Development: The Natural History of Genes Review - CBMEG

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Development: The Natural History of Genes Review - CBMEG

Cell30time. They manage it by undergoing a cell type–specific chromatin complex constitutes a form of cellular memoverreplicationof the genes (Calvi and Spradling, 1999). ory. The still mysterious workings of the Pc-G genesTrypanosomes have the challenge of tricking the im- have immense relevance to plans for modifying genemune system of the host. They have in their genome a activities to promote healing, because stimulating relargeassortment of alternative versions of a surface generation processes will very likely require derepresprotein,and they periodically rearrange their genes to sion of genes normally active only during embryonicexpress a different version (Cross, 1996).development. Chromatin protein complexes that op-Gene rearrangement, in which part of the genome is pose repression, such as the Trithorax group (Trx-G)excised, appears to be limited to special occasions of proteins first found in Drosophila, may be useful inwhen, for example, a large repertoire of related genes is manipulating genes for reactivation and healing. One ofcreated by combinatorial reassortment of gene pieces. the members of the Trx-G is brahma, which encodesEvidence for retention of a complete genome in differen- an ATPase subunit of a large complex necessary fortiated cells is based in part on experiments in which proper homeotic gene transcription. The Brahma comsomaticnuclei are transplanted into eggs or embryos plex is related to the Swi/Snf complex as well as to otherand their ability to grow into animals is assessed. Some activating chromatin complexes found in yeast. The HOnotable successes—in growing complex animals—have locus, encoding the endonuclease required for matingshownthat somatic nuclei can do a lot (Gurdon and type switching, is among the genes activated by Swi/Uehlinger, 1966). The difficulty of defining the “differenti- Snf. A plethora of large chromatin protein complexesated” character of any particular nucleus leaves the sta- battles for control of genes; how they interact with sebilityof the genome question incompletely resolved, but quence-specific DNA-binding proteins is a researchit is clear that adult cells exist that can be “cloned” into area of great importance (Mannervik et al., 1999).animals (Wakayama and Yanagimachi, 1999).An additional hurdle for gene activation, not presentin Drosophila or C. elegans, is the clamping off of geneSilent Genesexpression resulting from methylation of DNA, an inter-Needham (1942, p. 101) noted that “one of the most esting process that is also linked to cellular memory.fundamental processes in development consists in the The imprinting of genes, so that they are selectivelyclosing of doors, i.e. in determination, in the progressive accessible for activation depending on whether they arerestriction of the possible fates.” In most cell types, only transmitted from the mother or father, is among the mosta fraction of genes is active at detectable levels. The dramatic kinds of regulation by methylation (Reik andmechanisms for keeping genes quiescent must be heri- Walter, 1998).table, yet reversible in at least some cells such as thegermline. Yeast MAT regulation has been a useful sourceLocalized Intracellular mRNA in Differentiationof information about how genes are kept off, becauseThe regulation of the HO nuclease during yeast cell typethe HML and HMR loci in fact contain complete genesswitching has been traced to a localized mRNA thatthat can become active under the mischievous controlcodes for a regulator of HO. HO transcription is regulatedof a biologist. Normally the information at HML or HMRby, among other things, a protein called Swi5p. Swi5pis expressed only after it is copied into the MAT locus.is found in mother cell nuclei, due to the regulation ofThe HML and HMR genes are flanked by “I” and “E”SWI5 transcription by the Ash1p transcription factor,sequences that silence the gene in cis. Proper represwhichmay directly repress SWI5 in daughter cells. Insion requires histones, the DNA origin replication comthisway the restriction of HO function to precise cellsplex, acetylases and deacetylases, four Silent Informainthe lineage has been reduced to understanding howtion Repressor (SIR) proteins, and chromatin assemblycomplexes (Haber, 1998). By analogy to the visibly comlocalizedto one region of cytoplasm in mother cells priorAsh1p is restricted to daughter cells. ASH1 mRNA ispact, relatively silent chromatin of other eukaryotes, the3 kb of DNA that is silenced by this entourage of proteinsto cell division (Bobola et al., 1996; Sil and Herskowitz,is described as heterochromatin. This 3 kb is transcripmyosin-likeMyo4p. Presumably ASH1 RNA localization1996). The localization is controlled by actin and thetionally silent, resistant to endonuclease, and is associisone aspect of the many structural