History of Apoptosis
Research
Lijing Jiang, Center for Biology and Society, Arizona State University, Tempe, Arizona, USA
Apoptosis-like cell death was first observed in developing
tissues using histological methods in the mid-nineteenth
century. Having been frequently rejected as experimental
artefacts, such biologically active, well-regulated cell
death phenomena were reconfirmed in various research
contexts during the first half of the twentieth century. In
1972, three pathologists observed cell death in patho-
logical tissues and coined the term ‘apoptosis’ to dis-
tinguish the concept of physiological cell death from the
concept of passive cell death, necrosis. In the 1980s and
1990s, modern molecular biotechnology transformed
apoptosis research from a subject for mostly morpho-
logical investigation to a multivalent, interdisciplinary
field important to developmental biology, biogerontol-
ogy and cancer research.
Introduction
Since the mid-1980s, research on apoptosis, regulated
physiological cell death, has progressed from an obscure
subject to an important field promising answers to crucial
biological and biomedical questions. During development,
groups of cells undergo apoptosis to form structures such
as lumens and digits. Apoptosis also serves to eliminate
cells with defective deoxyribonucleic acid (DNA) to pre-
vent potential tumours. Although balanced apoptosis is
crucial to morphogenesis and tissue homoeostasis, too
much apoptosis may impede biological functions and is
implicated in certain degenerative diseases such as Alz-
heimer disease. Because of the importance of the subject, in
recent years, research projects to understand and
manipulate apoptosis have attracted considerable funding,
eLS subject area: Science & Society
How to cite:
Jiang, Lijing (June 2012) History of Apoptosis Research. In: eLS.
John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0023954
eLS & 2012, John Wiley & Sons, Ltd. www.els.net
Introductory article
. Introduction
Article Contents
. Phase I: Early Histological Descriptions of Cell Death
. Phase II: Morphological and Functional Study of
Apoptosis
. Phase III: Molecular Study of Apoptosis
. Current Understanding about Apoptosis
Online posting date: 15th June 2012
brilliant minds, competitions and prizes. With the expan-
sion of apoptosis research, the evolving concept of apop-
tosis and its changing research method in history have
become important knowledge for understanding the cur-
rent field. See also: Apoptosis and the Cell Cycle in Human
Disease; Apoptosis in Developmental Processes; Apop-
tosis: Regulatory Genes and Disease
First proposed in 1972 as a process of cell deletion that
counterbalances cell proliferation, apoptosis has none-
theless been studied under various other names since the
mid-nineteenth century. After the early 1990s, the term
apoptosis has been misused, questioned and even
redefined. To circumvent unnecessary conceptual conun-
drums, this article follows the original 1972 definition of
apoptosis from Kerr et al. (1972) and the clarifications
given by the Nomenclature Committee on Cell Death in
2009. Apoptosis, according to the Nomenclature Com-
mittee, is a process of cell death that demonstrates all or
several of characteristic morphological changes that
include ‘rounding-up of the cell,’ ‘reduction of cellular
volume,’ ‘chromatin condensation, nuclear fragmen-
tation,’ ‘plasma membrane blebbing,’ ‘engulfment by
resident phagocytes,’ etc. (Kroemer et al., 2009). Cell death
in normal development is often referred to as programmed
cell death, with the understanding that death is part of
the development programmed genetically. When pro-
grammed cell death shows apoptotic morphology, the
two concepts can be used interchangeably. See also:
Apoptosis: Molecular Mechanisms; Apoptosis: Morpho-
logical Criteria and Other Assays; Cornification of the
Skin: A Non-apoptotic Cell Death Mechanism
This article traces the changing focuses and methods of
apoptosis research and describes three temporal phases for
the field, beginning in the mid-nineteenth century. The first
phase lasted from the mid-nineteenth century to the 1930s.
The period brought about a number of histological
observations of cell death whose morphological changes
were similar to what later became known as apoptosis. The
second phase spans from the 1940s to the mid-1970s. With
the advent of higher resolution microscopes and utilisation
of specialised dyes, researchers extensively recorded and
studied the morphology of apoptotic cells, leading to the
introduction of the term ‘apoptosis’ in 1972. Research in
this phase was not only morphological, but also began to
1
 History of Apoptosis Research
question the functions and mechanisms of apoptosis. The
third phase features the biochemical and molecular study
of apoptosis and runs from the late 1970s to the present. In
this period, scientists elucidated various biochemical
changes accompanying apoptosis, and discovered a num-
ber of gene products that initiate, encourage, prevent or
inhibit apoptosis. As many molecules that regulate apop-
tosis turned out to be evolutionarily conserved and to be
implicated in diseases, the research on apoptosis under-
