Fungal Genetics and Biology 48 (2011) 1001–1003
Contents lists available at SciVerse ScienceDirect
Fungal Genetics and Biology
journal homepage: www.elsevier.com/locate/yfgbi
Editorial
The contribution of John Pateman to Fungal Genetics: A personal reminiscence
Professor John Arthur Pateman FRS on 18th May 2011, aged
85 years. Dearly loved husband, father, grandfather and brother.
Private family funeral.
From this brief announcement in the Daily Telegraph, a few of
us learnt of the death of John Pateman. I though it appropriate to
write a short, personal note, to remind colleagues of his contribution to our field.
I first met John (I think we never addressed him in the lab by his
first name, but as Dr. Pateman, and among us students as ‘‘Jolly
John’’), in early October 1963. I had just arrived to Cambridge from
Uruguay and I felt slightly dazzled by it all. I cycled to the Dept. of
Genetics, then housed in a red-roofed construction off Milton Road,
next to the Molteno Institute. John explained to me what was going
on in the lab. One project concerned the am mutants of Neurospora,
the second the newly discovered induction of nitrate reductase in
Aspergillus nidulans. This second topic was to become dominant
and to determine the scientific life of John and of many of us.
In 1957 Seymour Benzer published his masterful piece ‘‘The elementary units of heredity’’ which formalised and refined the definition of the gene as a complementation group, called since
‘‘cistron’’, a concept based on pioneering work by Ed Lewis in Drosphila melanogaster and by Guido Pontecorvo, Alan Roper and Bob
Pritchard in A. nidulans (Benzer, 1957).
In the same year, John Fincham and John Pateman published an
article in Nature, ‘‘Formation of an Enzyme through complementation of mutant ‘alleles’ in separate nuclei in a heterocaryon’’. The
article concerned two different ‘alleles’ at the am locus of Neurospora crassa, which partially complemented in heterocaryons. It is
worth citing the final sentence of that article, which followed the
discussion and tentative rejection of other alternatives: ‘‘one can
imagine that the wild type am locus acts as a unit in producing a
single component of the enzyme-forming system, and that component can be partially reconstituted in the cytoplasm of the heterocaryons from two different nuclear products’’ (Fincham and
Pateman, 1957; Pateman, 1960). The ‘‘partial reconstitution’’ of
the enzyme activity is what we now call intracistronic or interallelic complementation.
The very same year, Norman Giles and co-workers described a
similar phenomenon at the ad-4 locus, encoding adenylosuccinase.
The final sentence of their article states ‘‘the present results appear
to make more difficult the general application of the cis–trans position effect test to delimit a locus as a functional unit’’ (Giles et al.,
1957). It is a sobering thought, that the same year that the gene
was defined rigorously as a linear array of sites that when mutated
do not complement with each other, this apparently flawless definition was questioned by work with N. crassa from two different
1087-1845/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.fgb.2011.07.010
laboratories. Of course, we now know, through the subsequent
work of John Fincham and others what is going on.
Young scientists familiar with the term ‘‘dominant negative’’
can perhaps ponder that the latter is a particular case of the phenomenon first described in 1957, which reflects the fact that the
genetic message is contained in one dimension, but proteins thrive
in three.
In the autumn of 1963, the lab of John Pateman in Cambridge
comprised three advanced graduate students, Maureen Reever,
David Roberts and Bobby Bürk, and one post-doctoral fellow, David
Cove, who had recently obtained his Ph.D. Bobby was still working
on the am system, while David Cove and Maureen were exploring a
fascinating phenomenon described by David the previous year (see
below). David Roberts was applying his skills in immunology to
both problems. He went on to become a distinguished Drosophila
geneticist.
It is fair to say that it was David Cove he who converted John
and eventually the whole laboratory to study regulation in
A. nidulans.
David had isolated serendipitously a large number of mutants
lacking the enzyme nitrate reductase. To David’s and John’s surprise they represented mutations in at least six independently segregating loci (Cove and Pateman, 1963). It was further found that
mutations at several of the loci also resulted in loss of xanthine
dehydrogenase activity. These results led to the hypothesis that
some of the loci (cnx) could specify steps in the synthesis of a
co-factor common to both enzymes (Pateman et al., 1964). I do
not know who first shouted ‘‘Molybdenum!’’ in the laboratory,
but this early work led to the discovery of a new cofactor, molybodpterin, conserved with some variations from prokaryotes to
mammals, and whose structure was elucidated in Rajagopalan’s
laboratory in the 1980s (Johnson et al., 1980).
Among the loci identified in these early screens, some were
non-inducible for both nitrate and nitrite reductases, they define
a gene, nirA, one of the very first positive control genes to be identified in either prokaryotes or eukaryotes (Pateman et al., 1967;
Pateman and Cove, 1967).
