xIv CONTENTS CHAPTER 15 AGING: THE BIOLOGY OF SENESCENCE 571 Postembryonic Development: Genes and Aging 571 Genes encoding DNA repair proteins 571 Metamorphosis, Regeneration, Aging and the insulin signaling cascade 573 and Aging 547 Integrating the conserved aging pathways 575 Environmental and Epigenetic Causes METAMORPHOSIS: THE HORMONAL of Aging 575 REACTIVATION OF DEVELOPMENT 541 I S/DELIGHTS SPECULATIONS Exceptions to the Aging Amphibian Metamorphosis 542 Rule 579 Morphological changes associated with amphibian Promoting longevity 579 metamorphosis Hormonal control of amphibian metamorphosis 545 Regionally specific developmental programs 547 CHAPTER 16 H S/DELIGHTS SPECULATIONS Variations on the theme The Saga of the Germ Line 583 of Amphibian Metamorphosis 548 Metamorphosis in Insects 550 Germ Plasm and the Determination of the Imaginal discs 551 Primordial Germ Cells 583 Determination of the wing imaginal discs 554 Germ cell determination in nematodes 584 Hormonal control of insect metamorphosis 556 Germ cell determination in insects 585 The molecular biology of 20-hydroxyecdysone Germ cell determination in frogs and fish 588 activity 556 Germ cell determination in mammals 588 REGENERATION 560 The inert genome hypothesis 589 bimorphic Regeneration of Salamand l SidELIGHTS SPECULATIONS Pluripotency, Germ Cells, Limbs 561 and Embryonic Stem Cells 590 Formation of the apical ectodermal cap and Germ Cell Migration 592 regeneration blastema 561 Germ cell migration in Drosophila 592 Proliferation of the blastema cells: The requirement Germ cell migration in vertebrates for nerves and the AEC 563 Meiosis 598 H SIDELIGHTS SPECULATIONS How Do the blastema Cells Know Their Proximal and Distal Levels? 564 i SIDELIGHTS SPECULATIONS Big Decisions: Mitosis or Meiosis? Sperm or Egg? 600 Morphallactic Regeneration in Hydra 566 Gamete Maturation 602 The head activation gradient 567 The head inhibition gradient 567 Maturation of the oocytes in frogs 603 The hypostome as an"organizer"568 Gene transcription in amphibian oocytes 604 The basal disc activation and inhibition Meroistic oogenesis in insects 606 gradients 569 Gametogenesis in Mammals 607 Compensatory Regeneration in the Mammalian S 607 Liver 570 Oogenesis 610
xiv CONTENTS CHAPTER 15 Postembryonic Development: Metamorphosis, Regeneration, and Aging 541 METAMORPHOSIS: THE HORMONAL REACTIVATION OF DEVELOPMENT 541 Amphibian Metamorphosis 542 Morphological changes associated with amphibian metamorphosis 542 Hormonal control of amphibian metamorphosis 545 Regionally specific developmental programs 547 • SIDELIGHTS & SPECULATIONS Variations on the Theme of Amphibian Metamorphosis 548 Metamorphosis in Insects 550 Imaginal discs 551 Determination of the wing imaginal discs 554 Hormonal control of insect metamorphosis 556 The molecular biology of 20-hydroxyecdysone activity 556 REGENERATION 560 Epimorphic Regeneration of Salamander Limbs 561 Formation of the apical ectodermal cap and regeneration blastema 561 Proliferation of the blastema cells: The requirement for nerves and the AEC 563 • SIDELIGHTS & SPECULATIONS How Do the Blastema Cells Know Their Proximal and Distal Levels? 564 Morphallactic Regeneration in Hydra 566 The head activation gradient 567 The head inhibition gradient 567 The hypostome as an "organizer" 568 The basal disc activation and inhibition gradients 569 Compensatory Regeneration in the Mammalian Liver 570 AGING: THE BIOLOGY OF SENESCENCE 571 Genes and Aging 571 Genes encoding DN A repair proteins 571 Aging and the insulin signaling cascade 573 Integrating the conserved aging pathways 575 Environmental and Epigenetic Causes of Aging 575 • SIDELIGHTS & SPECULATIONS Exceptions to the Aging Rule 579 Promoting longevity 579 CHAPTER 16 The Saga of the Germ Line 583 Germ Plasm and the Determination of the Primordial Germ Cells 583 Germ cell determination in nematodes 584 Germ cell determination in insects 585 Germ cell determination in frogs and fish 588 Germ cell determination in mammals 588 The inert genome hypothesis 589 • SIDELIGHTS & SPECULATIONS Pluripotency, Germ Cells, and Embryonic Stem Cells 590 Germ Cell Migration 592 Germ cell migration in Drosophilci 592 Germ cell migration in vertebrates 594 Meiosis 598 • SIDELIGHTS & SPECULATIONS Big Decisions: Mitosis or Meiosis? Sperm or Egg? 600 Gamete Maturation 602 Maturation of the oocytes in frogs 603 Gene transcription in amphibian oocytes 604 Meroistic oogenesis in insects 606 Gametogenesis in Mammals 607 Spermatogenesis 607 Oogenesis 610 Coda 613
