Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases
The story of cell death began with the origins of cell biology, including important observations by Elie (Ilya) Metchnikoff, who realized that phagocytes engulfed dying cells. Most of the early studies were observational. By the middle of the 20th C, researchers were beginning to explore how cells d...
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Maghsoudi, N. Zaketi, Z. Lockshin, R.A. 2018-06-19T12:18:19Z 2018-06-19T12:18:19Z 2012 Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases / N. Maghsoudi, Z. Zaketi, R.A. Lockshin // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 146-152. — Бібліогр.: 64 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138730 The story of cell death began with the origins of cell biology, including important observations by Elie (Ilya) Metchnikoff, who realized that phagocytes engulfed dying cells. Most of the early studies were observational. By the middle of the 20th C, researchers were beginning to explore how cells died, had recognized that cell death was a physiologically controlled process, that the most common mode of death (“shrinkage necrosis”, later apoptosis) was tightly controlled, and were speculating whether lysosomes were “suicide bags”. Just prior to 1990 several discoveries led to rapid expansion of interest in the field and elucidation of the mechanisms of apoptosis. Closer to the beginning of the 21st C comprehensive analysis of the molecules that controlled and effected apoptosis led to the conclusion that autophagic processes were linked to apoptosis and could serve to limit or increase cell death. Today, realizing that knowledge of the components of cell death has not yet produced pharmaceuticals of therapeutic value, research is turning to questions of what metabolic or other mechanisms indirectly control the activation or suppression of the cell death positive feedback loop. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. Supported in part by the International Cell Death Society and by NIH grants 1R1541094351 (National Institute of Infectious Diseases) and 5T34GM070387-08 (National Institute of General Medical Sciences) to ZZ. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases Article published earlier |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases Maghsoudi, N. Zaketi, Z. Lockshin, R.A. Reviews |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases |
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Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases |
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programmed cell death and apoptosis — where it came from and where it is going: from elie metchnikoff to the control of caspases |
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Maghsoudi, N. Zaketi, Z. Lockshin, R.A. |
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Maghsoudi, N. Zaketi, Z. Lockshin, R.A. |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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The story of cell death began with the origins of cell biology, including important observations by Elie (Ilya) Metchnikoff, who realized that phagocytes engulfed dying cells. Most of the early studies were observational. By the middle of the 20th C, researchers were beginning to explore how cells died, had recognized that cell death was a physiologically controlled process, that the most common mode of death (“shrinkage necrosis”, later apoptosis) was tightly controlled, and were speculating whether lysosomes were “suicide bags”. Just prior to 1990 several discoveries led to rapid expansion of interest in the field and elucidation of the mechanisms of apoptosis. Closer to the beginning of the 21st C comprehensive analysis of the molecules that controlled and effected apoptosis led to the conclusion that autophagic processes were linked to apoptosis and could serve to limit or increase cell death. Today, realizing that knowledge of the components of cell death has not yet produced pharmaceuticals of therapeutic value, research is turning to questions of what metabolic or other mechanisms indirectly control the activation or suppression of the cell death positive feedback loop. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
|
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1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/138730 |
| citation_txt |
Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases / N. Maghsoudi, Z. Zaketi, R.A. Lockshin // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 146-152. — Бібліогр.: 64 назв. — англ. |
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146 Experimental Oncology 34, 146–152, 2012 (September)
PROGRAMMED CELL DEATH AND APOPTOSIS — WHERE IT CAME
FROM AND WHERE IT IS GOING: FROM ELIE METCHNIKOFF
TO THE CONTROL OF CASPASES
N. Maghsoudi1,2, Z. Zakeri2, R.A. Lockshin3*‡
1Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Department of Biology, Queens College of CUNY, 65–30 Kissena Blvd., Flushing NY 11367 USA
3Department of Biological Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439 USA
The story of cell death began with the origins of cell biology, including important observations by Elie (Ilya) Metchnikoff, who
realized that phagocytes engulfed dying cells. Most of the early studies were observational. By the middle of the 20th C, researchers
were beginning to explore how cells died, had recognized that cell death was a physiologically controlled process, that the most
common mode of death (“shrinkage necrosis”, later apoptosis) was tightly controlled, and were speculating whether lysosomes
were “suicide bags”. Just prior to 1990 several discoveries led to rapid expansion of interest in the field and elucidation of the
mechanisms of apoptosis. Closer to the beginning of the 21st C comprehensive analysis of the molecules that controlled and ef-
fected apoptosis led to the conclusion that autophagic processes were linked to apoptosis and could serve to limit or increase cell
death. Today, realizing that knowledge of the components of cell death has not yet produced pharmaceuticals of therapeutic value,
research is turning to questions of what metabolic or other mechanisms indirectly control the activation or suppression of the cell
death positive feedback loop. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
Key Words: programmed cell death, apoptosis, caspase, history, autophagy, lysosomes.