went rapid expansion in the early 1990s. The significance of
apoptosis research has been recognised in many ways in
this period, including the awarding of the 2002 Nobel
Prize in Physiology or Medicine to three scientists who
contributed to the knowledge about apoptosis in the
nematode Caenorhabditis elegans (Horvitz, 2003). See also:
Cell Death in C. elegans
Phase I: Early Histological Descriptions
of Cell Death
From the mid-nineteenth century through the early twen-
tieth century, scattered histological observations of cell
death were reported in a variety of tissues and organisms
and in different developmental stages. This included espe-
cially regulated cell death in metamorphic insects and
amphibians. These early morphological descriptions often
mentioned a kind of granules visible in the histological
section as a sign of cell death. These granular patterns were
later identified as condensed chromatin, a characteristic of
apoptosis (Majno and Joris, 1995; Clarke and Clarke,
1996).
One of the earliest reports about naturally occurring cell
death emerged soon after botanist Matthias Schleiden and
physiologist Theodor Schwann formulated the cell theory
by around 1839. In 1842, German histologist Carl Vogt
reported about cell death in a monograph that described his
microscopic study of cellular activities throughout the life
cycle of midwife toads. Talking about the process of
amphibian metamorphosis when the anuran notochord
began to be replaced with vertebrae, Vogt described the
notochord cells as being ‘resorbed,’ ‘destroyed’ or ‘dis-
appearing’ (Clarke and Clarke, 1996). See also: History of
Cell Biology; Schleiden, Matthias Jacob; Schwann, Theo-
dor Ambrose Hubert
Cell death was also reported in many other biological
processes, such as in endochondral ossification, ovarian
follicles, neuronal development and tissue turnover.
Because these reports were sporadic and isolated, authors
often gave new names to the cell death phenomena they had
seen. The variety of these names, such as ‘coagulation
necrosis,’ ‘autolysis,’ ‘pyknosis,’ ‘karyolysis’ and ‘chro-
matolysis,’ although descriptive, probably have prevented
scientist from recognising the shared characteristics of
these phenomena (Majno and Joris, 1995).
The many terms attest to the fact that cell death was not
yet clearly conceptualised for both technological and
2 eLS & 2012, John Wiley & Sons, Ltd. www.els.net
philosophical reasons. Technologically, the limited reso-
lution of microscopes and histological stains could only
reveal coarse granular patterns. It was tedious and difficult
to reconstruct the whole sequence of morphological change
involved in apoptotic cell death from glimpses of histo-
logical sections in which structures of cells were often dis-
torted. In fact, many embryologists regarded the granules
as experimental artefacts generated from poor slide prep-
aration. Philosophically, the notion that death might
happen in these developing or living organisms just did
not seem right, since life was conventionally defined
as the absence or resistance of death (Glücksmann, 1951).
See also: History of Developmental Biology; History of the
Optical Microscope in Cell Biology and Medicine
During the first phase that introduced the idea of cell
death, research on apoptotic cell death remained isolated
and conceptually undeveloped. As a consequence, many of
the early investigators did not follow up their initial
observations. Without clearer definitions of the phenom-
enon of cell death and understandings of how it occurs, the
occasional efforts to discuss the function or mechanism of
cell death remained little more than speculation.
Phase II: Morphological and
Functional Study of Apoptosis
Programmed cell death in development
Beginning in the 1940s, experimental embryologists often
unexpectedly encountered apoptotic cell death when
investigating how cells divide and differentiate to form
certain tissues and organs. With improved dyes that
selectively stain certain types of cells, biologists eventually
established cell death as a real phenomenon and started to
ask questions about why and how cells die at various times
during development.
Some of these discoveries surprised researchers, going
against common beliefs about how development occurs.
Cell death observed in development offered puzzles that
needed to be explained and challenged the established view.
Viktor Hamburger and Rita Levi-Montalcini’s discovery
of neuronal cell death during the development of the chick
central nervous system was one such serendipitous inves-
tigation that challenged existing ideas and led to a new
understanding of cell death and development. See also:
Apoptosis in Developmental Processes; Levi-Montalcini,
Rita
In the early 1930s, the German embryologist Viktor
Hamburger arrived at the University of Chicago to study
the development of chick nervous system with techniques
of classical experimental embryology such as extirpation
and transplantation. He found that if he removed the chick
wing bud on one side of the developing embryo, the size of
the neuron columns would decrease on that same side.
Following his advisor Hans Spemann’s influential concept
of organiser and induction, Hamburger suggested that the