differences betweenated with hypoacetylated histones. SIR proteins alsoaffect mitotic chromatin structure and rDNA recombina- mother cell and bud.tion, and are necessary for DNA ligation. These findings Localized mRNAs are absolutely critical for the develemphasizethe links between chromatin structure and opment of many organisms, most notably in the mater-both transcription and DNA modification.nal dowry provided to oocytes (Bashirullah et al., 1998).In multicellular developmental contexts, gene silencprimordiaDramatic examples include bicoid RNA localized in heading also depends on chromatin protein complexes. Theto polarize the A–P axis of the Drosophila egg,complexes may activate or repress genes, and the reguencodedand nanos RNA, which is a posterior determinant. Thelation can be reversible. Genes of the Polycomb groupproteins are often transcription factors, RNA-(Pc-G) are required to repress Hox and other genes in binding proteins, or both. Some RNA molecules areDrosophila (Pirrotta, 1998). Related mammalian genes moved to specific locations within cells, including thoseare implicated in Hox control, skeletal development, and coding for many cytoskeletal proteins. The relevant con-hematopoiesis (Gould, 1997). Proteins encoded by Pc-G trol elements, usually in the 3 untranslated regions,genes form complexes that maintain genes in repressed work in multiple species, suggesting ancient origins forstates. In the fly embryo, the initial repression of genes the elements. Asymmetric cell divisions of the sort thatby transient spatial regulators is replaced by Pc-G maintenanceoccur in yeast also occur frequently in neurogenesis,systems. As more cells are produced, the Pc-G and again localized mRNAs or proteins such asprospero


Review31are prominent in controlling the different dowries of the type switching, promoters and enhancers of genes activatedtwo daughter cells (Hawkins and Garriga, 1998).by myogenic proteins are assembly sites for protwotein complexes (Firulli and Olson, 1997). Once the rightRegulation of Batteries of Genesgenes are activated, the cells can start to have fun,by Transcription Factorsmating or differentiating.DNA rearrangement, though found in diverse organisms,is still viewed as the exception to having identical Wild Genes and Mating Habitsgenomes in every cell. Transcription appears to be a The romance between haploid yeast cells of oppositemuch more prevalent level of regulation than gene re- mating-type begins with the differential gene expressionarrangement.described above. Yeast cells of opposite mating-typeThe transcription factors encoded by MAT are well must find each other to combine their haploid genomesunderstood, but new information is providing a more to form diploids. The process occurs through a systemcomplete picture of what they do (Johnson, 1998). MAT of signals. The a cells secrete a protein signal called ais active in cells and codes for two proteins, MAT1p factor that binds to the Ste2p receptor on cells. Whenand MAT2p. MAT1p is a transcription factor that acti- the signal is received, the receptor, a transmembranevates the transcription of -specific genes. MAT2p, a protein, triggers a signal transduction process that cul-repressor protein that contains a homeodomain, re- minates in changes in cell shape and formation of surfacepresses a-specific genes. In a cells, a-specific genesstructures suitable for mating. Concomitantly, are activated by STE12p transcription factor, which is factor protein secreted by cells is received by themade by a and cells. The combined actions of Ste12p Ste3p receptor on a cells, and triggers the appropriateand Mcm1p, a protein that is made in all three cell types, differentiation events for mating in those cells. The twoturns on a-specific genes. a-specific genes are not activesignals and their two receptors are transcribed in thein cells despite the presence of Ste12p and proper haploid cell types under the control of MAT al-Mcm1p, due to the MAT2p repressor.leles. In cells, MAT1p, in combination with the non–Yeast MAT products work together with other pro- cell type specific transcription factor Mcm1p, activatesteins. For example, repression by MAT2p in a cell requiresthe -specific genes’ factor and STE2, while MAT2pMcm1p and a repressor composed of Tup1p and (working with Mcm1p, Tup1p, and Ssn6p) repressesSsn6p, all proteins that are produced in a, , and a/ the a-specific genes’ a factor and Ste3p. In a cells, thecells. The other possible resident at the MAT locus, a-specific genes are constitutive and the -specific genesMATa, is active in a and a/ cells and codes for MATa1p. are silent because MAT1 is repressed by MATa1p.In diploids MATa1p cooperates with MAT2p and the Mating behavior in animals involves evolutionarySsn6/Tup1 repressor to repress haploid-specific genes flourishes ranging from the huge antlers of Irish elk toand MAT1. The complex binds to a target sequence that the elaborate nests of bowerbirds. Genes