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The introduction of Xenopus laevis into developmental biology: Of empire, pregnancy testing and ribosomal genes

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The Xenopus pregnancy text. (A) Lancelot Hogben in 1952, from Hogben and tive animal husbandry’ (Hogben, 1939, p. 39) which Hogben (1998). Reproduced by permission of The Merlin Press Ltd, Rendlesham, Suffolk, produced the so-called ‘captivity effect’, suggesting England. (B) Test jar, from Elkan (1938). Reproduced by permission of the Syndics of that the test required freshly caught animals and so Cambridge University Library. would be useless outside South Africa. The dispute was never resolved (Shapiro and Zwarenstein, 1946; Aschheim (Oakley, 1984, pp. 96-98), and was then very widely Zwarenstein, 1985). discussed. It involved injecting five immature female mice twice a Shortly after arriving back in Britain, Hogben had sent Crew day for three days with morning urine, and then killing them to see some Xenopus and encouraged him to investigate their suitability if the ovaries were enlarged and congested. The later Friedman for pregnancy testing (Hogben, 1939). Initially, the Edinburgh test, which used rabbits, gave quicker results, but demanded Station had difficulty maintaining the frogs, and was perhaps put off young does of which the history was rigorously known. In 1929, by the ‘captivity effect’, but by 1937 Crew was keen enough to Hogben’s friend Crew opened a Pregnancy Diagnosis Station import 1500 animals from the Cape. He kept Xenopus by thirties in associated with his Edinburgh Institute (Crew, 1929; Johnstone, galvanised metal tanks, transferring frogs overnight into individual 1929), which by 1935 was performing on mice and rabbits for glass jars with perforated platforms for the test itself (Fig. 4B). He hospitals and general practitioners about 6000 tests a year (Crew, and others compared Xenopus, mouse and rabbit results, and 1936). concluded that ‘the Hogben test’ was quickest and for most By 1930, perhaps because he was disenchanted with racism in purposes the best (Crew, 1939; Landgrebe, 1939). Just one South Africa and concerned about the worsening political climate, injection of urine containing gonadotrophic hormone into the dorsal Hogben was easily persuaded to take a new chair of social biology lymph sac induced egg-laying 8-12 h later. The Edinburgh labora- at the London School of Economics. There he became a leading tory carried out tens of thousands of tests over the next two critic of the class bias of the eugenics movement and, drawing on decades. Other British laboratories offered a similar service, and his experience in South Africa, a prominent campaigner against after the War the frogs were also available for consultation in the scientific racism (Dubow, 1995, pp. 191-195). To continue re- basement of the Family Planning Association clinic in Sloane search in reproductive physiology, he imported Xenopus and set Street, London (Oakley, 1984, p. 97). up a colony in the basement of his laboratory, a building he Crew encouraged New York gynaecologist Abner Weisman’s described as ‘like a delapidated early-nineteenth-century Baptist interest in importing Xenopus for pregnancy testing into the United chapel’ (Hogben and Hogben, 1998, p. 121). Hogben recruited States, and Weisman proved a tireless campaigner for the frog Charles Bellerby, who had experience with pituitary extracts, to (Weisman and Coates, 1944). Other enthusiasts ensured that by attempt to establish ovulation of Xenopus as a reliable bioassay. the end of the War there were Xenopus colonies in laboratories and This did not simply follow from Hogben’s preliminary work; they had clinics all over the world. Breeding in captivity was still regarded as to confirm lack of spontaneous ovulation and determine conditions relatively difficult. Shapiro (1935) had established that crude hor- for a reproducible response. The major threat to the test, however, mone preparations could be used to obtain fertilised eggs and was Zwarenstein and Shapiro’s report (1933) of ovarian atrophy in embryos throughout the year. He injected an acid extract of unoperated animals kept in captivity. Bellerby (1933) showed that sheep’s anterior pituitary or of pregnancy urine into Xenopus if instead of keeping the frogs in a cold underground room, he females and males to induce coupling and production of fertilised housed them in warm and well lit surroundings he could eliminate eggs outside the normal season, and reared the tadpoles for the ‘captivity effect’ and achieve reliability of testing close to 100% several months. Landgrebe and Purser (1941) raised adult frogs. Other reports followed (Gasche, 1943; Aronson, 1944), but impor-
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EGF, epithelium and Xenopus in developmental biology 43
The introduction of
Xenopus laevis
into developmental biology:
of empire, pregnancy testing and ribosomal genes
Int. J. Dev. Biol. 44: 43-50 (2000)
0214-6282/2000/$20.00
© UBC Press
Printed in Spain
www.lg.ehu.es/ijdb
JOHN B. GURDON
1
* and NICK HOPWOOD
2
1
Wellcome CRC Institute and
2
Department of History and Philosophy
of Science, University of Cambridge, Cambridge, United Kingdom
Introduction
The ever greater concentration of biomedical research on fewer
and fewer species is a striking general feature of the postwar era. In
developmental biology, the South African clawed frog
Xenopus
laevis
is, with
Drosophila
, the mouse, the chick,
C. elegans
and the
zebrafish, one of only half-a-dozen ‘model’ organisms used for the
vast majority of research. How did a species which occurs naturally
only in Southern and Central Africa rise to such international promi-
nence? Developmental biologists routinely answer this question by
listing the main reasons currently assembled for using
Xenopus
:
ease of maintenance of a wholly aquatic vertebrate in the laboratory;
exceptional resistance to disease; a life cycle that among Amphibia
is relatively short; large numbers and size of eggs suitable for
microsurgery; and above all its year-round reproductive response to
commercial hormone preparations compared to the limited breeding
seasons of other amphibians (Kay and Peng, 1991; Tinsley and
Kobel, 1996). Another kind of answer is historical, and this is what we
offer here.
