History and highlights in apoptosis research
Encyclopedia
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
.
'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:
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", 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":
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.
that results from acute tissue injury. They adopted the Greek word for the process of leaves falling from trees or petals falling from flowers. The word apoptosis is a combination of the prefix 'apo' and the root 'ptosis'. Apo means away, off or apart. Ptosis means to fall. 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 it is 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.
. Researchers had been hot in the track of oncogene
s, 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.
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.
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.
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". 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", written by an important contributor to apoptosis research, Pierre Golstein, in the 28 August 1998 issue of Science:
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
.
Early research, and the "worm people" at Cambridge
Sydney BrennerSydney Brenner
Sydney Brenner, CH FRS is a South African biologist and a 2002 Nobel prize in Physiology or Medicine laureate, shared with H...
's studies on animal development began in the late-1950s
1950s
The 1950s or The Fifties was the decade that began on January 1, 1950 and ended on December 31, 1959. The decade was the sixth decade of the 20th century...
in what was to become the Laboratory of Molecular Biology
Laboratory of Molecular Biology
The Laboratory of Molecular Biology is a research institute in Cambridge, England, which was at the forefront of the revolution in molecular biology which occurred in the 1950–60s, since then it remains a major medical research laboratory with a much broader focus.-Early beginnings: 1947-61:Max...
(LMB) in Cambridge
Cambridge
The city of Cambridge is a university town and the administrative centre of the county of Cambridgeshire, England. It lies in East Anglia about north of London. Cambridge is at the heart of the high-technology centre known as Silicon Fen – a play on Silicon Valley and the fens surrounding the...
, UK. It was at this lab that during the 1970s and 1980s, a team led by John Sulston succeeded in tracing the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
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
H. Robert Horvitz
Howard Robert Horvitz is an American biologist best known for his research on the nematode worm Caenorhabditis elegans.-Life:Horvitz did his undergraduate studies at MIT in 1968, where he joined Alpha Epsilon Pi...
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
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
with Brenner, and Horvitz would go back to the US in 1978 to establish his own lab at the Massachusetts Institute of Technology
Massachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...
.
Brenner's original interests were centered in genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
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.
Programmed cell death had been known long before "the worm people" began to publish their celebrated findings. In 1964 Richard A. Lockshin
Richard A. Lockshin
Richard A. Lockshin is an American cellular biologist known for his work on apoptosis.He was educated at Harvard University where, in 1959, he obtained his bachelor's degree. This was followed by doctoral studies at Harvard University under the guidance of Carroll Williams...
and Carroll Williams
Carroll Williams
Carroll Milton Williams was an American zoologist known for his work in entomology and developmental biology -- in particular, metamorphosis in insects...
published their contribution on "Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths", 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
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 necrosisNecrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
that results from acute tissue injury. They adopted the Greek word for the process of leaves falling from trees or petals falling from flowers. The word apoptosis is a combination of the prefix 'apo' and the root 'ptosis'. Apo means away, off or apart. Ptosis means to fall. 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 it is 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-2Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
. Researchers had been hot in the track of oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
s, 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". 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.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.
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.
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". 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", 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