Australian Academy of Science|
Biographical Memoirs of Deceased Fellows
By Bruce Holloway and Paul Broda
William Hayes, physician, microbiologist and geneticist, made
his own special contribution to modern genetics and molecular
biology in a manner quite different from that of any of his contemporaries.
Bill, as he was universally known, was an unlikely candidate for
such distinction. It is interesting to speculate on the events
that transformed someone likely to have had a distinguished but
still traditional medical career into a world renowned scientist
who influenced a whole generation of microbiologists and geneticists.
He did not come from a family with a history of scientific or
academic activities, nor did he study at the centres of biological
research. Moreover, at the beginning of his meteoric rise to eminence,
he did not have the support of the scientific elite or access
to research resources. It is likely that had he been born twenty
years later his originality that he brought to microbial genetics
would have been lost to us. Perhaps the situation he encountered
in India during the Second World War and the relative freedom
of the research system operating in the United Kingdom in the
'fifties ideally suited the talents of Bill Hayes. He was a dedicated
experimentalist with a talent for improvisation, and his major
contributions were through experiments that he did by himself,
rather than with the aid of an assistant or graduate student.
He would not have described himself as a leader, although his
associates willingly gave him their loyalty and support. Nor would
he have thought of himself as having charisma - indeed, he was
unusually self-effacing. When he gave up experimental work to
write his outstanding and extraordinarily influential book, The
Genetics of Bacteria and their Viruses, he typed all the first
draft himself. Administration and the power it can provoke were
anathema to Bill. Nevertheless, he created first at Hammersmith
Hospital in London and then at the University of Edinburgh research
groups that were the envy of his peers in terms of their productivity
Bill was born in 1913 at Edmondstown Park, Rathfarnham, Co. Dublin,
to William Hayes and Miriam Hayes nee Harris, the only child of
his father's second marriage and when his father was aged 73.
William Hayes senior was given £3,000 by his own father,
which he used to establish a pharmaceutical business known as
Hayes, Conyngham and Robinson Ltd that prospered and became a
chain of chemist's shops in Dublin. William Hayes senior became
President of the Pharmaceutical Society of Ireland. Bill's mother,
the daughter of a Church of England clergyman, was aged in her
thirties when he was born. A much older first cousin, A. D. Barton,
was Church of Ireland Archbishop of Dublin. Sir John Crofton,
sometime President of the Royal College of Physicians of Edinburgh,
was the son of another first cousin.
Bill was brought up in a large Georgian house in Dublin and apart
from during the war he lived there until 1950 when he moved to
London. His father died when he was five, so that most of his
upbringing was undertaken by his mother and grandmother. Bill
has written (in an unpublished memoir that has been of great value
to us) of this time as one which encouraged his introspection
and liking for solitude. There was a strong religious aspect of
his life at this time with family prayers twice a day, and because
his mother was steadfastly Protestant he did not mix with the
predominantly Roman Catholic local population. He was tutored
by a governess from the age of eight until in 1923 he went to
a preparatory boarding school for boys, Castle Park, Dalkey, Co.
Dublin. Bill disliked this experience but the education he obtained
must have been satisfactory in that he did well in the entrance
examination for his secondary school, St Columba's College, Rathfarnham,
Co. Dublin. During his time at Castle Park he associated with
a classmate, the writer Patrick Campbell, who stuttered badly,
and Bill found this infectious to the point that he developed
a life-long stutter, although it never prevented him from giving
Bill entered St Columba's in 1927 and at about that time he began
to develop an interest in science, particularly radio and electronics.
He constructed his own crystal set and was able to receive signals
from Daventry 5XX until the set was destroyed during a storm when
the aerial collapsed on to an uninsulated DC electric cable, which
started a fire in his dormitory. He continued to build more complicated
radios, and retained this enthusiasm for many years. His formal
training did not include science but, as was the custom of the
day, focused on the classics. In 1929 he won the Lord Pembroke
Prize for Mathematics. Bill particularly appreciated the efforts
of one master, Dr Sandham Willis, who encouraged willing students
to read beyond the school curriculum. He introduced Bill to Galsworthy,
Shaw, H.G. Wells and Sir Arthur Eddington and this created a love
of the English language that served Bill well for the rest of
his life. At about this time he lost his faith in orthodox Christianity.
Towards the end of his time at St Columba's, Bill responded to
an advertisement to compete in an International Oratorical Contest
sponsored by the newspaper, The Washington Star. He was
selected to represent Ireland at the competition, and his mother
arranged for him to have elocution lessons from Frank Fay of the
Abbey School of Acting. In Washington DC the audience turned out
to be some 5,000 strong, including President Hoover. Bill did
not win but he did receive an invitation to Hollywood for a screen
test, an invitation that he refused. Who knows what the movie
world lost and science gained?
Bill then chose to study medicine, partly as a result of peer
pressure and indecision, but also because of its scientific content
and prospect of financial security. He entered Trinity College
Dublin in 1981 and enjoyed studying the various science subjects,
but it was not until his third year that there was any indication
of his future career activities. He started to learn bacteriology
and immunology under Professor J.W. Bigger, which stimulated his
interest to the point that he enrolled to take an extra year to
read for an Honours Degree (Moderatorship) in Natural Science
in which he could specialize in bacteriology. This was Bill's
first real exposure to research, studying aspects of streptococcal
fibrinolysin and he obtained First Class Honours. He continued
with his medical course but was not attracted to the clinical
aspects. He was no ordinary student in that he won the Haughton
Prize for Medicine, was awarded the Silver Medal of the Dublin
University Biological Association, read three papers to the Dublin
University Biological Association and was awarded the Adrian Stokes
Memorial Travelling Fellowship which he never took up because
of the outbreak of war.
After graduating in medicine, Bill was retained by Bigger at Trinity
as a General Assistant (1938-1939) and then Senior Assistant (1939-1941).