In one sense, the story of cell death has some
relationship to the Ukraine. Cell death plays a major
role in development, homeostasis, and pathology but,
although dying cells were recognized almost as soon
as techniques permitted the examination of cells, its
importance was largely underestimated because dying
cells were so rarely seen. They are rarely seen because,
while the newly synthesized DNA of a dividing cell can
be labeled and that division can be identified as long
as the cell survives, perhaps for many years, a dying
cell is identifiable for 20 minutes to one hour, after
which it is gone. It is gone because, most typically,
it has been consumed by a phagocytic cell or phago-
cyte. Phagocytes were of course first described and
documented — against considerable disbelief —
by one of The Ukraine’s gifts to world science, Ilya (Elie)
Metchnikoff. In fact, through the history of the field,
the story of cell death pops up periodically as a factor
in our understanding of cell biology.
In the mid-19 century, the German dye chemists
were discovering that many plant, animal, and mine-
ral extracts colored various fabrics. As can be seen
in many paintings, the variety of colors of dresses and
garments increased remarkably during that period.
Scientists realized that these same dyes could color
the frustratingly transparent cells that they were trying
to study. Thus the science of histology was born, and,
almost as soon as scientists could see cells, they rea-
lized that some of the cells would die. In 1842, Karl Vogt,
studying the metamorphosis of amphibians, realized
that the notochord disappeared, and he indicated that
the death of the notochord cells had to be physiological
[1]. In 1864, August Weissman, also in metamorpho-
sis, pointed out the death of most cells in the pupae
of insects [2]. He introduced the term “histolysis”, and
described the appearance of dying cells. During the
remainder of the 19th century, many other cells were ob-
served to die during normal development or metamor-
phosis: chondrocytes, cells in the ovarian follicle, post
lactational mammary glands, myocytes and myofibrils,
sensory neurons, and many others. Even Metchnikoff,
looking at the number of phagocytes in the regressing
muscles of the tadpole tail, pointed out that the muscles
were in fact dying [3]. Throughout the first third of the
20th century, there were many studies of cell death,
mostly in embryos and metamorphosing animals. The
first mention of cell death appears in the mid-19th C,
with the writings of the great Walther Flemming [4], who
described the involution of Graafian follicles in mam-
mals, followed by incidental reports by others on what
appeared to be dying cells in the nervous system and
elsewhere. In the beginning of the 20th C, a noticeable
interest in metamorphosis of insects and amphibians,
primarily in France, led to several publications, mar-
velous for their length and for their elaborate line and
water-color drawings, particularly of the destruction
of musculature and nervous system in insects and
tadpoles at metamorphosis. Biologists like von Reck-
linghausen [5] had even clearly distinguished between
oncosis, what we would today term necrosis, and the
more physiological cell death that most commonly is de-
scribed as apoptosis. However, techniques were very
limiting. Most cell deaths were observed in small tissues
or animals, over a very short period of time, and only
a small percentage of the cells could be dissected free.
Thus the scientists at that time did not dare to hope that
Received: May 8, 2012.
*Correspondence: E-mail: rlockshin@gmail.com
‡Emeritus
Exp Oncol 2012
34, 3, 146–152
INVITED REVIEW
Experimental Oncology 34, 146–152, 2012 (September)34, 146–152, 2012 (September) (September) 147
they would be able to understand the causes or mecha-
nisms of the deaths that they observed.
Starting in the 1930s, the situation began to change.
Victor Hamburger was exploring the mechanisms
whereby tissues stimulated the growth of neurons [6] —
the story that later would become the story of nerve
growth factor. A few years later, he, together with Rita
Levi-Montalcini, would clearly demonstrate that many
neurons were born in each sensory ganglion, but in the
absence of supporting tissue generating nerve growth
factor, many of the neurons that were born would soon
die [7]. Honor Fell, later Dame Honor Fell, began to exa-
mine in cell culture how chondrocytes died [8]. And
John Saunders, recognizing specific patches of dying
cells in chick embryos, wondered if he could dissect
them free and study the control of their death [9].
