HADORN, ERNST

(b. Forst, Switzerland, 31 May 1902: d. Wohlen, Switzerland, 4 April 1976)

developmental biology.

Hadorn was the son of Christian Hadorn, a farmer, and of Elisabeth Lehner Hadorn. His ancestors had been farmers in the same place for centuries. He studied at the teachers’ college at Muristalden from 1918 to 1922, then taught in the primary school of a village close to his home. When he had saved some money, Hadorn entered the University of Bern (1925), where he studied zoology under the embryologist Fritz Baltzer, himself a student of Theodor Boveri. On 21 October 1930 he married Marie Daepp; they had a son and two daughters. He received the doctorate the following year and returned to teaching, this time at the secondary school level. At the same time, in the basement of his home he continued experimental work on the topic he had treated in his dissertation. With this work he qualified as Privatdozent in 1935 with a Habilitationsschrift on nucleocytoplasmic interactions.

In 1936 Hadron was awarded a Rockefeller fellowship, which enabled him to do research at the University of Rochester. His original plan was to work with the distinguished embryologist Benjamin Willier on the chicken, but he soon switched to Drosophila, working first with Curt Stern, then by himself. After returning to Switzerland in 1937, he again taught school, this time at the gymnasium in Biel. In 1939 Hadorn was appointed professor at the University of Zurich, and in 1942 he was named head of the Institute of Zoology in Zurich. He held this position until his retirement in 1972, building the institute from a small, provincial institution to one of the leading centers of developmental genetics. He served from 1962 to 1964 as rector of the university of Zurich and was a member of the Swiss Council of Science. After his retirement from the university he lived in Wohlen, not far from the village of his birth.

Hadorn’s first scientific experiments were extensions of Baltzer’s work, using hybrids between two species of newts. “Hybrid merogonic” embryos were produced, that is, embryos containing the haploid nucleus of one species in the cytoplasm of the other. Such embryos undergo normal cleavage and gastrulation but die in early embryonic stages, in part because they are haploid. Diploid hybrids between these two species die also, but much later in development. Haploid embryos from the same species die later than those containing nucleus and cytoplasm from different species. By aningenious use of transplantation and explantation experiments. Hadorn could show that the primary damage occurs in the head mesoderm. The difference in the damage between homogenic and hybrid merogones must be due to a disharmony between the nucleus (that is, the genes) and the cytoplasm of the two species in the latter.

At this point Hadorn saw that continuing this work with newts would be futile because they are not suitable for the genetic analysis of development. Hence he gave up his work with amphibians and, at Rochester, intended to work on chickens, an organism on which both embryological and genetic experiments had been carried out. Not that he gave up amphibians altogether: throughout his life he published papers on various aspects of amphibian development, notably a paper dealing with the influence of the notochord on the breakdown of yolk (1951). He also published a popular book on the experimental embryology of amphibians that went through two German editions.

At Rochester, Hadorn started to work with Willier, whose reputation was based on his work on the development of the chicken feather. The chicken feather seemed a suitable object of research because many genes affecting it were known. Hadorn was coauthor with Willier and Mary Rawles of a paper on transplantation experiments with the wings of chicken embryos that demonstrated the autonomy of feather pigmentation. But at this time (1936) the classical work of George Beadle and B. Ephrussi appeared that developed the technique of transplantation in Drosophila. Hadorn saw that this technique was exactly what he was looking for and, with Curt Stern, who had just finished his fundamental work on somatic crossing over, started to apply the transplantation method to developmental problems. They demonstrated that the sterility of XO males is an autonomous character, and that the pigmentation of the male genital apparatus is also autonomous at the cellular level, though individual pigmented cells can migrate from the testis sheath to the sperm ducts.

From this time on, transplantation in Drosophila remained Hadorn’s primary experimental technique, and he applied it to a large number of different topics. The first concerned lethal mutations that kill the animal in the late larva or early pupa. Around this time a great many developmental geneticists were interested in the action of lethal genes—for instance, the work of D. F. Poulsen on embryonic lethals in Drosophila, of H. Grüneberg and S. Gluecksohn-Waelsch in the mouse, of W. Landauer in the chicken. But this work was mostly morphological, while Hadorn used transplantation experiments to analyze late lethals.

Hadorn’s first lethal mutation was “lethal giant larvae” (lgl), a stock obtained from Beadle. Larvae homozygous for this gene develop normally but are unable to undergo pupation. In this transplantation work on lgl, Hadorn asked James V. Neel, a graduate student of Stern’s, to collaborate with him, saying that two people work not twice, but four times, as efficiently as a single person. This was his method of work ever after: His transplantation experiments were carried out with one or two assistants working at the same table, one partner preparing the tissues while the other injected the grafts into the host. This concern with the efficiency of experimental techniques contributed greatly to the large amount of experimental work Hadorn accomplished.

