The Research Enterprise
John Kerr and apoptosis
Michael G E O'Rourke and Kay A O Ellem
MJA 2000; 173: 616-617
On 14 March 2000, John Foxton Ross Kerr, Emeritus Professor of
Pathology at the University of Queensland, received the Paul Ehrlich
and Ludwig Darmstaedter Prize for his description of apoptosis, a
form of cell death. The prize, which he shared with Boston biologist
Robert Horvitz, is considered to be one of the most prestigious
European awards in science, second only to the Nobel Prize.
John Kerr's discovery, initially called "shrinkage necrosis" but
which he later renamed "apoptosis", came about in the late 1960s, when
his attention was caught by a curious form of liver cell death during
his studies of acute liver injury in rats. The findings of this seminal
study were first published in 1965.1 Subsequently, Kerr and his
co-authors (including Jeffrey Searle) described the unique
morphological changes of this type of cell death, compared with those
of necrosis, in a series of articles published during the 1970s and
1980s.2-4 These studies extended
the range of pathological and physiological states in which
apoptosis is known to occur. Further studies with other
collaborators (who later included Alastair Currie and Andrew
led to an increase in the understanding of the role
of apoptosis in embryogenesis, spermatogenesis, cancer growth, and
tissue remodelling during healing or functional regression. At
first thought to be somewhat arcane as a topic, the literature on
apoptosis initially grew slowly. However, recognition of the
significance of this "protected" form of cell death on immune
function and regulation was followed by an explosion of related
publications in immunology. Biochemists now recite a mantra of
enzymes involved in apoptosis, and chant a list of factors capable of
modulating or regulating its expression. It has become de rigueur
to adorn seminars and lectures with charts of the increasingly
complex interactions which occur between signalling pathways as
they are traversed by the informing reactions (which either trigger
or defuse the suicidal steps leading to apoptotic cell death).
The astonishing total number of publications on apoptosis is now over
35 539, including some of the world's leading scientific journals,
such as Nature6-8 and
Science.9-11 Apoptosis is now a growth
industry, the clinical implications of which can be applied to
chemotherapy, the endocrine treatment of cancer, autoimmune
disease and neurodegenerative disease. This body of evidence is a
tribute to the catalytic influence that John Kerr's insights have had
in so many disparate disciplines and areas of biological study. These
insights revealed the importance of this process as a universal
microphenomenon in the macroevents of tissue and organismal
function, and in disease.
- Kerr JF. A histochemical study of hypertrophy and ischaemic injury
of rat liver with special reference to changes in lysosomes. J Path
Bact 1965; 90: 419-435.
Kerr JF, Cooksley WG, Searle J, et al. The nature of piecemeal
necrosis in chronic active hepatitis. Lancet 1979; 20:
Searle J, Lawson TA, Abbott PJ, et al. An electron-microscope study
of the mode of cell death induced by cancer-chemotherapeutic agents
in populations of proliferating normal and neoplastic cells. J
Pathol 1975; 116: 129-138.
Weedon D, Searle J, Kerr JF. Apoptosis. Its nature and implications
for dermatopathology. Am J Dermatopathol 1979; 2: 133-144.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological
phenomenon with wide-ranging implications in tissue kinetics.
Br J Cancer 1972; 26: 239-257.
Wallach D. Apoptosis: Placing death under control. Nature
1977; 388: 123-126.
Hengartner MO. Apoptosis: death cycle and Swiss army knives.
Nature 1998; 391: 441-442.
Martinou JC. Apoptosis: key to the mitochondrial gate.
Nature 1999: 399; 411-412.
Barinaga M. Apoptosis: forging a path to cell death.
Science 1996; 273: 735-737.
Barinaga M. Apoptosis: death by dozens of cuts. Science
1998; 280: 32-34.
Brenner C, Kroener G. Apoptosis: Mitochondria -- the death cell
integrators. Science 2000; 289: 1150-1151.