Likewise, immunologists began to recognize that many
thymocytes died in mammalian embryos, and even
as the white blood cell count fell after an infection, this
drop in white blood cells derived from the death of the
circulating cells. In 1951, Alfred Glücksmann published
a major review listing nearly 100 types of cell death
during early vertebrate development [10]. Though his
classifications are more focused on the purpose of the
deaths, which today we would find not very helpful,
he very effectively demonstrated that all cell death was
a very normal aspect of development and homeostasis.
The 1950s bore witness to a major expansion in the
technology of cell biology. Microscopy was ra pidly
improving with the development and rapid growth
of the capabilities of the phase contrast and electron
microscopes, and the technology of homogenizing,
osmotically protecting, and separating cell orga nelles
by differential centrifugation was rapidly coming
on board. Christian de Duve and his collaborators were
examining the properties of mitochondria, which they
could remove and purify by differential centrifugation.
One enzyme that they considered to be mitochondrial
was acid phosphatase. One night, they inadvertently left
their samples on the desktop, rather than returning them
to the refrigerator for storage overnight. They neverthe-
less tried to use their samples the next day and found,
to their surprise, that the acid phosphatase activity was
hugely increased. This led to their discovery of lyso-
somes and their exploration of the property of these
organelles [11]. They learned that the lysosomes were
distinct from the mitochondria and that they contained
many acid hydrolases. Trying to discover the function
of the lysosomes, they exposed rats to carbon tetra-
chloride, a known hepatotoxin, and looked at the effect
on the lysosomes of the liver. They therefore proposed
that the lysosomes were suicide bags, killing cells
when they ruptured. We know today that this result was
specific to carbon tetrachloride, since this lipid-soluble
toxin directly attacks cell and lysosomal membranes.
Nevertheless, it was the first hypothesis concerning
the mechanism of cell death. As we describe below,
this was one lead that we followed.
Meanwhile, John Saunders was becoming curious
about the mechanisms by which cells died. He took
cells from the axillae of embryonic chicken wings, which
would die in the near future, and explanted them into
tissue culture. They did well in the tissue culture until the
time that they would have died in the embryo, at which
time in culture they died. One could say that the cells
were already moribund at the time he explanted them,
but Saunders demonstrated that this was not true, for,
when he transplanted them not to a culture dish but
to the back of another embryo, they healed in and sur-
vived, contributing to the epidermis on the back of the
host. Thus, as he would observe later, the cells were
not already dying, but “the death clock was ticking” [9].
Personal comments RAL [“When I entered graduate
school, my potential mentor, Carroll M. Williams, sug-
gested a series of possible projects to me. One was the
fate of larval tissues during metamorphosis. Because
he could store pupae in the refrigerator and take them
out year around, he sugges ted that the death of the
intersegmental muscles in the freshly emerged adult
would be a non-season-limited tissue on which I could
work. Since my undergraduate degree was in biochemi-
cal sciences, I considered that I could test the hypothesis
of suicide bags. Howe ver, it is never a good idea for
a graduate student to bet on only one horse — what
if it doesn’t work? — and I elected to consider also neu-
rological and endocrine mechanisms, and to invest some
time in looking at the tissues by electron microscopy.
Briefly, what we learned was the following:
• For the muscles to die, they needed to be potentia ted
by the initial endocrine signal that led to the metamor-
phosis of the adults. If one interfered with that, one
could also interfere with the death of the muscles [12].
• As the development advanced and the insect ap-
proached ecdysis, the number of lysosomes in the
tissue began to increase rapidly [13].
• At the moment of emergence of the adult from its
cocoon, there was a neural signal later (demon-
strated by Truman et al. [14] to be also neurose-
cretory) that triggered the conversion to the active
phase of death. Chemically or surgically removing
the neural activity led to the premature death of the
muscles, while chemically or electrically driving the
activity prevented the death of the muscles at the
appointed time [15, 16].
• Shortly after the activity of ecdysis ceased, there was
a rapid expansion of the lysosomal system, includ-
ing the development of autophagic vacuoles and
autophagosomes, and death became irreversible.
• As we were to learn later, the events immediately
surrounding ecdysis required synthesis of new
messenger RNA and protein and could be blocked
by administration of drugs that inhibited these pro-
cesses [17].
• Also determined later, during the first 8 to 12 hours
after ecdysis, the ensuing death was occult; the
muscles were physiologically normal and could
contract and respond normally. After 12 hours,
by which time approximately ⅓ of the myofilaments
had already been resorbed, the muscles rapidly
148 Experimental Oncology 34, 146–152, 2012 (September)
depolarized, became non-contractile, and were
quickly resorbed [18].