SYSTEMS BIOLOGY Expanding PART Developmental Biology to Medicine, Ecology, and Evolution 617 Context-Dependent Properties 619 Heterogeneous Causation 620 Emergence 619 Integration 621 Level-Specific Rules 620 Modules and Robustness 622 CHAPTER 17 Adult stem cells and regeneration therapy 653 Medical Aspects of Developmental Direct transdifferentiation 655 Coda 655 Biology 625 DISEASES OF DEVELOPMENT 626 CHAPTER 18 Genetic Errors of Human Development 626 Developmental Plasticity and The Nature of Human Syndromes 627 Genetic Heterogeneity and Phenotypic Symbiosis 659 Heterogeneity 628 The Environment as a Normal Agent in Producing Teratogenesis: Environmental Assaults on Human Phenotypes 659 Development 628 Diet-induced polyphenisms 661 I S/DEL/GHTS SPECULATIONS Prenatal Diagnosis and Predator-induced polyphenisms 663 Preimplantation Genetics 629 ol as a teratogen 631 Temperature as an environmental agent 664 Retinoic acid as a teratogen 633 Environmental Induction of Behavioral Phenotypes 667 Endocrine disruptors 634 Adult anxiety and environmentally regulated DNA Other teratogenic agents 639 methylation 667 I SIDELIGHTS SPECULATIONS Testicular Dysgenesis Syndrome and the Transgenerational Effects of Endocrine Learning: The Developmentally Plastic Nervous System 667 Experiential changes in mammalian visual Cancer as a Disease of Development 643 athwa Context-dependent tumors 643 Life Cycles and Polyphenisms 670 e cancer stem cell hypothesis: Cancer as a disease of stem cell regulation 644 Larval settlement 670 Cancer as a return to embryonic invasiveness Migration reactivated 645 The spadefoot toad: A hard life 671 Cancer and epigenetic gene regulation 645 l SIDELIGHTS SPECULATIONs Life Cvcle Choices Dictyostelium 672 l SIDELIGHTS SPECULATIONS The Embryonic Origins of dult-Onset Illnesses 646 Developmental Symbioses 675 DEVELOPMENTAL THERAPIES 648 Mechanisms of developmental symbiosis: Gettin Anti-Angiogenesis 648 The Euprymnd-Vibrio symbiosis 677 Stem Cells and Tissue Regeneration 649 Obligate developmental mutualism 677 Embryonic stem cells 649 Symbiosis in the mammalian intestine 678 Induced pluripotent stem cells 651 oda 680
l_UINItlNl i XV PART I \ / SYSTEMS BIOLOGY Expandin Developmental Biology to Medicine, Ecology, and Evolution 617 Context-Dependent Properties 619 Emergence 619 Level-Specific Rules 620 Heterogeneous Causation 620 Integration 621 Modules and Robustness 622 CHAPTER 17 Medical Aspects of Developmental Biology 625 DISEASES OF DEVELOPMENT 626 Genetic Errors of Human Development 626 The Nature of Human Syndromes 627 Genetic Heterogeneity and Phenotypic Heterogeneity 628 Teratogenesis: Environmental Assaults on Human Development 628 • SIDELIGHTS & SPECULATIONS Prenatal Diagnosis and Preimplantation Genetics 629 Alcohol as a teratogen 631 Retinoic acid as a teratogen 633 Endocrine disruptors 634 Other teratogenic agents 639 • SIDELIGHTS & SPECULATIONS Testicular Dysgenesis Syndrome and the Transgenerational Effects of Endocrine Disruptors 640 Cancer as a Disease of Development 643 Context-dependent rumors 643 The cancer stem cell hypothesis: Cancer as a disease of stem cell regulation 644 Cancer as a return to embryonic invasiveness: Migration reactivated 645 Cancer and epigenetic gene regulation 645 • SIDELIGHTS & SPECULATIONS The Embryonic Origins of Adult-Onset Illnesses 646 DEVELOPMENTAL THERAPIES 648 Anti-Angiogenesis 648 Stem Cells and Tissue Regeneration 649 Embryonic stem cells 649 Induced pluripotent stem cells 651 Adult stem cells and regeneration therapy 653 Direct transdifferentiation 655 Coda 655 CHAPTER 18 Developmental Plasticity and Symbi )iosis 659 The Environment as a Normal Agent in Producing Phenotypes 659 Diet-induced polyphenisms 661 Predator-induced polyphenisms 663 Temperature as an environmental agent 664 Environmental Induction of Behavioral Phenotypes 667 Adult anxiety and environmentally regulated DNA methylation 667 Learning: The Developmentally Plastic Nervous System 667 Experiential changes in mammalian visual pathways 668 Life Cycles and Polyphenisms 670 Diapause 670 Larval settlement 670 The spadefoot toad: A hard life 671 • SIDELIGHTS & SPECULATIONS Life Cycle Choices: Dictyostelium 672 Developmental Symbioses 675 Mechanisms of developmental symbiosis: Getting the partners together 676 The Euptymna-Vibrio symbiosis 677 Obligate developmental mutualism 677 Symbiosis in the mammalian intestine 678 Coda 680