Cotran R, Kumar V, Collins T, editors. Pathological basis of
disease. 6th ed. Philadelphia: W. B Saunders, 1997: 18-24.
Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in
cancer and cancer therapy. Cancer 1994; 73: 2013-2026.
Walker NI, Harmon BV, Gobe GC, et al. Patterns of cell death.
Methods Achiev Exp Pathol 1988; 13: 18-32.
Sandford N, Searle JW, Kerr JF. Sucessive waves of apoptosis in the
rat prostate after repeated withdrawal of testosterone
stimulation. Pathology 1984; 16: 406-410.
Soubrane C, Mouawad R, Antoine EC, et al. A comparative study of Fas
and Fas-ligand expression during melanoma progression. Br J
Dermatol 2000; 143: 307-312.
Andrane F, Casciola-Rosen L, Rosen A. Apoptosis in systemic lupus
erthymatosus. Clinical implications. Rheum Dis Clin North
Am 2000; 26: 215-227.
|John Kerr (right) with Roland Koch, Prime
Minister of Hesse, Germany, and Honorary Chairman of the Board of Trustees
of the Paul Ehrlich Foundation, at a dinner for award recipients.
|1: Other awards and lectures recognising John Kerr's achievements
- Keynote opening addresses at the Cold Spring Harbor, New York, Symposia,
- Opening lecture, The cell and molecular biology of apoptosis, at the
Queensland Institute of Medical Research Cell and Molecular Biology
- Opening lecture at the conference Apoptosis in AIDS, Paris, 1993.
- 12th Mildford D. Schultz Lecture, Harvard Medical School, Boston,
- Bancroft Medal (Queensland AMA), 1993.
- John Earnshaw Memorial Lecture, International Melanoma Conference,
- Fred W Stewart Award, Memorial Sloane-Kettering Cancer Center, New
York, for contribution to cancer research, 1995.
- Doctor of Science honoris causa, University of Queensland, 1998.
- Fellowship of the Australian Academy of Science, 1998.
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|2: Apoptosis: programmed cell death
- The term "apoptosis" is derived from the Greek for "falling
off" and describes a distinct form of cell death whereby cells
die in a tightly regulated and morphologically uniform fashion.12
- Morphologically, there is condensation of the nucleus and cytoplasm,
membrane blebbing, and the formation of discrete, packaged apoptotic
bodies which are phagocytosed by nearby cells, without provoking an
- In contrast to necrosis, a degenerative process in which cells swell
and lyse after irreversible tissue injury, apoptosis appears to be an
active process14 which is subject to genetic
- Apoptosis can be triggered either from within the cell, or from outside
the cell (mediated by binding of surface membrane receptors to "death
activators" such as Fas-ligand and tumour necrosis factor).
|Electron micrograph showing apoptosis
occurring spontaneously in cell culture. Note the discrete, membrane-enclosed
nuclear fragments, with characteristic segregation of uniformly compacted
chromatin, the crowding of well preserved cytoplasmic organelles and the
marked convolution of the cellular surface, which is a prelude to conversion
of the cell into a number of membrane-bound fragments or apoptotic bodies.
N = nucleus, O = organelles.
- Apoptosis may occur in several different physiological, adaptive and
pathological settings. For example, apoptosis acts as a homoeostatic
mechanism for controlling cell populations, and in hormone-dependent
tissue involution such as endometrial breakdown during menstruation,
prostatic atrophy after castration,15 and cessation
of lactation after weaning.12 Localised apoptosis
plays a role in embryonic development, such as formation of interdigital
clefts and involution of phylogenetic vestiges.5
In malignant tumours, apoptosis may occur spontaneously, or may increase
in response to cytotoxic chemotherapy or irradiation.13
Impaired regulation of apoptosis is known to be associated with the
development of various types of cancer,16 and
with the pathogenesis of some autoimmune diseases such as systemic lupus
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