It was known from earlier experiments by Gottfried Fraenkel (1935) that a center for the induction of pupation in flies must be located in the head region. Hadorn accordingly transplanted several organs from the heads of normal larvae into lgl larvae and found that implantation of one organ of unknown function called Weismann’s ring (described by August Weismann in 1864) was able to induce puparium formation in lgl larvae. With Berta Scharrer, Hadorn established the glandular nature of this structure, now called the ring gland, and showed that in lgl larvae these glands are reduced in size. But this reduction of the ring gland was not the only effect of the mutant gene: In the induced puparia, development did not reach completion because the imaginal disks and the testes degenerated, and even the ovaries, which can develop further after transplantation into wildtype hosts, were unable to produce normal structures. Hadorn concluded that reduction of the ring glands was only one of several effects of the lgl gene.

These experiments immediately placed Hadorn in the first rank of developmental geneticists. The induction of insect metamorphosis by hormones was a very popular topic at the time. Since 1935, experiments with several insects had suggested such hormonal effects, and in some insects glandular structures had been implicated as sources of these hormones. Hadorn was the first, however, to prove that a puparium-inducing hormone is secreted by the ring gland in dipterans, and that genes are involved in the growth and functioning of this gland. This experiment formed the basis for his great scientific reputation.

Hadorn continued for some time to study a great number of late lethal mutations in Drosophila. He attracted to Zurich a large number of graduate students who participated in this research. He summarized his research on lethal mutations in a review article in 1951 and in a book in 1955. He observed in all cases that each mutation produces a specific pattern of damage while other organs remain unaffected, and he accounted for this finding by assuming a pleiotropic pattern of gene manifestation. Genes are not active in all cells, but are called into action gradually during development, and only in some tissues. Hadorn was able, in some cases, to demonstrate that some or all of the effects in a pattern of damage go back to a unitary primary damage: All lethal effects of the gene “lethal-meander” are consequences of starvation due to inability of the larva to digest or absorb proteins. But, probably because of his experience with lgl gonads. Hadorn did not exclude the possibility of “primary pleiotropy,” different activities of the same gene in different tissues. Consequently, he did not try to establish “pedigrees of causes” going back to one primary cause, as Grüneberg had done for lethals in the mouse.

In 1950 Hadorn was awarded another Rockefeller fellowship, which enabled him to work at the California Institute of Technology with Herschel K. Mitchell. In these experiments they devised a remarkably simple and sensitive method to study pleiotropic gene action at the biochemical level: paper chromatography of isolated organs of Drosophila and the study of the chromatogram in ultraviolet light. In this way a number of fluorescent spots could be identified in different organs at different stages and under the influence of specific mutant genes. After his return to Zurich, Hadorn continued this work in close collaboration with Alfred Kühn and Albrecht Egelhaaf of the Max Planck Institute for Biology at Tübingen. They devised a method to determine the amounts of fluorescent substances in the spots by fluorescent and applied it to eye color mutations in Drosophila and in the moth Ephestia.

At the same time, Hadorn collaborated with the chemist M. Viscontini in identifying the fluorescent substances chemically. It turned out that most of them, including red eye pigments, are pteridines, and the aberrations induced by mutant genes were used to elucidate pteridine metabolism. Of great importance is the demonstration, with Ilse Schwinck (1956), that the mutant gene “rosy” (ry) blocks the synthesis of isoxanthopterine and that this character is nonautonomous. This work forms the basis of extensive studies of the ry locus, the gene determining the structure of the enzyme xanthine dehydrogenase. In particular the work of A. Chovnick and his col laborators has made the rosy locus one of the bestinvestigated genes of Drosophila.

At the same time as he was conducting these studies in biochemical pleiotropism. Hadorn initiated another important series of investigations, the developmental study of imaginal disks in Drosophila. The imaginal disks are clusters of undifferentiated cells present in the larva that after pupation develop into adult structures. Some of the main conclusions about this system emerged from the basic work of Hadorn, Bertani, and Gallera (1949) on the male imaginal disk, a group of cells that gives rise to all internal and external sexual structures except the testes. It could be shown by transplantation of different parts of this disk that it represents a mosaic of different domains, each of which is determined to develop into specific structures; in this way a map indicating domains of specific developmental fates could be established for the mature imaginal disk. While each of these domains gives rise, after transplantation, to specific adult structures, parts of these domains have the ability to regulate into a complete structure; they possess the properties of a “morphogenetic field.” The occurrence of regulation depends in turn on a certain amount of growth of the piece of imaginal disk implanted: Pieces transplanted to adult larvae shortly before pupation cannot regulate, since the pupation hormone stops the tissue’s ability to grow.

