吞噬细胞（Phagocytes）是Ilya (Elie) Metchnikoff（梅契尼科夫）首先描述和记录的，他意识到吞噬细胞吞噬了死亡的细胞。到20世纪中叶，研究人员开始探索细胞是如何死亡的，已经认识到细胞死亡是一个生理控制的过程，最常见的死亡模式（“萎缩坏死”，后来的凋亡）受到严格控制，在1990年之前，一些发现阐明了细胞凋亡的机制。21世纪初，认为自噬过程与细胞凋亡有关，可以限制或增加细胞死亡。之后，研究转向了什么代谢或其他机制间接控制细胞死亡正反馈回路的激活或抑制的问题。
推动这一领域发展的是三项科学进步：
技术上的突破：DNA电泳技术可以证明细胞凋亡，因为在坏死细胞中随机降解的DNA会产生涂片，而在细胞凋亡中，DNA在核小体之间以更有序的方式切割。
概念上的突破：认识到一些疾病，特别是癌症，与细胞死亡的异常模式有关。
理论上的突破：认识到细胞死亡的机制，甚至细胞死亡的组成部分，在从线虫到哺乳动物的进化过程中是保守的。
Table. Important events in the history of cell death Exp Oncol. 2012 Oct;34(3):146-52
Year Event Classification Refe-rence
19th and early 20th C: DESCRIPTIONS OF CELL DEATH IN MOSTLY PHYSIOLOGICAL SITUATIONS
1842 Vogt describes resorption of notochord during amphibian metamorphosis, notes that it is physiological Physiological; metamorphosis
1864 Weismann: massive cell loss in insect metamorphosis; describes histolysis Physiological; metamorphosis; description
1872 Stieda: death of chondrocytes during ossification Physiological; development [33]
1883 Metchnikoff: loss of muscles during amphibian metamorphosis; activity of phagocytes Physiological; metamorphosis [3]
1885 Flemming: cell death in rabbit ovarian follicle (chromatolysis) is physiological Physiological; development
1889 Felix: denervated myocytes die Pathological [34]
1890 Arnheim: margination of chromatin Description of apoptosis [35]
1906 Collin: morphology of dying motor and sensory neurons in chicks Physiological; development; [36]
1910 von Recklinghausen: oncosis from ischemia or toxic agents Non-physiological; necrosis
1914 Gräper: Chromatolysis of all cells eliminated from organs; phagocytosis of neighboring cells Physiological; apoptosis (not yet named) as general [37]
1934–1951: ACCEPTANCE OF CELL DEATH AS PHYSIOLOGICAL
1934 Hamburger: A factor that controls number of neurons Physiological; development
1949 Hamburger and Levi-Montalcini: emphasize death of neurons in CNS of embryos Physiological; development
1951 Gluecksmann reviews cell death in ontogenesis; a normal part of animal development Physiological; development
1955–1973: PHYSIOLOGICAL MECHANISMS; DEFINITION OF PROGRAMMED CELL DEATH AND APOPTOSIS
1955–1959 De Duve and others recognize lysosomes and identify them as “suicide bags” Physiological and pathological; mechanism
1961 Bellairs: describes cell death in chick embryo Physiological; description [38]
1964–1965 Lockshin and Williams: Programmed cell death in insect metamorphosis Physiological; mechanism; programmed cell death
1966 Saunders: “The death clock is ticking;” cell death is a suicide Physiological; development
1966 Tata: Programmed cell death requires protein synthesis (confirmed 1969, 1971 in insect metamorphosis and thymocytes involution; later in neuronal death; otherwise not general) Physiological; mechanism
1972 Kerr, Wyllie, Currie: Apoptosis is general in morphology and among animals Physiological; mechanism
1973 Schweichel and Merker: classify types of death Physiological [39]
1973–1992: MECHANISMS OF APOPTOSIS AND IDENTIFICATION OF GENETICS OF APOPTOSIS
1976 Skalka et al.: DNA fragmentation is typical of apoptosis
[40]
1976 Sulston: nuc-1, a gene involved in cell death Caenorhabditis [41]
1979 Farber and Fisher: Free radicals can cause cell suicide
[42]
1982 Horvitz et al.: Genetic paths of cell death Caenorhabditis [43]
1983 Hedgecock: mutants of cell death genes Caenorhabditis [44]
1984 Wyllie et al.: relate chromatin condensation to DNA fragmentation
[24]
1989–1992 Identification of a cell surface receptor that can lead to cell death (Fas/APO-1/CD95)
1986 Ellis and Horvitz: ced-3 and ced-4, genes that can kill cells Caenorhabditis [45]
1992 Hengartner et al.: ced 9, a gene that can protect cells Caenorhabditis [46]
1991–1994 p53 can induce apoptosis
1992 Phosphatidylserine is a marker of apoptosis
[47]
1992–2000: Discovery of the genes of cell death
1992 Vaux et al.: Bcl-2 equivalent to ced-9
[48]
1993 Yuan et al.: CED-3 is related to ICE
1993 Baculovirus p35 can inhibit apoptosis
[49]
1994 Hengartner and Horvitz: CED-9 is similar to Bcl-2
[50]
1996 Caspases defined
[50]
1996–1997 Importance of release of cytochrome c for inducing apoptosis
[51]
1997 Zou et al.: identify Apaf-1, similar to CED-4
[52]
1998 Del Peso et al.: EGL-1 inhibits CED-9
[53]
2000 ff RECOGNITION OF DIFFERENT TYPES OF CELL DEATH
1970’s Most cell death is considered to be lysosomal; many papers
1973 Schweichel and Merker: classify types of death Physiological [43]
1995 Majno and Joris: Apoptosis, oncosis, necrosis
[54]
Lockshin and Zakeri: Other types of cell death
[55]
2005 Broker et al.: cell death independent of caspases
[56]
2005 Kroemer et al.: Classification of cell death
[57]
2008 Degterev and Yuan: Cell death programs, including necroptosis
[58]
Kroemer et al.: Role of autophagy
[59, 60]
2008, 2012 Klionsky et al.: Guidelines for evaluating autophagy
[61]
主要参考文献
Am J Pathol 1990; 136: 593–608
Nature 1993; 362: 847–9
Cell 1993; 75: 641–52
Programmed cell death and apoptosis — where it came from and where it is going: From Elie Metchnikoff to the control of caspases，Exp Oncol. 2012 Oct;34(3):146-52.