At this time a distinguished refugee from Nazi Germany, Professor
Hans Sachs, came to work in the laboratory, typing blood for the
Irish Medical Research Council. Sachs had been Professor of Bacteriology
at Heidelberg University and was well-known for the Sachs-Gyorgy
precipitation test for syphilis. He had also been an intimate
friend of Paul Ehrlich. Bill wrote in his memoir as follows:
Sachs initiated me into the mysteries of serology and it was from him that I first learnt that what the text books say and the latest hypotheses proclaim are usually grossly over-simplified approximations to reality. Together we studied the nature of an unusual human serum that was falsely positive in the Wassermann Reaction; when heated to destroy the human complement, this serum inactivated the haemolytic properties of the standardised guinea pig complement used in the test. All the ideas in this research came from Sachs's great knowledge and experience, but he generously insisted on my being senior author of the paper that followed - my second publication.
Another refugee from Germany at that time was the noted theoretical physicist Erwin Schrödinger, invited by de Valera to work in Dublin. I occasionally met him at lunch in the College but did not know of his developing interest in biology until much later, when I got to know Max Delbrück at the California Institute of Technology in 1953.
As part of his medical training, Bill had house physician posts
in Dublin and at the Victoria Hospital in Blackpool, where he
met his future wife, Nora Lee, daughter of Joseph and Margaret
Lee of Oldham. They were eventually married in 1941 but almost
immediately had to separate for four years due to the war. Nora
Hayes, who died in 1996, was a remarkable person in her own right
who provided a lifetime of extraordinary support for her husband
and also devoted herself to the many people who worked with Bill
in various capacities. They had one son, Michael, now practising
medicine in Sydney.
In late 1941, Bill was accepted by the Royal Army Medical Corps,
and after an initial period as a pathologist was trained in tropical
medicine and pathology at Liverpool and eventually arrived in
India in late 1942. His first post, with the rank of Major, was
the command of the Army Enteric Reference Laboratory at Kasauli
near Simla and subsequently at the new Central Military Pathology
Laboratory in Poona. He spent ten months at Kasauli, where his
functions were to identify numerous salmonella strains isolated
from Army personnel, and also to provide standardized diagnostic
sera and agglutinable salmonella suspensions to military laboratories
throughout India and Ceylon.
His time at Kasauli revealed his gift for improvization. The demand
for these reagents could no longer be satisfied by producing anti-sera
in rabbits and suspensions from Petri dish cultures. He therefore
obtained a small herd of goats for the former, which proved a
success, and large metal trays for the latter. Agar was very scarce
since it had largely come from Japan and it therefore needed to
be recycled. Bill allowed the harvested nutrient agar to reset
in the trays after autoclaving, cut it into cubes and then washed
these in running water. The agar was finally separated from the
water in which it was dissolved by exposure on the laboratory
roof at night, and was then standardized by hydrolysing samples
for glucose assay.
The four senior staff of the Central Laboratory included Bill
as bacteriologist and Douglas (now Sir Douglas) Black as biochemist.
They ran three-monthly courses in clinical pathology, and by several
accounts Bill was an outstanding teacher. One of their notable
students was Michael (now Sir Michael) Stoker, who was retained
at Poona as a member of the Typhus Research Unit, a decision that
launched him into rickettsial research and thence into virology.
Bill also became responsible for assaying every batch of penicillin
imported for army use. The methods he adopted depended on inhibition
of staphylococcal growth and Bill improved the reproducibility
of these methods. He was also sent to the UK, via flying boat,
to obtain the latest information on the laboratory aspects of
penicillin from Florey and Fleming and their groups. Following
this trip, he wrote a booklet on the laboratory control of penicillin
therapy that was circulated to all the laboratories of India Command.
While in London he had himself transferred to the Indian Army
so that Nora could join him in India. In the event, she spent
nearly ten months there; he was demobilized in 1946 and they returned
Other work in India provided the basis for Bill's interest in
bacterial genetics. He later wrote as follows in his unpublished
The Salmonella work was a source of constant interest from several points of view. For example the number of species and types received offered much scope for ecological and epidemiological studies. One of the most interesting of these was the frequency of strains of S. enteritidis isolated by blood culture from cases of septicaemia on the Burma front. S. enteritidis, which is enzootic among ducks, is normally non-invasive in man and causes simple gastroenteritis. Similar invasive variants were first reported during the Paraguayan-Bolivian war in 1932-1938 (the Chaco War) and designated S. enteritidis var. chaco. The evidence suggested that the Indian strains were introduced into Burma by the Japanese. I tested them for the presence of an alkali-labile 'virulence Vi' antigen, analogous to those demonstrated by Felix in S. paratyphi A,B and C but failed to find one.
Another example was the isolation of a novel salmonella from the
stool of an African cook in Chittagong (now in Bangladesh). Dr
E.S. Anderson, who was working in London at the time (early 1946)
writes: 'It proved to be a salmonella which seemed to be new.
The organism was passed to me by Dr Joan Taylor, Director of the
Salmonella Reference Laboratory. Its antigenic formula, which
was a hard nut to crack, proved to be (I).III.X.(XIX).XXVI.;bZ35,
'Z35' being at that time a new antigen. It had been reported that
three strains of the paracolon group of organisms, isolated from
snakes, had flagellar antigens closely related to phase 2 of Salmonella
chittagong. It seemed possible that the serotype may have
originated from a snake, because West Africans ate these reptiles,
which were commonly found in their kitchens in India'. It was
only after Bill's arrival at Hammersmith in 1950 (where be inherited
Anderson's laboratory) that he and Anderson first met in person.
