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William Hayes: Pioneering
Contributions Remembered

After Hayes proposed oriented partial chromosome transfer during
bacterial conjugation, microbial genetics took a great leap forward

SIMON SILVER, JAMES SHAPIRO, NEIL MENDELSON, PauL BRoDA, AND JON BECKWITH

William Hayes, who died in January 1994 in Aus-
tralia, made a series of striking discoveries in microbial
genetics 40 years ago. While serving as a senior lec-
turer at the Royal Postgraduate Medical School at
Hammersmith Hospital in London during the early
1950s, his insights describing the nature of bacterial
conjugation and gene transfer set the stage for major
advances in bacterial genetics and, more broadly, mo-
lecular biology in the decades that followed. In a
remarkably productive 2 years, Hayes outlined how
bacterial conjugation involves ordered transfer of chro-
mosome segments from a donor (“male”) cell to a
recipient (“female”) cell rather than by cell fusion,
identified the nonchromosomal F factor in Escherichia
coli that determines maleness in such bacterial cells,
and isolated a male donor strain with 10 thousand
times the ordinary gene transfer frequency. In addition
to his research on conjugation and sex plasmids, Hayes
established the first microbial genetics research unit
and wrote the defining textbook on microbial molecular
genetics.

Hayes was educated and had his first exposure to

 

Simon Silver (corresponding author) is at the De-
partment of Microbiology and Immunology, University
of Illinois, Chicago; James Shapiro is at the Depart-
ment of Biochemistry and Molecular Biology, Univer-
sity of Chicago, Chicago, Ill.; Neil Mendelson is at the
Department of Molecular and Cell Biology, University
of Arizona, Tucson; Paul Broda is at the Department of
Biochemistry, University of Manchester Institute of
Science and Technology, Manchester, United Kingdom;
and Jon Beckwith is at the Department of Microbiology
and Molecular Genetics, Harvard Medical School, Bos-
ton, Mass. All were associated with William Hayes in

the 1960s.
ASM Meets ( At

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medical research in Ireland before World War II. Dur-
ing the war, he served as a medical officer with the
British in India, where he also began conducting bac-
terial research.

After the war, Hayes returned to Dublin with an
appointment in bacteriology at Trinity College, but he
soon moved to London to become a senior lecturer at
the Royal Postgraduate Medical School. There, moti-
vated by a desire to apply genetic analysis to the phase
variation problem, he began work in earnest on bacte-
rial genetics. During the year of his move to London,
Hayes met Luigi L. Cavalli-Sforza at a summer course
in bacterial chemistry in Cambridge. The meeting
proved crucial, as it was Cavalli who provided Hayes
with the E. coli K-12 strains with which he conducted
his pivotal studies in bacterial genetics.

In striking contrast to the high technology of cur-
rent molecular genetics, Hayes’ best work was done
with very limited technical facilities. For example,
incubators in India were cooled by fans, and calibrated
wire loops rather than glass pipettes were used in
analyzing conjugation kinetics in London. Despite (or
perhaps because of) limited facilities, elegant thinking
more than made up for lack of equipment, and Hayes’
experiments were to prove of fundamental importance.

Hayes’ 1952 Model for Conjugation Was an
Intellectual Bombshell

Although bacterial conjugation was recognized as
early as 1946, the investigators studying it had diffi-
culty understanding the mechanism. When Hayes pre-
sented a clear, straightforward, and ultimately correct
model for bacterial conjugation at a small meeting in
Pallanza, Italy, in September 1952, it seemed that “a

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hw-ohshell had .exploded.” as James Watson later
wrote. In his deceptively modest way, Hayes abruptly
overturned layers of speculative explanations that
members of the microbial genetics community had put
forward in an effort to make sense of a set of then-
confaong ohservations,

Until that meeting in Italy, most microbial geneti-
erets took little note of Hayes’ results, although he had
propesed his model of unidirectional gene transfer that
Ane] at 4 meeting in Axford and published his exper-
‘mantal results and model a few months. earlier in
January 1942. Instead. the attention of that research
community had focused on the explanations for conju-
gation championed by Toshua J ederberg, who was then
at the University of Wisconsin. Lederberg, who had
discovered bacterial conjugation some 6 years earlier,
evplamed the phenomenon in terms of the fusion of two
hacterial cells,

According to Lederberg’s model, this process of cell
fusion was followed by a complex series of steps involv-
ing the segregation and selective loss of genetic mark-
ers from the two complete sets of chromosomes that
were initially present in the fusion cell.

Hayes’ results and his model were no secret when
they were presented in Italy. Nonetheless, they proved
a bombshell to the consciousness of the scientific com-
munity. Lederberg did not immediately accept the
simplifying model. Instead, he continued to explore his
radically different model of cell fusion. Nevertheless,
the data were wonderfully reproducible in, and ex-
changed freely between, both laboratories.

