In the early 1960s, John W. Saunders Jr., Mary T. Gasseling, and Lilyan C. Saunders in the US investigated how cells die in the developing limbs of chick embryos. They studied when and where in developing limbs many cells die, and they studied the functions of cell death in wing development. At a time when only a few developmental biologists studied cell death, or apoptosis, Saunders and his colleagues showed that researchers could use embryological experiments to uncover the causal mechanisms of apotosis. The researchers published many of their results in the 1962 paper 'Cellular death in morphogenesis of the avian wing.'

The Hayflick Limit is a concept that helps to explain the mechanisms behind cellular aging. The concept states that a normal human cell can only replicate and divide forty to sixty times before it cannot divide anymore, and will break down by programmed cell death or apoptosis. The concept of the Hayflick Limit revised Alexis Carrel's earlier theory, which stated that cells can replicate themselves infinitely. Leonard Hayflick developed the concept while at the Wistar Institute in Philadelphia, Pennsylvania, in 1965. In his 1974 book Intrinsic Mutagenesis, Frank Macfarlane Burnet named the concept after Hayflick. The concept of the Hayflick Limit helped scientists study the effects of cellular aging on human populations from embryonic development to death, including the discovery of the effects of shortening repetitive sequences of DNA, called telomeres, on the ends of chromosomes. Elizabeth Blackburn, Jack Szostak and Carol Greider received the Nobel Prize in Physiology or Medicine in 2009 for their work on genetic structures related to the Hayflick Limit.

Apoptosis, or programmed cell death, is a mechanism in embryonic development that occurs naturally in organisms. Apoptosis is a different process from cell necrosis, which is uncontrolled cell death usually after infection or specific trauma. As cells rapidly proliferate during development, some of them undergo apoptosis, which is necessary for many stages in development, including neural development, reduction in egg cells (oocytes) at birth, as well as the shaping of fingers and vestigial organs in humans and other animals. Sydney Brenner, H. Robert Horvitz, and John E. Sulston received the Nobel Prize in Physiology or Medicine in 2002 for their work on the genetic regulation of organ development and programmed cell death. Research on cell lineages before and after embryonic development may lead to new ways to reduce or promote cell death, which can be important in preventing diseases such as Alzheimer's or cancer.

The review article “Cell Deaths in Normal Vertebrate Ontogeny” (abbreviated as “Cell Deaths”) was published in Biological Reviews of the Cambridge Philosophy Society in 1951. The author, Alfred Glücksmann, was a German developmental biologist then working at the Strangeways Research Laboratory, Cambridge, England. In “Cell Deaths,” Glücksmann summarizes observations about cell death in normal vertebrate development that he had compiled from literature published during the first half of the twentieth century. “Cell Deaths” emphasizes the frequent occurrence of cell death in various locations and stages of development, and suggests that cell death functions as a crucial mechanism in integrating cells into tissues and organs in normal vertebrate ontogeny.

In an effort to develop tissue culture techniques for long-term tissue cultivation, French surgeon and biologist Alexis Carrel, and his associates, produced and maintained a series of chick heart tissue cultures at the Rockefeller Institute in New York City. From 1912 to 1946, this series of chick heart tissue cultures remained alive and dividing. Since the duration of this culture greatly exceeded the normal chick life span, the cells were deemed immortal. Although this conclusion was challenged by further experiments in the 1960s, the publicity surrounding the immortal chick heart tissue significantly influenced the concept of cell immortality and cellular aging from the 1920s through the 1960s. Carrel's experiment convinced many biologists to accept immortality as an intrinsic property of all cells, not just the cell line through which genetic material is passed to offspring, called the germ line. Consequently, the phenomenon of cellular aging was regarded not as an intrinsic characteristic, but was attributed to external factors such as the accumulation of waste products within the cell.

The HeLa cell line was the first immortal human cell line that George Otto Gey, Margaret Gey, and Mary Kucibek first isolated from Henrietta Lacks and developed at The Johns Hopkins Hospital in Baltimore, Maryland, in 1951. An immortal human cell line is a cluster of cells that continuously multiply on their own outside of the human from which they originated. Scientists use immortal human cell lines in their research to investigate how cells function in humans. Though the HeLa cell line has contributed to many advancements in biomedical research since the twentieth century, its usage in medical research has been controversial because Lacks did not consent to having her cells used for such purposes. As of 2020, scientists continue to use the HeLa cell line for numerous scientific advancements, such as the development of vaccines and the identification of many underlying disease mechanisms.

An important question throughout the history of embryology is whether the formation of a biological structure is predetermined or shaped by its environment. If both intrinsic and environmental controls occur, how exactly do the two processes coordinate in crafting specific forms and functions? When Viktor Hamburger started his PhD study in embryology in the 1920s, few neuroembryologists were investigating how the central neurons innervate peripheral organs. As Hamburger began his research, he had no clue that central-peripheral relations in the development of the central nervous system (CNS) would become one of his major interests for the next seventy-five years. In fact, this research trajectory would lead him to discover programmed cell death as a pivotal mechanism mediating central-peripheral relations, as well as to Nobel-Prize-winning work on nerve growth factors (NGF).

The p53 protein acts as a pivotal suppressor of inappropriate cell proliferation. By initiating suppressive effects through induction of apoptosis, cell senescence, or transient cell-cycle arrest, p53 plays an important role in cancer suppression, developmental regulation, and aging. Its discovery in 1979 was a product of research into viral etiology and the immunology of cancer. The p53 protein was first identified in a study of the role of viruses in cancer through its ability to form a complex with viral tumor antigens. In the same year, an immunological study of cancer also found p53 due to its immunoreactivity with tumor antisera. Although a series of studies found p53 through various routes, and various researchers called it different names, it was eventually confirmed that they had all encountered the same protein, p53.

"Apoptosis: A Basic Biological Phenomenon with Wide-Ranging Implications in Tissue Kinetics" (hereafter abbreviated as "Apoptosis") was published in the British Journal of Cancer in 1972 and co-authored by three pathologists who collaborated at the University of Aberdeen, Scotland. In this paper the authors propose the term apoptosis for regulated cell death that proceeds through active, controlled morphological changes. This is in contrast to necrosis, a passive mode of cell death that results from uncontrolled cellular reactions to injury or stress. The journal article also suggests that apoptosis plays crucial roles in various pathological and physiological conditions including the shaping of digits and the shrinking of vestigial organs in developing embryos.

Once perceived as an unimportant occurrence in living organisms, cell degeneration was reconfigured as an important biological phenomenon in development, aging, health, and diseases in the twentieth century. This dissertation tells a twentieth-century history of scientific investigations on cell degeneration, including cell death and aging. By describing four central developments in cell degeneration research with the four major chapters, I trace the emergence of the degenerating cell as a scientific object, describe the generations of a variety of concepts, interpretations and usages associated with cell death and aging, and analyze the transforming influences of the rising cell degeneration research.

Subscribe to Cell Death