From the 1880s and the early work of Wilhelm Roux and others
in Germany, experimental embryologists favoured Amphibia
(Beetschen, 1996; Nieuwkoop, 1996), but they used the local
European and North American species, initially mostly of the frog
Rana
(Maienschein, 1991). By the early twentieth century urode-
les were preferred; Hans Spemann (Hamburger, 1988; Fäßler,
1997) experimented mainly on species of the newt
Triton
(now
Triturus
) and Ross Harrison on the axolotl
Amblystoma
. Following
Spemann in the 1930s, even Joseph Needham and colleagues’
biochemical analysis of the organizer used newts (Haraway,
1976). Only during and after World War II did
Xenopus
begin its
rise to dominance. But developmental biologists in Europe and
North America did not choose an African frog after a detached and
comprehensive survey of world fauna. It turns out that the intro-
duction of
Xenopus
into developmental biology laboratories was
more fortuitous, and is more interesting. Its eventual embryologi-
cal exploitation was made possible by specific histories of empire
and of endocrinology which happen to have centred to a substan-
tial extent in Britain; demand was ensured by a reorientation of
embryology towards biochemical methods. Here we trace the
scientific domestication of the South African clawed frog, focusing
especially on how, between the 1930s and the early 1960s, it was
introduced into European and North American laboratories, where
not only developmental biologists but also converts from bio-
chemistry took it up.
Natural history, anatomy and laboratory culture
Xenopus laevis
was first described by a French naturalist at the
beginning of the nineteenth century; at the turn of the twentieth a
British zoologist first reported culturing its embryos in the labora-
tory. European men of science took advantage of imperial explo-
ration to define and domesticate this exotic species. They were
interested primarily in its natural history and in comparing the
distinctive anatomy to that of other Amphibia.
*Address for reprints: Wellcome CRC Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, United Kingdom. FAX: 44 1223 334185. e-mail:
j.gurdon@welc.cam.ac.uk
44 J.B. Gurdon and N. Hopwood
François Marie Daudin’s
Histoire naturelle des rainettes, des
grenouilles, et des crapauds
(‘Natural History of Tree-frogs, Frogs
and Toads’; 1802/03) contained the briefest description of what he
called
Bufo laevis
, or ‘Crapaud lisse’ (‘smooth toad’). Based on a
single preserved specimen of unknown provenance in the Mu-
seum of Natural History in Paris, his drawing (Fig. 1) is just
sufficient for a modern zoologist to recognise it as
Xenopus
from
the lateral line system and dorsal eyes. But, analysing a specimen
from South Africa, the Museum’s great comparative anatomist,
Georges Cuvier (1829, p. 107), was critical of Daudin’s efforts, not
least his failure to show claws, and pointedly renamed the animal
Dactylethra
(or ‘finger thing’), a translation of Cuvier’s ‘dé à coudre’
(thimble).
In the following decades, research on the taxonomy and anatomy
of what appeared neither a typical frog nor a typical toad continued
sporadically in the scientific centres of empire, especially London’s
museums and zoo, as and when specimens were received from
Africa. Albert Günther (1858), an assistant at the British Museum,
refined the classification of this tongueless anuran; his superior,
Keeper of Zoology John Edward Gray (1864), published the first
description and figure of a larva, based on fixed specimens sent via
Liverpool from Lagos, Nigeria. William Kitchen Parker, Hunterian
professor of comparative anatomy at the Royal College of Sur-
geons and a man ‘once known to speak for four hours continuously
on the lower jawbone of the raven without saying anything that was
other than valuable’ (Prosser, 1895-96, p. 292), used larvae from
the same bottle as Gray to include
Dactylethra
in two truly massive
descriptions of the development of the batrachian skull (Parker,
1876, 1881). By studying lower vertebrates he amassed evidence
against Richard Owen’s vertebral theory of the skull and in favour
of the views of his friend and Owen’s arch-enemy T.H. Huxley. In
a note from the South African Cape, J.M. Leslie (1890) gave the
earliest account of the breeding habits in swamps and ponds of
what he called
Xenopus laevis
, a name proposed by Wagler
(1827), and one which has stuck (see Deuchar, 1975). Leslie noted
that the natural spawning season in South Africa is spring (August).
Around this time living specimens began to be imported, and Frank
Evers Beddard, prosector of the Zoological Society of London,
reported (1894) the natural spawning in the Gardens of the Society
of some animals newly arrived from Zanzibar. This first account of
Xenopus
breeding outside Africa showed drawings of larvae of 5
mm and up (Fig. 2A).
Meanwhile, in the hands of the German zoologist Ernst Haeckel
and the Cambridge morphologist Francis Maitland Balfour, Darwin’s
theory of evolution had greatly stimulated comparative embryol-
ogy, not least of colonial fauna (MacLeod, 1994). A couple of years
after Beddard, Edward J. Bles, a zoologist formerly of Owens
College in Manchester and then in Cambridge, began an extended
study of
Xenopus
development. Obtaining four adults from a dealer
in 1896, he maintained them for two years on a diet of earthworms
and strips of liver, and then arranged a space in a corner of the
tropical lily tank in the Cambridge University Botanic Garden (Bles,
1901). In February 1899 he achieved a natural spawning, at a
temperature of 22-24°C, and noted the black nuptial pads on the
forearms of the males. In 1905, now an assistant (i.e. lecturer) in
the Department of Zoology at Glasgow University, Bles published
a fine article, which not only contains A.K. Maxwell’s exquisitely
drawn figures from the unfertilised egg right through to the late
feeding larva (Fig. 2B-E), but also meticulously describes condi-
tions for the ovulation, fertilisation and rearing of
Xenopus
in the
laboratory. Bles kept the animals in a bell-jar over a Bunsen burner
(Fig. 3), a set-up designed by John Samuel Budgett, a ‘Balfour
Student’ at Cambridge (Shipley, 1907; MacLeod, 1994). Bles
Fig. 1. The first published picture of
Bufo laevis
, from Daudin (1802/03).