Carroll Williams was always known for his colorful
phraseology, and as graduate students we always tried
to emulate him. Because computers were just begin-
ning to be talked about at the time, programmed cell
death seemed to be a particularly modern and colorful
way of describing what we saw. It was a metaphor sta-
ting what I thought was pretty obvious — if a biological
process occurs at a defined location and time, then
it must in some fashion be programmed or written into
the genetics of the organism — but, as in poetry, meta-
phors help people see things that they otherwise would
have not have noticed. Thus a relatively straightforward
observation gained some currency”].
Meanwhile, with growing improvement in technical
ability, many other laboratories beginning to investigate
the mechanisms of cell death. To a very large extent,
these studies focused on very appearance, number,
and changes in morphology, of lysosomal bodies.
In 1996 Jamshed Tata, exploiting the recent discovery
that actinomycin D could inhibit the synthesis of pro-
teins, established that protein synthesis was required
for the death of explants of tadpole tail [19]. Lockshin
confirmed the findings for insect muscle [17], as did
Munck and White [20] for find thymocytes exposed
to glucocorticoids. Likewise, Oppenheim confirmed
that protein synthesis was necessary for the death
of neurons in chick embryos [21]. (This requirement
later proved to be restricted to embryonic and other
immature cells, as opposed to post mitotic or differen-
tiated cells, but the findings provoked more interest
in the mechanisms of cell death.) Another paper that
provoked some interest was that of Kerr, Wyllie, and
Currie [22]. In this paper the authors drew on Kerr’s ear-
lier observations that “shrinkage necrosis” was com-
mon to most physiological forms of cell death [23] and
that, unlike osmotic lysis in necrosis, there was no good
mechanistic explanation of how it occurred, and they
proposed that this type of cell death was the comple-
ment of mitosis, and suggested the name “apoptosis”.
We were becoming more comfortable with the idea that
death was not a random event, but rather a controlled
event, for which mitosis was the compensation.
However, what really launched the field was a group
of three scientific advances. Fittingly, each was of a dif-
ferent type: technical, conceptual, and theoretical.
The technical breakthrough was that in 1990, Arends
and Wyllie, expanding Wyllie’s earlier interest in chro-
matin rearrangement in apoptosis, published a paper
indicating that the simple technique of electrophoresing
DNA could demonstrate apoptosis, since in necrotic
cells randomly degraded DNA would produce a smear,
whereas in apoptosis the DNA was cut in a more orderly
fashion, between nucleosomes [24]. The technique
and its expansion to more sensitive (labeling) versions
was simple and cheap, enabling many laboratories
to look for apoptosis. Spontaneous apoptosis hard
to spot — the entire liver is replaced in approximately
3 years, and an apoptotic cell may be identifiable for
only 20 minutes, thereafter leaving no trace, whereas
with appropriate labels a mitotic event may be traced
years later. Even at the turnover rate of the liver, only
one cell in 72.000 would be apoptotic at any time. Thus
a technique that could reveal apoptosis allowed many
researchers to observe apoptosis in many pathological
and non-pathological (e.g., expansion and contraction
of immunocompetent cells) situations, and to convince
the research community of its importance.
The conceptual breakthrough was the recognition
that several diseases, notably cancers, were associated
with abnormal patterns of cell death. Thus in rapid suc-
cession B-cell lymphoma was recognized to be a failure
of lymphocytes to die on time, deriving from the trans-
location of a gene that prevented cell death (Bcl-2)
to a position of constitutive activation [25, 26]. The gene
p53, known to be mutated in the majority of cancers,
had been assumed to act by preventing mitosis of cells
in which DNA had been damaged, but was now recog-
nized to provoke apoptosis if these cells had left G0 [27,
28]. Finally, a cell surface protein, variously named Fas
Ligand, Apo-1, and CD95, was recognized as capable
of killing cells when linked to a soluble or cell-bound
component [29, 30]. Peter Krammer displayed spec-
tacular pictures of tumor regression when the ligand was
engaged. Ameisen [31] suggested that the devastation
of AIDS was generated by the death of not seriously in-
fected bystander cells, which might be prevented. Thus
cell death in general, and apoptosis in particular, were
recognized as being important in medicine.