One gene was correctly identified as the structural gene for nitrate reductase, and it was logical to assume, that if we were to select mutations defective in xanthine dehydrogenase, we should
recover again co-factor mutations together with specific mutations
affecting the latter enzyme. This mutation screen was entrusted to
two newly arrived graduate students, Andy Darlington and myself.
Indeed we found the co-factor mutations again, together with
mutations in almost all the structural genes encoding the enzymes
involved in the purine utilisation pathway (Darlington et al., 1965).
1002
Editorial / Fungal Genetics and Biology 48 (2011) 1001–1003
In addition we isolated mutations in a second positive control
gene, uaY, and in hxB which, as established much later, encodes
an enzyme catalysing a modification in the molybdenum co-factor
specific for the xanthine dehydrogenase family of enzymes (see
Gournas et al., 2011 for the present status of purine utilisation in
A. nidulans).
In autumn 1964, Herb Arst joined the laboratory as the first
Ph.D. student of David Cove. He exploited the recent finding that
mutations in one of the cnx loci (cnxE) could be phenotypically suppressed by high concentrations of molybdenum, which was the
first solid experimental evidence that the hunch about the ‘‘molybdenum cofactor’’ was correct (Arst et al., 1970), work which eventually led to the study of pH regulation, one of the major success
stories of A. nidulans genetics.
This is not the place for a historical review on the regulation of
the nitrate utilisation pathway of A. nidulans, a system, which
surely deserves paradigmatic status. But it can be said that at the
time a search for constitutive mutants was a must. This search
was carried out by John Pateman himself, who in a real tour de force
obtained, by a clever selection technique, the nirAc1 mutation,
resulting in pleiotropically constitutive expression of both niaD
(nitrate reductase) and niiA (nitrite reductase) genes, and one of
the first constitutive mutations to be isolated in a eukaryote
(Pateman and Cove, 1967). It is satisfying, that the nature of this
mutation, as a one amino acid change in a nuclear export sequence,
which prevents the export of NirA from the nucleus, was elucidated 40 years later in the laboratory of Joseph Strauss, a former
research student of mine and thus a scientific grand-child of John
Pateman (Bernraeiter et al., 2007).
The Ph.D. years in John’s lab were exciting, as pioneering work
was carried out in two directions, the regulation of two pathways
(nitrate and purine utilisation) related by a common requirement
for the molybdenum cofactor, and genetic studies bearing on the
cofactor itself. It was a blessed time, when work was thought
intensive rather than labour intensive, when conviviality was more
important than competition, and when, last but not least the
expressions ‘‘impact factor’’ and ‘‘PI’’ (Principal Investigator) did
not exist. The latter is particularly relevant, as pressure from grant
writing and reporting was minimal and team leaders devoted a
substantial proportion of their time to lab work. Besides the isolation of the nirA constitutive mutants, John developed himself two
different assays for xanthine dehydrogenase and ran the first polyacrylamide gels in the lab. When I left the lab, at the end of 1966,
John was also leaving to take up a Chair of Biology at Flinders University, at Adelaide. The attached photograph was taken by John,
just before we both left Cambridge (Fig. 1).
John Pateman had a special relationship with Australia. He went
from Sheffield, where in the lab of John Thoday he carried out his
work on intracistronic complementation, to Melbourne as lecturer
in Botany (1958–1960). In 1960 he moved to Cambridge as a lecturer in Genetics, and in 1966, as stated above, to Flinders. In
1970 he was appointed to the Chair of Genetics at Glasgow, appropriately, as a successor of Guido Pontecorvo (Fig. 2). Eventually he
moved back to Australia, to the Australian National University in
Melbourne (1979–1988) as successor of Bill Hayes, and eventually
as Executive Director of the Centre for Recombinant DNA Research.
After retirement, he returned to the UK, living in Oxford.
Through the years, John supervised a number of graduate students, at Cambridge, at Glasgow and in Australia. While I will not
give an exhaustive list, it is worth mentioning that a number of
these graduate students continued working on different aspects
of metabolism and regulation in A. nidulans, resulting eventually
in what could be called the ‘‘Cambridge School of Aspergillus’’;
the first research group to exploit the superb genetic system developed by Guido Pontecorvo and co-workers to dissect metabolism
and its regulation. Besides those already mentioned above, Michael
Fig. 1. The laboratory of John Pateman ca. autumn 1966. Photograph taken by John
Pateman, conserved by the author. From left to right, Ted Cox, Senior Technician,
Angela Bowen, Adrian Simpson, Richard Newman, Technicians, Olive Overhill,
media preparation, Claudio Scazzocchio (face covered with a drawing-pin rust
stain), Herb Arst, David Cove, Sharon Griggs, technician. Note, sign of the times, that
the technicians all wear white lab-coats, while the ‘‘scientists’’ don’t!
