PROFILE PROFILE Profile of Edward M. De Robertis

Jennifer Viegas Science Writer describes Montevideo in the 1950s as an idyllic place to grow up. “These were peaceful, safe, and innocent times,” he says. “ Curiosity about the mysterious workings of gator, is interested in how cells in the I attended a primary and high school embryos fuels the research of embryologist vertebrate embryo communicate with one run by American Methodist Missionaries Edward M. De Robertis (also known as another over long distances. Deciphering who provided a good education mostly ” Eddy), who was elected to the National such cell signaling remains a fundamental in English. Academy of Sciences in 2013. His isolation problem in stem cell biology and cancer. During high school, his biology teacher, of genes that control head-to-tail and back- De Robertis has been a member of the Mr. Lagomarsino, lent him the keys to the to-belly patterning in early frog and mouse Jonsson Comprehensive Cancer Center at laboratory. At lunchtime, De Robertis embryos led to the discovery that animal UCLA since 1985. He is also a member of would go to the laboratory to reproduce development is controlled by an ancient fi experiments he had read about in Scien- the Ponti cal Academy of Sciences and fi genetic toolkit. De Robertis dissected the the Latin American Academy of Sciences, ti c American, which, at the time, high- process of embryonic induction, in which lighted news about the emerging genetic and is a Fellow of the American Academy “ groups of cells called “organizers” control of Arts and Sciences. code. At that time, it was also customary tissue differentiation. Earlier work by De to read inspiring science books such as Robertis and colleagues contributed to the Childhood in Uruguay Microbe Hunters by Paul de Kruif (1) and beginning of the scientific discipline known De Robertis was born in 1947 in Boston, TheLifeoftheBeeby Maurice Maeterlinck as evo-devo, which takes an evolutionary MA, while his neurobiologist father was a (2) as part of children’seducation,” he says, perspective on development. postdoctoral researcher at the Massachu- mentioning his early interest in biology. De Robertis, Norman Sprague Professor setts Institute of Technology. The family His parents divorced when he was five. of Biological Chemistry at the University moved to Montevideo, Uruguay, when he De Robertis stayed in Uruguay with his of California, Los Angeles (UCLA) and a was three. His parents were Argentinians mother. His father returned to Argentina Howard Hughes Medical Institute Investi- exiled by General Juan Perón. De Robertis but visited regularly. Introduction to Embryology De Robertis’ family assumed that he would follow in his father’sfootsteps.“Conse- quently, I did not have to invest any energy in choosing a career,” he says. Students interested in biology were steered toward the field of medicine, so De Robertis went down that path. He earned a degree in medicine in 1971 from the University of Uruguay’s School of Medicine. There he was an assistant to Roberto Narbaitz, who introduced him to embryology. De Robertis married his childhood sweetheart, Ana Marazzi, the day after his final examination at the University of Uruguay. The newlyweds moved to Buenos Aires three days later, and De Robertis entered the Faculty of Sciences at the Instituto Leloir to start his doctorate of philosophy studies in chemistry. His advisor was biochemist, Héctor Torres, who taught De Robertis about enzyme ki- netics. Another early mentor was the di- rector, Nobel Laureate Luis Federico Leloir, who was in the adjoining laboratory. De Robertis has never forgotten Leloir’s

This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article Edward M. De Robertis. Image courtesy of Ana De Robertis. 10.1073/pnas.1319745110.