growing wing bud might send out inductive signals to
stimulate the growth of central neurons. The side with the
missing wing bud would lack such signals, resulting in the
diminished size of the neuron columns (Hamburger, 1934).
See also: Spemann, Hans
More than a decade later, around 1946, Hamburger
encountered a paper published in Italian that addressed the
same question. There the author Rita Levi-Montalcini
described development of central neurons not as inductive
growth of cells, but as a process of surplus growth of neu-
rons, followed by massive cell death. Hamburger soon
invited Levi-Montalcini to co-investigate the issue at the
Washington University at St. Louis, where he had moved.
Hamburger and Levi-Montalcini eventually confirmed the
‘large-scale, localised and patterned degeneration pro-
cesses,’ that is, cell death, in the normal development of
chick nervous system. They published the result in 1949
(Hamburger and Levi-Montalcini). Their finding about
the important role of cell death in development exposed
the limitations of the Spemann school’s approach to
development. As historian Allen (2004) has pointed out,
the paradigm of induction was ‘a context in which naturally
occurring cell death was simply not part of the picture’.
American biologist John W. Saunders was similarly
surprised when he tried to observe cell activities in the
developing chick wings while working at Marquette Uni-
versity around 1960. The dye Saunders used, Nile Blue,
could stain living cells without interfering with normal
cell activities. Saunders found that some of the cells in
the developing chick wing became an unusual dark colour
when being stained with Nile Blue. Initially taking these
cells to be pigment cells, Saunders eventually realised
that they were going through shrinkage and degeneration,
thus condensing the Nile Blue to higher concentrations
within the cells. In other words, these cells were going
through the process of death and he was watching it hap-
pen. Intrigued, Saunders started to investigate the patterns
and roles of apoptosis in chick wing and digit development
and became a pioneer of apoptosis research (Saunders
et al., 1962).
Meanwhile, American insect physiologist Richard A.
Lockshin was observing the way pupal muscle structures
disappear after completion of the adult development in
large American silkmoths. His 1964 study of the process of
intersegmental muscle breakdown was credited as the first
to propose the term ‘programmed cell death’ (Lockshin
and Williams, 1964). With more and more observations
and discussions adding to the list of occasions in which cells
seem to die for a biological purpose, biologists started to
recognise cell death as an important and conserved process
to maintain cell number and carve out certain structures.
Several critical reviews of this second period summarised
and classified cell death phenomena. Some, such as
Glücksmann (1951) review in Biological Reviews and
Saunders (1966) review in Science, were later recognised as
important milestones within the history of apoptosis
research. See also: The Siren’s Song: This Death That
Makes Life Live
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History of Apoptosis Research
Morphological definition of apoptosis
The term apoptosis solidified in the early 1970s from a
collaboration of three pathologists who examined cell
death in ischaemic livers and chemically exposed adrenal
cortices. Having observed cell fragments resulting from
dying cells using histochemical methods in the early 1960s,
the Australian pathologist John FR Kerr started to use
electron microscopy to investigate the morphological
changes of these cells. Kerr initially called the mode of cell
death he saw ‘shrinkage necrosis’ (Kerr, 1971).
Around that time, two other pathologists working at the
University of Aberdeen, Sir Alstair R Currie and Andrew
H Wyllie found a similar kind of cell death in the inner
adrenal cortices of rats exposed to carcinogens. They
invited Kerr to come to Aberdeen in 1970 to compare their
results. There they not only confirmed the morphological
changes of the cell death they had independently observed
were identical, but also discovered similar cell death phe-
nomena in the regression of rat breast carcinoma following
the removal of ovaries. Kerr, Currie and Wyllie eventually
realised that programmed cell death had been known
among embryologists. After confirming that the cell deaths
in injured tissue, tumours and during development went
through parallel morphological steps, the three path-
ologists became convinced that the cell death is a con-
served, pivotal cellular process important for diverse
biological conditions.
Kerr et al. (1972) coined the term apoptosis to define an
active, inherently programmed cell-deleting mechanism
with distinct patterns of morphological changes. The
Greek word apoptosis describes the shedding of leaves from
trees, or petals from flowers, was suggested by James
Cormack, a professor of Greek language at the University
of Aberdeen. The term metaphorically captures the sig-
nificance of apoptosis in multicellular organisms: it plays
an opposite, but complementary role to that of mitosis to
regulate cell populations.
Kerr et al. (1972) described the common morphological
changes in apoptosis with the aid of one diagram, four
histological staining pictures, and 20 electron microscope
micrographs (Figure 1). The whole sequence of apoptotic
cell death was divided into two stages. In the first stage, the
nucleus and cytoplasm show considerable condensation
and fragmentation. The cell membranes protrude and
extend to form blebs, which eventually separate from the
cell and become what the authors called ‘apoptotic bodies’.
In the second stage, these apoptotic bodies are engulfed and
digested by the neighbouring cells. Following the mor-
phological description, the authors enumerated the
occurrences of apoptosis in a wide range of biological
processes, such as the formation of limbs, interdigital clefts,
lumina in tubular structures, the degeneration of phylo-
genetic vestiges and in pathological processes such as in
teratogenesis, malignant tumours, tumour regression and
in injured organs and tissues. At the end of the article, the
authors called for extensive further biological and bio-
medical research on apoptosis. See also: Cancer
3
 History of Apoptosis Research

