History of apoptosis research

Last updated August 25, 2023

Apoptosis is the process of programmed cell death. From its early conceptual beginnings in the 1950s, it has exploded as an area of research within the life sciences community. As well as its implication in many diseases, it is an integral part of biological development.

Early research, and the "worm people" at Cambridge

Sydney Brenner's studies on animal development began in the late 1950s in what was to become the Laboratory of Molecular Biology (LMB) in Cambridge, UK. It was at this lab that during the 1970s and 1980s, a team led by John Sulston succeeded in tracing the nematode Caenorhabditis elegans entire embryonic cell lineage. In other words, Sulston and his team had traced where each and every cell in the roundworm's embryo came from during the division process, and where it ended up.

H. Robert Horvitz arrived from the US at the LMB in 1974, where he collaborated with Sulston. Both would share the 2002 Nobel Prize in Physiology or Medicine with Brenner, and Horvitz would go back to the US in 1978 to establish his own lab at the Massachusetts Institute of Technology.

Brenner's original interests were centered in genetics and in the development of the nervous system, but cell lineage and differentiation inevitably led to the study of cell fate:

One aspect of the cell lineage particularly caught my attention: in addition to the 959 cells generated during worm development and found in the adult, another 131 cells are generated but are not present in the adult. These cells are absent because they undergo programmed cell death - Horvitz: "Worms, Life and Death," 2002.^[1]

Programmed cell death had been known long before "the worm people" began to publish their celebrated findings. In 1964 Richard A. Lockshin and Carroll Williams published their contribution on "Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths",^[2] where they used the concept of programmed cell death during a time when little research was being carried out on this topic. John W. Saunders, Jr., stated the following in his 1966 contribution titled "Death in Embryonic Systems":

Abundant death, often cataclysmic in its onslaught, is part of early development in many animals; it is the usual method of eliminating organs and tissues that is useful only during embryonic or larval life^[3]

Saunders and Lockshin reciprocally acknowledged that they benefited from each other's work, and both pointed out the possibility that cell death might be regulated. Their observations helped to lead later work toward the genetic pathways of programmed cell death.

Coining of the term apoptosis

In a signal article published in 1972, John F. Kerr, Andrew H. Wyllie and A. R. Currie, coined the term "apoptosis" in order to differentiate naturally occurring developmental cell death, from the necrosis that results from acute tissue injury.^[4] They adopted the Greek word for the process of leaves falling from trees or petals falling from flowers.^[5] The word apoptosis is a combination of the prefix 'apo' and the root 'ptosis': 'apo' means 'away', 'off' or 'apart', and 'ptosis' means 'falling'. Based on the origin of the word it makes sense that it should be pronounced "APE oh TOE sis". The pronunciation "a POP tuh sis", although commonly used, ignores the origin of the word.

They also noted that the characteristic structural changes of apoptosis were present in cells that died in order to maintain an equilibrium between cell proliferation and death in a particular tissue.

Discovery of bcl-2

Landmark research by David L. Vaux and colleagues described the anti-apoptotic and tumorigenic (tumor-causing) role of the human cancer gene bcl-2 .^[6] Researchers had been hot in the track of oncogenes, and now more and more of the pieces were falling into place. However, although bcl-2 was the first component of the cell death mechanism to be cloned in any organism, identification of other components of the vertebrate mechanism had to await the linking of apoptosis with the mechanism for programmed cell death in the worm.

1990s and later

In 1991, Ron Ellis, Junying Yuan and Horvitz released a rounded and up-to-date account of research on programmed cell death in their "Mechanisms and Functions of Cell Death".^[7] Among other important work at Horvitz's laboratory, graduate students Hilary Ellis and Chand Desai had made the first discovery of genes that encode apoptosis-inducing proteins: ced-3 and ced-4. Michael Hengartner also identified a gene with an opposite effect: ced-9. The product of this gene, which is similar to bcl-2, protects cells from programmed cell death, so its expression conveys a life-or-death decision on individual cells.^[8]

In 1992, it was shown by David Vaux and Stuart Kim at Stanford that human bcl-2 gene could inhibit programmed cell death in the worm, thus linking programmed cell death and apoptosis - revealing them to be the same, evolutionarily conserved process.^[9]

In 1993, graduate students Shai Shaham and Junying Yuan working in Horvitz's laboratory identified interleukin-1-beta-converting enzyme as the mammalian homolog of the CED-3 enzyme.^[10] In 1994, Michael Hengartner published a paper showing that ced-9 had similar sequence to bcl-2.

In 1997, a protein similar to CED-4 was identified and named Apaf-1 (apoptotic protease activating factor). The team published their results in an article entitled "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3".^[11] It identified and reconstituted the mitochondrial pathway to apoptosis and illuminated whole new avenues of research on inflammatory diseases, cancer, and apoptosis in general.

By 1998, research on the topic had already increased, as attested in the editorial "Cell Death in Us and Others",^[12] written by an important contributor to apoptosis research, Pierre Golstein, in the 28 August 1998 issue of Science:

Although there have been scattered reports on the topic of cell death for more than a century, the 20,000 publications on this topic within the past 5 years reflect a shift from historically mild interest to contemporary fascination^[12]

Related Research Articles

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, approximately twenty to thirty billion cells die per day.