The species was eventually re-named
Xenopus laevis
. Reproduced by
permission of the Syndics of Cambridge University Library.
Fig. 2. The first published pictures of
Xenopus laevis
larvae and
embryos. (A
) Tadpole of
Dactylethra
(subsequently
Xenopus laevis
), from
Gray (1864).
(B-E)
A.K. Maxwell’s drawings of eggs and embryos of
Xenopus laevis
, from Bles (1905).
(B)
Unfertilized egg;
(C)
mid-blastula;
(D)
neurula;
(E)
feeding tadpole. Reproduced by permission of the Syndics of
Cambridge University Library.
EGF, epithelium and Xenopus in developmental biology 45
brought the
Xenopus
to 22°C several days before coupling, and
changed the water just before egg-laying. He found that it helped
to allow them to hibernate before attempting to induce egg-laying;
apparently, the same female lived for a decade and spawned
spontaneously for at least three consecutive years.
Endocrinology and the
Xenopus
pregnancy test
During the early twentieth century,
Xenopus
continued to be
imported occasionally for research, and increasingly also for hobby
aquaria in Europe. At first it was only among the scientific colonists
in South Africa that
Xenopus
was bound up in a more general shift
from comparative work, which might require only a few museum
specimens, to anatomical and, increasingly, physiological studies
which demanded large numbers of animals of the same species
(Clarke, 1987). In South Africa the ‘Plathander’, ‘Platanna’, or
‘Platie’ as
Xenopus
was known for short, was a readily available
substitute for that ‘old martyr of science’, the frog (Holmes, 1993).
Xenopus
was used both as a ‘type’ animal in school and university
teaching, and by the 1920s also in physiological research (Dreyer,
1913, p. 341; Zwarenstein
et al.
, 1946, Preface and pp. 2-5;
Deuchar, 1975, p. 2). But only from the 1930s did it become a
regular inhabitant of European and North American laboratories.
The establishment of laboratory colonies of
Xenopus
outside
Africa depended on its introduction into endocrinological research
and its adoption as the bioassay of choice in the early diagnosis of
pregnancy. This depended in turn on the peripatetic career of the
left-wing British biologist Lancelot Hogben (Wells, 1978; Werskey,
1978; Hogben and Hogben, 1998).
Hogben (Fig. 4A) was born in 1895 into the poor family of a
Methodist evangelist. His mother, grateful for his safe delivery two
months premature, pledged that Lancelot would become a medical
missionary. But the scientific pursuits she had intended as prepara-
tion for this career actually led him to militant atheism and socialism.
He won a scholarship to Trinity College, Cambridge, where he
studied physiology under such luminaries as Lord Adrian and Sir
Joseph Barcroft, and decided to pursue biological research rather
than medical practice. In 1917 Hogben married the mathematician
Enid Charles, and during the 1920s they had four children. But unlike
other socialist scientists with whom in the 1930s they would be linked
—J.B.S. Haldane, J.D. Bernal and Joseph Needham— he had no
private means with which to support the family, and was forced in
search of a higher salary to take a succession of academic jobs. After
lecturing at Birkbeck College and then Imperial College, London, he
moved to the University of Edinburgh in 1922, initially as deputy to
F.A.E. Crew in the newly established Animal Breeding Research
Department (later the Institute of Animal Genetics; see Hogben,
1974), and then as a senior lecturer in the Physiology Department.
Having moved to McGill University in Canada, he was tempted to
South Africa by a well-paid professorship of zoology at the University
of Cape Town, and there he moved in 1927.
Most of Hogben’s experimental work was in the new field of
comparative endocrinology. While in Edinburgh, he had begun
studying the physiology of the pituitary gland, using primarily
hypophysectomy and the provision of pituitary extracts to investi-
gate the hormonal control of skin colour change in frogs. Once in
Cape Town, Hogben took advantage of the local fauna. Following
the example of South African physiologists, notably W.A. Jolly, he
continued the work, conducted until then on European amphibia,
with
Xenopus laevis
. Such ‘a godsend’ (Hogben and Hogben,
1998, p. 101) did he find it that he named his house after the animal.
The Communist printer and editor Eddie Roux recalled that, with
the ‘brilliant and outrageous’ Hogben as host, ‘Parties at Xenopus
were rarely formal’ (quoted in Hogben and Hogben, 1998, p. 215).
With David Slome and Enid Charles, Hogben initiated a programme
to investigate various physiological changes following removal of the
pituitary. On 17 March 1930, he reported to the Royal Society of
South Africa that hypophysectomised female
Xenopus
suffered
ovarian involution, whilst both implantation of glands and injection of
ox anterior pituitary extracts induced ovulation (Hogben, 1930).
Removal of the anterior lobe also prevented the animals’ character-
istic secretion of slime in response to handling. Hogben presented
this work as demonstrating more definitively than had been possible
in mammals the effect of the pituitary on the ovaries, and generalising
it to all land vertebrates (Hogben
et al.
, 1931; on the mammalian
studies, see Oudshoorn, 1994). He inspired H. Zwarenstein of the
Department of Physiology in Cape Town to come and learn his
method of hypophysectomising
Xenopus
, and Zwarenstein and his
student H.A. Shapiro began a series of studies following up issues
raised by the research of Hogben and his group (Shapiro and
Zwarenstein, 1933).
Hogben’s communication (1930) would later be taken to have
shown in principle that
Xenopus
might be used as an indicator of
the presence of gonadotrophins in the urine of pregnant women,
but neither this nor the full report (Hogben
et al.
, 1931) mentioned
pregnancy testing. He appears initially to have had other priorities,
and it was at the outset far from clear that it would prove possible
to make
Xenopus
the test animal of choice. But with pregnancy
diagnosis a prominent early product of the reproductive sciences
(Clarke, 1998), these endocrinologists can hardly have been
unaware of the possibility of clinical application. The first reliable
laboratory pregnancy test had just been invented in Berlin in 1928
by the gynaecologist Bernhard Zondek and the chemist Selman
Fig. 3. The ‘Tropical Aquarium’ devised by J.S. Budgett and used by E.J.