Parenchymal cells

Condensation

Separation

Fragmentation

Phagocytosis

Autolysis
Lysosomal
digestion

Residual body

′Histiocyte′

Figure 1 A diagram describing the morphology of apoptosis. Adapted from Kerr et al. (1972), with permission from Nature Publishing Group (hyperlinked
to http://www.nature.com/bjc/index.html).

Although its publication receive little recognition for
more than a decade, in retrospect Kerr et al.’s 1972 paper
clearly defined apoptosis, stated the significance of the
phenomenon and pointed out the work needed for possibly
establishing a field of apoptosis research. Thus the paper
itself became an anchor for later researchers to perceive
apoptosis research as a coherent field with its own agenda.
It has been widely cited since the mid-1980s (Garfield and
Melino, 1997).
Phase III: Molecular Study of
Apoptosis
Biochemical signatures of apoptosis
The rapid development of analytical tools for biochemistry
and molecular pathways in the late twentieth century
transformed the way apoptosis was studied. In the 1960s
and the 1970s, before the spread of recombinant DNA

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 History of Apoptosis Research

technology, many projects attempting to elucidate the a 3h MN 5h MN

process of apoptosis were biochemical. As early as the mid-
1960s, researchers showed that apoptosis, such as cell death
in the tadpole tails, requires synthesis of new ribonucleic
acids (RNAs) and proteins. This reconfirmed biochemi-
cally that apoptosis is a biologically active process, rather
than a passive reaction to adverse environmental con-
ditions (Tata, 1966).
An important biochemical revelation in the 1970s was
that the chromosomes within apoptotic cells break into
segments composed of integral units of nucleosomes.
Therefore, the dying cells’ DNAs can produce a ladder-like
pattern when they are separated by mass and visualised by
DNA dyes. This feature was first discovered in 1974, when
three researchers at Harvard University showed that
human and rodent cells had characteristic patterns of DNA
degradation when treated with agents that triggered

