It gave the greatest of pleasure to learn that two of our Editorial Board members, Paul Nurse and Tim Hunt, are to share this year’s Nobel Prize for Physiology or Medicine together with Lee Hartwell. On behalf of the Journal of Cell Science and the Company of Biologists, for which Tim is also a Director representing the interests of the journal, I would like to congratulate each of them on this well-deserved award

Glover, David M.

English

Caltech Authors - Main

3953
…still cycling
It gave the greatest of pleasure to learn
that two of our Editorial Board members,
Paul Nurse and Tim Hunt, are to share
this year’s Nobel Prize for Physiology or
Medicine together with Lee Hartwell.
On behalf of the Journal of Cell Science
and the Company of Biologists, for
which Tim is also a Director representing
the interests of the journal, I would like
to congratulate each of them on this well-
deserved award.
Such news gives just cause for
reflection about the impact of the work
of these three men that has been
recognised by this accolade.
Their research has defined the
tenet of cell cycle regulation and
is not just about their discovery of
the major cell cycle kinases and
their regulatory cyclin subunits,
but the importance of cycles of
phosphorylation and degradation
of regulatory proteins. The
discovery of these central players
in cell cycle progression stems
from Lee Hartwell’s seminal
work published in the early 70s. I
first became aware of Lee’s work
at coffee table discussions when I
was a graduate student at the
Imperial Cancer Research Fund. I
was surrounded by people
influenced by Renato Dulbecco’s
studies on the small DNA tumour
viruses SV40 and Polyoma. Lee
had worked in Dulbecco’s lab and
naturally enough conversations
turned to how Lee was trying to
solve the yeast cell cycle by
systematically assembling a
collection of temperature-
sensitive cell division cycle mutants. His
series of papers on this topic began with
the description of how he proposed to
achieve his goal (Hartwell et al., 1970)
and went on to describe mutants
affecting every stage of cell cycle
progression. In characterising the
phenotypes of these mutants he defined
not only the major cell cycle transitions
in budding yeast but also the principal
checkpoints, including START, the point
at which nutritional, hormonal and cell
size controls are imposed to regulate cell
cycle progression. Above all, Lee’s
insight was to recognise the one key
player, the CDC28 gene, that we now
know to encode the major cell cycle
kinase that is activated at START.
Paul Nurse’s work was undoubtedly
influenced by Hartwell. Paul began
characterising cell division cycle
mutants in fission yeast in the mid 70s,
his first description being of wee
mutants, so called because they enter
mitosis before they have grown big
enough (Nurse, 1975). The appreciation
of the cellular physiology of the division
cycle apparent in Paul’s papers from this
time, and indeed throughout his career,
shows the guiding influence of Murdoch
Mitchison, in whose lab he carried out
this early work. My first contacts with
Paul were in 1983, when he was kind
enough to let us have the cloned c c2
gene in order that we could look by
nucleic acid hybridisation for its
Drosophila counterpart. At that time, we
were newcomers to the cell cycle field
and Paul was particularly encouraging
of our efforts. Paul had himself
recognised at that time the importance of
cdc2 in regulating mitotic entry in
fission yeast. Together with David
Beach he had also shown cdc2 to be the
functional counterpart of the all-
important budding yeast gene cdc28
(Beach et al., 1982). Our own
experiments to isolate the fly cdc2 failed
miserably – there is simply insufficient
homology between the fly and yeast
genes at the nucleic acid level. Paul, by
contrast, was much more courageous.
He encouraged Melanie Lee to try and
rescue a cdc2 mutant with human
cDNA, and the outcome was a
spectacular success (Lee and Nurse,
1987). The central mitotic kinase was
conserved in function from yeast to
man! Later Paul’s lab was to teach us
some fission yeast tricks, and together
we successfully isolated the fly cdc2
gene and genes for two fly isoforms of
cdc25. The latter had been shown by
Paul Russell, with Nurse, to activate
Cdc2 function in fission yeast (Russell
and Nurse, 1986) and indeed, it seemed,
in all metazoans. 
Meanwhile, in what then seemed to
be another biological
universe, Tim Hunt had been
studying patterns of protein
synthesis in marine
invertebrates – at the time not
an unusually eccentric
endeavour for Tim (Rosenthal
et al., 1980; Evans et al.,
1983). What Tim and his
colleagues found was an
immediate cause for
speculation: proteins that
were synthesised throughout
the early embryonic division
cycles and underwent
periodic degradation late each
mitosis, which they conse-
quently termed cyclins. Could
the cyclins be instrumental in
mediating the mitotic
oscillations seen in anucleate
egg cytoplasm (Hara et al.,
1980)? Could they even be a