The study of the behavior of imaginal disks and their parts after transplantation was the main tool for the analysis of development by Hadorn and his collaborators and students in the later part of his life. One aspect of this work was serial transplantation of pieces of imaginal disks into larvae. The pieces were first transplanted from one larva into another, and this process was repeated several times, some pieces being permitted to undergo metamorphosis by remaining in the host. It appeared that the pieces that were serially transplanted continued to produce the structures for which they had been determined; on further serial transplantation, however, there appeared a tendency to produce only part of the structures for which the disk had been determined, possibly because of the dilution of determined cells induced by continued growth.

These experiments on serial transplantation in larvae led to transplantation of parts of disks into adults. It was found that in adult hosts the grafts grew and proliferated, but did not differentiate. They behaved, thus, as cell cultures. If pieces of these cultures were transplanted into larvae and permitted to undergo metamorphosis, they developed according to their original determination. But if disks cultured in adults were further subcultured in adults, then tested for their state of determination at intervals, sooner or later the subcultures gave rise to foreign structures: For instance, in cultures that originally had been male genital disks, legs and antennae appeared. In still further subcultures, wing structures, and still later, thoracic structures, could appear.

This finding, called “transdetermination,” constitutes an important discovery. In classical embryology it had been assumed that once a group of cells has been determined, it can differentiate only into the structures to which it has been determined, and that this state is irreversible. The state of determination is transmitted by cellular heredity. Theserial transplantations in larvae supported this prediction, and only prolonged subculture in adults could show that determination is not a final state but one that can change and, in the long run, be lost. After this discovery, Hadorn thoroughly investigated the rules of transdetermination—which imaginal disks can be transformed into which other structures and in which order they can be transformed. The discovery of transdetermination must be regarded as Hadorn’s most important contribution.

Hadorn introduced a large number of other techniques into the study of insect development. He showed that one could dissociate imaginal disks by means of the enzyme trypsin. The cells could then be mixed with similarly dissociated cells from another genetically marked strain, so that they could form mosaic structures. He also showed that embryonic cells could be grown in adult hosts. All these discoveries and techniques opened up a very fruitful field of investigation that Hadorn himself was not able to explore completely. The developmental physiology of imaginal disks continues to be a very active field, and it is due mainly to Hadorn that Drosophila has become one of the most widely investigated subjects of embryological studies.

Hadorn was primarily a brilliant experimenter. He constantly devised new techniques and adapted techniques from other branches of science to his problems. In this way he left a large and varied amount of experimental work. The theoretical formulation of conclusions followed the experiments and led to further experiments, always carefully designed to answer specific questions.

Hadorn was a man of great physical strength and working capacity. This enabled him to carry out his transplantation work while being involved in many other activities. He enjoyed teaching and lectured regularly. He carried a considerable administrative load as head of his institute and, later, as rector of the University of Zurich. He provided much initiative in international scientific undertakings. Foremost among these was the journal Developmental Biology, which he founded with Paul Weiss and Jean Brachet. The three men constituted the editoral board in the journal’s first decade (1959– 1969) and gave it its specific scientific character.

Hadorn was informal and jovial in his contacts with friends and students. He proved helpful and generous to his numerous students and colleagues and was extremely popular with them. He practiced severe self-discipline; his life was tightly regulated, and the schedule of his activities strictly determined. He went to church regularly and had no difficulty in combining his faith with his scientific way of thinking.

In the history of biology Hadorn represents a bridge between classical embryology and modern developmental biology. Classical experimental embryology is based mainly on experiments in amphibians. It lost favor among the younger generation of biologists in the late 1930’s and 1940’s, partly because it appeared that most of the important problems had been solved. But more important was the disregard of many investigators of the genetic basis of development and the rejection of the reductionist approach taken by geneticists. Hadorn, in his experiments with larval lethals, introduced genetic thinking into developmental studies, and he defended the reductionist approach throughout his life, the last time in a speech given a few weeks before his death to a meeting of chemists in Zurich. His original work on imaginal disks in Drosophila led further toward the modern approach to development in object, techniques, and concepts. His discovery of transdetermination was a major starting point for a new line of developmental research that has not yet been exhausted.