The theoretical breakthrough was the realization that
the mechanism of cell death, and even the components
of cell death, were conserved in evolution from nema-
tode worms to mammals. Thanks primarily to research
coming from the laboratory of Horvitz and collaborators,
the primary effector gene of apoptosis in worms, ced-3,
was identified as a protease very similar to mammalian
proteases, leading to the discovery of a new class
of proteases (caspases) mostly associated with apop-
tosis [32]. The basic mechanism of control — all mature
cells containing an inactive protease capable of kill-
ing the cell; the protease is activated by an activating
molecule that interacts with it; and the activator is held
in check by other molecules that normally suppress
it — is common to worms and mammals. Even the com-
ponents are evolutionarily related: ced-3 to caspases,
Bcl-2 to ced-9, and Apaf-1 to EGL-1. This conserva-
tion argues for a highly important biological role for
cell death. The history is summarized in the Table. The
basic pathways of apoptosis, summarized from many
sources, are shown in Fig. 1, and the formal and mo-
lecular relationships of worm and mammalian apoptosis
are illustrated in Fig. 2.
In the 21st century there have been many advances,
too numerous to describe, and which have been
reviewed in many other competent reviews. In brief,
these can be summed into two categories: first, now
that apoptosis is well understood, it has become pos-
sible and to recognize many other forms of cell death.
Second, although we have considerable understanding
Experimental Oncology 34, 146–152, 2012 (September)34, 146–152, 2012 (September) (September) 149
of the mechanisms of cell death, medical interventions
based on this understanding has not been forthcoming.
The first category illustrates a common problem
in the history of science: Although autophagy was con-
sidered a major mechanism of cell death in the 1970s,
and was extensively studied, excitement over apopto-
sis led to the presumption that apoptosis was the only
meaningful form of cell death. By the beginning of the
21st century, it was apparent that not all forms of cell
death represented classical apoptosis. There were
of course the situations in which cells differentiated
into nonviable forms, such as lens epithelium, keratino-
cytes, platelets, and erythrocytes. Several laboratories
recognized that sometimes cells begin apoptosis but
fail to complete it, since apoptosis require energy and
it is possible to exhaust that energy before apoptosis
is completed. Some forms of cell death were clearly
programmed but more closely resembled necrosis and
were given names such necroptosis and paraptosis.
To some extent, the biology determined the situation:
the normal fate of an apoptotic cell is to be phagocy-
tosed, but if phagocytes cannot reach the apoptotic
cell, it may end in a form of necrosis. More problematic
is the situation in insect metamorphosis. Although
insect cells like those other animals can undergo
apoptosis, in metamorphosis apoptosis is not seen.
Instead, the cells undergo massive autophagy before
fragmenting and being consumed by phagocytes. This
situation obtains also for large mammalian cells with
substantial cytoplasm, such as mammary epithelium
in post lactational stage. Such situations gave rise
to the concept of autophagic cell death.
65. Lizarbe Iracheta MA. El suicidio y la muerte cellular. Rev R Acad Cienc Exact Fis Nat 2007; 101: 1–33 (in Spanish).
150 Experimental Oncology 34, 146–152, 2012 (September)
Fig. 1. Primary routes of apoptosis. Apoptosis may be initiated
commonly by two routes: In the first (top) or extrinsic route an extra-
cellular molecule (Tumor Necrosis Factor — TNF) or Fas interacts with
a membrane receptor, activating the Death Initiating Signaling Complex
or DISC, which includes a defined sequence called the Death Domain
(Fas-associated Death Domain FADD/TNF-Receptor with a Death
Domain TRADD). In the complex an initiator caspase (cysteine protease
hydroly zing at aspartic acid), caspase 8 or 10, is activated. This in turn
activates an effector caspase, caspase 3, 6, or 7, which destroys many
cytoplasmic proteins and, by entering the nucleus, destroys chromatin
and nucleoplasmic proteins, permitting cleavage of DNA. In the second,
or intrinsic, route, the initiator caspase may cleave Bid (BH3 interact-
ing domain death antagonist) to produce truncated Bid (t-Bid), which
as a pro-death molecule, can compete with death antagonists at the
mitochondrial outer membrane. Alternatively, metabolic conditions
may also lead to the same mitochondrial outer membrane. In any
event, the mitochondrion leaks cytochrome C, endonuclease G, and
apoptosis-initiating factor (AIF) to the cytoplasm. In the cytoplasm,
cytochrome C and AIF bind to and activate a multimeric complex termed
the apoptosome, thus activating another initiator caspase, caspase 9.