controllingis distinct from the sequence recognized by MAT2p sex differentiation also exhibit rapid evolution and aalone. Thus, Mcm1p is particularly interesting, since remarkable range of mechanisms. Intensive studies ofit acts as an activator in a cells and as a repressor in sexual differentiation in worms and flies have providedthe other two cell types. When neither MAT allele is exceptionally well-understood pathways (Cline andactive, the default state is a, since the relevant target Meyer, 1996; Marin and Baker, 1998) and major progressgenes are constitutive without repressor around. In this has been made with mammals (Swain and Lovell-Badge,situation -specific genes are silent due to the absence 1999). In flies and worms, the X chromosome to au-of MAT1p.tosome ratio is measured with known counting elements,From the MAT studies, some generalities emergesetting in motion a cascade of RNA splicing and(Johnson, 1998): transcription factors are fairly ineffec- transcription regulatory events that has been traced alltive alone but powerful in complexes, the DNA acts as the way to the production of differentiation productsa nucleation site for assemblies of protein complexes, such as yolk protein. Although most of the moleculesand proteins (like scientists) can have positive or negativeinvolved in controlling sexual differentiation and dosageeffects depending on their collaborators.compensation differ between worms, flies, and mam-With the advent of recombinant DNA, specific genes mals, some of the genetic logic is similar. Critical elecouldbe assessed in differentiated cell types. The myo- ments for sex determination, in particular Sry, have beengenic transcription factors are a notable case of coordinateidentified on the mouse and human Y chromosome, andgene regulation. In muscle cells transcripts for all now will come the filling in of the pathway between thisthe structural proteins appear with similar kinetics upon most upstream regulatory element and sexual differenti-stimulation by activating genes such as myogenin and ation. Elaborate dosage compensation systems are necessaryMyoD in susceptible cell types. We now recognize twoto provide the developing animal with the propermain families of proteins that stimulate muscle develop- ratio of X chromosome products and autosome-derivedment: the bHLH family that includes myogenin and products (Lyon, 1999). The mechanisms are quite differ-MyoD, and the myocyte-enhancing factor (MEF) family ent in mammals, flies, and worms, with one X chromosome(Yun and Wold, 1996). Members of the two families cooperate,inactivated in mammalian females, transcriptionin both vertebrates and invertebrates (Baylies heightened on one X chromosome in male flies, andet al., 1998), to promote muscle differentiation by activatinglowered transcription from one X chromosome in wormmuscle-specific genes. The regulation of muscle hermaphrodites. Different chromatin regulators havedifferentiation has parallels with regulation in the growth been adapted, different ones by different organisms, inof the peripheral nervous system. As in yeast mating– order to regulate sex-specific levels of gene expression.


Cell34Figure 2. Example of Conserved Genes Affecting Dorsal–VentralCell Fates in Insect and Mammalian Nervous SystemsIn situ hybridizations from serial sections are superimposed at theleft and diagrammed at the right. Corresponding genes are shownin the same color. The order of expression of the genes is preservedfrom mice (left) to flies (right). Modified from Weiss et al. (1998).form the neural tube does the flipping. Other types ofregulation in neural development, such as the determinationof neuronal subtypes by bHLH proteins, alsoseem similar in Drosophila and mammals (Chan andJan, 1999).What exactly does the dedication of particular transcriptionfactors to particular tissues or patterningevents mean? Let us take Tinman as an example. Presumably,more than half a billion years ago, Tinmanbecame irreversibly associated with one or more targetgenes involved in building some sort of pump, or perhapseven earlier to define a particular type of mesoderm.An ancestral Nk-class homeobox gene would activatesome generally useful target genes in many celltypes. If Tinman arose as a duplicate of another NKgene, it might have been free to change either its spatialFigure 1. Segmentation and Homeosis; the Same Two Houses atDifferent Timesregulation or its binding specificity for DNA or cofactorAfter segmentation produces repeating structural elements (top), proteins. Since modern day Tinman can bind in vitro toaction of Hox genes in specific segments gives them individual sequences that other NK proteins bind, either the bind-properties (bottom). Photographs by Robert S. Brantley (Brand, ing differences are subtle or they are irrelevant. So, let1995). us suppose that the original distinguishing change in thetinman gene was due to the acquisition of a regulatoryabsent genes, and at least some of their