Bill also wrote of this time:
S. enteritidis posed problems of a different nature which, much later, were to determine my ultimate research interests. High titre antisera prepared against the somatic (O) antigens of some strains, which we may call A, agglutinated other (B) strains to only a relatively low titre: conversely, antisera to these B strains agglutinated both A and B strains to roughly the same titre. Strains were then found in which all the cells were agglutinated to titre by B antisera, but only a proportion of the cells by A antisera. When such strains were plated and individual colonies tested some behaved like A and others like B strains. Finally if, say, an A-like colony was plated and daughter colonies tested, with some strains as many as 5% might have reverted to B-type and vice versa. This, therefore was a high frequency diphasic variation involving a somatic antigen which later turned out to be what was then termed antigen XII2: this antigen was highly antigenic and was present in phase A but absent from phase B. Since it is also one of the major antigens of S. typhi, its striking variation was clearly a potential source of error in the preparation of agglutinable suspensions for use in the Widal Test, and of diagnostic antisera. However what really interested me was the mechanism of diphasic variation and I seemed to have a good system to study it. I took up this research again five years later when it led me into the then embryonic field of bacterial genetics.
To sum up, it is fair to say that I enjoyed my war service which gave me considerable experience of teaching and the responsibilities of administration, and initiated me into the pleasures and rewards of independent research that resulted in eleven publications. The war as such hardly touched me and I never heard a shot fired in anger.
With the ending of the war with Japan, Bill was demobilized in
August 1946 and returned to Trinity College Dublin, as Lecturer
in Bacteriology. During this time he was able to do little research,
since his time was largely taken up in teaching and routine diagnostic
work. In 1949 he used his presidential address to the pathology
section of the Royal Academy of Medicine in Ireland to explain
the recent developments in bacterial genetics and their significance
for medicine. He submitted his accumulated published work for
the degree of Doctor of Science and this degree was duly conferred
by Dublin University in 1948. However, he was only runner-up for
a College Fellowship and was also disappointed by the lack of
opportunity for research there. When the opportunity arose he
therefore applied for and was accepted for the position of Senior
Lecturer in Bacteriology at the Royal Postgraduate Medical School
at Hammersmith in London in 1950.
With his arrival at Hammersmith, Bill again had the opportunity
to do research, since his teaching duties were light. The Head
of Department, Lord Stamp, put no constraints on his topic of
research, and so Bill chose to return to the mechanism of somatic
phase variation in Salmonella enteritidis. He had begun
to realise the potentialities of genetic analysis inherent in
the recent discovery by Lederberg and Tatum [iv] of conjugation
in Escherichia coli, and wondered whether its relatives,
the Salmonellae, could also conjugate, He recorded in his research
notes of March 1950 the design of an experiment involving growth
in mixed culture of a pair of genetically marked Salmonella
strains, stabilized in each phase, and the selection and examination
of recombinants for restoration of the variation. The experiment
itself was never attempted.
An opportunity arose to become acquainted with conjugation in
E. coli when, towards the end of 1950, he went on
a course on bacterial chemistry at Cambridge, organised by E.F.
Gale. At that course he met L. Cavalli (later Cavalli Sforza),
who had worked with Joshua Lederberg on conjugation at Wisconsin,
and who was currently a visitor in R.A. Fisher's Department of
Genetics at Cambridge. Cavalli provided him with the basic E. coli
K12 auxotrophic parental strains, and Bill started to work
with them early in 1951.
Bill was initially interested in the kinetics of the mating process,
in particular at what time recombinant cells were formed after
mixing and plating the parent strains. He therefore spread a mixture
of a streptomy-cinresistant mutant of one parent (A) and a sensitive
strain of the other (B) on several minimal plates, and at intervals
thereafter respread the plates, in turn, with a lethal concentration
of streptomycin. No colonies arose when streptomycin was added
prior to two hours after mating but thereafter they increased
in number with time. To confirm this result, Bill did a similar
experiment in which a sensitive strain A was mated with a resistant
strain B. This time the results were quite different. About the
same number of recombinant colonies emerged from all the samples,
even when streptomycin was added immediately after plating the
Bill writes in his unpublished memoir: 'I discussed these results
with Denny Mitchison and I think it was he who first suggested
that one of the parents, A, might be acting as a gene donor and
the other, B, as a recipient'. Bill tested this hypothesis by
treating each sensitive parent with streptomycin to a survival
of less than 10-6 colony-forming cells, and then mating
with an untreated suspension of the other. The crosses in which
strain B had been treated were invariably sterile while treated
A suspensions always generated recombinants although their numbers
might be markedly reduced as compared with normal crosses.
It was from this experiment that the concept of asymmetry in bacterial
sexuality arose. Parent B was the recipient or 'female', the continued
viability of which was essential for the whole process of recombination
and segregation, while the A donor or 'male' cell was dispensable
once genetic transfer had been effected. Bill suggested that the
male cell extruded a surface 'gamete' that was taken up by the
female cell on contact, and that blocking male protein synthesis
by streptomycin did little to inhibit its fertility. This hypothesis,
and the experiments supporting it,, were published under the title
'Recombination in Bact. coli K12: unidirectional transfer of genetic
material'. It was also presented in a paper at the April 1952
meeting of the Society for General Microbiology in Oxford. The
meeting featured a symposium on 'Virus Replication' and was attended
by André Lwoff and Gunter Stent from the Pasteur Institute
and the young James Watson who had recently come to work on DNA
structure with Francis Crick at Cambridge.
Bill's next step was based on a report four years previously (Haas
et al 1948) that ultra-violet irradiation of a mating mixture
markedly increased the number of recombinants. Was this due to
stimulation of the male or of the female? Experiment showed that
exposure of the male before mating to a dose of UV, permitting
about 50% survival, resulted in a 5- to 10-fold increase in the
frequency of recombinants. In contrast, irradiation of the female
led to a fall in the number of recombinants that paralleled that
of the survivors. In the previous year, Lwoff and his colleagues
had described the UV induction of a Bacillus megaterium prophage
(Lwoff et al 1950), and Weigle and Delbrück (1951)
had investigated a similar induction of the E. coli K12
prophage lambda. Since both phage induction and the enhancement
of male fertility required post-irradiation-incubation in a rich
medium, Bill thought it possible that the male 'gamete' might
be 'a gene-associated virus', although this was unlikely to be
phage lambda, which lysogenized both male and female cells. Later
studies of a non-lysogenic male obtained from Elie Wollman confirmed
this. At that time Zinder and Lederberg had not yet published
their discovery of transduction in Salmonella.