Base pairs
apoptosis. The 1974 experiment separated the resulting
DNA segments with an alkaline sucrose gradient techni-
que, which could only give rough estimates of molecular
weight (Williams et al., 1974). In 1980, Wyllie found that
such DNA degradation patterns were associated with the
simultaneous condensation of chromatin within the
nucleus, a morphological change characteristic of apop-
tosis. In addition, Wyllie ran the DNA molecules with
agarose gel electrophoresis that could measure molecular
weight of with higher resolution. He identified the differ-
ence between adjacent DNA segments on the gel as
approximately 180 base pairs (bp), which equals to the
length of a nucleosome (Wyllie, 1980). This showed that
chromosomes break into nucleosomal fragments during
apoptosis and suggested that apoptosis involves activation
of endonuclease, a type of enzyme that cuts DNA mol-
ecules from within at specific sites. The pattern of DNA
degradation that produces multiples of 180–200 bp was
later known as the ‘DNA ladder,’ the first widely used Figure 2 The ‘DNA ladder’ produced with electrophoresis from DNAs of
biochemical marker for detecting apoptotic cells (Figure 2). apoptotic cells. Adapted from Wyllie (1980), with permission from Nature
See also: Apoptosis: Morphological Criteria and Other Publishing Group (hyperlinked to http://www.nature.com/).
Assays

Killer genes and protectors
With the rise of modern genetic techniques, especially the
recombinant DNA technology in the 1980s, it became
feasible to identify gene products involved in apoptosis.
Scientists discovered a number of molecules relevant to
apoptosis and tried to piece them together into apoptotic
pathways. It became increasingly clear to scientists that
apoptosis involves integrating complex signals and initi-
ating well-regulated, multistep pathways. With the findings
of a few apoptotic genes whose homologues play a role in
carcinogenic process, links between the pathology of can-
cer and apoptosis began to be recognised, facilitating the
expansion of apoptosis research to biomedical research.
Molecular biologist H Robert Horvitz’s study of apoptosis
in C. elegans, which was recognised with a Nobel Prize in
2002, captured the excitement typical of the many fruitful
research programs in the 1980s and 1990s.
When Horvitz started working on the nematode
C. elegans in the late 1970s at the Laboratory of Molecular
Biology led by Sydney Brenner in Cambridge, UK,
C. elegans was not yet established as a model organism.
Researchers still needed to figure out the basics about
the worm’s developmental processes to study complex
functions. One of the advantages of C. elegans is that
developmental lineage of each of the 959 adult somatic cells
is invariant between individuals. Horvitz’s initial work on
C. elegans was to piece together the complete lineage map
of each somatic cell (Sulston and Horvitz, 1977). Working
on the cell lineage, Horvitz knew that of the 1090 somatic
cells ever generated during the worm’s development, not all
survived. A total of 131 somatic cells underwent apoptosis
and died. Horvitz would eventually follow this line of
research and identify genes involved in apoptosis. See also:
Brenner, Sydney; Cell Death in C. elegans; Laboratory of
Molecular Biology (LMB)

