rosa grew up in rural southern England where she excelled at school, not only academically but also in sport and at art, which might have been her career. Her childhood was not always happy and this influenced her attitudes in later life. She went to Oxford as an undergraduate intending to pursue a career in medicine but decided that this was not for her. In 1977, she began her research work as a graduate student in the Sir William Dunn School of Pathology, working with Ginny Papaioannou, where, from the beginning, she focused on central questions: which cells in the early mouse embryo give rise to which tissues and how are such decisions controlled? And from the beginning her experimental dexterity was apparent: in her third paper she reported a technique for transplanting early postimplantation embryos from their mother to another pregnant mouse. All who have struggled to learn how to dissect such an embryo from its deciduum without damaging it, let alone to transplant it so that it can continue growth and development, wonder at how she did it. After completing her PhD in 1981, she stayed in Oxford, in the Zoology Department, for a further ten years, as a postdoctoral fellow with Richard Gardner and then as an independent investigator, first as a Fellow of the Lister Institute, and then as a member of the Imperial Cancer Research Fund's Developmental Biology Unit. She became interested in gastrulation, a topic that was to occupy her for much of her subsequent career. While further developing her microsurgical skills, she also became interested in the emerging possibilities for applying genetic approaches to the problems of early development. In 1989, she and her long-time collaborator and great friend, Liz Robertson, made the important observation that embryonic stem (ES) cells, while contributing to all tissues of the conceptus, are specifically excluded from the extraembryonic lineages. This technique, allowing partitioning of cells of different genotypes into distinct tissue compartments, has been widely exploited to understand gene function in the early embryo. In 1991 she moved to the Agricultural and Food Research Council's Centre for Genome Research in Edinburgh as a Senior Research Fellow. There she pursued her interest in gastrulation through studies of the cell autonomous function of the brachyury gene product, and with colleagues, notably Bill Skarnes, undertook a gene trap screen in ES cells which was designed to identify genes encoding secreted and membrane proteins. The mutations derived from this screen, and the region-specific cDNA libraries that she made later, were freely distributed and have been invaluable resources to the community. Figure 1 Rosa moved again, in 1993, to take up the position of Head of the Division of Mammalian Development at the Medical Research Council's National Institute for Medical Research at Mill Hill, on the outskirts of London. Within a year of her arrival, a paper appeared in Development, with Rosa as sole author. It showed that the node of the mouse embryo could, when transplanted, induce a second neural axis, thus establishing the functional relationship between the mouse node and Spemann's organizer in amphibia and Hensen's node in birds. She noted briefly that anterior neural structures were not present in the induced axes. Two years later, Rosa and an Australian postdoctoral fellow, Paul Thomas, showed that the anterior visceral endoderm, a tissue previously thought to serve a nutritive or protective function, is patterned at the time of primitive streak formation. Removal of these endodermal cells disrupts the patterning of the underlying ectoderm and thus, the formation of the most anterior CNS. The discussion of this paper finds Rosa in her most magisterial form as she reinterprets the data of others in support of her hypothesis. The marker used in these experiments was the expression of the Hesx1 gene that Rosa and her colleagues subsequently showed is required for normal forebrain development in mice and humans. They subsequently went on to show that another diverged homeobox gene, Hex, had an even more provocative expression pattern. Hex expressing cells are found in the endoderm at the distal tip of the egg-cylinder stage embryo. Lineage tracing experiments showed that these cells then move into the anterior endoderm. She had discovered the earliest molecular asymmetry in the mouse embryo and had shown that the anterior-posterior axis is derived from a preexisting proximo-distal axis. The anterior endoderm cells marked by Hex are responsible for inducing anterior character in the adjacent ectoderm. In collaboration with Mike Jones and Jim Smith, she showed that this patterning mechanism also operates in the frog embryo, Xhex marking a population of deep endodermal cells close to Spemann's organizer. Rosa once told me that when she began her embryological research she never dreamed that she would one day discover a novel induction. That she