From Hopeful Monsters to Homeotic Effects: Richard Goldschmidt's Integration of Development, Evolution, and Genetics

Richard Goldschmidt's research on homeotic mutants from 1940until his death in 1958 represents one of the first seriousefforts to integrate genetics, development, and evolution. Usingtwo different models, Goldschmidt tried to show how differentviews of genetic structure and gene action could provide a mechanismfor rapid speciation. Developmental systems were emphasizedin one model and a hierarchy of genetic structures in the other.While Goldschmidt tried to find a balance between developmentand genetics, critics, such as Sewall Wright, urged him andeventually helped him incorporate population dynamics into hismodels as well. As such, the history of Goldschmidt's researchon homeotic mutants highlights the continuing challenge of producinga balanced and integrated developmental evolutionary genetics.     

Richard Goldschmidt: hopeful monsters and other 'heresies'

Richard Goldschmidt is remembered today as one of the most controversial biologists of the twentieth century. Although his work on sex determination and physiological genetics earned him accolades from his peers, his rejection of the classical gene and his unpopular theories about evolution significantly damaged his scientific reputation. This article reviews Goldschmidt's life and work, with an emphasis on his controversial views.     

R. Goldschmidt and J. Huxley: creative parallelisms

The comparative analysis of scientific heritage of Richard Goldschmidt and Julian Huxley shows convincingly the resemblance of these two scientists' views over the core problems of evolutionary theory, genetics and development biology. They both contributed to developing a triad "genetics--development--evolution". The problem of a relative growth of animals was the central point in both Goldschmidt's and Huxley's works. Huxley developed a formula of the allometric growth (law of constant differential growth) while Goldschmidt was the first to draw up the broad interpretation of the consequences of that phenomenon. Both scientists belonged to initiators of development genetics and used the "non-morganian" genetics in their efforts of solving problems of macroevolution. Goldschmidt tended toward an idea of an important role of macromutation in the process of macroevolution, though Huxley adhered to more moderate views. But at the same time the concept of preadaptive mutations proposed by Huxley was close to Goldschmidt's idea of macromutants. It is shown that both scientists analyzed profoundly the changes in early stages of embryogenesis in respect to macroevolution. It is not likely to be reasonable to oppose firmly Goldschmidt's saltationism to the evolutionary synthesis of Huxley. They developed the larger biological problems in a similar way, and undoubtedly their works in the field helped to enrich the development of the views over genetics and evolution. The open-minded analysis of Goldschmidt's and Huxley's concepts leads to creating modern and up-to-date views over the theory of evolution where seemingly incompatible things go together rather well and supplement each other. Evo-Devo rediscovered Goldshmidt's Biology and Huxley's Synthesis.     

Mitochondrial DNA variation among worldwide populations of gypsy moths, Lymantria dispar

Gypsy moth populations from Japan, mainland Asia, Europe, Tunisia, and North America were analyzed for variation in mitochondrial DNA (mtDNA) sequences from three gene regions. These samples resolve into four groups, representing gypsy moths from (1) Okinawa, Japan, (2) Hokkaido, Japan, (3) Honshu and Kyushu, Japan and mainland Asia, and (4) Europe, Tunisia, and North America. Some patterns of geographic variation observed for mtDNA (for example, the distinctiveness of gypsy moths from Hokkaido, Japan) coincide with those observed by Goldschmidt from analyses of morphology, life history, and intersexuality. Other patterns (relative sequence homogeneity across Asia, Honshu, and Kyushu and reduced levels of variation in mainland Japan) do not.     

Epigenetics and the renaissance of heresy.

Classic neo-Darwinian theory is predicated on the notion that all heritable phenotypic change is mediated by alterations of the DNA sequence in genomes. However, evidence is accumulating that stably heritable phenotypes can also have an epigenetic basis, lending support to the long-discarded notion of inheritance of acquired traits. As many of the examples of epigenetic inheritance are mediated by position effects, the possibility exists that chromosome rearrangements may be one of the driving forces behind evolutionary change by exerting position effect alterations in gene activity, an idea articulated by Richard Goldschmidt. The emerging evidence suggests that Goldschmidt's controversial hypothesis deserves a serious reevaluation.     