The Hayes Model Produced Immediate Ripples

Haves’ Pallanza bombshell provided a simple and
elegant--.if highly unorthodox in the history of genet-
ics~-hasis for explaining the available results, He soon
attracted several important collaborators.

For example, Elie L. Wollman of the Institut Pas-
teur in Paris, France, who had heard of Hayes’ find-
ings, visited him in London, where they agreed to do
joint experiments on the kinetics of conjugation. Woll-
man and Frangois Jacob, who was also at the Institut
Pasteur. conducted detailed studies of chromosomal
linkage based on the kinetics of gene transfer from
donor to recinient cells during conjugation. Within a
few years, these findings led to the correct understand-
ing of the linear order of E. coli genes on a single
ctrenlar chromosome.

Watson hegan visiting Hayes in London after the
Pallanza meeting, and they soon published an analysis
of genetic linkage relationships in E. coli. Hayes was
invited to the 1953 symposium held in Cold Spring
Harbor, New York, where Watson announced the dou-
ble-helical structure of DNA.

At thet symposium, Hayes described the discovery
of the second high-frequency (Hfr) donor E. coli strain
and its use in unraveling the mysteries of the conjuga-
tion process. The two first independently discovered

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Hfr strains are still called Hfr Cavalli and Hfr Haves.
Hayes’ presentation helped set the stage for use of E.
coll as the standard organism for investigating micro-
bial genetics and molecular biology.

During the 1953 visit to the United States, Haves
continued to study the kinetics of bacterial conjugation
during a 6-month sabbatical leave with Max Delbriick
at the California Institute of Technology (CalTech) in
Pasadena, Calif. The friendship with Delbriick contin-
ued, leading to a postretirement sabbatical year that
Hayes spent at CalTech some 25 years later.

Hayes’ Early Achievements in Perspective

During 1950-1953 Hayes made three extraordi-
nary discoveries and realizations: (i) he demonstrated
that bacterial conjugation involves the unidirectional
transfer of genes from a donor toa recipient cell rather
than something equivalent to cell fusion (as between
egg and sperm) or reciprocal exchange of nuclei (as in
Paramecium spp.); (ii) he discovered the fertility factor
F, the first recognized nonchromosomal bacterial plas-
mid, and showed that it is present in donor cells but
absent in recipient cells: and (iii) he helped to outline
the process of high-frequency, ordered gene transfer
from the Hfr donor, studies of which led eventually to
the single genetic map and a rational explanation of
earlier recombinational mapping data.

These efforts radically changed then-current think-
ing on bacterial conjugation from baroque to simple.
Hayes’ contributions seemed at first counter-intuitive
but proved correct as well as elegant. In appreciating
the general agonizing that often accompanies such
turnabouts, Hayes referred to a favorite passage from
the Hilaire Belloc poem, “The Microbe.” It ends with
the following ironic lines: “But scientists, who ought to
know, assure us that they must be so... Oh! let us
never, never doubt what nobody is sure about!”

According to Hayes, “There (was) little doubt as to
the validity of the results themselves. Their interpre-
tation, however, [was] controversial.” His first bacte-
rial genetics paper in 1952 established the mequality of
the two partner cells in conjugation. He found that only
one of the partners needs to be alive; the other could be
killed (even hours earlier) by streptomycin and still
participate! From those results, he concluded intu-
itively that one cell acted as donor (and need not be
viable) and the other as recipient in a process of
one-way transfer of genetic material. Years passed
before there was a compelling proof of this hypothesis
by micromanipulation experiments, which analyzed
the properties of single exconjugant cells.

Hayes and, independently, Lederberg and col-
leagues found that bacterial “fertility’—that is, the
ability of a bacterial strain to participate in conjuga-
tion—is itself a hereditary property and is associated
with a transferrable nonchromosomal factor called F.
Hayes initially thought this gene transfer property
could be attributed to a “gamete” similar to a phage

ASM News
 

 

particle, rather than to the naked DNA plasmid and
actual cell-to-cell direct transfer that we now under-
stand.

Hayes later remembered that he devised but dis-
carded a number of other hypotheses to explain aspects
of conjugation, including one calling for three separate
or branched chromosomes to explain complex recom-
binational data. These ideas frequently proved wrong,
and near the end of his career he
said he was glad that he published
very few papers during this early
period.

Subsequent Career

In 1957, the British Medical
Research Council recognized Hayes’
achievements by establishing a
Microbial Genetics Research Unit
at Hammersmith Hospital, where
he gathered a group of younger
investigators (including at differ-
ent times all of us) and encouraged
a broad range of experimental work.

Over the years, the British
members of the staff included Roy
Clowes, Willie Donachie, Ken
Fisher, Stuart Glover, Elinor Mey-
nell, Bob Pritchard, Ken Stacey,
and Neville Symonds. Paul Broda, Ken Fisher, Julian
Gross, Marilyn Monk, Don Ritchie, and John Scaife
made up the cadre of early Ph.D. students. An extraor-
dinary number went on to head their own research
efforts elsewhere. Naomi Datta did her pioneering
work on antibiotic resistance plasmids in a nearby
building at Hammersmith. As unit head, Hayes was
exceptional in facilitating the work of others without
intruding or narrowly directing it.