Bles (1905) to obtain spawning of
Xenopus laevis
.
A bell-jar of 20 inches
diameter is supported on a tripod in contact with a galvanised iron tank
heated by a Zeiss micro-burner. Reproduced by permission of the Syndics
of Cambridge University Library.
46 J.B. Gurdon and N. Hopwood
Aschheim (Oakley, 1984, pp. 96-98), and was then very widely
discussed. It involved injecting five immature female mice twice a
day for three days with morning urine, and then killing them to see
if the ovaries were enlarged and congested. The later Friedman
test, which used rabbits, gave quicker results, but demanded
young does of which the history was rigorously known. In 1929,
Hogben’s friend Crew opened a Pregnancy Diagnosis Station
associated with his Edinburgh Institute (Crew, 1929; Johnstone,
1929), which by 1935 was performing on mice and rabbits for
hospitals and general practitioners about 6000 tests a year (Crew,
1936).
By 1930, perhaps because he was disenchanted with racism in
South Africa and concerned about the worsening political climate,
Hogben was easily persuaded to take a new chair of social biology
at the London School of Economics. There he became a leading
critic of the class bias of the eugenics movement and, drawing on
his experience in South Africa, a prominent campaigner against
scientific racism (Dubow, 1995, pp. 191-195). To continue re-
search in reproductive physiology, he imported
Xenopus
and set
up a colony in the basement of his laboratory, a building he
described as ‘like a delapidated early-nineteenth-century Baptist
chapel’ (Hogben and Hogben, 1998, p. 121). Hogben recruited
Charles Bellerby, who had experience with pituitary extracts, to
attempt to establish ovulation of
Xenopus
as a reliable bioassay.
This did not simply follow from Hogben’s preliminary work; they had
to confirm lack of spontaneous ovulation and determine conditions
for a reproducible response. The major threat to the test, however,
was Zwarenstein and Shapiro’s report (1933) of ovarian atrophy in
unoperated animals kept in captivity. Bellerby (1933) showed that
if instead of keeping the frogs in a cold underground room, he
housed them in warm and well lit surroundings he could eliminate
the ‘captivity effect’ and achieve reliability of testing close to 100%
(see further Alexander and Bellerby, 1935). (
Rana
,
incidentally, was found to be wholly unsuitable.)
In a preliminary report to the Royal Society of South
Africa in October 1933, Shapiro and Zwarenstein
announced that in the previous month they had suc-
cessfully used
Xenopus
in 35 pregnancy tests. The
following spring
Nature
carried an excerpt from this
report (Shapiro and Zwarenstein, 1933) and short
papers from both Bellerby (1934) and Shapiro and
Zwarenstein (1934) describing this new rapid diagno-
sis of early pregnancy. Priority for the
Xenopus
test
became publicly contested between Hogben and
Zwarenstein when in response to Crew’s (1939) at-
tachment of Hogben’s name to the test, the South
African group insisted that they had independently
performed it first (Gunn, 1939a,b). Hogben (1939,
1946a,b) claimed that their work derived from his own
in South Africa, where he had left members of his
laboratory (inconclusively) pursuing a test, and from
Bellerby’s, about which he said Zwarenstein had
learned on a visit to London. He further accused
Zwarenstein of delaying things by the ‘exploit in defec-
tive animal husbandry’ (Hogben, 1939, p. 39) which
produced the so-called ‘captivity effect’, suggesting
that the test required freshly caught animals and so
would be useless outside South Africa. The dispute
was never resolved (Shapiro and Zwarenstein, 1946;
Fig. 4. The
Xenopus
pregnancy text. (A)
Lancelot Hogben in 1952, from Hogben and
Hogben (1998). Reproduced by permission of The Merlin Press Ltd, Rendlesham, Suffolk,
England.
(B)
Test jar, from Elkan (1938). Reproduced by permission of the Syndics of
Cambridge University Library.
Zwarenstein, 1985).
Shortly after arriving back in Britain, Hogben had sent Crew
some
Xenopus
and encouraged him to investigate their suitability
for pregnancy testing (Hogben, 1939). Initially, the Edinburgh
Station had difficulty maintaining the frogs, and was perhaps put off
by the ‘captivity effect’, but by 1937 Crew was keen enough to
import 1500 animals from the Cape. He kept
Xenopus
by thirties in
galvanised metal tanks, transferring frogs overnight into individual
glass jars with perforated platforms for the test itself (Fig. 4B). He
and others compared
Xenopus
, mouse and rabbit results, and
concluded that ‘the Hogben test’ was quickest and for most
purposes the best (Crew, 1939; Landgrebe, 1939). Just one
injection of urine containing gonadotrophic hormone into the dorsal
lymph sac induced egg-laying 8-12 h later. The Edinburgh labora-
tory carried out tens of thousands of tests over the next two
decades. Other British laboratories offered a similar service, and
after the War the frogs were also available for consultation in the
basement of the Family Planning Association clinic in Sloane
Street, London (Oakley, 1984, p. 97).
Crew encouraged New York gynaecologist Abner Weisman’s
interest in importing
Xenopus
for pregnancy testing into the United
States, and Weisman proved a tireless campaigner for the frog
(Weisman and Coates, 1944). Other enthusiasts ensured that by
the end of the War there were
Xenopus
colonies in laboratories and
clinics all over the world. Breeding in captivity was still regarded as
relatively difficult. Shapiro (1935) had established that crude hor-
mone preparations could be used to obtain fertilised eggs and
embryos throughout the year. He injected an acid extract of
sheep’s anterior pituitary or of pregnancy urine into
Xenopus
females and males to induce coupling and production of fertilised
eggs outside the normal season, and reared the tadpoles for
several months. Landgrebe and Purser (1941) raised adult frogs.