homologs are element (responsive to Hox genes or TGF inducers?)required for fish and mouse eye development (Gehring to make tinman active in only a subset of the mesodermand Ikeo, 1999).cells. This might turn up transcription of a Tinman targetDorsal-ventral patterning in the early vertebrate and gene in that subset of cells, resulting in changed morflyembryo requires localized expression and action of phology, electrical conduction, or whatever. Once anysignaling proteins of the TGF class, such as Dpp in useful change along these lines occurred, Tinman’s as-flies and BMP2 and 4 in vertebrates. The proteins direct sociation with the particular subset of cells would bepolarization of the embryo and are restricted in their selectable. Now other genes could fall under Tinman’sactions by antagonist proteins of the Sog/Chordin class influence in those cells simply by acquisition of the shortworking from the opposite pole. In flies Dpp acts in DNA enhancer sequences necessary for Tinman regula-dorsal cells and Sog in ventral cells, whereas in verteofa piece of DNA containing Tinman target enhancertion. Point mutations might do it, as would transpositionbrates BMPs are ventral and Chordin dorsal. This andother evidence has suggested that the axes may have sequences. There would be strong selection for animalsbeen flipped during evolution (Holley et al., 1995). Furorvisceral mesoderm function.where Tinman had acquired targets that enhanced heartther support for this view comes from conserved expressionpatterns of three homeobox genes in early neural Whatever the original course of events, the dedicationdevelopment (Chan and Jan, 1999). In flies the order of of a transcription factor to a particular organogenesisgene expression is ventral-vnd-ind-msh-dorsal, and in event implies conservation of at least some targetthe vertebrate neural tube, the order for the genes genes, which we could call the primeval target genes.most closely related in sequence is ventral-Nkx2.2(vnd)- They may be but a small subset of the current arrayGsh1,2(ind)-Msx1(msh)-dorsal (Figure 2). The apparent of targets, and distinguishing them from subsequentlydiscrepancy—the axis does not look flipped—is resolvedbecause the invagination of the neural plate to recruitment of genes for aacquired targets may unveil the process of evolutionarytask.


Cell36relatively recent theft (and duplication) of an immunologicalfunction. Other genes have probably been cooptedfrom basic metabolic processes.One of the most interesting questions is whether thereis any logic to which types of regulators are used inwhich processes. Why is a zinc finger protein used hereand a homeodomain protein there? Is the present scenarioa historical accident, or does it reflect featuresof the proteins that make them especially suitable forcertain tasks? The origins of the machinery that regulatesdevelopment remain mostly unknown.DeathAs young biologists who assisted the explosive advancesin developmental biology have become middleagedbiologists, the developmental biology communityhas become fascinated with death. This at first took themild form of an interest in cell death (Horvitz, 1999),which was comfortably separate from real death. Celldeath is an extremely important mechanism during development,for example in shaping digits or allowingFigure 3. High Precision in Spatial Gene Regulation and SignalingSpatial regulation of a Hedgehog target gene. Mouse embryo withonly functional neurons or the right lymphocytes to surpatched1expression shown. Hedgehog signals induce expressionvive, and in disease, for example by regulating (or failingof patched1 and other target genes in precisely controlled spatialto regulate) inappropriate growth. Now the trend is a and temporal patterns, as is shown here using a lacZ gene insertedgreater interest in avoiding death altogether; the field into the patched1 locus. The regulatory relationships in Hedgehogof aging research is flourishing as never before. It is signaling are largely conserved in all animals where they have beenfascinating that both cell death and aging appear to be tested. From Ljiljana Milenkovic.programmed genetically just as the construction of theorganism is programmed (Kenyon, 1996; Defossez et normal developmental roles, APC in the Wnt signalingal., 1998; Guarente et al., 1998; Lin et al., 1998). Individual pathway and Rb in eye development. The presenilincells age too. The earliest known event associated with proteases that are crucial in familial Alzheimer’s diseasethe aging of yeast cells is genetic instability in the cluster have been linked to roles in processing Notch signalingof ribosomal DNA genes (Defossez et al., 1998). Non- proteins that are active in many developmental eventstransformed eukaryotic cells in culture also have a life- (Levitan and Greenwald, 1998). An insulin receptor-liketime timer running, quite possibly linked to telomerase gene, daf-2 of C. elegans, was discovered due to itsfunction and chromosome