BIBLIOGRAPHY

1. Original Works. Hadorn’s writings include “Über die Entwicklungsleistungen bastardmerogonischer Gewebe von Triton palmatus (♀) χ Triton cristatus (♂) im Ganzkeim and als Explantat in vitro,” in Wilhelm Roux Archiv für Entwickl, -Mech. d. Organismen, 131 (1934), 238–284; “An Accelerating Effect of Normal’ Ring-Glands’ on Puparium-Formation in Lethal Larvae of Drosophila melanogaster,” in Proceedings of the National Academy of Sciences, 23 (1937), 478–484; “The Structure of the Ring-Gland (corpus allatum) in Normal and Lethal Larvae of Drosophila melanogaster,” ibid., 24 (1938), 236–242, written with Berta Scharrer: “The Relation Between the Color of Testes and Vasa Efferentia in Drosophila.’ in Genetics. 24 (1939). 162–179, written with Curt Stern: “Die Auswirkung eines Letalfaktors (lgl) bei Drosophila melanogaster auf Wachstum und Differenzierung der Gonade,” in Revue Suisse de Zoologie. 49 (1942), 228– 236, written with Hans Gloor “Zur Pleiotropie der Genwirkung,” in Archiv Julius Klaus-Stiftung für Vererbforschung, 20 spec. iss. (1945), 82–95; “Regulationsfahigkeit und Feldorganisation der mannlichan Genital-Imaginalscheibe von Drosophila melanogaster,” in Wilhelm Roux Archiv für Entwickl-Mech. d. Organismen. 144 (1949). 31–70, written with Giuseppe Bertani and J. Gallera; “Developmental Actions of Lethal Factors in Drosophila, ’ in Advances in Genetics, 4 (1953), 53–85: “Properties of Mutants of Drosophila melanogaster and Changes During Development as Revealed by Paper Chromatography,” in Proceedings of the National academy of Scinces. 37 (1951), 650–665, written with Herschel K. Mitchell.

See also “Chromatographische und fluorometrische Untersuchungen zur biochemischen Polyphänie von Augenfarb-Genen bei Ephestia kühniell.’ in Zeit. Naturforsch., 8B (1953), 582–589, written with Alfred Kühn: Letalfaktoren in ihrer Bedeutung f¨r Erbpathologie und Genphysiolgie der Entwicklung (Stuttgart, 1955), trans. by Ursula Mittwoch as Developmental Genetics and Lethal Factors (New York, 1961); “Patterns of Biochemical and Developmental Pleiotropy,” in Cold Spring Harbor Symposia on Quantitative Biology, 21 (1956), 363–373; “Fehlen von Isoxanthropterin und Nicht-Autonomie in der Bildung der roten Augenpigmente bei einer Mutante (rosy²) von Drosophila melanogaster, “in Zeitschr. ind. Abstamm-II Vererb. Lehre. 87 (1956), 582–553. written with Ilse Schwinck; Experimentelle Entwicklungsforschung, im besonderen an Amphibien (Berlin, 1961, 2nd enl. ed., 1970), trans, by David Turner as Experimental Studies of Amphibian Development (New York, 1974); “Weitere Untersuchungen über Musterbildung in Kombination aus teilweise dissoziierten Flügel-Imaginalscheiben von Drosophila melanogaster, ’ in Developmental Biology.4 (1962), 40–66, written with Heinrich Ursprung: “Differenzierungsleistungen wiederholt fragmentierter Teilstucke männlicher Genitalscheiben von Drosophila melanogaster nach Kultur in vivo” ibid., 7 (1963), 617–629: “Genetics on Its Way,” presidential address, in S. J. Geerts, ed., Proceedings of the XI International Congress of Genetics: Genetics Today, II (Oxford and New York, 1965), lxiii-lxxii; and “Konstanz, Wechsel und Typus der Determination und Differenzierung in Zellen aus mannlichen Genitalanlagen von Drosophila melanogaster nach Dauerkultur in vivo, ’ in Developmental Biology. 13 (1966). 424–509.

II. Secondary Literatre. Hadorn’s life and work are discussed in Dietrich Bodenstein, “For the 70th Birthday of Ernst Hadorn,” in Heinrich Ursprung and Rolf Nothiger, eds., The Biology of Imaginal Discs (New York, 1976), vii–ix; Walter J. Gehring, In Mermoruam Ernst Hadorn,” in Developmental Biology, 53, no. I (1976). iv–vi; and Rolf Nothiger, “Nachruf. Ernst Hadorn (31. Mai 1902–4. April 1976);” in Wilhelm Roux’s Archives of Developmental Biology180 no. 2 (1976). i–vi, and “Ernst Hadorn (1902–1976).” in Genetics. 86 (1976). I–4.

Ernst Caspari