Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. Preface N MY FIRST BOOK ON THE HISTORY of genetics, The Gene: A Critical History,I Ishowed how the concept of the gene emerged from a series of con- tending views and how each of about one dozen disputes was resolved with the preservation of one view and the disappearance of the other. This, my fourth book on historical issues, once again traces the devel- opment of a concept, this time “mutation,” a term that has undergone significant change in the hands of professional scientists and also become significant in popular culture. The idea of mutation is rooted in our awareness of change over time. In the life sciences, consideration of change is essential to evolutionary biology and also, perhaps less obviously, to the study of genetics. Ideas or concepts also change, or evolve, over time. Each generation of scholars is bound by the terminology and ideas current in its period but as new tools and approaches generate new findings, the scholars’ vocabulary changes to accommodate what has been discovered. This book examines the meaning of mutation when the term was first adopted, how the meaning changed, and why that alteration was forced on the terminology. Among professional scientists, there is further complexity, with the coexistence of contending terms for the same phenomenon used in different fields (e.g., microbial and Drosophila genetics). I also show that a somewhat different sense of the term mutation prevails among the general public. Many scientists tend to be unaware of how their colleagues of many generations ago conceived their field. Examination of this process is the task of an historian but has the added benefit of informing us about the way ideas help or hinder the development of a field of science. I am grateful to Jan Witkowski for organizing a conference on mutation in May 2010 at the Banbury Center of Cold Spring Harbor Laboratory. It inspired me to think about my own contribution to that conference and vii Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. viii Preface to reflect on the history of the concept of mutation. This book is a result of that reflection and research. I thank the staff of Cold Spring Harbor Laboratory Press for the out- standing work they have done in making this book possible: John Inglis, Publisher; Judy Cuddihy, Acquisition and Developmental Editor; Jan Argen- tine, Director of Development, Marketing, and Sales; Inez Sialiano, Project Manager; Carol Brown, Permissions Coordinator; Kathleen Bubbeo, Pro- duction Editor; Denise Weiss, Production Manager; and Elizabeth Powers, Marketing and Sales Manager. I am especially grateful to Judy Cuddihy and Kathleen Bubbeo for their useful suggestions as my manuscript shifted from a working manuscript to final page proofs. I also thank Krishna Dronamraju, Michael Lynch, and Evelyn Witkin for their helpful discussions about mutation. The Biology Library at Jordan Hall and the Wells Library, both at Indiana University in Bloomington, had the references I needed and provided the comfort to take notes. ELOF AXEL CARLSON Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. 1 A Brief Overview of the Concept of Mutation ODAY MOST GENETICISTS THINK OF THE TERM “mutation” as a technical Tterm for some change in the individual gene. This concept dates to the early 1920s, and Hermann Joseph Muller (1890–1967) forcefully argued 1 this restricted definition. In this history, I will provide the background to that conclusion and show how this view permeated biological thinking and how it became modified as the attributes of genes became augmented. Breeding analysis was supplemented by cytology, population genetics, physiological attributes of gene expression, developmental studies of the origin of mutations in the life cycle, biochemical studies of the genetic control of biochemical pathways, molecular analysis of gene products, the identification of genes as nucleic acids, the various ways chemical and physical agents act as mutagens, and the analysis of how genes function at the molecular level. As the attributes and process of mutation were worked out, the potentials for using mutations increased. Mutations entered the thinking of population genetics, evolutionary studies, horticulture, plant and animal commercial development, and human genetics. They also entered politics in the form of worldwide eugenics movements, racist ideology, and genocidal programs, as well as the state control of what could be taught about mutation as it applied to human benefit and social needs. With the discovery of the induc- tion of mutations by X rays in 1927 and the founding of the field of radiation genetics, mutation took on a new significance as the use of radiation in soci- ety increased. After the use of atomic bombs in Japan during