component of maturation
promoting factor (MPF), an
activity described much
earlier (Masui and Makert,
1971) that was present in M-phase frog
eggs and that could mediate M-phase
entry assayed by meiotic maturation? It
wasn’t until 1988 that MPF was
eventually purified by Jim Maller’s lab
(Lohka et al., 1988) and shown to
comprise two major polypeptides: one
was indeed the frog homologue of Cdc2,
and the other was later identified as
cyclin B. Tim’s lab was then soon able
to use antisense oligos to show that
cyclin B is necessary for mitotic entry in
an in vitro system (Minshull et al.,
1989). Complementary experiments by
Murray and Kirschner indicated that that
translation of cyclin B mRNA is alone
sufficient to drive similar extracts into
mitosis (Murray and Kirschner, 1989).
EDITORIAL
Tim Hunt (left) and Paul Nurse (right), photographed at Imperial 
Cancer Research Fund Central Laboratories, London. Photograph 
courtesy of the ICRF
3954
The excitement of these times was
electric. The realisation that the same
molecular engine is required to drive
cells into mitosis in yeasts, frogs, flies
and man was intoxicating. I remember
particularly the euphoria of a Roscoff
cell cycle meeting at about this time
when the participants would give each
other rather silly Churchillian-style
‘Cdc2-finger’ salutes.
The Nobel Prize is a fitting
recognition of how the understanding of
a phenomenon of major medical
significance has been made by three
scientists each working with small
research groups and using ‘low-tech’
approaches on model systems to
examine a fundamental problem in cell
biology. This is a success that stems
from modest beginnings. In the UK,
Paul’s career was forged during a time
when he did not have a secure position
but was moving from one ‘soft’ post to
another at Edinburgh and Sussex
Universities before taking a position at
ICRF. Tim’s insights also came through
simple and elegant experiments, much
of the work being carried out in
dilapidated laboratories on the Downing
Street site in Cambridge, UK (although
he was frequently ‘let out’ to visit
Wood’s Hole), before he too escaped to
ICRF. He has been as equally
encouraging to his wider field of
colleagues as Paul and would be
constantly popping in and out of one or
another lab to find out how we were all
getting along. In Britain and further
afield, Tim and Paul have had an
influence that goes beyond their own
science. They have been ambassadors
for cell biology, and their enthusiasm
has encouraged the first steps of many a
young scientist. Indeed, features
common to each of the three laureates
are not only their ability to recognise
within biological complexity the key
steps of fundamental importance but
also their scientific generosity and the
help they have given to others. Lee, Tim
and Paul: congratulations! 
David M. Glover
Journal of Cell Science 114, 3953-3954 (2001)
© The Company of Biologists Ltd
REFERENCES
Beach, D., Durkacz, B. and Nurse, P. (1982).
Functionally homologous cell cycle control
genes in budding and fission yeast. Nature 300,
706-709.
Evans, T., Rosenthal, E. T., Youngblom, J.,
Distel, D. and Hunt, T. (1983). Cyclin: a
protein specified by maternal mRNA in sea
urchin eggs that is destroyed at each cleavage
division. Cell 33, 389-396.
Hara, K., Tydeman, P. and Kirschner, M.
(1980). A cytoplasmic clock with the same
period as the division cycle in Xenopus eggs.
Proc. Natl. Acad. Sci. USA 77, 462-467.
Hartwell, L. H., Culotti, J. and Reid, B. (1970).
Genetic Control of the cell diviision cycle in
yeast I. Proc. Natl. Acad. Sci. USA. 66, 352-359.
Lee, M. and Nurse, P.(1987). Complementation
used to clone a human homologue of the fission
yeast cell cycle control gene. Nature327, 31-35.
Lohka, M. J., Hayes, M. K. and Maller, J. L.
(1988). Purification of maturation promoting
factor, an intracellular regulator of early mitotic
events. Proc. Natl. Acad. Sci. USA 85, 3009-
3014.
Masui, Y. and Makert, C. L. (1971).
Cytoplasmic control of nuclear behaviour
during meiotic maturation of frog oocytes. J.
Exp. Zool. 177, 129-136.
Minshull, J., Blow, J. J. and Hunt, T. (1989).
Translation of endogenous B-type cyclin
mRNA is necessary for extracts of activated
Xenopus eggs to enter mitosis. Cell 56, 947-954.
Murray, A. W. and Kirschner, M. (1989). Cyclin
synthesis drives the early embryonic cell cycle.
Nature339, 275-281.
Nurse, P. (1975). Genetic control of cell size at
cell division in yeast. Nature256, 547-551.
Rosenthal, E. T., Hunt, T. and Ruderman, J. V.
(1980). Selective translation of mRNA controls
the pattern of protein synthesis during early
development of the surf clam, Spisula
solidissima. Cell20, 487-494.
Russell, O. and Nurse, P. (1986). cdc25+
functions as an inducer in the mitotic control of
fission yeast. Cell 45, 145-152.
JOURNAL OF CELL SCIENCE 114 (22)


... still cycling

https://authors.library.caltech.edu/105876/1/3953.full.pdf

... still cycling

Abstract

Similar works

Full text

Available Versions

Caltech Authors - Main