Caspase 9 then activates the same effector caspases
Fig. 2. Parallelism of Caenorhabditis and mammalian
pathways of apoptosis. In these widely divergent creatures
death is effected by a caspase. In mammals the effector cas-
pase is activated by initiator caspases. The caspase is activated
through interaction with an adaptor, but the adaptor is normally
held in check by a regulator. In certain cells at certain times, the
normally-on regulator is blocked by a pro-death protein that
releases the death pathway. The worm proteins Ced-9, Ced-4,
and Ced-3 have not only formal but partial structural similarity
to the corresponding mammalian genes
Today the situation for autophagy seems far more
complex. Heavily stressed cells, such as those infected
by with viruses, use autophagy as a defense mechanism.
Those stressed cells that can undergo autophagy survive
better than those that cannot. If we were to reassess the
situation today, it would appear that autophagy is normally
a defense mechanism that under some circumstances
continues until all necessary resources of the cell are
consumed and the cell finally dies. What controls the onset
and limitation of autophagy, and why the cell does not initi-
ate apoptosis, are unknown and worthy of further study.
Finally, the reason that cell-death-based therapy
is not yet available is becoming clear. For the most part,
the origin of cell death based disease is not a failure
of the mechanism of cell death — that is, of the caspas-
es or other controllers of death. The problem is normally
the inappropriate activation or failure of activation of the
cell death mechanism. Other than the case of B cell
lymphoma, in which the Bcl-2 gene is translocated
to a position in which it is constitutively active, the prob-
lem is not with the effectors themselves but rather the
threshold at which cell death is activated. We do not yet
understand what determines the threshold or sensitivity
of the cell. Identifying and targeting these thresholds
will ultimately produce cell death controlled therapy.
This essay has tried where possible to cite some
of the originators of our current thinking in their original
publications. Several histories have been published
that give expanded or alternate views and are well
worth reading in their own right. These reviews include
those by Clarke and Clarke [62], Lockshin and Zakeri
[63], Vaux [64], and Lizarbe Iracheta [65]. Some of the
material in the tables and figures reflects observations
originally made by these authors.
ACKNOWLEDGMENTS
Supported in part by the International Cell Death So-
ciety and by NIH grants 1R1541094351 (National Institute
of Infectious Diseases) and 5T34GM070387-08 (Na-
tional Institute of General Medical Sciences) to ZZ.
REFERENCES
1. Vogt C. Untersuchungen uber die Entwicklungsge-
schichte der Geburtshelerkroete (Alytes obstetricians). Solo-
thurn: Jent und Gassman, 1842.
2. Weismann A. Die nachembryonale Entwicklung der
Musciden nach Beobachtungen an Musca vomitoria und Sar-
cophaga carnaria. Z Wiss Zool 1864; 14: 187–336.
3. Metschnikoff E. Untersuchungen über diemesodermalen
Phagocyten einiger Wirbeltiere. BiolZentralb 1883; 3: 560–5.
4. Flemming W. Über die bildung von richtungsfiguren
in säugethiereiern beim untergang graaf’scher follikel. Arch
Anat Physiol 1885: 221–44.
5. von Recklinghausen F. Unter suchungen über Rachitis
und Osteomalacie. Jena, Verlag GustavFischer, 1910.
6. Hamburger V. The effects of wing bug extirpation
in chick embryos on the development of the central nervous
system. J Exp Zool 1934; 68: 449–94.
7. Hamburger V, Levi-Montalcini R. Proliferation, diffe-
rentiation and degeneration in the spinal ganglia of the chick
embryo under normal and experimental conditions. J Exp Zool
1949; 111: 457–502.
8. Fell HB, Canti RG. Experiments on the development in vi-
tro of the avian knee-joint. Proc R Soc Lond B 1934; 116: 316–51.
9. Saunders JW, Jr. Death in embryonic systems. Science
1966; 154: 604–12.
10. Glücksmann A. Cell deaths in normal vertebrate onto-
geny. Biol Rev Camb Phil Soc 1951; 26: 59–86.
Experimental Oncology 34, 146–152, 2012 (September)34, 146–152, 2012 (September) (September) 151
11. De Duve C. The lysosomes, a new group of cytoplasmic
granules. J Physiol (Paris) 1957; 49: 113–5.
12. Lockshin RA, Williams CM. Programmed cell death.
II. Endocrine potentiation of the breakdown of the interseg-
mental muscles of silkmoths. J Insect Physiol 1964; 10: 643–9.