CONTENTS CHAPTER 79 Morphogenetic constraints: The reaction-diffusios Developmental Mechanisms of Phyletic constraints 700 Evolutionary Change 683 Selectable Epigenetic Variation 702 Transgenerational inheritance of environmentally Inity of Type"and"Conditions of Existence induced traits 702 Charles Darwin's Synthesis 683 Genetic assimilation 705 Preconditions for Evolution through a S/DELIGHTS SPECULATIONS Hsp90 and Genetic Developmental Change 684 Modularity: Divergence through dissociation 684 Fixation of environmentally induced Molecular parsimony: Gene duplication and divergence 686 A Developmental Account of Evolution 709 eep Homology 688 Mechanisms of Evolutionary Change 689 Glossary G-1 Heterotopy 689 Heterochrony 691 Chapter-Opening Credits C-I erom Author index A-7 Heterotype 696 Subject Index 1-1 Developmental Constraints on Evolution 697 Physical constraints 697 AnOverviewofPlantDevelopmentbySusanR.Singerisavailableatwww.devbio.com Gamete Production in Angiosperms Vegetative Growth Gametophytes Meristems Root development Fertilization Shoot development Shoot development Embryonic Development Embryogenesis The Vegetative-to-Reproductive Transition Dormancy Juvenility Germination Floral signals Inflorescence development Floral meristem identity Senescence
XVI CONTENTS CHAPTER 19 Developmental Mechanisms of Evolutionary Change 683 "Unity of Type" and "Conditions of Existence": Charles Darwin's Synthesis 683 Preconditions for Evolution through Developmental Change 684 Modularity: Divergence through dissociation 684 Molecular parsimony: Gene duplication and divergence 686 Deep Homology 688 Mechanisms of Evolutionary Change 689 Heterotopy 689 Heterochrony 691 Heterometry 692 Heterotypy 696 Developmental Constraints on Evolution 697 Physical constraints 697 Morphogenetic constraints: The reaction-dimisio model 697 Phyletic constraints 700 Selectable Epigenetic Variation 702 Transgenerational inheritance of environmental!' induced traits 702 Genetic assimilation 705 • SIDELIGHTS & SPECULATIONS Hsp90 and Genetic Assimilation 706 Fixation of environmentally induced phenotypes 708 A Developmental Account of Evolution Glossary G-1 Chapter-Opening Credits C-J Author Index A~1 Subject Index 1-1 An OverView Of Plant Development by Susan R. Singer is available at www.devbio.com Gamete Production in Angiosperms Gametophytes Pollination Fertilization Embryonic Development Embryogenesis Dormancy Germination Vegetative Growth Meristems Root development Shoot development Shoot development Leaf development The Vegetative-to-Reproductive Transition Juvenility Floral signals Inflorescence development Floral meristem identity Senescence
Preface It has become increasingly embarrassing for me to ask stu- in the entire field of developmental biology. We are seeing dents to read the Eighth Edition of this textbook It's so, an inversion of relationships within the biological sciences ell, 2006. Developmental biology has progressed so rap- Genetics is more and more becoming a subset of develop idly in the past four years that my lectures have fundamen- ment. Similarly, the dynamic of evolution is being studied tally diverged from their reading My"big"lecture on tran- as a question of gene expression as well as gene frequen- scription now focuses on the ability of transcription factors cies And developmental biology may be on the threshold to reprogram cell fates; and my lectures on stem cells and of changing medicine as much as microbiology did at the cloning have scrapped the notion of therapeutic clonin turn of the twentieth century altogether, focusing instead on induced pluripotent stem I began the Preface of the last edition with a quotation cells In both instances, we discuss what this means for from the Grateful Dead, recalling"What a long, strange understanding normal development, as well as what impli- trip it's been. The