shortening. Reactivation of role in inhibiting dauer formation (a developmental formtelomerase allows cells to continue dividing in culture of the worm adapted for diapause) but has also beenbeyond the time they would otherwise enter crisis and implicated in affecting longevity (Kimura et al., 1997;die. In accordance with this view, most human tumor Tissenbaum and Ruvkun, 1998). In worms insulin signalcellscontain active telomerase, whereas most somatic ing may be required to steer metabolism away from fatcells do not (Hodes, 1999). The rapid advances in aging formation and is also involved in embryonic developresearchdemand frequent review; I will review them- ment. Dauer formation also requires a worm homologagain in 2050 and 2100.of the PTEN gene, which is a tumor suppressor gene inhumans (Rouault et al., 1999). Genes required to determineDevelopmental Biology, in Sickness and in Healthneuronal cell type in nematodes are closely relatedGenes discovered for their roles in development are also to genes involved in human polycystic kidney disease;critical in human disease. Linnaeus was interested in the worm’s genetic pathway including these genes pro-nosology, the classification of diseases. Continuing dis- vides ideas about what other proteins are relevant (Emmonscoveries of the roles of developmental genes in diseaseand Somlo, 1999). A gene related to the Drosophilawill allow more rigorous and unambiguous diagnosis. epithelial polarity gene crumbs is the cause of a formExcitement has come from finding genes that guide cell of retinitis that affects 1.5 million people (den Hollanderdifferentiation and pattern formation and that are linked et al., 1999). In each of these cases, the excitementto human disease. For example, mutations in -catenin comes from connecting a protein involved in humancontribute to human colon and other cancers (Morin et disease to a whole pathway of interacting components.al., 1997). Mutations in human Sonic hedgehog result in The elucidation of the ras pathway, so important in hu-holoprosencephaly; mutations in the hedgehog receptor man cancer and development, has benefited dramaticallyPatched (Figure 3) lead to polydactyly and spina bifidafrom its connections to developmental events inin Gorlin’s syndrome and to basal cell carcinoma, medul- flies and worms (Kayne and Sternberg, 1995; Wassarmanloblastoma, and rhabdomyosarcoma (Goodrich andet al., 1995).Scott, 1998). Mutations in the tinman-related human Developmental biology has great potential for impactgene Nkx2.5 cause heart disease (Schott et al., 1998). on the clinic. Already, treatments involving skin graftsCell cycle regulators such as APC and Rb are critical in and growth hormones have helped many people. Isolationhuman cancer and are now viewed in the context of theirof stem cells for a variety of tissues and better


Review37manipulations of stem cells based on newfound knowl- limits to child design or selection, which many peopleedge of growth and differentiation controls will surely find offensive, will almost certainly become a consider-make regeneration more useful for healing and tissue able social problem. The present controversies overreplacement (see reviews by Fuchs and Segre, 2000 and modification of tomato ripening properties, bovineWeissman, 2000 [both in this issue of Cell]). We see growth hormone produced in bacteria, and pesticidesprogress in identifying signals for producing neurons genetically introduced into plants are forerunners of de-that are lost in Parkinson’s disease, in inducing growth of bates about the proper limits of intervention in medicine.hair, in following pancreas differentiation to learn about The current tremendous inequities in access to medicaldiabetes, in stimulating growth of lung buds in culture, care may or may not be improved by new types ofand in growing arteries in culture. The biggest obstacle developmental medicine.is likely to be finding out how to create cells with theability to respond rather than to find the best cocktail What New Tools Are Needed?of signals.Our present picture of gene activation during develop-The developmental biology of parasites also holds ment is largely dependent on static views of embryos.enormous promise for new approaches to dread dis- Major limitations include the following: (1) Detection ofeases (Teixiera, 1998). Trypanosomes, leishmania, and markers like fluorescent proteins is slow because themalaria parasites together account for hundreds of mil- time needed for the protein to fold delays detection forlions of infected people. The lifecycles of parasites are significant periods of development. (2) At present wefascinating for their evasions of the immune response cannot watch more than four proteins, or gene expresandfor the adaptability of many parasites to multiple sion patterns, at a time. In the seething cytoplasm, thouhostorganisms, as well as for unusual molecular fea- sands of changes occur, while we watch a few eventstures such