13. Lockshin RA, Williams CM. Programmed cell death.
V. Cytolytic enzymes in relation to the breakdown of the interseg-
mental muscles of silkmoths. J Insect Physiol 1965; 11: 831–44.
14. Schwartz LM, Truman JW. Peptide and steroid regulation
of muscle degeneration in an insect. Science 1982; 215: 1420–1.
15. Lockshin RA, Williams CM. Programmed cell death.
III. Neural control of the breakdown of the intersegmental
muscles of silkmoths. J Insect Physiol 1965; 11: 601–10.
16. Lockshin RA, Williams CM. Programmed cell death.
IV. The influence of drugs on the breakdown of the interseg-
mental muscles of silkmoths. J Insect Physiol 1965; 11: 803–9.
17. Lockshin RA. Programmed cell death. Activation
of lysis by a mechanism involving the synthesis of protein.
J Insect Physiol 1969; 15: 1505–16.
18. Lockshin RA, Beaulaton J. Cytological studies of dying
muscle fibers of known physiological parameters. Tissue Cell
1979; 11: 803–19.
19. Tata JR. Requirement for RNA and protein synthesis
for induced regression of tadpole tail in organ culture. Dev
Biol 1966; 13: 77–94.
20. Makman MH, Dvorkin B, White A. Evidence for in-
duction by cortisol in vitro of a protein inhibitor of transport
and phosphorylation processes in rat thymocytes. Proc Natl
Acad Sci USA 1971; 68: 1269–73.
21. Oppenheim RW, Prevette D, Tytell M, Homma S.
Naturally occurring and induced neuronal death in the chick
embryo in vivo requires protein and RNA synthesis: evidence
for the role of cell death genes. Dev Biol 1990; 138: 104–13.
22. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic
biological phenomenon with wide-ranging implications in tis-
sue kinetics. Br J Cancer 1972; 26: 239–57.
23. Kerr JF. Shrinkage necrosis: a distinct mode of cellular
death. J Pathol 1971; 105: 13–20.
24. Arends MJ, Morris RG, Wyllie AH. Apoptosis: The
role of the endonuclease. Am J Pathol 1990; 136: 593–608.
25. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes
haemopoietic cell survival and cooperates with c-myc to im-
mortalize pre-B cells. Nature 1988; 335: 440–2.
26. Vaux DL, Korsmeyer SJ. Cell death in development.
Cell 1999; 96: 245–54.
27. Yonish-Rouach E, Resnitzky D, Lotem J, et al. Wild-
type p53 induces apoptosis of myeloid leukaemic cells that
is inhibited by interleukin-6. Nature 1991; 352: 345–7.
28. Lowe SW, Schmitt EM, Smith SW, et al. p53 is required
for radiation-induced apoptosis in mouse thymocytes. Nature
1993; 362: 847–9.
29. Trauth BC, Klas C, Peters AM, et al. Monoclonal
antibody-mediated tumor regression by induction of apoptosis.
Science 1989; 245: 301–5.
30. Itoh N, Yonehara S, Ishi A, et al. The polypeptide
encoded by the cDNA for human cell surface antigen Fas can
mediate apoptosis. Cell 1991; 66: 233–43.
31. Ameisen JC, Capron A. Cell dysfunction and depletion
in AIDS: The programmed cell death hypothesis. Immunol
Today 1991; 12: 102–5.
32. Yuan J, Shaham S, Ledoux S, et al. The C. elegans
cell death gene ced-3 encodes a protein similar to mammalian
interleukin-1β-converting enzyme. Cell 1993; 75: 641–52.
33. Stieda L. Die Bildung des Knochengewebes. Festschrift
des Naturforschervereins zu Riga zur Feier des fünfzigjährigen
Bestehens der Gesellschaftpractischer Aertze zu Riga. Engel-
mann, Leipzig, 1872.
34. Felix W. Ueber Wachsthum der quergestreiften Musku-
latur nach Beobachtungen am Menschen. Z Wiss Zool 1889;
48: 224–59.
35. Arnheim G. Coagulations nekrose und Kernschwund.
Virchows Arch Pathol Anat 1890; 120: 367–83.
36. Collin R. Recherches cytologiques sur le développe-
ment de la cellule nerveuse. Névraxe 1906; 8: 181–309.
37. Graper L. Eine neue Anschauung Oberphysiologische
Zellausschaltung. Arch Zellforsch 1914; 12: 373–94.
38. Bellairs R. Cell death in chick embryos as studied
by electron microscopy. J Anat 1961; 95: 54–60.