epigram for this edition might be ations these technologies have for the future of medicine. Eminem's " Be careful what you wish for. We may achieve Neither induced pluripotential stem cells nor"transdiffer- biological powers that are"tenfold"what we had hoped entiation"was established when the last edition of this to have. And it is axiomatic for this generation that"with book was published great power comes great responsibility. Even my most basic lectures have changed. The lecture I hope this Ninth Edition of Developmental Biology pres on fertilization has to cover the new data on mammalian ents a better way of teaching and learning (and question- egg activation. My lectures on sea urchin development ing)developmental biology. The introductory section has n area of study that has been fundamental to develop been streamlined from six chapters to three-one each on mental biology for over a century--now include systems developmental anatomy, the mechanisms of gene regula theory operations involving double-negative gates and tion during differentiation, and cell-cell communication feedforward loops, and my evo-devo talks have led to dis- during morphogenesis. Another new feature is the addi- cussions of mathematical modeling and parasitism. I can't tion of short part-opening "chaplets" that address key talk about limb development without including the vari- concerns in developmental biology. These provide an ations seen in dachshunds and bats, and I can't discuss sex introduction to the subsequent chapters, placing the forth- determination without using the B-catenin model for mam- coming information into a specific context. Each chapter malian ovary production. None of these areas were cov- ends with a guide to web-based resources relevant to that red in earlier editions of my book. So this is really a very chapters content, and the Ninth Edition is the first to new edition. My editor tells me it has close to 700 new ref- include an extensive glossary of key terms erences; she only wishes I had deleted at least that many During the writing of this edition, I re-read some of th ones papers written by the first generation of experimental Developmental biology is in a state of rapid met tamor embryologists, scientists who were experiencing a Gestalt phosis. And, as in insect and amphibian metamorphosis, change as important as what we are experiencing today some old tissues remain the same, some get substantially What impressed me was not necessarily their answers modeled, and some old tissues perish altogether; and (although some of them were remarkably good even by all the while, new tissues are forming new structures. I todays standards); rather, it was their asking the "right" hope that I have gotten these correct, and that the added questions. Some of their research did not give us any new material will stand the test of time. I have tried to answers at all. But the results told the next generation of model the retained material into new narratives that are biologists what questions to ask. These embryologists more inclusive of the data, and to appropriately jettison stood in awe of the complexity of the embryo; yet they e information that was needed for earlier stages of the began to remove, transplant, destroy, and recombine cells book's development but which is no longer needed by in order to find out just how the fertilized egg could give undergraduates rise to a structured body composed of different cell types c Embryologist John Fallon once wrote me that new data They had faith that these were scientific questions and that nge the story one tells. It is, he said, like putting togeth- science would eventually be able to answer them er a picture puzzle. At first, you think the structure in front The glory of developmental biology is that we now have if you is a sailboat; but you add another piece, and-no, interesting answers to many of their questions. But numer- wait--it's a mountain. Psychologists call these alterations ous questions that were asked a century ago still lack Gestalt changes, and I think that we are seeing these answers. How does the human brain become organized so changes in both our day-to-day interpretations of data and that we can think, plan, recall, interpret, hate, and love?