In September 1952, Bill was invited to the Second International
Symposium on Microbial Genetics, sponsored by the Rockefeller
Foundation and held at Pallanza on the shores of Lake Maggiore,
Italy. There he met most of the rather small numbers of Europeans
in the field at that time, as well as some of the Americans including
Jim Watson. He therefore had the opportunity to present his donor-recipient
hypothesis to a well-informed and critical audience, while Cavalli-Sforza
supported the more orthodox homothallic viewpoint. This occasion
was recalled for a larger public by Watson in his book, The
Double Helix (Watson 1968). In it, he remarks that 'Bill's
appearance was the sleeper of the three day gathering; before
his talk no one except Cavalli-Sforza knew he existed. As soon
as he had finished his unassuming report, however, everyone in
the audience knew that a bombshell had exploded in the world of
It should, however, be noted that this dramatic account is a simplification
since Watson, Lwoff and Stent had all been present at the Oxford
meeting, and Bill's work had already appeared in Nature in
January 1952. Gunther Stent has written to us: 'I heard him (i.e.
Bill Hayes) give a talk ... on the polarity of K12 crosses as
revealed by UV and antibiotic treatment of either parent strain.
It was on my instigation that Elie (Wollman) went to visit the
then totally unknown Bill at Hammersmith, and that the Hayes-Wollman-Jacob
axis ... came to be formed. At the summer l952 Royaumont Phage
Colloquium, I managed to persuade Max Delbrück, who trivialised
Bill's results as reflecting no more than a differential radio-
and drug-sensitivity of the parent strains, that Bill was for
real. The 1952 Microbial Genetics meeting, in Pallanza, to which
Bill was invited, was held in the fall of 1952. Watson errs, if
he claims that no one except Cavalli knew of Bill before that
meeting. Jim and Max certainly knew of him, and Elie was already
collaborating with Bill.'
Dr E. Wollman has written of this time (Wollman 1966): 'in the
Spring of that year I visited William Hayes for the first time
in his laboratory at the postgraduate medical school in London.
His working conditions were then so modest that they made our
musty attic in the Pasteur Institute look almost luxurious by
comparison. I was particularly impressed by his tiny petri plates,
3-4 cm in diameter and cut out from the bottom of vials, and by
the watchmakers eye lens with which he counted the minute colonies
of recombinants appearing on these plates. Shortly after this
visit, I gave an account of the new developments in recombination
in bacteria, and of the genetic basis of lysogeny, at the first
international conference on Bacteriophage, held at Royaumont.
Max Delbrück, who was present at Royaumont and who had been
all along somewhat suspicious of genetic recombination of genetic
bacteria, listened with interest to my description of his work.
Though still far from convinced that there was anything to this
sexual polarity business at all, he decided to invite Hayes to
give a paper at the following Cold Spring Harbor symposium on
Bill's next achievement was to elucidate the nature of the agent
responsible for sexuality, and this arose by serendipity. At about
the time of the Pallanza meeting, a friend of his in London, Dr
Clive Spicer, who had worked with the Lederbergs and with whom
Bill had discussed his hypothesis, told him that he had a pair
of parental K12 strains, similar to Bill's A and B parents, that
on storage had lost their capacity to produce recombinants. Bill
had been attempting without success to isolate a male strain that
had lost its postulated vector, by looking for A colonies that
were no longer fertile with the R female; perhaps Spicer's strain
was one such infertile male. To test this possibility, Bill crossed
Spicer's strains with his own; the outcome showed that it was
indeed the male strain that was defective.
Bill's most crucial experiment was to ask whether the fertility
that had been lost could be infectively restored by contact with
a normal male. Accordingly, he labelled the defective A (Spicer)
strain with two independent markers (resistance to sodium azide
and to streptomycin), and then grew it overnight in mixed culture
with his own (fertile) strain, sensitive to both agents. Before
he knew the result he wrote to Cavalli, who was now working with
the Lederbergs at Wisconsin. He explained what he had done and
remarked that if the experiment worked he (Cavalli) would have
to accept the fact of infectious transfer. The experiment did
work; 25% of the colonies of the re-isolated strain A (Spicer)
were now normally fertile. When he got Cavalli's reply, it was
to say that he already knew the result of this experiment, since
he and the Lederbergs had done basically the same experiment three
weeks earlier, but using a quite different approach. Their experiment
showed that the fertility character was transferred by a transmissible
agent, which they called F or the sex factor, at a frequency some
10,000 times greater than that of recombinant formation. Thus
two quite different modes of experimentation and thinking converged
in the coincidental discovery of the first transmissible plasmid,
the F factor (Lederberg el al 1951). The Lederberg/Cavalli
interpretation was that the sex factor conferred on the parents
of a cross what they termed 'relative sexuality', which they did
not attempt to explain in mechanistic terms. As with the earlier
demonstration of unidirectional transfer, Bill was, by contrast,
thinking in precisely such terms.
A limited survey by Bill showed that F+ and F-
cells as defined by the Lederbergs and Cavalli corresponded unambiguously
to donors and recipients respectively. The ability of infectivity
to convert recipients to donors meant that it was possible to
study the genetical efforts of 'reversal of F polarity' by comparing
the outcome of A.F+ x B.F- crosses and B.F+
x A.F-. If, as Lederberg and his colleagues believed,
the two parents contributed equally to the zygote, both crosses
should give the same result. They did not. First, the recombinants
inherited most of their characters from the F- parent.