Caenorhabditis elegans is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek caeno- (recent), rhabditis (rod-like) and Latin elegans (elegant). In 1900, Maupas initially named it Rhabditides elegans. Osche placed it in the subgenus Caenorhabditis in 1952, and in 1955, Dougherty raised Caenorhabditis to the status of genus.

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

Programmed cell death is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.

Howard Robert Horvitz ForMemRS NAS AAA&S APS NAM is an American biologist best known for his research on the nematode worm Caenorhabditis elegans, for which he was awarded the 2002 Nobel Prize in Physiology or Medicine, together with Sydney Brenner and John E. Sulston, whose "seminal discoveries concerning the genetic regulation of organ development and programmed cell death" were "important for medical research and have shed new light on the pathogenesis of many diseases".

Sir John Edward Sulston was a British biologist and academic who won the Nobel Prize in Physiology or Medicine for his work on the cell lineage and genome of the worm Caenorhabditis elegans in 2002 with his colleagues Sydney Brenner and Robert Horvitz at the MRC Laboratory of Molecular Biology. He was a leader in human genome research and Chair of the Institute for Science, Ethics and Innovation at the University of Manchester. Sulston was in favour of science in the public interest, such as free public access of scientific information and against the patenting of genes and the privatisation of genetic technologies.

<span class="mw-page-title-main">Apoptosome</span>

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

John Graham White is an Emeritus Professor of Anatomy and Molecular Biology at the University of Wisconsin–Madison. His research interests are in the biology of the model organism Caenorhabditis elegans and laser microscopy.

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

Cell death abnormality gene 9 (CED-9), also known as apoptosis regulator CED-9, is a gene found in Caenorhabditis elegans that inhibits/represses programmed cell death (apoptosis). The gene was discovered while searching for mutations in the apoptotic pathway after the discovery of the apoptosis promoting genes CED-3 and CED-4. The gene gives rise to the apoptosis regulator CED-9 protein found as an Integral membrane protein in the mitochondrial membrane. The protein is homologous to the human apoptotic regulator Bcl-2 as well as all other proteins in the Bcl-2 protein family. CED-9 is involved in the inhibition of CED-4 which is the activator of the CED-3 caspase. Because of the pathway homology with humans as well as the specific protein homology, CED-9 has been used to represent the human cell apoptosis interactions of Bcl-2 in research.

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Ced-3 is one of the major protein components of the programmed cell death (PCD) pathway for Caenorhabditis elegans. There are in total 14 genes that are involved in programmed cell death, other important ones including ced-4 and ced-9 genes. The healthy nematode worm will require 131 somatic cell deaths out of the 1090 cells during the developmental stages. The gene initially encodes for a prototypical caspase (procaspase) where the active cysteine residue cleaves aspartate residues, thus becoming a functional caspase. Ced-3 is an executioner caspase that must dimerize with itself and be initiated by ced-4 in order to become active. Once active, it will have a series of reactions that will ultimately lead to the apoptosis of targeted cells.

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References

↑ "Horvitz's Nobel Lecture" . Retrieved 2006-12-17.
↑ Richard A. Lockshin; Carroll M. Williams (1964). "Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths". Journal of Insect Physiology. 10 (4): 643–649. doi:10.1016/0022-1910(64)90034-4.
↑ Saunders JW (November 1966). "Death in embryonic systems". Science. 154 (3749): 604–12. Bibcode:1966Sci...154..604S. doi:10.1126/science.154.3749.604. PMID 5332319.
↑ Kerr JF, Wyllie AH, Currie AR (August 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". Br J Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650 . PMID 4561027.
↑ Gilbert, S.F. (2003). Developmental Biology (7th ed.). Stamford: Sinauer Associates.
↑ Vaux DL, Cory S, Adams JM (September 1988). "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells". Nature. 335 (6189): 440–2. Bibcode:1988Natur.335..440V. doi:10.1038/335440a0. PMID 3262202.
↑ Ellis RE, Yuan JY, Horvitz HR (1991). "Mechanisms and functions of cell death". Annual Review of Cell Biology. 7: 663–98. doi:10.1146/annurev.cb.07.110191.003311. PMID 1809356.
↑ Hengartner MO, Ellis RE, Horvitz HR (April 1992). "Caenorhabditis elegans gene ced-9 protects cells from programmed cell death". Nature. 356 (6369): 494–9. Bibcode:1992Natur.356..494H. doi:10.1038/356494a0. PMID 1560823.
↑ Vaux DL, Weissman IL, Kim SK (December 1992). "Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2". Science. 258 (5090): 1955–7. Bibcode:1992Sci...258.1955V. doi:10.1126/science.1470921. PMID 1470921.
↑ Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (November 1993). "The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme". Cell. 75 (4): 641–52. doi: 10.1016/0092-8674(93)90485-9 . PMID 8242740.
↑ Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (August 1997). "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3". Cell. 90 (3): 405–13. doi: 10.1016/S0092-8674(00)80501-2 . PMID 9267021.
1 2 Golstein P (August 1998). "Cell death in us and others". Science. 281 (5381): 1283. Bibcode:1998Sci...281.1283G. doi:10.1126/science.281.5381.1283. PMID 9735040.