Preface It has become increasingly embarrassing for me to ask students to read the Eighth Edition of this textbook. It's so, well, 2006. Developmental biology has progressed so rapidly in the past four years that my lectures have fundamentally diverged from their reading. My "big" lecture on transcription now focuses on the ability of transcription factors to reprogram cell fates; and my lectures on stem cells and cloning have scrapped the notion of therapeutic cloning altogether, focusing instead on induced pluripotent stem cells. In both instances, we discuss what this means for understanding normal development, as well as what implications these technologies have for the future of medicine. Neither induced pluripotential stem cells nor "transdifferentiation" was established when the last edition of this book was published. Even my most basic lectures have changed. The lecture on fertilization has to cover the new data on mammalian egg activation. My lectures on sea urchin development— an area of study that has been fundamental to developmental biology for over a century—now include systems theory operations involving double-negative gates and feedforward loops, and my evo-devo talks have led to discussions of mathematical modeling and parasitism. I can't talk about limb development without including the variations seen in dachshunds and bats, and I can't discuss sex determination without using the p-catenin model for mammalian ovary production. None of these areas were covered in earlier editions of my book. So this is really a very new edition. My editor tells me it has close to 700 new references; she only wishes I had deleted at least that many old ones. Developmental biology is in a state of rapid metamorphosis. And, as in insect and amphibian metamorphosis, some old tissues remain the same, some get substantially remodeled, and some old tissues perish altogether; and all the while, new tissues are forming new structures. I hope that I have gotten these correct, and that the added new material will stand the test of time. I have tried to remodel the retained material into new narratives that are more inclusive of the data, and to appropriately jettison the information that was needed for earlier stages of the book's development but which is no longer needed by undergraduates. Embryologist John Fallon once wrote me that new data change the story one tells. It is, he said, like putting together a picture puzzle. At first, you think the structure in front of you is a sailboat; but you add another piece, and—no, wait—it's a mountain. Psychologists call these alterations "Gestalt changes," and I think that we are seeing these changes in both our day-to-day interpretations of data and in the entire field of developmental biology. We are seeing an inversion of relationships within the biological sciences. Genetics is more and more becoming a subset of development. Similarly, the dynamic of evolution is being studied as a question of gene expression as well as gene frequencies. And developmental biology may be on the threshold of changing medicine as much as microbiology did at the turn of the twentieth century. I began the Preface of the last edition with a quotation from the Grateful Dead, recalling "What a long, strange trip it's been." The epigram for this edition might be Eminem's "Be careful what you wish for." We may achieve biological powers that are "tenfold" what we had hoped to have. And it is axiomatic for this generation that "with great power comes great responsibility." I hope this Ninth Edition of Developmental Biology presents a better way of teaching and learning (and questioning) developmental biology. The introductory section has been streamlined from six chapters to three—one each on developmental anatomy, the mechanisms of gene regulation during differentiation, and cell-cell communication during morphogenesis. Another new feature is the addition of short part-opening "chaplets" that address key concerns in developmental biology. These provide an introduction to the subsequent chapters, placing the forthcoming information into a specific context. Each chapter ends with a guide to web-based resources relevant to that chapter's content, and the Ninth Edition is the first to include an extensive glossary of key terms. During the writing of this edition, I re-read some of the papers written by the first generation of experimental cmbryologists, scientists who were experiencing a Gestalt change as important as what we are experiencing today. What impressed me was not necessarily their answers (although some of them were remarkably good even by today's standards); rather, it was their asking the "right" questions. Some of their research did not give us any answers at all. But the results told the next generation of biologists what questions to ask. These embryologists stood in awe of the complexity of the embryo; yet they began to remove, transplant, destroy, and recombine cells in order to find out just how the fertilized egg could give rise to a structured body composed of different cell types. They had faith that these were scientific questions and that science would eventually be able to answer them. The glory of developmental biology is that we now have interesting answers to many of their questions. But numerous questions that were asked a century ago still lack answers. How does the human brain become organized so that we can think, plan, recall, interpret, hate, and love?