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 History of Apoptosis Research
In order to figure out what genes code for important
components in apoptotic pathways, Horvitz and his
graduate students induced mutations and tried to screen
mutants with abnormal patterns of cell death. Because the
cells undergoing apoptosis are often quickly engulfed by
neighbouring cells, the apoptotic scenes are fleeting and
hard-to-catch, especially when the research group was
trying to process many mutants in a short time. To cir-
cumvent these challenges, Horvitz utilised a ced-1 mutant,
where the engulfment function is obliterated and the
apoptotic cell debris cannot be eliminated (ced stands for
‘cell death abnormal’). When mutants derived from ced-1
had excessive or too little cell debris at the sites where cell
death normally occur, researchers could capture these
changes under Nomarski optics and isolate them as
mutants with abnormal cell death patterns (Hedgecock
et al., 1983). Based on ced-1, a graduate student Hilary M
Ellis generated a mutant worm in which no cell debris could
be found. The following research showed that all 131 cells
that would normally die survived in the mutant, indicating
that an essential gene for normal apoptosis was altered.
Horvitz named the gene ced-3 (Ellis and Horvitz, 1986).
Another essential gene for apoptosis, ced-4, was soon
identified using similar methods.
In the early 1990s, the advent of recombinant DNA
technology and modifications to make it work in a variety
of organisms enabled scientists to sequence and clone both
ced-3 and ced-4 (Yuan and Horvitz, 1992; Yuan et al.,
1993). Researchers used these sequences to search on-line
databases of genes and proteins, and eventually found that
the CED-3 protein is similar to a protease in humans called
ICE (interleukin-1-b-converting enzyme). CED-3 and ICE
later proved to belong to the family of caspase, a group of
cysteine protease that are essential for the activation and
execution of apoptosis (Grütter, 2000). See also: Caspases
and Cell Death; Caspases, Substrates and Sequential
Activation; DNA Sequence Analysis
The most important homology between human genes
and apoptotic genes in C. elegans for the expansion of
apoptosis research, however, do not come from what
Horvitz called ‘killer genes’ such as ced-3 and ced-4, but
from a gene that prevents cell death, ced-9, a ‘protector’.
Ced-9 was found to function against ced-3 and ced-4, pre-
venting cells from initiating apoptosis. Around 1994, when
Horvitz’s graduate student Michael Hengartner success-
fully cloned ced-9, he also figured out that the protein it
codes for has a sequence similar to the protein coded by the
human proto-oncogene BCL-2 (Hengartner and Horvitz,
1994). The homologous relationship indicated that the
protectors of apoptosis are evolutionarily close to genes
that induce cancer (Vaux et al., 1988). BCL-2 is often
activated in human follicular lymphoma, and was already a
noted molecule within oncology in the early 1990s. The
discovery that ced-9 and BCL-2 are homologous ignited
interests about apoptosis in the field of molecular oncol-
ogy. Together with additional discoveries that tumour
suppressors, such as P53, Myc and Rb proteins, could often
induce apoptosis, apoptosis research gained an increasing
6 eLS & 2012, John Wiley & Sons, Ltd. www.els.net
share of biomedical research from the early 1990s. As a
result, many investigators and biomedical companies have
been working to design therapeutics to trigger apoptosis in
tumour cells for effective cancer treatment. See also:
Apoptosis: Molecular Mechanisms; Drug Discovery in
Apoptosis; P53 and Cell Death; The BCL-2 Family
Proteins – Key Regulators and Effectors of Apoptosis;
Tumor Suppressor Genes
Current Understanding about
Apoptosis
The current molecular interpretation depicts apoptosis as
involving a cascade of energy-dependent cellular signalling
pathways and activations of caspases. The signals that
trigger apoptosis can be toxins, hormones, radiation,
hypoxia or damaged DNAs. Different signals often trigger
different sets of caspases, but eventually activate a common
‘execution pathway’ that leads to the degradation of DNAs
and proteins in the nucleus, and to the condensation of the
cytoplasmic components (Elmore, 2007). See also: Apop-
tosis: Molecular Mechanisms
Although the many molecules and pathways discovered
already have helped scientists to appreciate the complexity
involved in apoptosis, they have also created challenges for
understanding exactly how apoptosis should be defined. In
particular, how should apoptosis be defined and differen-
tiated from other kinds of cell death? What biochemical
and molecular process are unique in apoptosis? In fact,
some researchers express philosophical objections to the
use of the term apoptosis, suggesting that the concept is a
human construct which cannot reflect the complex pro-
cesses that defy unified definitions (Sloviter, 2002). To
address this issue, the Nomenclature Committee on Cell
Death was established in 2005. The committee attempted
to normalise terms used in cell death research by publishing
recommendations, which they did twice, in 2005 and 2009,
respectively (Kroemer et al., 2009).
References
Allen GE (2004) A pact with the embryo: Viktor Hamburger,
holistic and mechanistic philosophy in the development of
neuroembryology, 1927–1955. Journal of the History of Biology
37(3): 421–475.
Clarke PGH and Clarke S (1996) Nineteenth century research on
naturally occuring cell death and related phenomena. Anatomy
and Embryology 193(2): 81–99.
Ellis HM and Horvitz HR (1986) Genetic control of programmed
cell death in the Nematode C. elegans. Cell 44(6): 817–829.
Elmore S (2007) Apoptosis: a review of programmed cell death.
Toxicologic Pathology 35(4): 495–516.
Garfield E and Melino G (1997) The growth of the cell death field:
an analysis from the ISI-science citation index. Cell Death and
Differentiation 4(5): 352–361.

