A history of mammalian embryological research

Although Reinier DE GRAAF (1641-1673) can be considered the founder of modern reproductive biology, scientific knowledge of mammalian development did not progress significantly until the XlXth century. Determining contributions to this progress were the discovery of the ovum by Karl von BAER (1792-1876), his meticulous observations of the stages of embryogenesis, and, half a century later, the remarkable descriptions made by Edouard VAN BENEDEN (1845-1910) of egg development in rabbits and bats. Yet mammalian embryology remained a purely descriptive discipline until the second half of the XXth century, when a handful of exceptional scientists (notably including John D. BIGGERS, Ralph BRINSTER, Anne McLAREN, and W. WHITTEN) managed to obtain reproducibly the development of mouse eggs in a chemically defined medium and to transfer the eggs to the uterine horns of pseudopregnant females. Around the same time (1959), M.C. CHANG was the first to obtain a mammal (a rabbit) by in vitro fertilisation, thus opening the way to assisted procreation. This was achieved in our species in 1978, by Robert EDWARDS and Patrick STEPTOE. With these feats, mammalian embryology could at last become causal, as A. BRACHET already in 1912 had hoped it would. New concepts soon emerged from the delicate manipulations performed on mouse eggs by scientists such as A. TARKOWSKI, B. MINTZ, J. MULNARD, and R. GARDNER, concepts such as the oustside-inside hypothesis proposed to explain the determination of the ICM and trophectoderm or the clonal theory of cell determination during development. These new ideas were soon to become the focus of intense study. Other investigators, interested in the synthesis and roles of macromolecules, contributed in the late 1960's most of our knowledge on global trends in gene expression during the first stages of development. As for the many unfruitful attempts to obtain artificial parthenogenetic development in mice, these would lead to the discovery of parental genetic imprinting. In the 1950's, Leroy STEVENS and Barry PIERCE made famous a very rare tumour, the teratocarcinoma. This tumour soon became a model for studying mammalian development, adopted by an increasing number of research groups. It became the source of a first generation of pluripotent cells culturable in vitro: embryonal carcinoma (EC) cells. In the 1980's came the next generation: embryonic stem (ES) cells derived from the ICM of blastocysts, whose advent coincided with that of the first transgenic mice. Then came the era of knockout mice and cloning. Scientists now envisage with enthusiasm applications that were unimaginable just a few years ago. Such is the legacy of those few pioneers of the experimental embryology of mammals who, in the late fifties, were striving to make the wish expressed by A. Brachet in 1912 come true at last.