XviII PREFACe How is the development of plants and insects timed so that Small and Janice Holabird of Sinauer's production depart the flower opens at the same time when its pollinator has ment have put together the artwork, the photographs, and and how does our face come to resemble those of our par- ing. For a book of this size, this is a heroic undertaking ents more than any one elses? To these questions, we have And, more than any other edition of this book(and she has only very partial answers, but we are on our way. been with it since its inception), this incarnation has been a Developmental biology presents a nascent scientist with collaborative effort with my editor Carol Wigg. The book host of fascinating questions that are worth solving. And seems to have become a full-time job for both of us hat's the invitation this book offers. One can enter devel- I especially wish to thank Dr. Hannah Galantino-Homer opmental biology through many portals-genetics, cell of the University of Pennsylvania School of Veterinary biology, embryology, physiology, anatomy--and with Medicine, who took it upon her shoulders to compile a many valid motivations. This is a field that needs the help glossary for this book. Numerous people have said that of people with all sorts of competencies and talents. It is they wanted such a glossary for their students, and put an old field that is itself undergoing metamorphic change ting one together is an extremely difficult task, involving and emerging as a new field that welcomes newcomers an enormous amount of thought and expertise with open arms--full of questions This textbook officially entered the "electronic age"in themid90s,anditswebsegmentwww.devbio.com,has Acknowledgments grown more important with each subsequent edition. With this edition, the vade mecum companion that debuted in In addition to the remarkable reviewers listed below, 2002 is also on the web. Mary Tyler and Ron Kozlowski whose candid and thorough criticisms of early chapter not only created vade mecum, with its laboratory sections drafts made this book so much better, there are some peo- and its introductions to model animals, they have also pro- ple whose help was absolutely critical. In particular, David duced interviews and filmed the techniques of several McClay and Bill Anderson gave me many suggestions that developmental biologists. You really have to see these films were outstandingly important in constructing this edition. to realize what a valuable resource these are I also appreciate enormously the cooperation from all those I am blessed by teaching some remarkable students who scientists who sent me their photographs, and who even have not been shy about offering constructive criticism told me about others they had seen. The graphics of this Their suggestions will, I hope, benefit the next round of book are truly amazing, and this is due to the community tudents of developmental biologists And finally, this revising process has taken much longe The book's beauty and success is also the result of Al than expected. I apologize to my wife, Anne Raunio, who Sinauer's vision and the hard work of the immensely tal- has had to put up with me through it all, and to my friend ented staff he has assembled at Sinauer Associates. David who may have wondered where I've been I'll be back McIntyre's ability to find appropriate photographs from he public and private databases is almost uncanny. Chris ScoTT F. GILBERT
XVIII PREFACE How is the development of plants and insects timed so that the flower opens at the same time when its pollinator has left its cocoon? How does exercise increase muscle mass, and how does our face come to resemble those of our parents more than any one else's? To these questions, we have only very partial answers, but we are on our way. Developmental biology presents a nascent scientist with a host of fascinating questions that are worth solving. And that's the invitation this book offers. One can enter developmental biology through many portals—genetics, cell biology, embryology, physiology, anatomy—and with many valid motivations. This is a field that needs the help of people with all sorts of competencies and talents. It is an old field that is itself undergoing metamorphic change and emerging as a new field that welcomes newcomers with open arms—full of questions. Acknowledgments In addition to the remarkable reviewers listed below, whose candid and thorough criticisms of early chapter drafts made this book so much better, there are some people whose help was absolutely critical. In particular, David McClay and Bill Anderson gave me many suggestions that were outstandingly important in constructing this edition. I also appreciate enormously the cooperation from all those scientists who sent me their photographs, and who even told me about others they had seen. The graphics of this book are truly amazing, and this is due to the community of developmental biologists. The book's beauty and success is also the result of Andy Sinauer's vision and the hard work of the immensely talented staff he has assembled at Sinauer Associates. David Mclntyre's ability to find appropriate photographs from the public and private databases is almost uncanny. Chris Small and Janice Holabird of Sinauer's production department have put together the artwork, the photographs, and the text into a format that is both informative and pleasing. For a book of this size, this is a heroic undertaking. And, more than any other edition of this book (and she has been with it since its inception), this incarnation has been a collaborative effort with my editor Carol Wigg. The book seems to have become a full-time job for both of us. I especially wish to thank Dr. Hannah Galantino-Homer of the University of Pennsj'lvania School of Veterinary Medicine, who took it upon her shoulders to compile a glossary for this book. Numerous people have said that they wanted such a glossary for their students, and putting one together is an extremely difficult task, involving an enormous amount of thought and expertise. This textbook officially entered the "electronic age" in the mid 90s, and its web segment, www.devbio.com, has grown more important with each subsequent edition. With this edition, the vade mecum3 companion that debuted in 2002 is also on the web. Mary Tyler and Ron Kozlowski not only created vade mecum3 , with its laboratory sections and its introductions to model animals, they have also produced interviews and filmed the techniques of several developmental biologists. You really have to see these films to realize what a valuable resource these are. I am blessed by teaching some remarkable students who have not been shy about offering constructive criticism. Their suggestions will, I hope, benefit the next round of students. And finally, this revising process has taken much longer than expected. I apologize to my wife, Anne Raunio, who has had to put up with me through it all, and to my friends, who may have wondered where I've been. I'll be back. SCOTT E GILBERT