Glücksmann A (1951) Cell deaths in normal vertebrate ontogeny.
Biological Reviews of the Cambridge Philosophy Society 26(1):
59–86.
Grütter MG (2000) Caspases: key players in programmed cell
death. Current Opinion in Structural Biology 10(6): 649–655.
Hamburger V (1934) The effects of wing bud extirpation on the
development of the central nervous system in chick embryos.
Journal of Experimental Zoology 68(3): 449–494.
Hamburger V and Levi-Montalcini R (1949) Proliferation, dif-
ferentiation and degeneration in the spinal ganglia of the chick
embryo under normal and experimental conditions. Journal of
Experimental Zoology 111(3): 457–502.
Hedgecock EM, Sulston JE and Thomson JN (1983) Mutations
affecting programmed cell deaths in the Nematode Cae-
norhabditis elegans. Science 220(4603): 1277–1279.
Hengartner MO and Horvitz HR (1994) C. elegans cell survival
gene ced-9 encodes a functional homolog of the mammalian
proto-oncogene bcl-2. Cell 76(4): 665–676.
Horvitz HR (2003) Worms, life and death (Nobel Lecture).
ChemBioChem 4(8): 697–711.
Kerr JFR (1971) Shrinkage necrosis: a distinct mode of cellular
death. Journal of Pathology 105(1): 13–20.
Kerr JFR, Wyllie AH and Currie AR (1972) Apoptosis: a basic
biological phenomenon with wide-ranging implication in tissue
kinetics. British Journal of Cancer 26: 237–257.
Kroemer G, Galluzzi L, Vandenabeele P et al. (2009) Classifi-
cation of cell death: recommendations of the Nomenclature
Committee on Cell Death 2009. Cell Death and Differentiation
16(1): 3–11.
Lockshin RA and Williams CM (1964) Programmed cell death –
II. Endocrine potentiation of the breakdown of the interseg-
mental muscles of silkmoths. Journal of Insect Physiology 10(4):
643–649.
Majno G and Joris I (1995) Apoptosis, oncosis, and necrosis:
an overview of cell death. American Journal of Pathology 146(1):
3–15.
Saunders JW (1966) Death in embryonic systems. Science
154(3749): 604–612.
Saunders JW, Gasseling MT and Saunders LC (1962) Cellular
death in morphogenesis of the avian wing. Developmental
Biology 5(1): 147–178.
eLS & 2012, John Wiley & Sons, Ltd. www.els.net
History of Apoptosis Research
Sloviter RS (2002) Apoptosis: a guide for the perplexed. Trends in
Pharmacological Sciences 23(1): 19–24.
Sulston JE and Horvitz HR (1977) Post-embryonic cell lineages of
the Nematode, Caenorhabditis elegans. Developmental Biology
56(1): 110–156.
Tata JR (1966) Requirement for RNA and protein synthesis for
induced regression of the tadpole tail in organ culture. Devel-
opmental Biology 13(1): 77–94.
Vaux DL, Cory S and Adams JM (1988) Bcl-2 gene promotes
haemopoietic cell survival and cooperates with c-myc to
immortalize pre-B cell. Nature 335: 440–442.
Williams JR, Little JB and Shipley WU (1974) Association of
mammalian cell death with a specific endonucleolytic degrad-
ation of DNA. Nature 252(5485): 754–755.
Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is
associated with endogenous endonuclease activation. Nature
284(5756): 555–556.
Yuan J and Horvitz HR (1992) The Caenorhabditis elegans cell
death gene ced-4 encodes a novel protein and is expressed during
the period of extensive programmed cell death. Development
116(2): 309–320.
Yuan J, Shaham S, Ledoux S, Ellis HM and Horvitz HR (1993)
C. elegans cell death gene ced-3 encodes a protein similar
to mammalian interleukin-1ß-converting enzyme. Cell 75(4):
641–652.
Further Reading
Landecker H (2003) On beginning and ending with apoptosis: cell
death and biomedicine. In: Franklin S and Lock M (eds)
Remaking Life and Death: Toward an Anthropology of the
Biosciences, pp. 23–59. Santa Fe: School of American Research
Press.
Lockshin RA and Zakeri Z (2001) Programmed cell death and
apoptosis: origins of the theory. Nature Reviews. Molecular Cell
Biology 2(7): 545–550.
Vaux DL (2002) Apoptosis timeline. Cell Death and Differen-
tiation 9(4): 349–354.
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