as the polycistronic transcription and intron- at a time. We need new ways to see, and new represenlessgenome of trypanosomes.tations of what we see. (3) It is difficult to quantitatethe concentration of any of the relevant proteins as aWhat Can We Build?function of time, let alone their activity states. (4) Modifi-One measure of progress in developmental biology will cations of proteins, such as phosphorylation or glycosylation,be whether we can direct the growth of a useful tissue.are hard to monitor or manipulate. (5) The chromabeHere is a test of whether we really know how things tin is preset to allow a gene to respond or not, and thiswork: take cells growing in culture and manipulate them cannot readily be viewed, particularly not at the singleto make either of two alternative organs by manipulating cell level.signals and gene activities. Organ development means With in situ hybridization to RNA in tissues, and detec-not just activating differentiation markers but making a tion of proteins with antibody stains, we can discriminatefully functional, well-shaped tissue that works. Make the among previously indistinguishable cells. This has beenepithelium fold where a fold would be useful; cause an fantastically revealing about cell determination, as itorganizing center to appear in a certain spot; make some gives us one view of what the cell is “thinking,” longcells delaminate and form another layer; make differenti- before morphological changes occur. This has led to aated cell types appear; make some cells migrate to a few markers being used to indicate “ventral-ness” oruseful new position; direct the formation of a left-right “liverish-ness.” While this may be safe, cells might activatesymmetry and then asymmetry; and make a colorfula few indicator molecules without turning on thepattern! If we could direct the same cell population into full set characteristic of a tissue type or stage of development.either of two completely different paths, we must haveThe more complete views of gene activation thatlearned something.have arrived with microarrays will help to clarify whetherHow can such knowledge be useful? The shaping of this is a real problem.tissues during healing and regeneration is mostly done Until recently gene expression during developmentsurgically now, and major limitations leave people in has been viewed by reconstructing events from differenttherapy or with reduced opportunities for decades. Fa- individual animals. Progress here will come from noninvasivecilitating a patient’s natural healing processes to promoteimaging techniques such as MRI applied to anicilitatingmore complete healing, more rapid healing, or mals (Jacobs et al., 1999) and watching gene expressionbetter organized healing would help tremendous numbersusing proteins tagged with fluorescent markers, suchof people. Altering properties of cells to make them as green fluorescent protein (GFP) (Chalfie et al., 1994).more resistant to infection or more aggressive in fighting GFP has already been extremely useful in watching theinfection will also become possible. Stimulating natural movements of proteins and cells in living embryos. Fluorescencegrowth processes to repair nerve damage, to grow newresonance energy transfer (FRET) is a techgrowthteeth, to replace blood without a marrow transplant, or nique that detects interactions between proteins basedeven to regenerate limbs would be of clear benefit. on the proximity of an emitting fluorescent moleculeWhat are the risks? One is cancer. By stimulating and a sensing fluorescent molecule that emits at a newgrowth processes necessary for repair at a time in life wavelength if sufficiently stimulated by the first emitterwhen (perhaps) normal restraints are no longer op- (Periasamy and Day, 1999). GFP together with FRET,erating, cancer might be a higher risk. A second concern and refinements and variations to come, will allow theis misuse of the knowledge. The science fiction literature associations of proteins to be monitored in living embryos.is replete with examples of body modifications chosento be repugnant. Many people find blood donation or Our view of development, and what matters in development,cosmetic “repair” after injury acceptable, whereas themight very well be differently skewed if we