Other reports followed (Gasche, 1943; Aronson, 1944), but impor-
EGF, epithelium and Xenopus in developmental biology 47
tation from suppliers in South Africa continued to be the rule.
Hormone preparations increasingly were obtained commercially,
such as ‘Pregnyl’ from Organon (Oudshoorn, 1994). In the 1960s
the Hogben test was replaced by immunological methods, but by
this time
Xenopus
was firmly established in biological research.
Xenopus
and developmental biology
Pregnancy testing had made
Xenopus
a regular laboratory animal
(see e.g. Elkan, 1947), and during and after World War II biological
and biomedical scientists in many countries exploited its ready
availability (Zwarenstein
et al.,
1946; Zwarenstein and Burgers,
1955). With thousands of induced
Xenopus
ovulations a month,
embryologists moved to break the seasonal rhythm of their research
—for 40 years the newt spawning season had deprived Spemann of
spring (Mangold, 1942, pp. 390-391). Developmental biologists put
Xenopus
into service for traditional microsurgery, and especially for
the biochemical studies of development which demanded large
quantities of equivalent biological material and were around this time
becoming the cutting edge of the field.
The Utrecht zoologist Pieter D. Nieuwkoop (1917–1996; Fig.
5A), from 1953 to 1984 Director of the Hubrecht Laboratory
(Gerhart, 1997), played a key role in making
Xenopus
an effective
tool in embryology. Already during the War, he and J.C. van de
Kamer (1946) assessed the advantages (and some disadvan-
tages) of
Xenopus laevis
for microsurgery. They highlighted ease
of decapsulation of early stages compared to other anurans,
favourable tissue consistency for cutting, ready separation of germ
layers and excellent survival after operations. They did note that
smaller eggs and more rapid development than the commonly
used urodeles presented the microsurgeon with difficulties, but
concluded that it was ‘of utmost importance’ to ‘have an experimen-
tally easily accessible anuran species at our disposal’ (p. 118).
Nieuwkoop showed that presumptive
mesoderm cells are internal
even before gastrulation begins (Nieuwkoop and Florschütz, 1950),
and would later stress the difficulty of following the consequently
atypical gastrulation and neurulation (Nieuwkoop, 1996).
Since its foundation in 1917 the Hubrecht Laboratory had had an
international mission to make vertebrate embryos available to em-
bryologists. Nieuwkoop was keen to revive this tradition, which
included producing Normal Tables (Nieuwkoop, 1961), standards of
development which play an important role in domesticating animals
for the embryological laboratory (Hopwood, 2000). He had shown
Xenopus
to be suitable for experimental work, and was also inter-
ested in comparative studies of the ‘rather aberrant development of
this systematically somewhat isolated species’ (Nieuwkoop and
Faber, 1956, p. 1). The Greifswald anatomist Karl Peter (1931) had
completed Bles’s developmental series from
the British zoologist’s
material, and shortly after the introduction of the
Xenopus
pregnancy
test into North America, Paul Weisz (1945) of McGill University had
produced a brief series of normal stages. But in the early 1950s
Nieuwkoop extended his preliminary work on the early development
(Nieuwkoop and Florschütz, 1950) by organizing with Job Faber an
international collaboration to create the lavish and very substantial
Normal Table of
Xenopus laevis
(Daudin)
(Nieuwkoop and Faber,
1956), which soon became definitive and has been much reprinted
since.
By the early 1950s, developmental biological work on
Xenopus
was already appearing from laboratories in various countries,
especially Britain. Some of the first experimental studies were by
David Newth (1948, 1949), then working in London. In Edinburgh,
C.H. Waddington had taken over Crew’s pregnancy diagnosis
operation, and biochemically oriented studies on
Xenopus
soon
began to appear from the Institute of Animal Genetics (Deuchar,
1956; Curtis, 1957, 1958). Both Elizabeth Deuchar (1975, p.v) and
Adam Curtis (letter to J.B.G., 21 October 1996) recalled the limited
breeding season of the local newts as the main reason for turning
to the Pregnancy Diagnosis Laboratory for X
enopus
, which Curtis
Fig. 5. Pieter Nieuwkoop (left)
in about 1993.
(Photograph kindly supplied by the Hubrecht Laboratory, Utrecht, The Netherlands)
. Michaïl Fischberg
(right) in about 1960.
(Photographs from the collection of J.B. Gurdon).
48 J.B. Gurdon and N. Hopwood
(1960) continued to use for cortical grafting at University College
London.
The widespread availability of
Xenopus
in laboratories and the
ability reliably to obtain eggs in all seasons may sufficiently explain
its increasing employment in developmental biology. However, its
dominance over other amphibia was ensured by scientists with
primarily biochemical, cellular, and/or genetic interests who in the
1960s were increasingly entering the field (Oppenheimer, 1966).
Particularly important in attracting such people was the Oxford
laboratory of Michaïl Fischberg (1918–1988; Fig. 5B). Born in St
Petersburg, he was brought up by an aunt in Switzerland and studied
zoology in Zürich, where he remained for a doctorate on newt
heteroploidy under the supervision of Ernst Hadorn (Gloor and
Gurdon, 1989). Coming to Britain in 1948, he took a post in
Waddington’s institute and experimented on mouse embryos. Ap-
pointed to a lectureship in the Department of Zoology in Oxford in
1951, he established a breeding colony of
Xenopus
. Ten years later
he left for Geneva, where he and his group concentrated on collecting
new mutations in
Xenopus laevis
and on describing new species
collected on expeditions to Africa (see Tinsley and Kobel, 1996). In
Oxford, Fischberg had the wisdom to isolate a 1-nucleolated frog that
had turned up by chance in his laboratory (Elsdale
et al.
, 1958); he
and colleagues took advantage of the relatively short life cycle and
convenient laboratory maintenance of
Xenopus
to generate the
homozygous
O-nu from the heterozygous 1-nu originally discovered.
