Swarthmore College Works Biology Faculty Works Biology 9-1-1998 Conceptual Breakthroughs In Developmental Biology Scott F. Gilbert Swarthmore College, [email protected] Follow this and additional works at: https://works.swarthmore.edu/fac-biology Part of the Biology Commons Let us know how access to these works benefits ouy Recommended Citation Scott F. Gilbert. (1998). "Conceptual Breakthroughs In Developmental Biology". Journal Of Biosciences. Volume 23, Issue 3. 169-176. DOI: 10.1007/BF02720017 https://works.swarthmore.edu/fac-biology/189 This work is brought to you for free by Swarthmore College Libraries' Works. It has been accepted for inclusion in Biology Faculty Works by an authorized administrator of Works. For more information, please contact [email protected]. SCOTT F GILBERT Department of Biology, Martin Laboratories of Biology, Swarthmore College, Swarthmore, PA 19081, USA (Fax, +610-328-8663; Email, [email protected]) I 1. Developmental biologists can indeed explain Introduction development Revising a textbook is a fascinating exercise that allows Fifteen years ago, embryology was what could be char- one to see quite starkly the changes that have occurred acterized as the only field of science that celebrated its in one's discipline through the subsequent editions. As questions more than its answers. We had the greatest I revise a textbook that was originally published in 1985, problems one could imagine: How does the brain develop? I can see the numerous advances that have transformed How do the eyes form? How does our back develop the discipline of developmental biology. But even more differently than our front? How are the arteries and veins important and much rarer than the advances are the true connected to the heart? But we had very few answers. breakthroughs. A breakthrough is more than just an The field had not changed much from 1958, when advance. For something to be a breakthrough, it must molecular biologist Sol Spiegelman chided his embryo- have encountered resistance -it must have broken through logical colleagues at a meeting on development: something. In thinking about breakthroughs in develop- I have found it difficult to avoid the conclusion that mental biology, let me first construct three categories many of the investigators concerned with morphogene- of breakthroughs. (i) Conceptual breakthroughs: These sis are secretly convinced that the problem is insoluble. are critical. We rarely find things if we don't know to I get the feeling that many of the intricate phenomena look for them. Conceptual breakthroughs direct our described are greeted with a sort of glee as if to research into new areas. (ii) Methodological break- say,"My God, this is wonderful, it is so complicated throughs: Often we have the concept, but not the tech- we will never understand it." niques to follow the paths opened by the concept. It seems to me that perhaps the time has come to Methodological breakthroughs allow certain areas to be abandon this joyful pessimism and its attendant con- explored. (iii) Experimental breakthroughs: Once the viction of incomprehensible complexity. In particular, technique has become available, certain experiments pro- I should like to make a plea for a more optimistic vide new insights into the workings of nature. As view based'On a belief in simplicity. The phenomena historians of biology have long acknowledged, it is rare of morphogenesis can hardly be as complicated as that a single experiment creates a new paradigm. However, implied by the welter of apparently unrelated obser- the weight of several experiments in the same direction vations constituting the literature of embryology. can create a breakthrough into new realms. The first indication that this joyful pessimism was II over came from the laboratory of Christiane Nilsslein- Vol hard. It was her laboratory that fused together This essay will look at the conceptual advances in animal embryology and genetics through the mediator of developmental biology over the past fifteen years. I think molecular biology. First, Katherine Anderson discovered that we can identify seven particularly important con- a morphogenetic determinant that is an RNA. This was ceptual breakthroughs that have caused developmental the mRNA tor the snake protein. She was able to rescue biology to metamorphose into a new science. the eggs from homozygous ."nake mothers by injecting J. Biosci., 23, No.3, September 1998, pp 169-176. @ Indian Academy of Sciences 169 70 Scott F Gilbert them with small amounts of cytoplasm from wild-type transcription factor that had been characterized- eggs. Instead of developing entirely dorsal cuticle, the androgenreceptor. dorsoventral pattern was restored. Then, in a remarkable seriesof experiments,this laboratoryand others delineated the mechanism of anterior-posterior axis formation in Homologous genes and pathways exist between Drosophila. The analysis of bicoid not only showed that distantly related phyla a morphogen could be stored as an mRNA, but that it could be localized in one region of the cytoplasm