Secondly, the characters inherited from the F+ parent
were limited to a few linked ones and were quite different in
the two crosses. In Hayes' opinion, everything behaved as if the
F+ donor transferred only part of its genome to the
F- recipient, the particular part being that selected
to make good the auxotrophic defect of the F- recipient
which, of course, differed in the two crosses.
Joshua Lederberg's explanation was quite different. He still did
not accept the donor recipient hypothesis and proposed instead
that complete zygotes are formed (as everywhere else in biology)
but that a fraction of the F+ genome is then eliminated
- the 'post-zygotic exclusion' hypothesis for which a precedent
was known in Cheironomus. It was not until the hypothesis
of one-way partial chromosome transfer was proven beyond reasonable
doubt by the work of Wollman and Jacob four years later that Lederberg
accepted it. Hayes' own comment was that he 'had the great advantage
of knowing virtually no genetics while Lederberg knew too much'!
One result of the Pallanza meeting was that James Watson began
to take an increasing interest in E. coli genetics,
and when he was in Cambridge he would visit Bill on visits to
London to discuss x-ray diffraction analysis of DNA. Watson considered
that the results of Bill's genetic analyses provided good evidence
that the E. coli genome comprised three linkage groups.
Lederberg et al. (1951) had already defined three sets
of linked genes that showed non-linear interactions, the nature
of which they did not understand. Watson and Hayes submitted a
joint paper to Proceedings of the National Academy of Sciences,
through Max Delbrück, in which they presented their model.
This was that the three linkage groups reflected discrete chromosomes,
only one of which normally became associated with the transmissible
F vector at any one mating event, and thus was carried over to
the recipient cell. However, they supposed that occasionally the
F factor became associated with two chromosomes, so that both
were transferred in the same pairing, and. that this provided
an explanation of Lederberg's non-linear interactions.
At this time, Bill also made the accidental discovery of the Hfr
(for high frequency of recombinants) strain, HfrH (H for Hayes).
This arose spontaneously in a static culture of the A.F+
donor strain and yielded about 1,000 times more recombinants in
crosses with B.F+ than did the ancestral strain. As
Bill points out in his unpublished memoir, this discovery was
not original since Cavalli had first described the Hfr state (Cavalli,
1950). However, Bill discovered a number of important new features
in terms of mechanism, since he showed that the fertility of HfrH
was relatively unaffected by streptomycin treatment. Thus it was
its donor ability that was enhanced compared with the parent.
Moreover, UV-irradiation did not further increase the frequency
of recombinants that could be formed, implying that this frequency
was already maximal. The third observation was that the donor
state was no longer transmissible at high frequency. Fourthly,
only one of the three linking groups was transferred at high frequency.
Markers on the other linkage groups could be selected at low frequency,
and a proportion of the recombinants that were formed were found
to be Hfr donors like the parent strain.
All these observations seemed to fit well with the model that
Hayes and Watson had put forward, proposing that a mutant F factor
had become stably associated with one of the three chromosomes
that they had proposed. Bill commented in his memoir that 'this
hypothesis, of course, turned out to be basically incorrect although
not a bad approximation to the truth ...'. It was indeed incorrect
in supposing the existence of three chromosomes, but the observations
show how Bill was always thinking mechanistically about his strains.
The value of these observations was in illuminating the nature
of the F+ Hfr event.
The second half of the sentence quoted above reads '... but the
main importance of HfrH was that I gave it to Elie Wollman and
Francois Jacob of the Institut Pasteur, Paris, with whom I had
already established a close liaison, in whose hands it played
a key role in the many experiments of their brilliant series that
revealed the true nature of E. coli sexuality'. This
comment exemplifies for us Bill's grace, modesty and generosity.
It was through Watson and Wollman that Bill was invited by Max
Delbrück to contribute to the Cold Spring Harbor Symposium
in 1953, on Viruses (at which Watson also gave an historic account
of the structure of DNA). It was in the publication that emerged
from this meeting that Bill gave the most definitive account of
his experiments and hypotheses. Rather characteristically, he
chose to finish what was a very substantial and thoughtful article
as follows: 'Increasing evidence of the role of temperate phages
as genetic carriers enables the concept that F fulfils a similar
all more specialised and efficient, function in E. coli
to be fitted into a gene evolutionary picture. Perhaps Hilair
Belloc's poem 'The Microbe' can express, better than I can say,
my feelings on this matter.
'All these have never yet been seen -
But Scientists, who ought to know,
Assure us that they must be so...
Oh! Let us never, never doubt
What nobody is sure about!'
During the meeting Delbrück invited Bill to visit him for
six months at the California Institute of Technology, which came
about that autumn. It had been suggested that Bill should work
with Watson on E. coli conjugation. However in the
event Watson, fresh from the DNA triumph, chose instead to work
on RNA structure. Dr Watson has written to us as follows: 'I felt
guilty about not interacting more with him when he came to Caltech
during the fall of 1953. But then I cared only about the RNA structure,
believing bacterial genetics would never again get exciting. How
wrong I was, with Bill's work leading into that of Wollman and
Jacob and soon afterwards to the Monod-Jacob ideas about gene
expression in E. coli.'
At Caltech, Bill took over equipment and culture medium reagents
from Marguerite Vogt, who had been working with E. coli
K12 F+ x F- crosses but was about to
change topics. With these materials Hill's work had 'an interesting
but initially embarrassing denouement' since no recombinants arose
from crosses plated on the appropriate minimal media. The Caltech
media, highly purified, were not supporting the process of recombination
as had Bill's materials in London. Bill showed that crosses became
fertile when aspartate was added to the medium. This observation
led to the first analysis of the energetic requirements for conjugation,
by K.W. Fisher, who became Bill's first PhD student in London
in 1954 (Fisher 1957).