This provided an invaluable genetic marker which was immediately
deployed in nuclear transplantation (Fischberg
et al.
, 1958; Gurdon
et al.
, 1958), and was also used for ingenious germ-cell transplanta-
tions (Blackler and Fischberg, 1961). Especially the serial nuclear
transfer work required an animal that could be made to breed almost
on demand.
It was above all this mutation which attracted biochemists, luring
them to use
Xenopus
to study gene activity in early development.
Far from Nieuwkoop’s continuing interest in the diversity of verte-
brate embryogenesis, for them
Xenopus
was a convenient species
they could use throughout the year to establish principles they
expected would be universal. When still a medical student at the
University of Chicago, Donald D. Brown had chosen embryology,
of which he then knew only that “it was a field so primitive”, in his
view, “that no modern research was being done in it. And yet it had
this huge, incredible problem —how an egg develops into a
multicelled organism” (Brown, 1988). He took degrees in medicine
and biochemistry, and spent a year at the Pasteur Institute, before
starting biochemical work on
Rana pipiens
at the Carnegie
Institution’s Department of Embryology in Baltimore. In 1962 he
met Fischberg’s student John Gurdon, who was travelling around
the United States in search of a job, and they began to collaborate
on the biochemistry of the
O-nu mutant. Gurdon, having gained a
position in Oxford, sent material to Baltimore. Brown and Gurdon
(1964) showed that O-nu embryos fail to synthesize ribosomal
RNA, and so established that such a mutation could be used for
molecular analysis of gene function.
The mutant also provided material for the DPhil. thesis which
Hugh Wallace did with Fischberg, before moving to Edinburgh,
where he collaborated with Max Birnstiel (until that time a plant
biochemist) to show by direct gene separation on caesium chloride
gradients that it lacked ribosomal genes (Wallace and Birnstiel,
1966). By this time, Brown had switched entirely from
Rana
to
Xenopus
(e.g. Brown and Littna, 1964), and this stimulated Igor
Dawid, a newly appointed member of the Baltimore Department,
who had previously been in yeast biochemistry, to produce a major
paper on
Xenopus
mitochondrial DNA (Dawid, 1965). Gurdon,
Brown, Dawid and others had already established independent
laboratories in the early 1960s, and the suitability of
Xenopus
for
the combination of experimental embryological methods with mo-
lecular and genetic techniques was by then very clear. Use of
Xenopus
as a laboratory organism rose dramatically from that time
(Fig. 6).
Conclusion
Xenopus laevis
was made known to nineteenth-century science
through European anatomical and natural historical investigations
of imperial fauna. Used by South African scientists, but only
sporadically in Europe, Hogben’s endocrinological research intro-
duced
Xenopus
into the physiological mainstream. Historians of
biology stress that laboratory animals are not just found, they are
made -often literally by constructing stocks, but also by establish-
ing the material and social conditions for successful husbandry,
and by matching the characteristics of an animal to tasks it might
perform well (Clause, 1993; Kohler, 1994; Keller, 1996; de
Chadarevian, 1998). In the case of
Xenopus
and embryology, quite
a bit of the work of domestication had already been done before
developmental biologists appeared on the scene. Its adoption
depended above all on endocrinologists’ having shown how to
maintain the animal in captivity and, by injecting commercial
mammalian hormone, to make it lay eggs. In the 1940s and ’50s
medical demand for pregnancy testing made
Xenopus
very widely
available in European and North American laboratories, and it
needed relatively little further adaptation for developmental biol-
Fig. 6. Increase in developmental biology publications on
Xenopus
compared with other Amphibia.
Data were retrieved from Advanced
Medline Search by scoring those titles in
Journal of Embryology and
experimental Morphology
(subsequently Development) and
Developmental
Biology
that include
Xenopus
or (for other Amphibia)
Rana, Bufo, Triturus
(Triton
), or
Amblystoma (Ambystoma)
.
(combined scores)
EGF, epithelium and Xenopus in developmental biology 49
ogy. Microsurgery and embryo culture, already perfected for other
amphibians, were extended to
Xenopus
. It proved less convenient
than urodeles for certain embryological manipulations, but these
were not then a priority. Wild-type frogs could be bred or imported
directly from South African farms, and maintaining the anucleolate
mutant in the laboratory worked well. But
Xenopus
claimed the
mantle of experimental embryology once oriented primarily to-
wards urodeles because it became generally obtainable just be-
fore the field reoriented around cellular and biochemical ap-
proaches which intensified demand for large quantities of embryos
all year round. The
O-nu mutant notwithstanding,
Xenopus laevis
has not become an effective genetic organism, and the future may
see increasing interest in
Xenopus tropicalis
, as a diploid rather
than tetraploid species suitable for transgenesis (Amaya
et al.
,
1998). Molecular methods may open up study of amphibian
diversity (Malacinski and Duhon, 1996; Elinson, 1997), but
Xeno-
pus
will surely retain an important place in twenty-first-century
developmental biology. Whereas once the occasional specimen
had been valued as an ‘aberrant’ amphibian, in the 1950s and ’60s
the eggs from hundreds of frogs were used to initiate the molecular
analysis of early animal development.
Acknowledgements
We are grateful to Dr. I. Fischberg-Azimi, Dr. J. Faber, Dr. Milo Keynes,
and Caroline Webb for help in the preparation of the paper, and to Dr. Rob
Grainger for helpful comments on the manuscript.
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... Up until the 1970s and 1980s, nearly all of our understanding of the mechanisms of embryonic development in amphibians relied on either observation or relatively simple methods of experimentation and biochemical characterization ( Nieuwkoop 1973 ;Gurdon and Hopwood 2003 ). While these approaches, led in large part by the pioneering work of Peter Nieuwkoop and David Newth, fundamentally advanced our understanding of vertebrate development, they could not provide a mechanistic, molecular-genetic understanding of these processes. ...