www.pnas.org/cgi/doi/10.1073/pnas.1320552110 PNAS Early Edition | 1of3 Downloaded by guest on September 27, 2021 disciplined schedule in which he conducted two experiments nearly every day: one in the morning and one in the afternoon. A Fateful Meeting While on a tour of lectures in South America, renowned developmental bio- logist John Gurdon visited the Instituto Leloir. Gurdon was well known for his nuclear transplantation work as well as for synthesizing protein from mRNAs micro- injected into frog oocytes. De Robertis in- troduced himself, and later spotted Gurdon leaving alone to brave the Buenos Aires rush hour. “Seeing that he was on foot,” De Robertis says, “Iwenttomycar,drove to the bus stop, and casually pretended to be surprised of seeing him there and gave him a ride to his hotel in the city center. This small gesture of politeness was to change my life.” A few years later, De Robertis was De Robertis and colleagues at a 2007 EMBL symposium in Heidelberg, Germany. Image looking for a postdoctoral position, and was courtesy Iain Mattaj. referred to Gurdon. De Robertis wondered why Gurdon would even consider him. His professor informed De Robertis that, a professor of cell biology. It was a small of Medicine. He and colleague Larry few days after Gurdon’s visit, the British department, and he and his colleagues had Zipursky started the weekly Embryology Embassy sent someone to Leloir to say joint group meetings together with noted Club modeled around European semi- that if De Robertis ever wanted training Drosophila geneticist, Walter Gehring. “In nars in Cambridge and Basel. “It is still in Britain, there would be a fellowship truth, I completed my education in de- running and has provided a wonderful available for him. A few months later, in velopmental biology there,” De Robertis forum for discussions,” De Robertis says. 1975, De Robertis and his family moved to says. “These were very exciting times, for In 1988, a book (6) by embryologist Viktor Cambridge, England. Gehring’s group had discovered a gene Hamburger, as well as one by embry- With Gurdon, De Robertis transplanted sequence conserved in several Drosophila ologist Hans Spemann (7) who taught somatic kidney nuclei from Xenopus into genes, called ‘homeotic genes,’ which reg- Hamburger, sparked discussion in the the oocytes of a salamander and was able ulate anteroposterior cell differentiation. club about the possibility of isolating to show nuclear reprogramming using the After one of these seminars, Walter and genes involved in embryonic induction. then-new technique of 2D gels (3). De I had a brainstorm in his office and de- In 1924, Spemann and a colleague had Robertis and a coworker also showed, for cided to search for similar sequences in shownthataregionoftheamphibian the first time, that a gene cloned using vertebrate gene libraries.” embryo was able to induce the formation of recombinant DNA could be translated into Although De Robertis’ rationale for the Siamese twins after transplantation into protein using the frog oocyte as a test tube experiment was wrong because he thought another embryo (7). The cells from this (4). “What I did not know until arriving the genes would encode secreted neuro- region induced their neighbors to differen- there was that the MRC Laboratory of peptides, they nevertheless isolated the first tiate into tissues such as those for the Molecular Biology where Gurdon was Hox gene from a vertebrate (5). At the end central nervous system, muscles, or kid- working was the Mecca of molecular bio- of the paper’s abstract, De Robertis boldly neys, so it was called the “organizer region.” logy,” De Robertis says. “Francis Crick, wrote: “This gene could perhaps represent De Robertis and his team advanced those Max Perutz, Fred Sanger, Sydney Brenner, the first development-controlling gene findings by isolating a homeobox tran- and Cesar Milstein were all working in identified in vertebrates.” It indeed was. scription factor gene called goosecoid,which a relatively small building. One learned Before the discovery, it was thought that provided the first molecular marker for the so much simply listening to teatime con- development would be entirely different organizer (8). They microinjected synthetic versations at the cafeteria. Cambridge between Drosophila and Xenopus,but mRNA for goosecoid, inducing Siamese was electrifying for a young molecular afterward came the realization that de- twins in Xenopus embryos. De Robertis “ biologist.” velopment is directed by a conserved recalls, When my postdoc showed me genetic toolkit shared by all animals. This these embryos, it was a great joy, so much Evo-Devo discovery marked the beginning of the new so that I jumped on top of the bench! Afterthreeyearsasapostdoctoralscholar discipline of evo-devo. Goosecoid was a DNA-binding protein, so and three years as a staff scientist work- we reasoned it had to activate other genes ing on nuclear transport of proteins, De Unraveling Cell Differentiation that diffused to neighboring cells.” Robertis moved to the Biozentrum at the In 1985, De Robertis accepted a position The team isolated many genes encoding University of Basel, Basel, Switzerland. of Endowed Chair at the Department of secreted proteins enriched in Spemann’s There, at the age of 33, he became full Biological Chemistry at the UCLA School organizer and, surprisingly, most were