Cell38could observe activation of kinase cascades in space thank Roel Nusse and the anonymous reviewers for helpful com-and time rather than gene transcription and protein acwithments on the manuscript, Drs. Tim Galitski and Gerry Fink for helpingmicroarray analysis, and Drs. Ljiljana Milenkovic and Josephcumulation. The ability to detect only activated formsWeiss for figures. I am particularly grateful to Allan Spradling andof a kinase with specific antibodies (e.g., Gabay et al., Mary Lou Pardue for inspiration, guidance, and friendship, and I1997) is valuable, but does not allow imaging fast thank my students and colleagues for all the excitement they haveenough to keep up with the rapid dynamics of living cell brought. The Howard Hughes Medical Institute and grants from themetabolism.NIH, DARPA, and the Parseghian Foundation support research inThere is a dearth of small molecules in our understandingmy laboratory.of development. We have steroids in hormonalcoordination of metamorphosis and growth, cAMP inReferencesmany events, nitric oxide in vascularization, and a few Ashburner, M. (1990). Puffs, genes, and hormones revisited. Cell 61,others, yet it seems likely that small molecules are as 1–3.ubiquitous and crucial in development as they are in Bashirullah, A., Cooperstock, R.L., and Lipshitz, H.D. (1998). RNAregulation of bacterial metabolism. How could we under- localization in development. Annu. Rev. Biochem. 67, 335–394.stand Trp repressor without knowing about tryptophan? Baylies, M.K., Bate, M., and Ruiz Gomez, M. (1998). Myogenesis: aview from Drosophila. Cell 93, 921–927.Where Did We Come From?Beachy, P.A., Cooper, M.K., Young, K.E., von Kessler, D.P., Park,W.J., Hall, T.M., Leahy, D.J., and Porter, J.A. (1997). Multiple rolesHow can developmental biology help us look into theof cholesterol in hedgehog protein biogenesis and signaling. Coldpast and understand human origins? Our own place in Spring Harb. Symp. Quant. Biol. 62, 191–204.the animal kingdom was noted in a letter written by Beermann, W. (1952). Chromomeren Konstanz und SpezifischeLinnaeus to a friend in 1747: “You disapprove my having Modifikation der Chromosomenstruktur in der Entwicklung und Organlocated Man among the Anthropomorphi. But manDifferenzierung von Chironomus tentans. Chromosoma 5,knows himself . . . I demand of you, and of the whole 139–198.world, that you show me a generic character—one that Bobola, N., Jansen, R.P., Shin, T.H., and Nasmyth, K. (1996). Asym-is according to generally accepted principles of classifiametric accumulation of Ash1p in postanaphase nuclei depends onmyosin and restricts yeast mating–type switching to mother cells.cation—by which to distinguish between Man and Ape.Cell 84, 699–709.I myself most assuredly know of none. I wish somebodyBrand, S. (1995). How Buildings Learn: What Happens After They’rewould indicate one to me. But, if I had called man an Built (New York: Penguin Books).ape, or vice versa, I should have fallen under the banCalvi, B.R., and Spradling, A.C. (1999). Chorion gene amplificationof all the ecclesiastics. It may be that as a naturalist I in Drosophila: a model for metazoan origins of DNA replication andshould have done so” (Greene, 1909). S-phase control. Methods 18, 407–417.Now we know ourselves somewhat better and realize Cedar, H., and Bergman, Y. (1999). Developmental regulation ofthat to know ourselves better still we must know all life immune system gene rearrangement. Curr. Opin. Immunol. 11,better. At age 25 Linnaeus took an adventurous 3000 64–69.mile journey through Lapland that had an influence on Chalfie, M., Tu, Y., Euskirchen, G., Ward, W.W., and Prasher, D.C.his science reminiscent of the effect of the Beagle voy- (1994). Green fluorescent protein as a marker for gene expression.Science 263, 802–805.age on young Darwin. Linnaeus observed the naturalChan, Y.-M., and Jan, Y.N. (1999). Conservation of neurogenic genesworld intensely despite storms, whitewater boat acciandmechanisms. Curr. Opin. Neurobiol. 9, 582–588.dents, and near starvation. Along the way he encoun-Chu, S., DeRisi, J., Eisen, M., Mulholland, J., Botstein, D., Brown,tered frog development while helping a woman whoP.O., and Herskowitz, I. (1998). The transcriptional program of sporubelievedshe had three frogs in her stomach (she heard lation in budding yeast. Science 282, 699–705. Erratum: Sciencethem croaking) as a result of drinking water containing 282 (5393), 1998.frog spawn. Even without such medical interludes, we Cline, T.W., and Meyer, B.J. (1996). Vive la difference: males vscan learn as Linnaeus did, by searching for natural surprises.females in flies vs worms. Annu. Rev. Genet. 30, 637–702.Our few model organisms provide an incomplete Cohn, M.J., Izpisua-Belmonte, J.C., Abud, H., Heath, J.K., and Tickle,view. We must first preserve what remains of the natural C. (1995). Fibroblast growth factors induce additional limb develop-world around us and then, like Linnaeus and Darwin, ment from the flank of chick embryos. Cell 80, 739–746.walk through and watch developments and developsurfaceCross, G.A. (1996). Antigenic variation in trypanosomes: secretsment with open eyes and minds.slowly. Bioessays 18, 283–291.Developmental biology is a celebration of naturalDarwin, C. (1871). The Descent of Man and Selection in Relation toSex (New York: Hurst and Co.).beauty combined with the elegance of molecular controlDefossez, P.A., Park, P.U., and Guarente, L. (1998). Vicious circles:systems. The more we know, the more astounding thea mechanism for yeast aging. Curr. Opin. Microbiol. 1, 707–711.renewal of life becomes. 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