Bill then returned to his initial project, on the kinetics of
the mating process, this time using his Hfr strain. His method
also involved the use of high multiplicities of the virulent phage
T6 instead of streptomycin. He was therefore able to kill the
sensitive donor at intervals after mixing with a resistant recipient
in broth, and the results were clear-cut and reproducible. When
untreated samples were plated, recombinants began to appear immediately
after mixing the parental cultures. On the other hand, the treated
samples yielded no recombinants if phage was added at times less
than ten minutes after the initial mixing. Recombinants then began
to appear and their numbers increased linearly with time until
a plateau was reached about thirty minutes later.
Bill had supposed that the donor genome, which he visualised as
a discrete 'nucleoid', would be transferred en bloc over a very
short period. Therefore he expected that the donor lac+
and phage T63 alleles, which were located on the
same linkage group as the selected markers (thr+
and leu+) would be inherited among these recombinants.
He ascribed their absence to killing of the T63 recombinant
segregants by the phage. It was only with the publication by Wollman
and Jacob (1955) of their interrupted mating experiment that the
correct explanation emerged.
Bill had succeeded in producing 'zygote suspensions' from which
Hfr bacteria had been eliminated by the treatment with phage.
He used this system to study the kinetics of segregation. Thus
if a suspension of newly-formed zygotes was diluted and incubated
in fresh broth and samples then plated at intervals for recombinants,
the time at which the number of recombinants began to increase
indicated the commencement of division among the recombinant segregants
so that in this way the time of segregation could be assessed.
Furthermore, if zygotes were plated on media containing the inhibitory
or lethal substance, only those in which the resistance gene is
dominant can segregate resistant recombinants, so that a comparison
of the kinetics of segregation and of expression distinguished
dominant from recessive alleles.
These new methods were developed at Caltech and the definitive
experiments were completed during 1954. An abstract was published
in 1955 but the work was not published in full until Wollman,
Jacob and Hayes collaborated on a joint paper that was presented
at the 1956 Cold Spring Harbor Symposium (1956).
In 1957, Bill was invited by Sir Harold Himsworth to set up a
Medical Research Council Unit, the Microbial Genetics Research
Unit, at Hammersmith Hospital, where a generation of to-be-successful
British, European and North American bacterial geneticists established
themselves. The initial members of the Unit were Ken Fisher, Neville
Symonds, Royston Clowes and Stuart Glover. They were joined by
Robert Pritchard and Julian Gross, and later by Kenneth Stacey
and Elinor Meynell. The initial postgraduate students were John
Scaife and Donald Ritchie, followed by Marilyn Monk and Paul Broda.
There was also an extensive list of visitors, who included Raymond
Devoret, Jeff Schell, Jon Beckwith, Simon Silver, Millard Susman,
Gerard Venema, Robert Weisberg, David Goldfarb, and Stephen Cooper.
Bill preferred to let people get on with the job so as to give
him time to do his own scientific work rather than being an administrator
and manager, which he detested. However, his hopes of returning
to the bench were never realised since he set himself the all-consuming
task of writing a book. In the words of Neville Symonds: 'The
Genetics of Bacteria and their Viruses published in 1964,
was the first comprehensive textbook on microbial genetics and
became a trusted companion to students and research workers all
over the world. In many ways the book typifies the character of
the author. It evokes a kind of old-world charm, talking with
a sense of wonder about the ideas it is portraying, and being
scrupulously fair to the scientists under discussion. Nonetheless
behind it all is the ability to see through the often complex
experiments and confusing theories and expound them simply: it
is this which made the book so successful.'
Nora Hayes recalled later how for several years she lived in a
silent house, as Bill worked day and night on his book. The book
emerged more than three years later and three times the expected
length. However, coming so soon after the heroic decade of molecular
biology from 1952 to 1962, it appeared at the perfect time. Bill
wrote in his memoir: 'shortly after publication the book came
to the attention of J.B.S. Haldane when he was recovering from
his cancer operation not long before his death in 1964; he told
me that he proposed to review it. He seemed especially intrigued
by the final chapter on transmissible plasmids but wrote me a
number of letters criticising my amateurish accounts of 'classical'
genetics which I found most valuable when I came to write the
second edition. One letter began, 'Dear Hayes, in this letter
I am going to give you hell' - and did!'
The book had been reprinted four times by 1967 and in 1968 a second
edition appeared. The fact that the first edition had 740 pages
and the second had 925 pages and almost twice as many references
shows both the scale of the undertaking and the rate at which
the subject was growing. It is not surprising that Bill never
attempted a third edition. The effort involved in creating this
book, the changing nature of science, and his other duties together
frustrated his expressed hope to return to the laboratory.
Characteristic of Bill's open style, it was decided to promote
molecular genetics (and the Unit) at the international level.
Bill had a special interest in links with Eastern European countries,
which had been so deprived of modern molecular genetical developments
during the Lysenko period. The principal means chosen was a series
of courses of about four weeks duration, comprising lectures and
practical classes; they were roughly modelled on the Cold Spring
Harbor course. Four courses were held between 1960 and 1964; each
was attended by about twenty students, ranging from professors
to postgraduates, from diverse disciplines with a fair proportion
coming from other countries. Hayes and Clowes edited a book, Experiments
in Microbial Genetics, that was based on the courses. The
Unit also made available stocks of the strains used in the course
and produced an international registry of laboratories that were
willing to help in disseminating these strains. These activities
made Bill and the Unit very well known and valued.
In 1964 Bill was elected FRS and in short order Symonds, Stacey
and Pritchard left to be founding professors in the Universities
of Sussex, Kent and Leicester respectively, whilst Clowes and
Fisher departed for the USA. Also at this time Martin Pollock,
who headed a biochemistry group at the National Institute for
Medical Research, proposed that their two groups should merge
as a new university department of Molecular Biology. This appealed
greatly to Bill since such an integrated department would be the
first of its kind in Britain and would attract undergraduate students
into the field. Moreover, most of the Unit staff welcomed the
idea of some teaching. These ideas came to fruition through the
good offices of Michael (later Lord) Swann at Edinburgh. It was
finally agreed with the Vice-Chancellor, Sir Edward Appleton,
that the new department would be allocated the top three floors
of an extended eight-storey Forestry building that was being planned.