Hayes’ gift for working with junior scientists was
recognized as unusual, and some colleagues have con-
sidered these mentoring efforts equal in value to his
experimental achievements. Moreover, Hayes was un-
usually egalitarian, particularly during this postwar
period in socially stratified England. Thus, Norrie
Bonfil, who ran the microbiology kitchen, and Deidre
Nadal, who handled the office with skill and under-
standing, were equal members of his Hammersmith
“family.”

Besides encouraging young investigators and di-
recting a new unit, Hayes committed at least 2 solid
years to writing his outstanding book, The Genetics of
Bacteria and their Viruses, which was known affection-
ately as “The Bible” for a time. Many microbiologists
consider this book his third major achievement. And
certainly no single author has felt up to the task of
writing such a comprehensive volume since.

In 1968, the Medical Research Council (MRC) Unit
at Hammersmith moved from Lundon to Edinburgh
(along with another London MRC group). There, Hayes

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and Martin Pollock fturmed the first department of
molecular biology in a British university. With a cure
group from their London laboratories and a number of
equally gifted new statt members, the Edinburgh lab
oratory proved a second great leadership success to
wards the end of the mainly adrniiistrative phase of
Haves’ career.

With the Edinburgh effort runmug effectively.
Hayes moved 6 years later to oe-
cupy the chair of genetics at the
Australian National University in
Canbei.a. Although he hoped tu be
relieved of administrate duties
by this maye and tu get “back to
the bench,” the conditions in Can-
berra did not permit hun tu seabiee
that wish. Hayes retired 1 1908,
and after a stay at Call ech (agalii
with Max Delbriick), he ended his
career as a visiting fellow at the
Australian National Univeisity.
working with his protege Peter
Gresshoff, who subsequently
moved to the University of Tennes-
see,

In retirement, Hayes cemained
in Australia, ineving in 1956 to
north of Sydney. During these fi-
nal years, Bill gicw increasingly
frustrated by progressive Alzhei-
mer’s disease. He died peacefully
on 7 January 1994, of coronary failure.

Bill Hayes’ version of the discovery of F and the
nature of bacterial conjugation is presented in the 1966
Festschrift to Max Delbriick. From what we know of
his modest and direct way of expressing himself, this
account can be taken as fair and accurate. A detailed

for a memoir for the Royal Society of Bsitain. Lu

Suggested Reading

Brock, T. D. 1990. Section 5.4. ‘The pre-Hayes eva of bacterial
genetics, p. 87-88, and Section 5.5, The wok of William Hayes, p.
68-90. In Emergence of bacterial genetics. Cold Spring Harber
Press, Cold Spring Harbor, N.Y.

Coakley, D. 1992. William Haves b 1918, p. 345-357. In Trish masters
of medicine. Town House, Dublin.

Hayes, W. 1952. Recombination in Bact. colt K 12: unidirectional
transfer of genetic material. Nature (London) 169:118-119.

Hayes, W. 1952. Genetic recombination in Bact. coli K12: analysis of
the stimulating effect of ultra-violet light. Nature (London) 169:
1017-1018.

Hayes, W. 1953. Observations on a transmissible agent deteriaining
sexual differentiation in Bacteritun coli. J. Gen. Microbiol. §:72~88.

Hayes, W. 1953. The mechanism of genetic recombinatien in Esche-
richia coli, Cold Spring Harbor Symp. Quant. Biol. 18:75-93.

Hayes, W. 1964. The genetics of bacteria and their virures. Blackwell
Scientific Publishers, Oxfe:d. (Also a 2nd cd.. 190d)

Hayes. W. 1960, Seaual diifei cutialion in bacte.ia, p. 201-215. in J.
Cairns. G.3S. Stent, and J. i). Watson (cd i. Phage and the crigins
of molecular bivlegy Cold Spiny He. bor Lal satery of Quanta

 

ig

 

 

 

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tive Biology, Cold Spring Harbor, N.Y.

Judson, H. F. 1979. The eighth day of creation. Simon and Schuster,
New York.

Lederberg, J., L. L. Cavalli, and E. M. Lederberg. 1952. Sex compat-
ibility in Escherichia coli. Genetics 37:720-730.

Stent, G. S. 1971. Chapter 10. Conjugation, p. 251-297. In Molecular

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genetics. An introductory narrative. W. H. Freeman and Company,
San Francisco.
Watson, J. D. 1968. The double helix. Atheneum, New York.
Wollman, E.-L., F. Jacob, and W. Hayes. 1956. Conjugation and
genetic recombination in Escherichia coli K-12. Cold Spring Harbor
Symp. Quant. Biol. 21:141-162.

 

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