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1320552110 Viegas Downloaded by guest on September 27, 2021 PROFILE antagonists of known growth factors. They The work takes De Robertis a step closer signaling pathways is taking us in unexpec- were hoping to find new signaling path- to his goal of solving the long-standing ted directions...Iwanttounderstandhow ways, but discovered novel antagonists in- mystery of embryonic self-organization. embryonic cells communicate with each stead (9–11). One such antagonist was the “Study of the cross-talk between cell- other to form a perfect baby time after time.” protein Chordin, which the team showed works by binding to growth factors and blocking their signaling (12–15). 1 De Kruif P (2002) Microbe Hunters (Mariner Books, Boston, MA), 10 Bouwmeester T, Kim SH, Sasai Y, Lu B, De Robertis EM (1996) 3rd Ed. Cerberus is a head-inducing secreted factor expressed in the Spotlight on Chordin 2 Maeterlinck M (2013) The Life of the Bee (CreateSpace anterior endoderm of Spemann’s organizer. Nature 382(6592): ’ Independepent Publishing Platform, Seattle, WA). 595–601. Chordin is the focus of De Robertis In- 3 De Robertis EM, Gurdon JB (1977) Gene activation in somatic 11 Leyns L, Bouwmeester T, Kim SH, Piccolo S, De Robertis EM augural Article in this issue of PNAS, in nuclei after injection into amphibian oocytes. Proc Natl Acad Sci USA (1997) Frzb-1 is a secreted antagonist of Wnt signaling expressed in 74(6):2470–2474. the Spemann organizer. Cell 88(6):747–756. which he and his colleagues report that 4 De Robertis EM, Mertz JE (1977) Coupled transcription-translation 12 Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral chordindiffusesintheembryoinanarrow of DNA injected into Xenopus oocytes. Cell 12(1):175–182. patterning in Xenopus: Inhibition of ventral signals by direct binding layer of extracellular matrix that separates 5 Carrasco AE, McGinnis W, Gehring WJ, De Robertis EM (1984) of chordin to BMP-4. Cell 86(4):589–598. Cloning of a Xenopus laevis gene expressed during early 13 Piccolo S, et al. (1997) Cleavage of Chordin by Xolloid the ectoderm from the mesoderm (16). De embryogenesis that codes for a peptide region homologous to metalloprotease suggests a role for proteolytic processing in Robertis explains, “These results are novel Drosophila homeotic genes: Implications for vertebrate the regulation of Spemann organizer activity. Cell 91(3): because they suggest a way in which em- development. Cell 37:409–414. 407–416. 6 Hamburger V (1988) The Heritage of Experimental Embryology: 14 Reversade B, De Robertis EM (2005) Regulation of ADMP and bryonic induction of tissue types can take Hans Spemann and the Organizer (Oxford Univ Press, Oxford). BMP2/4/7 at opposite embryonic poles generates a self-regulating place coordinately in two different germ 7 Spemann H (1938) Embryonic Development and Induction morphogenetic field. Cell 123(6):1147–1160. (Hafner, New York); reprinted 1962. 15 Lee HX, Ambrosio AL, Reversade B, De Robertis EM (2006) layers, even as cells undergo the extensive 8 Cho KWY, Blumberg B, Steinbeisser H, De Robertis EM (1991) Embryonic dorsal-ventral signaling: Secreted frizzled-related proteins movements known as gastrulation.” Tissue Molecular nature of Spemann’s organizer: The role of the Xenopus as inhibitors of tolloid proteinases. Cell 124(1):147–159. differentiation affecting both ectodermal homeobox gene goosecoid. Cell 67(6):1111–1120. 16 Plouhinec JL, Zakin L, Moriyama Y, De Robertis EM (2013) 9 Sasai Y, et al. (1994) Xenopus chordin: A novel dorsalizing Chordin forms a self-organizing morphogen gradient in the and mesodermal cells may therefore factor activated by organizer-specific homeobox genes. Cell extracellular space between ectoderm and mesoderm in the Xenopus happen simultaneously. 79(5):779–790. embryo. Proc Natl Acad Sci USA,10.1073/pnas.1319745110.

Viegas PNAS Early Edition | 3of3 Downloaded by guest on September 27, 2021