The MRC agreed to this, the first example of an MRC Unit being
an integral part of a university department with full teaching
responsibilities. The Unit acquired the new title of Molecular
Genetics Unit. Bill was appointed to a personal chair in the university
and the Unit moved to Edinburgh in May 1968.
In Edinburgh Bill again did little research of his own, his time
being consumed by teaching and organization, invited lectures
and trips abroad, and a very heavy burden of committee work for
the Royal Society, the University Grants Committee and the recently-funded
European Molecular Biology Organisation. He was also President
of the British Genetical Society in 1971-1973.
In 1971 he accepted an invitation to tour New Zealand and he spent
three months there and then visited Australia on the way home.
He felt an immediate affinity with Canberra and the Australian
National University, and told Nora that this was where he would
like to spend the rest of his professional career. John Langridge,
then Professor of Genetics at the Research School of Biological
Sciences, asked Bill if he knew of anyone who would like to come
and take up an appointment at the RSBS. Bill said he would like
to come, and Langridge replied that they really weren't looking
for anyone so distinguished. However, the seed was sown and in
1973 when Langridge left the Department of Genetics and returned
to CSIRO, Bill was invited to be the next Professor of Genetics
at the Research School of Biological Sciences of the Australian
National University. He duly arrived in early 1974, just a few
days after he turned 61. Before accepting the position, Bill wrote
to one of us (BH) asking if he was also a candidate for the chair
(which was not the case) and if that was so, then he would not
accept the position - a typical example of Bill's constant generosity
and concern for others.
Bill's departure resulted in the closure of the MRC Unit rather
than its continuation with a new Director. After a period of great
uncertainty, four of the untenured staff were granted tenure after
application to the Council by Bill as one of his final acts. Together
with two borrowed tenured staff, these individuals joined the
University Department, with their salaries and other support provided
by the MRC. The Unit had published 253 papers during the period
1957 - 1973.
Bill's first impressions of Canberra were happily confirmed. He
was finally able to return to laboratory work, he loved the lack
of traffic, the ease with which the nearby high country could
be reached and the warm Australian climate. He travelled to most
parts of Australia in the first three or four years. Always, this
travel was an interlude from his laboratory work, his major activity.
He continued to gain great satisfaction and enjoyment from classical
music, particularly opera and piano works. He loved walking in
Canberra, both in the city and in the surrounding bush, and was
an enthusiastic but in his own words not very competent swimmer.
Bill and Nora found the emphasis on home entertainment in Canberra
very much to their liking. Bill was somewhat disdainful of dining
and good food, and frequently suggested that he would prefer to
be supplied in the form of capsules or pills so that that part
of living could be got over and done with quickly. On the other
hand, conversation after a meal was an entirely more serious pursuit.
In 1976 he was elected to the Australian Academy of Science and
in 1977 invited to give the prestigious Burnet Lecture at the
Academy's annual general meeting. He was not a regular participant
at such meetings because he didn't much like dressing up and one
of the features of Australian life he enjoyed was the informality.
He only ever attended one Academy dinner, on the day that he was
formally inducted into the Fellowship, because these are traditionally
Bill's research work at the Research School of Biological Sciences
was focused on the nature of an E. coli temperature-sensitive
mutant called tif-1, which had a pleiotropic phenotype
affecting induction of the lambda prophage and formation of filamentous
shaped cells. This was done in collaboration with Dr Erela Ephrati-Elizur,
who had been a visitor to the Hammersmith MRC Unit and who happened
to be in Canberra because she was the wife of the Israeli ambassador.
This work resulted in a few publications, but with her departure
the activity gradually diminished.
On retirement from the ANU in 1979, Bill was invited to Caltech
by Max Delbrück and awarded a Fairchild Distinguished Scholar
appointment there for about eighteen months, reinforcing the contacts
that he had made there 25 years earlier. He enjoyed the Pasadena
social life and Nora and Manny Delbrück, Max's wife, shared
the shopping and cooking so as to provide home entertainment for
the international Delbrück research group. At the end of
his period at Caltech, Bill was offered appointments at many prestigious
universities, including Edinburgh and a variety of locations in
the USA, but he had no hesitation in accepting the offer of an
Emeritus Professorial appointment at the Australian National University.
He did not want to work in the Research School of Biological Sciences,
considering that he would be an inhibition to the new Professor
of Genetics, so he insisted that he be located in the School of
General Studies in the Department of Botany headed by Peter Gresshof.
He did some teaching and spent a lot of time working on his undergraduate
lectures and with research that was a continuation of his work
with Max Delbrück at Caltech. In about 1985 be decided that
he had had enough, and announced that he had given his last lecture
and discontinued his work in the laboratory. At about this time
he became aware of memory deficiencies. These changes were the
forerunner of a dementia that gradually diminished his faculties
over the years. Characteristically, he participated in a brain
donor programme and it would have appealed to his sceptical nature
to know that a clinical diagnosis of Alzheimer's Disease was not
confirmed pathologically. He spent more time with Nora, he walked,
and - what for Bill must have been a new experience - he relaxed
and did not involve himself with scientific activities. As his
health deteriorated, Nora sold their Canberra home and moved to
Sydney to a retirement village where he could get increasing medical
care. Michael Hayes, in a eulogy delivered at Bill's funeral service,
said of this time: 'During these last difficult years he was lovingly
cared for by both my mother and the staff at Bowden Brae. Within
the last couple of years we were able to celebrate the fiftieth
anniversary of an exceedingly happy marriage and more recently
Dad's eightieth birthday.'
In his personal life Bill had simple tastes. He listened to music
almost every day of his active life. He loved poetry, mainly the
Romantics, and was a competent though only occasional painter.
We have already referred to the central importance to him of his
marriage, which was to be the fixed point in his life. Together
Nora and he were magnificent hosts.
