An interactive three-dimensional digital atlas and quantitative database of human development

Digital reconstruction of human development The detailed morphology of human development has intrigued scientists and the medical field alike. However, the scarcity of specimens hampers detailed mapping of tissue architecture. Furthermore, inaccuracies in the description of human development have crept into textbooks from observations of animal models that are extrapolated to humans. By mapping normal developmental processes and patterns, such as the growth and relative placement of organs, congenital anomalies can be better understood. de Bakker et al. generated interactive three-dimensional digital reconstructions based on the Carnegie collection of histologically sectioned human embryos spanning the first 2 months of gestation. These interactive models will serve as educational and scientific resources for normal and abnormal human development. Science, this issue p. 10.1126/science.aag0053 Interactive three-dimensional models unveil early human development. INTRODUCTION The basic human body plan, the arrangement of organs in the body, is laid down during embryonic development. Insight into the formation of this plan informs researchers and clinicians about normal development versus the development of congenital malformations, the latter of which have an incidence of 3% in the human population and cause up to one-quarter of all neonatal deaths. Despite modern technologies such as three-dimensional imaging, the intricate morphogenesis of the developing human body is difficult to understand. Textbooks on human development are often based on the works of early embryologists, some published more than 100 years ago. Because of the limited availability of human embryonic specimens, it is difficult or impossible to independently verify the information carried in these textbooks, or even to assess whether this information is derived from studies on human or animal models. RATIONALE Current imaging and computer technology make it possible to reconstruct human development with sufficient resolution to visualize organ development. Stained histological sections (mainly from the Carnegie Collection of human embryos) were digitized, tissues and organs were identified, and knowledge-driven modeling was applied to correct imperfections in the three-dimensional reconstructions. RESULTS We created a digital atlas with 14 interactive three-dimensional models of human embryology and a database encompassing 34 embryos spanning the first 2 months of human development. Approximately 15,000 histological sections from the Carnegie Collection were analyzed by trained biomedical students under expert supervision, and up to 150 organs and structures were identified and digitally labeled in each section. The labeled structures were then spatially reconstructed in such a way that the relation between the reconstruction and the original images was preserved. We tested the reproducibility of the manual tracing of the different organs and found that the variability in volumes of segmented structures ranged from 0.3% to 2% between students for simple and complex structures, respectively. The 3D models, supplemented by an object tree with structures named in accordance with the international standard of embryonic terminology, the Terminologia Embryologica, are presented as interactive 3D-PDFs, which facilitates exploration of the complex relations between the different organs and allows researchers to develop an independent view of their spatial relations. The 3D reconstructions enable the measurement of the growth of the individual organs and structures, the assessment of the changing position of organs relative to vertebral segments during development, and the verification of remaining ambiguities in the descriptions of the development of organs. CONCLUSION The morphology presented in this atlas is directly connected to the original sections of the embryos in the Carnegie Collection—a connection that was in danger of being lost, with present-day textbook morphology becoming increasingly schematic and deviating from the original substrate. A number of detailed analyses of the development of the kidney, pharyngeal arch cartilages, and notochord show that the current descriptions of the development of these organs are based on comparative animal models rather than on factual observations in human specimens. These examples demonstrate the scientific value of the atlas. This atlas will therefore serve as an educational and reference resource for students, clinicians, and scientists interested in human development and development-related congenital diseases. The 3D-PDFs of the reconstructions, as well as original and labeled images, are freely available (http://3datlasofhumanembryology.com). Lateral views of a model of a 7.5-week-old human embryo (16 mm). Left: Skeletal system. Center: Cardiovascular system with transparent heart muscle. Venous system is shown in blue, arterial system in purple, liver vessels in red, and umbilical vein in pink. Right: Reconstructed organs, except skin. Note, for example, the neural tube in green and the nerves in yellow. Scale bar, 2.5 mm. Current knowledge about human development is based on the description of a limited number of embryonic specimens published in original articles and textbooks, often more than 100 years ago. It is exceedingly difficult to verify this knowledge, given the restricted availability of human embryos. We created a three-dimensional digital atlas and database spanning the first 2 months of human development, based on analysis of nearly 15,000 histological sections of the renowned Carnegie Collection of human embryonic specimens. We identified and labeled up to 150 organs and structures per specimen and made three-dimensional models to quantify growth, establish changes in the position of organs, and clarify current ambiguities. The atlas provides an educational and reference resource for studies on early human development, growth, and congenital malformations.