39. Schweichel JU, Merker HJ. The morphology of various
types of cell death in prenatal tissues. Teratology 1973; 7: 253–66.
40. Skalka M, Matyasova J, Cejkova M. DNA in chromatin
of irradiated lymphoid tissues degrades in vivo into regular
fragments. FEBS Lett 1976; 72: 271–4.
41. Sulston JE, Brenner S. The DNA of Caenorhabditis
elegans. Genetics 1974; 77: 95–104.
42. Farber E, Fisher MM. Toxic Injury of the Liver, part A.
New York, Marcel Dekker, 1979.
43. Horvitz HR, Ellis HM, Sternberg PW. Programmed cell
death in nematode development. Neurosci Comment 1982; 1: 56.
44. Hedgecock EM, Sulston JE, Thomson JN. Mutations
affecting programmed cell deaths in the nematode Caenorhab-
ditis elegans. Science 1983; 220: 1277–9.
45. Ellis HM, Horvitz HR. Genetic control of programmed
cell death in the nematode C. elegans. Cell 1986; 44: 817–29.
46. Hengartner MO, Ellis RE, Horvitz HR. Caenorhabditis
elegans gene ced-9 protects cells from programmed cell death.
Nature 1992; 356: 494–9.
47. Faddok VA, Voelker DR, Campbell PA, et al. Exposure
of phosphatidylserine on the surface of apoptotic lymphocytes
triggers specific recognition and removal by macrophages.
J Immunol 1992; 148: 2207–16.
48. Vaux D, Weissman IL, Kim SK. Prevention of pro-
grammed cell death in Caenorhabditis elegans by human bcl-2.
Science 1992; 258: 1955–7.
49. Clem RJ, Fechheimer M, Miller LK. Prevention
of apoptosis by a baculovirus gene during infection of insect
cells. Science 1991; 254: 1388–90.
50. Salvesen GS, Dixit VM. Caspases: intracellular signa-
ling by proteolysis. Cell 1997; 91: 443–6.
51. Liu XS, Kim CN, Yang J, et al. Induction of apoptotic
program in cell-free extracts — requirement for dATP and
cytochrome c. Cell 1996; 86: 147–57.
52. Zou H, Henzel WJ, Liu X, et al. Apaf-1, a human protein
homologous to C. elegans CED-4, participates in cytochrome
c-dependent activation of caspase-3. Cell 1997; 90: 405–13.
53. del Peso L, Gonzalez VM, Nunez G. Caenorhabditis el-
egans EGL-1 disrupts the interaction of CED-9 with CED-4 and
promotes CED-3 activation. J Biol Chem 1998; 273: 33495–500.
54. Majno G, Joris I. Apoptosis, oncosis, and necrosis.
An overview of cell death. Am J Pathol 1995; 146: 3–15.
55. Zakeri Z, Bursch W, Tenniswood M, Lockshin
RA. Cell death: programmed, apoptosis, necrosis, or other?
Cell Death Differ 1995; 2: 87–96.
56. Broker LE, Kruyt FA, Giaccone G. Cell death
independent of caspases: a review. Clin Cancer Res 2005;
11: 3155–62.
57. Kroemer G, El-Deiry WS, Golstein P, et al. Classifi-
cation of cell death: recommendations of the Nomenclature
Committee on Cell Death. Cell Death Differ 2005; 12 (Suppl
2): 1463–7.
152 Experimental Oncology 34, 146–152, 2012 (September)
58. Degterev A, Yuan J. Expansion and evolution of cell
death programmes. Nat Rev Mol Cell Biol 2008; 9: 378–90.
59. Debnath J, Baehrecke EH, Kroemer G. Does auto-
phagy contribute to cell death? Autophagy 2005; 1: 66–74.
60. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G.
Self-eating and self-killing: crosstalk between autophagy and
apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741–52.
61. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guide-
lines for the use and interpretation of assays for monitoring
auto phagy in higher eukaryotes. Autophagy 2008; 4: 151–
75 (also 2012 update, in press, Autophagy).
62. Clarke PGH, Clarke S. Nineteenth century research
on cell death. Exp Oncol 2012; 34: 139–45.
63. Lockshin RA, Zakeri Z. Programmed cell death and
apoptosis: origins of the theory. Nature Rev Mol Cell Biol
2001; 2: 545–9.
64. Vaux DL. Apoptosis timeline. Cell Death Differ 2002;
9: 349–54.
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