... While these approaches, led in large part by the pioneering work of Peter Nieuwkoop and David Newth, fundamentally advanced our understanding of vertebrate development, they could not provide a mechanistic, molecular-genetic understanding of these processes. The development of widely used molecular techniques such as in situ hybridization and immunohistochemistry ( Clarke et al. 1984 ;Hemmati-Brivanlou et al. 1990 ) positioned Xenopus as a system that could rapidly provide key insights into the roles of molecules and genes during vertebrate development ( Gurdon and Hopwood 2003 ). Within the last two decades, an expanded arsenal of powerful new technologies, including morpholinos and antisense RNA ( Heasman et al. 2000 ), CRISPR/Cas9-mediated genome editing ( Nakayama et ( Wühr et al. 2014 ), and single-cell sequencing ( Briggs et al. 2018 ) became available, greatly expanding the Xenopus developmental biologists' toolkit and providing unparalleled insights into embryo development. ...
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... Laboratories across the world keep living populations of X. laevis to such extents that it is the most widely distributed amphibian (Measey et al., 2012). This frog's history as a laboratory subject is linked to its usage as a human pregnancy test around the 1930s (Gurdon & Hopwood, 2000) and as a model research animal (Van Sittert & Measey, 2016). The global pet trade is also a contributor to Idwi's dispersal out of Africa (Weldon et al., 2007). ...
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This article presents a Pedagogical Framework for Invasive Species to shift how we understand, teach, and study invasive species, especially when people are responsible for their expansion into new ecosystems. The focus is on a species originating from countries in Sub-Saharan Africa that humans extracted and introduced in certain regions of the Americas, Europe, and Asia: Xenopus laevis, African Clawed Frog, or Idwi in the Zulu language. This article re-introduces the frog Idwi through lenses of de/post-colonial theory, Indigenous studies, and Critical Race Theory to create counternarratives. Through a popular press analysis, the article uncovers how humans in colonial contexts extracted species from de/colonizing spaces to export to other regions of the world. When the frogs were profitable, the entrepreneurs who exported them were valorized. However, once seen as invasive, frogs were targeted with xenophobic projections. This article foregrounds counternarratives that challenge and critique universal application of the “invasive species” label.
... There are advantages to using organisms such as D. rerio or Xenopus sp. in environmental toxicology studies [97][98][99]. Both models share a short life cycle [100,101], which can be studied from the oogenesis period to the late development in controlled conditions. The developmental stages, molecular signalling, genetic compositions, and the neurodevelopmental processes of both models are well characterised [102,103]. ...
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Aluminium (Al) is the most common natural metallic element in the Earth’s crust. It is released into the environment through natural processes and human activities and accumulates in aquatic environments. This review compiles scientific data on the neurotoxicity of aluminium contamination on the nervous system of aquatic organisms. More precisely, it helps identify biomarkers of aluminium exposure for aquatic environment biomonitoring in freshwater aquatic vertebrates. Al is neurotoxic and accumulates in the nervous system of aquatic vertebrates, which is why it could be responsible for oxidative stress. In addition, it activates and inhibits antioxidant enzymes and leads to changes in acetylcholinesterase activity, neurotransmitter levels, and in the expression of several neural genes and nerve cell components. It also causes histological changes in nerve tissue, modifications of organism behaviour, and cognitive deficit. However, impacts of aluminium exposure on the early stages of aquatic vertebrate development are poorly described. Lastly, this review also poses the question of how accurate aquatic vertebrates (fishes and amphibians) could be used as model organisms to complement biological data relating to the developmental aspect. This “challenge” is very relevant since freshwater pollution with heavy metals has increased in the last few decades.
... MPF (maturation promoting factor), which is composed of cdc2 and B-type cyclins, is also critical for the G2-M transition [35,39] MPF activity is initiated by Mos, which activates the classical MAPK pathway, after which it is regulated in a cell cycle dependent manner by the CSF (cytostatic factor) [40]. Due to historical advantages of Xenopus laevis for developmental biology research [41], work has focused on the later stages of oocyte meiotic progression rather than early meiosis initiation, and will not be discussed further here. The Xenopus system and cell cycle are extensively reviewed in [34,42,43]. ...
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Meiosis facilitates diversity across individuals and serves as a major driver of evolution. However, understanding how meiosis begins is complicated by fundamental differences that exist between sexes and species. Fundamental meiotic research is further hampered by a current lack of human meiotic cells lines. Consequently, much of what we know relies on data from model organisms. However, contextualising findings from yeast, worms, flies and mice can be challenging, due to marked differences in both nomenclature and the relative timing of meiosis. In this review, we set out to combine current knowledge of signalling and transcriptional pathways that control meiosis initiation across the sexes in a variety of organisms. Furthermore, we highlight the emerging links between meiosis initiation and oncogenesis, which might explain the frequent re-expression of normally silent meiotic genes in a variety of human cancers.
... Individuals from contrasting altitudes could, therefore, exhibit adaptive physiological responses to their respective thermal environments. Xenopus laevis is also a global model organism for various biological studies due to ease of laboratory husbandry and breeding using hormonal stimulants (Nieuwkoop and Faber, 1956;Gurdon and Hopwood, 2003). This makes X. laevis a suitable vertebrate study species to characterise potential adaptive physiological phenotypes in a common garden environment. ...