did so was a source of great pleasure and pride. Her overall thinking on asymmetry and axis formation is seen at its best in a review, again authored with Liz Robertson, that appeared in this journal in January 1999. Her scientific achievements were widely recognized; she was an International Scholar of the Howard Hughes Medical Institute, a member of the European Molecular Biology Organisation and of the Academia Europaea, and she received the Waddington Medal (which she herself had designed some years earlier) of the British Society for Developmental Biology. In 1999, she was elected to the Fellowship of the Royal Society, an honor from which she derived great satisfaction. I have often said that I think that the most important thing that I did when at Mill Hill was to persuade Rosa to move there. I first encountered her in the mid-1980s when I was working on developmental problems using model systems, teratocarcinoma cells, and ES cells. I went to Oxford to give a seminar about this work. As soon as I stopped talking, a striking looking woman with long gray hair began questioning me intently. What did these cells have to do with the embryo? How was I going to prove it in the real world? And how, exactly, were our cDNA libraries made and analyzed? Before the questions finished she had vanished, leaving me asking, “who is this person?” I made sure that I found out. In the years that followed, developmental biology flourished at Mill Hill, but we lacked expertise in the real embryology of the mouse. We had tried to persuade Rosa to join us, and even when she went instead to Edinburgh, we did not give up. Eventually, over dinner one night, perhaps aided by the good food and several bottles of wine, Robin Lovell-Badge and I convinced her. Rosa herself thought that her eight years at NIMR were the most enjoyable and productive of her career. It was the perfect match. Rosa's knowledge of the mouse embryo and her skills in manipulating it empowered all of us, while she delighted in assimilating the approaches of molecular biology and in working with colleagues expert in other systems. Developmental biology at Mill Hill during the 1990s was the most amazing fun and Rosa was at the center of all of it. What she did herself was of the greatest importance, but her contributions went way beyond that because she was the ideal colleague. Her influence suffused everything that was done around her. In the British Civil Service, it is a great compliment to say that someone has a “Rolls-Royce mind.” It implies that their thinking is smooth, effortless, always well controlled and, perhaps, never too challenging. Rosa (who would like the analogy as she loved cars and driving them to the limit) had a mind like a Ferrari 250 GTO. It was incredibly fast, unbelievably agile, not at all comfortable on a rough road, and capable of 100 mph in reverse! She knew almost everything there was to know about development and she understood it at a profound level. Her artist's intuition allowed her to visualize the three-dimensional gymnastics of the cells in the early mouse embryo in a way that escapes most of us. There was no better person than Rosa on whom to try an idea, nobody who would give your manuscript or grant application a better going over. These sessions were sometimes uncomfortable—Rosa could be quite fierce and always said exactly what she thought. But she could do so while being enormously encouraging and supportive. You got shredded, but walked away feeling good about it! It was a remarkable gift from which so many have benefited. She retained it to the end. The last time I saw her we drank some wine, as was our custom. We gossiped about people we knew and the events of the world. We talked about the work going on in her lab, with which she was still totally in touch, and I told her about my latest research, with which I was quite pleased. She was excited with me, saw several possibilities for the future that had escaped me, berated me for having missed a couple of key points, and lectured me on the necessity of publishing the work. I enjoyed every moment; it is the way I will always remember her, the best colleague one could have. Rosa was diagnosed with breast cancer in early 1995. Following surgical intervention, she returned to the lab, a period during which much of her best work was done. But then in late 1998, the neurological effects of metastases forced her to stop work. She fought on and returned to Mill Hill in the autumn of 1999. She knew that the clock was ticking and she was relentless in her focus; papers were written, postdocs and students were taken care of, things were organized. In May of last year she left the lab for the last time and went home to the beautiful vicarage at Great Tew in Oxfordshire, where she and her husband, Robin Denniston, found such peace and happiness, and where she died. Rosa Beddington was a great scientist and a wonderful person. All who knew her will miss her most terribly.