Michael Hayes, again from his eulogy, said 'From a personal viewpoint,
if I had to single out the most striking features of Dad's personality,
I would nominate both his honesty and his modesty. As a father
he adopted something of a laissez-faire attitude and was both
generous and accepting. He never attempted to impose his own ideas,
and if he disagreed he would carefully expound his reasons. By
nature he was a sceptic. As a boy I remember being taken aback
at his professed admiration for Doubting Thomas and by quoting
G.B. Shaw that faith was one of the seven deadly sins. He was
equally unsympathetic to the atheist tradition.
For him, the great appeal of science was as an expression of the
creative process. To have an original idea and to then set about
rigorously examining its validity was the great endeavour ...
He once described his favourite pastime in Who's Who as 'doing
nothing' which was based more on whimsy than reality. As for his
intellect, the achievements speak for themselves and his peers
remain the best judge.'
Possibly as a result of his period in India, Bill loved the sun
and with the international success of his book he decided to buy
a house on the Maltese island of Gozo, where he spent part of
the summers. He did not maintain close links with Ireland, and
seemed to find it easy to move from London to Edinburgh and then
Bill's life has encompassed the span of the 'short twentieth century'
to a remarkable degree. His childhood was still a world of horse-drawn
carriages, family prayers morning and evening, addressing his
father as 'Sir', and education by a governess. There was an old-fashioned,
almost courtly, element to his make-up that no doubt came from
his upbringing. To Naomi Datta his demeanour seemed paradoxical:
'He looked soldierly in being very upright and with shortcut hair.
One could imagine him in uniform, but his sandals and open-necked
shirts did not fit that image. Also, the Army is hierarchical
and Bill's unit was absolutely not - it was very friendly and
egalitarian.' To others he seemed shy, but it was a universal
view that the most striking features of his personality were his
intellectual curiosity and his modesty. He was informal in his
dealings, easy to get on with and endlessly helpful. These characteristics
served to make him probably the most popular microbial geneticist
of his generation, and he will be remembered with affection in
countless laboratories. Many of his colleagues can attest to his
acts of kindness, support and understanding, tendered in a most
unobtrusive way. In 1968, in his book's second edition, he wrote
about two colleagues who had died: 'I could not allow this edition
to go to press without paying tribute not only to their key contributions
to molecular biology, but also to their endearing qualities and
personality and their many acts of kindness for which they will
be long remembered by their friends.' This was his own combination
The authors wish to record their sincere thanks to Michael Hayes
for his help in compiling this memoir. Bill, in his characteristically
modest but effective way, provided a detailed personal memoir,
self-typed, that contained many details of his life unobtainable
in any other way. He told one of us (BH) after preparing the biographical
memoir for Max Delbrück that he would make it much easier
for whoever did it for him. We are also indebted to the many individuals
who offered reminiscences of their interactions and experiences
with Bill. Some are mentioned in the text.
Bill was elected to the Royal College of Physicians in Ireland
(1943), the Royal Society of London (1964), the Royal Society
of Edinburgh (1968) and the Australian Academy of Science (1976).
He was awarded Honorary Degrees from the University of Leicester
- Doctor of Science (1968), the University of Dublin - Doctor
of Laws (1970), the University of Kent - Doctor of Science (1973)
and the National University of Ireland - Doctor of Science (1973).
His awards included the Royal Society Leeuwenhoek Lecture (1965),
the Genetical Society Mendel Lecture (1965), the first Griffith
Memorial Lecture (1965), the Burnet Lecture and Medal of the Australian
Academy of Science (1977), and Fellowship of the Royal Postgraduate
Medical School, University of London (1985).
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Fischer, K.W. (1957). The nature of endergonic processes in conjugation in Escherichia coli K-12. J. Gen. Microbiol., 16, 136-145.
Haas, F., Wyss, O., and Stone, W.S. (1948). The effect of irradiation on recombination in Escherichia coli. Proc. Nat. Acad. Sci. Wash., 34, 229-232.
Lederberg J. and Tatum, E.L. (1946). Gene recombination in Escherichia coli. Nature, 158, 558.
Lederberg, J., Cavalli, L. L. and Lederberg, E.M. (1952). Sex compatibility in Escherichia coli. Genetics, 37, 720-731.
Lederberg, J., Lederberg, E.M. Zinder, N.D. and Lively, E.R. (1951). Recombination analysis of bacterial heredity. Cold Spring Harbor Symp. Quant. Biol., 16, 413-441.
Lwoff, A., Siminovitch, L., and Kjelgaard, N. (1950) Induction de la production de bacteriophages chez une bactérie lysogéne. Ann. Inst.Pasteur, 79, 815-859.
Watson, J. D. (1968) The Double Helix: A Personal Account of the Discovery of the Structure of DNA. Wodenfield and Nicolson, London.
Weigle, J.J. and Delbrück, M. (1951) Mutual exclusion between an infecting phage and a carried phage. J. Bacteriol., 62, 301-318.
Wollman, E.L. (1966). Bacterial Conjugation. In Phage and the Origins of Molecular Biology, ed. J. Cairns, G.S. Stent and J.D. Watson, pp. 216-225 (Cold Spring Harbor Laboratory of Quantitative Biology, Cold Spring Harbor).
Wollman, E.L. and Jacob, F. (1955). Sur le mécanisme du
transfer de matériel génétique au cours de
la recombination chez E. coli K12. Compt. Rend.
Acad. Sci., 240, 2449-2451
Bruce Holloway, Department of Genetics and Developmental Biology,
Monash University, Clayton Victoria 3168.
Paul Broda, Department of Biochemistry and Applied Molecular Biology,
UMIST, Manchester, UK
This memoir was originally published in Historical Records
of Australian Science, vol. 11, no. 2, December
1996, pp. 213-28 and also in Biographical Memoirs of Fellows
of the Royal Society of London, 1996.