A History of Cancer Research: Carcinogens and Mutagens

Abstract

Observations of the incidence of tumors among chimney sweeps in the eighteenth century and later experiments with coal tars provided early evidence that carcinogens in the environment can promote cancer. Subsequent studies of individuals exposed to radiation, work on fly genetics, and the discovery that DNA was the genetic material led to the idea that these carcinogens act by inducing mutations in DNA that change the behavior of cells and ultimately cause cancer. In this excerpt from his forthcoming book, Joe Lipsick looks back at how the concepts of mutagenesis and carcinogenesis emerged, how these converged with development of the Ames test, and how biochemistry and crystallography ultimately revealed the underlying molecular basis.

Figure 1.

On the plight of eighteenth-century English chimney sweeps. From William Blake's “The Chimney Sweeper,” in Songs of Experience, 1794.

Figure 2.

Cancer of the scrotum, illustrated by Horace Benge Dobell in 1848. (Reproduced from https:// wellcomecollection.org/works/njqbesup.)

Figure 3.

(Left) A rabbit's ear with cancers induced by coal tar. (Right) Yamagiwa's haiku: “Cancer was produced! Proudly I walk a few steps.” (Left, Image from Fujiki H 2014. Cancer Science 105: 143–149; originally from Yamagiwa K, Ichikawa K. 1915. Mitteilungen of Medical Faculty of Imperial University of Tokyo 15: 295–344; right, from Shimkin MB 1977. “Contrary to Nature,” HHS Publication No. (NIH) 76-720, U.S. Department of Health, Education and Welfare, Washington, DC.)

Figure 4.

Two polycyclic aromatic hydrocarbon carcinogens: 1,2:5,6-dibenzanthracene (left) and benzo[a]pyrene (right).

Figure 5.

(Left) Early X-ray of the hand of Wilhelm Roentgen's wife, Anna Berthe. (Right) Drawing of X-ray-induced damage to the hand. (Reproduced from Leonard Mark, 1908, from Saint Bartholomew's Hospital Museum and Archives; http://www.calmhosting01.com/BartsHealth/CalmView/Record.aspx?src=CalmView.Catalog&id=%2f35%2f22.)

Figure 6.

(Left) The pedoscope, a fixture in American shoe stores from the 1920s to the1960s. (Right) If the shoe fits, wear it. (Reprinted, with permission, from Oak Ridge Associated Universities [http://www.orau.org/ptp/collection/shoefittingfluor/shoe.htm], © ORAU.)

Figure 7.

(Left) Bloated wings caused by the X-ray-induced delta-49 inversion. (Right) Schematic and camera lucida drawings of paired X chromosomes from the larval salivary gland of a Drosophila that was heterozygous for the X chromosome with the delta-49 inversion. (Left, Reprinted from Muller HJ. 1930. J Genet 20: 299–334; right, reprinted from Painter TS. 1934. Genetics 19: 448–469.)

Figure 8.

Metabolically activated benzo[a]pyrene (BP) covalently bonds to DNA bases. (Modified, with permission, from Bauer J, et al. 2007. Proc Natl Acad Sci 104: 14905–14910, © National Academy of Sciences, USA.)

Figure 9.

Mutagenicity versus carcinogenicity. (Left) An oft-cited early report showing a strong correlation (R = ∼0.9). (Right) A more thorough study showing a much weaker correlation (R = ∼0.3). (AFB) aflatoxin B₁, (HAA) N-hydroxy-2-acetylaminofluorene, (SAC) saccharin. (Left, Reprinted from Meselson M, Russell K. 1977. In Origins of Human Cancer (ed. Hiatt H, et al.), pp. 1473–1481, © Cold Spring Harbor Laboratory Press; right, reprinted, with permission, from McCann, et al. 1988. Mutat Res 205: 183–195, © Elsevier.)

Figure 10.

The hydrophobic BP-DNA adduct prefers to intercalate between the hydrophobic bases of the DNA double helix (A,D). However, a hydrophobic pocket peculiar to the Y-family DNA polymerases flips the BP-DNA adduct out of the double helix (B,C,E,F), thereby permitting bypass synthesis. (Reprinted, with permission, from Bauer J, et al. 2007. Proc Natl Acad Sci 104: 14905–14910, © National Academy of Sciences, USA.)