through This is an important breakthrough,for the predominating its 3' untranslated region, and that a gradient of this concept had been set forth by people as illustrious as protein could activate different genes depending upon Theodosius Dobzhanskyand Ernst Mayr. As Mayr con- the protein's cQncentration.The joyful pessimism gave cluded in 1966, "... the search for homologous genes way to a joyous optimism that some of the problems is quite futile except in very close relatives." Embryo- that had been on the books for hundreds of years could logists agreed. Each organ was seen to develop very now be solved. differently from any other organ. This notion was de- Interestingly, as Michael Ashburner (1993) has noted, stroyed by the discovery of the Hox genes in vertebrates. the initial screens that detected the genes involved in We now have remarkable homologues. Tinman is used anterior-posterior axis determination could have been in both the flies and vertebratesto make hearts, Pax6 done forty years earlier. "All this required was some is used in both flies and vertebratesto make eyes. The standardgenetics, a mutagen,and a dissectingmicroscope, fringe, hedgehog,and serrateproteins are usedto generate all available in the 1930s ...It was the idea that limb patterns in both vertebratesand arthropods (Shubin counted." Keller (1996) has documented that this idea et al 1997). could not have come about until the techniquesand the In addition to homologous genes, there are also ethos of molecular biology enabled one to go further homologous pathways (see Gilbert 1996; Gilbert et al with the idea. 1996). One of the first to be noticed was the RAS pathway which is used in the construction of the Caenorhabditis elegans vulva, the Drosophila seventh photoreceptor,and the division pathway in mammalian The core of development consists of paracrine skin. We have also seen that the Wnt-hedgehog pathway factors, transcription factors, and the signal first elucidated in Drosophila is also conserved gene- transduction apparatus between them for-gene in the vertebrates.These two paracrine factors interact within the disc to specify the proximal/distal, Developmental biology is a science of arrows. In a dorsal/ventral,and anterior/posterioraxes. The samemole- search for specific transcription factors which began with cules that specify these axes in the eye also specify the operon model of Jacob and Monod, numerous trans- them in the leg and wing discs. So we have a serial regulatory factors and the enhancers and promoters to process homology. Moreover, the same pathway exists which they bind were elucidated. In addition, the paracrine in vertebrates.Every member of the pathway in insects factors-the TGFs, BMPs, Hedgehogs, FGFs, and Wnts- has a homologue in the vertebrate embryo, and the same slowly emerged from the' 'soluble filtrates" that were interactions that transmit the Drosophila Wingless signal seen to induce differentiation. Inducers were the paracrine to the nucleus through armadillo and pangolin protein ligands and competence was the ability to receive and are seen in the vertebrates, wherein the Wnt signal is prOCessthe signal from the bound receptor. Between the manifest in the entry of fJ-catenin and Lef -1 into the paracrine factors acting at the cell surface and the nucleus. The genes are the same and the protein inter- transcription factors working within the nucleus were actions are the same. Only the readout is changed from the signal transduction cascades, pathway~ initially tissue to tissue and from speciesto species.Interestingly, delineated by oncologists who were interested in cell the same Wnt/hedgehog interactions seen in producing division. We now have complex circuits not only within the fly limbs are seenin the interactions that are involved cells but between cells. The biochemistry of the embryo in the morphogenesisof vertebrate limbs. If a vertebrate has become intercellular as well as intracellular. hedgehog protein (which is usually synthesized only in The delineation of the pathways linking paracrine the posterior mesoderm)is expressedanteriorly, the limb factors, signal transduction cascades, and transcription develops a mirror-image duplication. This is the same factors was also a triumph of molecular biology. The phenomenon that occurs when hedgehog protein is techniques of biochemistry were not adequate to isolate induced to form in the anterior portion of the fly wing and purify the minute amounts of labile paracrine factors disc (see Ingham 1994). Similarly, the Rei-protein path- or transcription factors. The key advance was to isolate way is used for dorsal-ventralpatterning in the Drosophila the mRNA rather than the protein. Before the use of blastoderm and for immunocyte function in both flies molecular probes, I can think of only one selective and mammals (figure 1; see Shelton and Wasserman 2.3.-the Conceptual breakthroughs in developmental biology 171 embryo lymphocyte spittle 'y' Toll r IL.} < Plasma membrane membrane tc'[:;::~~; , "'~1aSm ',,-J-r '. ADP ;;/ ¥ NucleuS ~uI ..Of v ~ati~_.