World War II, 2 the public became conscious of radiation protection and radiation hazards. In the last decades of the 20th century, molecular interest in mutations led to the Human Genome Project and an attempt to identify all human 1 Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. H.J. Muller limits the term mutation. In this article Muller asks geneticists to consider the term mutation as limited to changes within the individual gene. He considered all other phenomena such as polyploidy, aneuploidy, and chromosomal rearrangements to be distinct phenomena. All played a role in evolution, but Muller believed the major events in evolution to be the mutations in individual genes. (Reprinted from Muller HJ. 1922. Variation due to change in the individual gene.AmNat56: 32–50.) Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. A Brief Overview of the Concept of Mutation 3 genes and later a comparative genomics of different phyla or organisms of social or evolutionary importance. That process has occupied the first decade of the 21st century. Molecular tools permit geneticists to shift altered genes from species to species; organisms can be engineered to perform specific functions depending on the introduced genes used in the design. Craig Ven- ter (1946–) and colleagues even devised means to replace the genome of one bacterial species with another that was synthesized from a computer print- out and annotated with words that Venter called “watermarks” that could be 3 decoded. Few geneticists today would be surprised if a paper appeared announcing the synthesis of prokaryotic cells containing a bare minimum of genes necessary for life to continue. Synthetic nuclei may some day be used to resurrect extinct species or putative common ancestors of related species. In this book, Chapters 2–4 discuss nonmolecular or classical genetic approaches to mutation. Chapters 5–8 cover biochemical and molecular approaches to mutation. Chapter 9 covers the emerging field of genetic engi- neering and comparative genomics, and Chapter 10 looks at the social uses and abuses of mutation. Finally, Chapter 11 explores the implications that mutation has for the philosophy and history of science. Mutation Evolved as a Concept Mutation, of course, involves change; but our understanding of that change is influenced by the time we live in. To Darwin, most changes of evolution- ary significance were “fluctuating variations,” mostly subtle, providing the raw material on which natural selection acted. What geneticists think of as mutations today are closer to what Francis Galton (1822–1911) thought them to be in the late 19th century. For him, mutations were shifts in dra- matic, qualitative, or discontinuous expression, like albinism from pig- mented populations or the sudden appearance of what breeders called “sports.” For example, Ancon sheep—a short-legged line with crooked fore- legs—were frequently cited as having a pedigreed origin from a spontane- ous appearance of a single short-legged lamb. Complicating this distinction between fluctuating variations and sports was the distinction between the terms “variation” and “heredity.” Variations were seen as the changes from the normal state of a trait, and they could be either more intense or less so in expression. Heredity was seen as the sum of species traits. Heredity and variation were considered to be separate phe- nomena. It should be kept in mind that in the last quarter of the 19th Copyright 2011 Cold Spring Harbor Laboratory Press. Not for distribution. Do not copy without written permission of Cold Spring Harbor Laboratory Press. 4Chapter1 century when these ideas were widely circulated, Mendelism was either forgotten or not considered relevant to the problem of mutation by those scientists discussing it. What forced a change in the thinking about mutation was the rediscovery of Mendelism in 1900 and the insistence by William Bateson (1861–1926) in 1894 that variations could be discontinuous and might be associated with the origin of species. This led to a bitter dispute between the loyalists to Darwinian fluctuating variations and Bateson’s school of Mendelians, who saw “discontinuous variations” of a more dramatic nature as significant for evolution. The first battles were largely fought in Great Britain, with W.F.R. Weldon (1860–1906) and Karl Pearson (1857–1936) supporting the Darwinian fluctuation model and Bateson supporting the discontinuous model of evolution by mutation. Francis Galton supported both models and contributed articles championing both, sometimes to the annoyance or sur- 4 prise of those who thought he was solidly behind one of these approaches. The Mendelian school emerged from the work of Hugo de Vries (1848– 1935), Carl Correns (1864–1933), and Erich von Tschermak-Seysenegg (1871–1962) in 1900.