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Environmental temperature variation generates adaptive phenotypic differentiation in widespread populations. We used a common garden experiment to determine whether offspring with varying parental origins display adaptive phenotypic variation related to different thermal conditions experienced in parental environments. We compared burst swimming performance and critical thermal limits of African clawed frog ( Xenopus laevis ) tadpoles bred from adults captured at high (∼ 2000 m above sea level) and low (∼ 5 m above sea level) altitudes. Maternal origin significantly affected swimming performance. Optimal swimming performance temperature had a >9°C difference between tadpoles with low altitude maternal origins (T opt : pure- and cross-bred 35.0°C) and high altitude maternal origins (T opt : pure-bred 25.5°C, cross-bred 25.9°C). Parental origin significantly affected critical thermal limits. Pure-bred tadpoles with low altitude parental origins had higher CT max (37.8±0.8°C) than pure-bred tadpoles with high altitude parental origins and all cross-bred tadpoles (37.0±0.8 and 37.1±0.8°C). Pure-bred tadpoles with low altitude parental origins and all cross-bred tadpoles had higher CT min (4.2±0.7 and 4.2±0.7°C) than pure-bred tadpoles with high altitude parental origins (2.5±0.6°C). Our study shows Xenopus laevis tadpoles’ varying thermal physiological traits is the result of adaptive responses to their parental thermal environments. This study is one of few demonstrating potential intraspecific evolution of critical thermal limits in a vertebrate species. Multi-generation common garden experiments and genetic analyses would be required to further tease apart the relative contribution of plastic and genetic effects to the adaptive phenotypic variation observed in these tadpoles.
... The South African clawed frog (Xenopus laevis), is a model species utilised worldwide, first used in the development of pregnancy tests [1,2]. Their availability, together with their ability to generate many large embryos throughout the year, marked their establishment as a research model for developmental biology, biochemistry and genetics [3][4][5]. ...
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Background Historically the main source of laboratory Xenopus laevis was the environment. The increase in genetically altered animals and evolving governmental constraints around using wild-caught animals for research has led to the establishment of resource centres that supply animals and reagents worldwide, such as the European Xenopus Resource Centre. In the last decade, centres were encouraged to keep animals in a “low microbial load” or “clean” state, where embryos are surface sterilized before entering the housing system; instead of the conventional, “standard” conditions where frogs and embryos are kept without prior surface treatment. Despite Xenopus laevis having been kept in captivity for almost a century, surprisingly little is known about the frogs as a holobiont and how changing the microbiome may affect resistance to disease. This study examines how the different treatment conditions, “clean” and “standard” husbandry in recirculating housing, affects the skin microbiome of tadpoles and female adults. This is particularly important when considering the potential for poor welfare caused by a change in husbandry method as animals move from resource centres to smaller research colonies. Results We found strong evidence for developmental control of the surface microbiome on Xenopus laevis; adults had extremely similar microbial communities independent of their housing, while both tadpole and environmental microbiome communities were less resilient and showed greater diversity. Conclusions Our findings suggest that the adult Xenopus laevis microbiome is controlled and selected by the host. This indicates that the surface microbiome of adult Xenopus laevis is stable and defined independently of the environment in which it is housed, suggesting that the use of clean husbandry conditions poses little risk to the skin microbiome when transferring adult frogs to research laboratories. This will have important implications for frog health applicable to Xenopus laevis research centres throughout the world.
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Frogs are an ecologically diverse and phylogenetically ancient group of living amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus . Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis , along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui , Engystomops pustulosus and Hymenochirus boettgeri . Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., centric) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding, surrounded by pericentromeric LINE/L1 elements. We explored chromosome structure across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (HiC) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible association of centromeric chromatin, and of telomeres, reflecting a Rabl configuration similar to the "bouquet" structure of meiotic cells. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.
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Xenopus laevis frogs have long been widely used as an animal model in research. However, their husbandry has scarcely evolved, although they are prone to environmental stress. Environmental enrichment has been shown to improve animal welfare and adaptation, as well as zootechnical indices, which have become very important in recent years. The aim of this study was to examine the preferences of X. laevis frogs for various elements of environmental enrichment: opaque polyvinyl chloride (PVC) pipes, artificial plants and clear spaces. A preferential study was conducted in two different tanks, each divided into six parts, where the two enrichment elements were rotated. Ten X. laevis frogs were introduced into each tank, and the number of frogs was counted in each division three times per day for six weeks. The number of frogs in the different spaces and different enrichments was evaluated through a Poisson regression model. Frogs preferred plants to PVC pipes and clear spaces regardless of the position of the enrichment element, time and day. This indicates that artificial plants should be used as the enrichment element rather than the commonly used PVC pipes. In addition, the use of plants facilitates the observation of frogs without disturbing them and reduces the accumulation of detritus, as it occurs inside the pipes.
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The Xenopus embryonic epidermis is a powerful model to study mucociliary biology, development, and disease. Particularly, the Xenopus system is being used to elucidate signaling pathways, transcription factor functions, and morphogenetic mechanisms regulating cell fate specification, differentiation and cell function. Thereby, Xenopus research has provided significant insights into potential underlying molecular mechanisms for ciliopathies and chronic airway diseases. Recent studies have also established the embryonic epidermis as a model for mucociliary epithelial remodeling, multiciliated cell trans‐differentiation, cilia loss, and mucus secretion. Additionally, the tadpole foregut epithelium is lined by a mucociliary epithelium, which shows remarkable features resembling mammalian airway epithelia, including its endodermal origin and a variable cell type composition along the proximal–distal axis. This review aims to summarize the advantages of the Xenopus epidermis for mucociliary epithelial biology and disease modeling. Furthermore, the potential of the foregut epithelium as novel mucociliary model system is being highlighted. Additional perspectives are presented on how to expand the range of diseases that can be modeled in the frog system, including proton pump inhibitor‐associated pneumonia as well as metaplasia in epithelial cells of the airway and the gastroesophageal region.
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In order to observe or produce the phenomena they study, all working scientists must obtain and manage research materials.1 In the United States at the turn of this century, the shift of emphasis from descriptive morphological approaches to experimental physiological approaches in the life sciences radically altered scientists’ needs for research materials and had significant consequences for the organization of such materials.2 This chapter focuses on the consequences of that shift for the acquisition and organization of research materials in the case of reproductive physiology during the first half of this century.