Early 20th-century research at the interfaces of genetics, development, and evolution: reflections on progress and dead ends

Three early 20th-century attempts at unifying separate areas of biology, in particular development, genetics, physiology, and evolution, are compared in regard to their success and fruitfulness for further research: Jacques Loeb's reductionist project of unifying approaches by physico-chemical explanations; Richard Goldschmidt's anti-reductionist attempts to unify by integration; and Sewall Wright's combination of reductionist research and vision of hierarchical genetic systems. Loeb's program, demanding that all aspects of biology, including evolution, be studied by the methods of the experimental sciences, proved highly successful and indispensible for higher level investigations, even though evolutionary change and properties of biological systems up to now cannot be fully explained on the molecular level alone. Goldschmidt has been appraised as pioneer of physiological and developmental genetics and of a new evolutionary synthesis which transcended neo-Darwinism. However, this study concludes that his anti-reductionist attempts to integrate genetics, development and evolution have to be regarded as failures or dead ends. His grand speculations were based on the one hand on concepts and experimental systems that were too vague in order to stimulate further research, and on the other on experiments which in their core parts turned out not to be reproducible. In contrast, Sewall Wright, apart from being one of the architects of the neo-Darwinian synthesis of the 1930s, opened up new paths of testable quantitative developmental genetic investigations. He placed his research within a framework of logical reasoning, which resulted in the farsighted speculation that examinations of biological systems should be related to the regulation of hierarchical genetic subsystems, possibly providing a mechanism for development and evolution. I argue that his suggestion of basing the study of systems on clearly defined properties of the components has proved superior to Goldschmidt's approach of studying systems as a whole, and that attempts to integrate different fields at a too early stage may prove futile or worse.     

THE THREE G's Meeting the Invertebrate Cell Culture Pioneers: Goldschmidt, Gaw, and Grace

It was my good fortune to meet personally the three invertebrate cell culture pioneers,Richard Goldschmidt,Zan-Yin Gaw,and Thomas D.C.Grace (Fig.1).In 1951 I met Goldschmidt at a symposium in Cold Spring Harbor,but I only knew that he was a prominent geneticist.I had no idea about his insect cell culture work at Yale University and daily contacts with Ross G.Harrison.In 1959 Zan Yin Gaw in Wuhan successfully cultured monolayers of silkworm cells for more than one year.I reported his breakthrough achievement at the 11th International Congress of Entomology in Vienna in 1960,but his work was completely ignored outside China.In 1982 Gaw invited me to Wuhan where he told me that he studied in the United States in the 1930s,working as postdoctoral scientist at the Rockefeller Institute,where he was daily meeting William Trager,and later at Yale University in the Osborn Laboratory,where he was inspired by Harrison.T.D.C.Grace worked in my laboratory at Rockefeller University during 1957 and 1958,then returned to CSIRO in Canberra,Australia.     

Reinventing Richard Goldschmidt: Reputation,Memory, and Biography

Richard Goldschmidt was one of the most controversial biologists of the mid-twentieth century. Rather than fade from view, Goldschmidt’s work and reputation has persisted in the biological community long after he has. Goldschmidt’s longevity is due in large part to how he was represented by Stephen J. Gould. When viewed from the perspective of the biographer, Gould’s revival of Goldschmidt as an evolutionary heretic in the 1970s and 1980s represents a selective reinvention of Goldschmidt that provides a contrast to other kinds of biographical commemorations by scientists.     

The ratio of 2nd to 4th digit length and male homosexuality

Sexual orientation may be influenced by prenatal levels of testosterone and oestrogen. There is evidence that the ratio of the length of 2nd and 4th digits (2D:4D) is negatively related to prenatal testosterone and positively to oestrogen. We report that (a) 2D:4D was lower in a sample of 88 homosexual men than in 88 sex- and age-matched controls recruited without regard to sexual orientation, (b) within the homosexual sample, there was a significant positive relationship between mean 2D:4D ratio and exclusive homosexuality, (c) overall, there was a decrease in 2D:4D from controls to homosexual men to bisexual men and (d) fraternal birth order, a positive predictor of male homosexuality, was not associated with 2D:4D in a sample of 240 Caucasian men recruited without regard to sexual orientation and 45 homosexual men.Further work is needed to confirm the relationships between 2D:4D and sexual orientation. However, these and other recent data tend to support an association between male homosexuality and high fetal testosterone. Very high testosterone levels may be associated with a sexual preference for both men and women.     