Fig. 2. John Pateman (left) talking to Guido Pontecorvo (right, in a red gown) on the
occasion of an honorary doctorate conferred to Pontecorvo (Glasgow 1978),
photograph courtesy of Bernie Cohen.
Hynes, the first graduate student of John at Flinders, created a vigorous research tradition, which accounts for much of the research
in fungal metabolism in Australia. From the Glasgow days two students continued working on different aspects of A. nidulans genetics, Nigel Dunn-Coleman, who branched into more applied aspects
including other filamentous fungi and Jim Kinghorn, who could be
said to have completed a cycle, through the molecular identification of the co-factor genes and through his collaboration with Sheila Unkles in unravelling nitrate uptake.
Thus, John’s contribution could be seen as twofold, conceptual
in his work on intracistronic complementation in N. crassa and in
the regulation of metabolism in A. nidulans, and educational, in fostering a scientific school through the subsequent work of his graduate students in three continents. As a former student, I would like
him to be remembered for his fairness, his ability to consider and
eventually accept dissent within his group and for the considerable
freedom he allowed graduate students, which permitted us,
throughout our Ph.Ds., to pursue our own ideas and initiatives.
I am personally very sorry, that after he returned from Australia
in 1988 he withdrew completely from research and we did not
have the opportunity to benefit from his input and criticism.
I thank Herb Arst, David Cove, Michael Hynes, Jim Kinghorn and
Adrian Simpson for their input to this short reminiscence.
Editorial / Fungal Genetics and Biology 48 (2011) 1001–1003
References
Arst Jr., H.N., MacDonald, D.W., Cove, D.J., 1970. Molybdate metabolism in
Aspergillus nidulans. I. Mutations affecting nitrate reductase and-or xanthine
dehydrogenase. Mol. Gen. Genet. 108, 129–145.
Benzer, S., 1957. The elementary units of heredity. In: McElroy, W.D., Glass, B. (Eds.),
A Symposium on the Chemical Basis of Heredity. John Hopkins University Press.
Bernraeiter, A., Ramón, A., Fernández-Martínez, J., Berger, H., Araújo Bazán, L.,
Espeso, E.A., Pachlinger, R., Gallmetzer, A., Anderl, I., Scazzocchio, C., Stauss, J.,
2007. Nuclear export of the transcription factor NirA is a regulatory checkpoint
for nitrate reduction in Aspergillus nidulans. Mol. Cell. Biol. 27, 791–802.
Cove, D.J., Pateman, J.A., 1963. Independently segregating genetic loci concerned
with nitrate activity in Aspergillus nidulans. Nature 198, 262–263.
Darlington, A.J., Scazzocchio, C., Pateman, J.A., 1965. Biochemical and genetical
studies of purine breakdown in Aspergillus. Nature 206, 599–600.
Fincham, J.R.S., Pateman, J.A., 1957. Formation of an enzyme through
complementary action of mutant ‘alleles’ in separate nuclei in a heterocaryon.
Nature 179, 741–742.
Giles, N.H., Partridge, C.W., Nelson, N.J., 1957. The genetic control of
adenylosuccinase in Neurospora crassa. Proc. Natl. Acad. Sci. USA 43, 305–317.
Gournas, C., Oestreicher, N., Amillis, S., Diallinas, G., Scazzocchio, C., 2011.
Completing the purine utilisation pathway of Aspergillus nidulans. Fungal
Genet. Biol. 48, 840–848.
Johnson, J.L., Hainline, B.E., Rajagopalan, K.V., 1980. Characterization of the
molybdenum cofactor of sulfite oxidase, xanthine oxidase and nitrate
reductase. Identification of a pteridine as a structural component. J. Biol.
Chem. 255, 1783–1786.
1003
Pateman, J.A., 1960. Inter-relationships of alleles at the am locus in Neurospora
crassa. J. Gen. Microbiol. 23, 393–399.
Pateman, J.A., Cove, D.J., 1967. Regulation of nitrate reduction in Aspergillus nidulans.
Nature 215, 1234–1237.
Pateman, J.A., Cove, D.J., Rever, B.M., Roberts, D.B., 1964. A common co-factor for
nitrate reductase and xanthine dehydrogenase which also regulates the
synthesis of nitrate reductase. Nature 201, 58–60.
Pateman, J.A., Rever, B.M., Cove, D.J., 1967. Genetic and biochemical studies of
nitrate reduction in Aspergillus nidulans. Biochem. J. 104, 103–111.
Claudio Scazzocchio
Department of Microbiology,
Imperial College London,
South Kensington Campus, Flowers Building,
Armstrong Road, London SW7 2AZ, UK
E-mail address: [email protected]
Institut de Génétique et Microbiologie,
Université Paris-Sud (XI),
91450 Orsay, France
Fax: +44 20 7594 3095.
Available online 4 August 2011