RESEARCH ARTICLE SUMMARY ◥ HUMAN DEVELOPMENT An interactive three-dimensional digital atlas and quantitative database of human development Bernadette S. de Bakker,* Kees H. de Jong, Jaco Hagoort, Karel de Bree, Clara T. Besselink, Froukje E. C. de Kanter, Tyas Veldhuis, Babette Bais, Reggie Schildmeijer, Jan M. Ruijter, Roelof-Jan Oostra, Vincent M. Christoffels, Antoon F. M. Moorman* 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 devel- opment 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 morphogene- sis of the developing human body is difficult to understand. Textbooks on human development are often based on the works of early embryol- ogists, 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 resolu- tion to visualize organ development. Stained histological sections (mainly from the Carne- gie Collection of human embryos) were digi- tized, 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 orig- inal images was preserved. We tested the re- producibility 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 TerminologiaEmbryologica , are presented as interactive 3D-PDFs, which facilitates exploration of the complex relations between the different organs and al- lows researchers to develop an independent view of their spatial relations. The 3D recon- structions enable the measurement of the growth of the individual organs and struc- tures, the assessment of the changing position of organs relative to vertebral segments during development, and the verification of remain- ing ambiguities in the descriptions of the de- velopment of organs. CONCLUSION: The morphology presented in this atlas is directly connected to the orig- inal sections of the embryos in the Carnegie Collection—a connection that was in danger of being lost, with present-day textbook mor- phology becoming increasingly schematic and deviating from the original substrate. A num- ber 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 inter- ested 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). ▪ RESEARCH SCIENCE sciencemag.org 25 NOVEMBER 2016 • VOL 354 ISSUE 6315 1019 The list of author affiliations is available in the full article online. *Corresponding author. Email: b.s.debakker@amc.uva.nl (B.S.d.B.); a.f.moorman@amc.uva.nl (A.F.M.M.) Cite this article as B. S. de Bakker et al., Science 354, aag0053 (2016). DOI: 10.1126/science.aag0053 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. ON OUR WEBSITE ◥ Read the full article at http://dx.doi. org/10.1126/ science.aag0053 .................................................. on November 24, 2016 http://science.sciencemag.org/ Downloaded from