Macromutation and evolution: the fixation of Goldschmidt's macromutations as species and genus traits. Hairlessness mutations in mammals

A brief survey of the development of concepts on the role of macromutations in evolution is given. Contrary to Iu. A. Filipchenko (1926, 1927), who introduced the "micro- and macromutation" terms and believed that regularities of macroevolution could not be reduced to microevolutionary processes, the majority of "synthetists" explained any form of evolution by changes in allele frequencies. From the studies of Drosophila homoeotic mutants R. Goldschmidt (1940) developed the concept of "hopeful monsters" and their role in macroevolution. However, the homoeotic mutants are of drastically reduced viability, which allows the gradualists to reject Goldschmidt's ideas. The distribution of hairlessness mutations (hairless, nude etc.) with the monogenic pattern of inheritance in mammals was studied. Hairless mutants are known in Peromyscus, Mus musculus, Rattus rattus, R. norvegicus, Canis familiaris, Ovis aries. Hairlessness as norm is found in 53 among contemporaneous 1037 mammalian genera. Part of these cases (hairlessness in all Cetacea and Sirenia) may be explained in terms of both macromutations and obligatory gradualism. There is no doubt as to the macromutational origin of hairlessness in the bat Cheiromeles and the rodent Heterocephalus (Bathyergidae); the genera systematically and ecologically close to these have normal pelage. It is quite possible that hairlessness of walrus (Odobenus) has the same origin. The appearance and fixation of single Goldschmidt's macromutation cannot yet be considered as a macroevolutionary process, though the possibility of fixation of a macromutation in nature as a species and genus character contradicts strongly the concept of obligatory gradualism of evolution.     

Darwin,Wallace, and Huxley,and Vestiges of the Natural History of Creation

Conclusion Publication of the Vestiges and the rather primitive theory of evolution it expounded thus played a significant role in the careers of Darwin and Wallace. In addition, in spite of his poor opinion of the Vestiges, it presented Huxley with a convenient topic for critical discussion and the opportunity to focus more attention on the subject of evolution. The dynamic interactions among these leading figures of nineteenth-century natural science helped spur the development of more sophisticated models of evolution.Darwin had a proper appreciation of Chambers's contribution to evolutionary thought, although he fully recognized the shortcomings of this work. He understood the importance of allowing fresh ideas about organic change to be ventilated. However, he was primarily concerned with his own theory and viewed all developments in evolutionary biology from this perspective. If he did not give full consideration to Chambers and his book early on, it was due mainly to his feeling that the concepts in the Vestiges were very different from his own; he was therefore reluctant to embrace them as the forerunners of his own theory. As a scholar, he was also troubled by the scientific errors in the book. However, the record demonstrates that he attempted to make amends for any oversight on his part. His generous letter to Chambers's daughter, and his gracious treatment of Chambers during the brief time the latter lived in London, are ample proof of that.The attacks of Huxley, Sedgwick, and other prominent natural historians and geologists at the time, the problems inherent in Chambers's evolutionary theory, and the publication of the Origin, are the major reasons why the Vestiges became a neglected work. Nevertheless, Chambers's contribution will always stand out because, together with those of other late eighteenth- and early nineteenth-century predecessors of Darwin, it laid the foundations of modern evolutionary thought and, more importantly, helped prepare the scientific community for the more fully developed ideas of Darwin and Wallace.     

Testing Miller's theory of alleles preventing androgenization as an evolutionary explanation for the genetic predisposition for male homosexuality

The genetic background of male homosexuality presents an evolutionary paradox, since homosexuality could be considered a reproductive disadvantage. We tested E.M. Miller's (2000) balanced polymorphism explanation, which states that alleles partially preventing androgenization in male fetuses during pregnancy would be associated with a homosexual orientation. Having all the alleles produces homosexuality, while heterosexual carriers with only a few of these alleles instead have a reproductive advantage; that is, they have more traits, which, by controlling for excessive aggressiveness and psychopathy, make them more attractive mates. Pairs of brothers were used to test these assumptions. If homosexuality is due to having all the androgenization-preventing alleles, then heterosexual men with homosexual brothers are more likely to also have some of the these alleles compared to heterosexual men with heterosexual brothers. These two categories were compared on variables related both directly and indirectly to reproductive success, with heterosexual men with a homosexual brother hypothesized to have an advantage on the variables. However, no statistically significant findings in support of the theory were detected. The results were discussed together with alternative explanations.     

Mendel's experiments: A reinterpretation

Conclusion My conclusion is that Mendel deliberately, though without any real falsification, tried to suggest to his audience and readers an unlikely and substantially wrong reconstruction of the first and most important phase of his research. In my book I offer many reasons for this strange and surprising behavior,⁵³ but the main argument rests on the fact of linkage. Mendelian genetics cannot account for linkage because it was based on the idea of applying probability theory to the problem of species evolution. Central to the theory is the law of probability according to which the chance occurrence of a combination of independent events is the product of their separate probabilities. This is the common basis of Mendel's first and second laws, but this is why Mendel's second law on independent assortment is enunciated in too general a way. From Morgan's work we now know that characters may not always be independent if their genes are located very close one to the other on the same chromosome. And this was also the basis of Mendel's personal drama: he surely observed the effects of linkage, but he had no theoretical tools with which to explain it. So he presented his results in a logical structure consistent with the central idea of his theory. Had he described the real course of his experiments he would have had to admit that his law worked for only a few of the hundreds of Pisum characters — and it would thus have been considered more of an exception than a rule. This is why he insisted on the necessity of testing the law on other plants, and this is why in his second letter to Carl Nägeli he admits that the publication of his data was untimely and dangerous.⁵⁴.We can argue that already in 1866 Mendel was less confident that his so-called second law had the same general validity as the first — and that later he lost his confidence altogether. Contemporary testimony indicates that in the end he became as skeptical as all his contemporaries as to the scientific relevance of his theory.⁵⁵ But he was wrong. His research is in no way the fruit of methodological mistakes or forgery, and it remains a landmark in the history of science. He was only the victim of a strange destiny in which the use of probability theory was responsible, at the same time, for the strength and for the weakness of his theory. We must still consider him the father and founder of genetics.     

The Case of Paul Kammerer: Evolution and Experimentation in the Early 20th Century

To some, a misguided Lamarckian and a fraud, to others a martyr in the fight against Darwinism, the Viennese zoologist Paul Kammerer (1880–1926) remains one of the most controversial scientists of the early 20th century. Here his work is reconsidered in light of turn-of-the-century problems in evolutionary theory and experimental methodology, as seen from Kammerer’s perspective in Vienna. Kammerer emerges not as an opponent of Darwinism, but as one would-be modernizer of the 19th-century theory, which had included a role for the inheritance of acquired characteristics. Kammerer attempted a synthesis of Darwinism with genetics and the chromosome theory, while retaining the modifying effects of the environment as the main source of favorable variation, and he developed his program of experimentation to support it. Kammerer never had a regular university position, but worked at a private experimental laboratory, with sidelines as a teacher and a popular writer and lecturer. On the lecture circuit he held forth on the significance of his science for understanding and furthering cultural evolution and he satisfied his passion for the arts and performance. In his dual career as researcher and popularizer, he did not always follow academic convention. In the contentious and rapidly changing fields of heredity and evolution, some of his stances and practices, as well as his outsider status and part-Jewish background, aroused suspicion and set the stage for the scandal that ended his career and prompted his suicide.     

Male death resulting from hybridization between subspecies of the gypsy moth,Lymantria dispar

We explored the origin of all-female broods resulting from male death in a Hokkaido population of Lymantria dispar through genetic crosses based on the earlier experiments done by Goldschmidt and by testing for the presence of endosymbionts that are known to cause male killing in some insect species. The mitochondrial DNA haplotypes of the all-female broods in Hokkaido were different from those of normal Hokkaido females and were the same as those widely distributed in Asia, including Tokyo (TK). Goldschmidt obtained all-female broods through backcrossing, that is, F1 females obtained by a cross between TK females (L. dispar japonica) and Hokkaido males (L. dispar praeterea) mated with Hokkaido males. He also obtained all-male broods by mating Hokkaido females with TK males. Goldschmidt inferred that female- and male-determining factors were weakest in the Hokkaido subspecies and stronger in the Honshu (TK) subspecies. According to his theory, the females of all-female broods mated with Honshu males should produce normal sex-ratio broods, whereas weaker Hokkaido sexes would be expected to disappear in F1 or F2 generations after crossing with the Honshu subspecies. We confirmed both of Goldschmidt''s results: in the case of all-female broods mated with Honshu males, normal sex-ratio broods were produced, but we obtained only all-female broods in the Goldschmidt backcross and obtained an all-male brood in the F1 generation of a Hokkaido female crossed with a TK male. We found no endosymbionts in all-female broods by 4,′6-diamidino-2-phenylindole (DAPI) staining. Therefore, the all-female broods observed in L. dispar are caused by some incompatibilities between Honshu and Hokkaido subspecies.     

Biology and war--American biology and international science

The German-born American scientist Jacques Loeb (1859-1924) was one of the most important promoters of experimental biology around 1900. He was best known for his physico-chemical explanations of psychological processes and his biotechnological approach to artificial parthenogenesis. At the start of the First World War, Loeb was deeply troubled by the deterioration of the international scientific community and the growing alienation of his German and American colleagues. The aim of this paper is to examine Jacques Loeb's activities aimed at advancing scientific internationalism before, during, and after the war. Loeb, for example, tried to negotiate the publication of German authors in American journals during the war, at a time when this was categorically rejected by publishers. Immediately after the war, he tried to create a specific system aimed at disseminating scientific literature and funding selected European colleagues, in order to overcome what he considered reactionary and hegemonic forces within German scientific institutions. His correspondence with eminent scientists from all over the world (amongst them Albert Einstein, Richard Goldschmidt, Otto Meyerhof, Otto Warburg, Paul Ehrlich, Wolfgang Ostwald, Wilhelm Roux, and Ross Harrison) will serve as a source for the analysis. Special emphasis will be placed on the question how Jacques Loeb integrated epistemology, his particular world view, and his social commitment into the workings of his own life and how he tried to extend his scientific goal of controlling biological systems to the sphere of international science.     

Macroevolution via secondary endosymbiosis: a Neo-Goldschmidtian view of unicellular hopeful monsters and Darwin’s primordial intermediate form

Seventy-five years ago, the geneticist Richard Goldschmidt hypothesized that single mutations affecting development could result in major phenotypic changes in a single generation to produce unique organisms within animal populations that he called “hopeful monsters”. Three decades ago, Sarah P. Gibbs proposed that photosynthetic unicellular micro-organisms like euglenoids and dinoflagellates are the products of a process now called “secondary endosymbiosis” (i.e., the evolution of a chloroplast surrounded by three or four membranes resulting from the incorporation of a eukaryotic alga by a eukaryotic heterotrophic host cell). In this article, we explore the evidence for Goldschmidt’s “hopeful monster” concept and expand the scope of this theory to include the macroevolutionary emergence of organisms like Euglena and Chlorarachnion from secondary endosymbiotic events. We argue that a Neo-Goldschmidtian perspective leads to the conclusion that cell chimeras such as euglenids and dinoflagellates, which are important groups of phytoplankton in freshwater and marine ecosystems, should be interpreted as “successful monsters”. In addition, we argue that Charles Darwin had euglenoids (infusoria) in mind when he speculated on the “primordial intermediate form”, although his Proto-Euglena-hypothesis for the origin of the last common ancestor of all forms of life is no longer acceptable.     

Profiles in genetics: George Wells Beadle and the origins of the gene-enzyme concept.

Beadle's success in establishing biochemical genetics on a firm foundation was due to a combination of several circumstances. These include the following: 1. Apt timing of his work, which Garrod's work clearly lacked, was important. Geneticists were receptive to his ideas and conclusions. As Beadle (1967, 1974) himself acknowledged, much ground was prepared earlier by Garrod and Haldane, who discussed gene action in terms of biochemical reactions, although it was largely ignored. The physiology of gene action was discussed and speculated on to a great extent in the preceding years by Bridges, Goldschmidt, Muller, and Wright. 2. Beadle's selection of Neurospora was most appropriate. It was a haploid organism (with no complications of dominance and recessivity) that could be grown and manipulated easily for isolating mutants to study their segregation and recombination within a short time. Its cytogenetics and the method of growing on chemically defined media were already worked out. It was devoid of the long generation time and more complex sex cycle (among other problems) that complicated the biochemical study of higher plants (e.g., Primula), which Haldane and Scott-Moncrieff had attempted earlier. 3. Beadle's striking ability to shift from one organism to another--from corn to Drosophila to Neurospora--must be acknowledged. He saw the limitations of existing methods and had the courage and skill to move on to more successful methods: from conventional breeding to tissue transplants to microbiological techniques. 4. Beadle's own curiosity about the biochemical nature of gene action and his good fortune in having had such outstanding teachers as Emerson, as well as his ability to collaborate with Ephrussi and Tatum, contributed largely to his success.