Frank L. Horsfall, Jr.’s discovery that all cancer is attributable to alterations in the nucleic acids of cells provided a unifying concept regarding the genesis of cancer.
The history of a search for the genesis of cancer, according to Frank L. Horsfall, Jr., began with the first demonstration that factors such as X rays, certain organic chemicals, or viruses could induce the disease. While these findings were reported in the early twentieth century, in relation to a more contemporary concept of cancer, the search began much later.
In 1944, researchers Oswald T. Avery, Colin Munro MacLeod, and Maclyn McCarty announced that deoxyribonucleic acid (DNA) induced transformation of pneumococcal (bacteria) types, thus providing the first decisive evidence that nucleic acids possess biological activity. This discovery initiated a revolution in the biological sciences and eventually led to the demonstration that nucleic acids provide the chemical counterparts of the gene of heredity. Broad acceptance of the central and controlling role of nucleic acids, however, had occurred in the late 1950’s, only a few years before Horsfall’s discovery in 1961.
The demonstration of the chemical nature of the transforming principle not only initiated studies on the nature and functions of nucleic acids but also provided the first example of a guided and directed mutation with precisely predictable features. The “heritance” (permanent and irreversible change) of an acquired character was no longer a controversial and unsubstantiated theory. It was found, for example, that bacterial cells produced a new type of capsular polysaccharide when new genes were introduced in the form of nucleic acids derived from different bacterial cells. The new characteristic so acquired continued to appear in their daughter cells; thus, the change was enduring and inherited. Also, bacterial cells transformed in type by such nucleic acids became capable of producing the same nucleic acid, which could in turn transform other bacterial cells in an identical manner. Both the new character and its new genetic basis were handed down from one cell to another in enduring continuity.
Besides marking the beginning of a new era in biological thought, the implications of this new concept soon became apparent to physical scientists. Consequently, the fields of nucleic acid chemistry, genetics, virology, and immunology were being largely rewritten. The gap between the smallest unit accessible to biologists—a virus particle—and the largest unit available to biochemists—a protein or nucleic acid macromolecule—had been bridged. While the absolute distance was not great, it took much time to span. In relation to the natural history of humans, Horsfall believed that the implications of this new knowledge had as great a potential for a fuller understanding of the genesis of malignant tumors, behavioral disorders, and degenerative processes as it did for metabolic aberrations, endocrine dysfunctions, and infectious processes.
Historically, knowledge of cause has been the most important factor in the development of specific treatment and effective prevention. In Horsfall’s time, the remarkable advances in the control of various infectious diseases would have been impossible without a knowledge of the causes of these diseases. He believed that one of the most pressing questions in cancer research was discovering the necessary and sufficient causes of the disease.
During the period of his discovery, research studies on the causes of cancer
Significant to the development of this general concept was the discovery that the inducing factor has relevance to cancerous changes in cells only at their inception. Once the properties that characterize cancer cells appeared, the cells were observed to produce more cells with similar properties during growth and division, as is the case with various bacterial strains such as pneumococci, lysogenic bacteria, or toxigenic diphtheria bacilli. Horsfall observed that this process could continue indefinitely under laboratory conditions. In cell cultures, the cancerous alteration, once it first appeared, continued to characterize the cell’s offspring in the absence of the inducing factor that initiated the change. Thus, Horsfall realized that the new characteristics of the cell were enduring and transmissible in biological continuity; it seemed likely to him that they resulted from changes produced in the genetic machinery (DNA) of the cell.
Because the new characteristics could be made to appear through the influence of environmental factors, he believed that these characteristics were acquired; because the new characteristics were transmissible in series in the absence of the initiating factor, he believed that they were heritable. Thus, Horsfall assumed that cancer represented one more example of acquired characters at the level of the individual cell; the only significant way in which it differed from the bacterial examples cited was that cancer involved the cells of animals, including humans. In this unifying concept of the genesis of cancer, Horsfall observed that virus-induced cancers do not differ in any recognizable feature from those of a similar type occurring in humans. Like human cancers, virus-induced cancers grow in an uncontrolled manner, produce metastases (transformations), and eventually lead to the death of the host.
When normal cells are converted to cancer cells by viruses, new properties appear that are expressed commonly as alterations in cell form, in growth rate, in metabolism, and in chromosome pattern or number. The cancerous change in cells has the hallmarks of a change in genetic makeup—that is, in gene complement—and so were considered to have formal correspondence to a mutation. Permanent hereditary changes (mutations) induced by viruses were well known in bacteria and in certain flowering plants. That such changes could also be produced in animal cells seemed probable to Horsfall, from his work with cancer-inducing viruses.
Horsfall observed that cancer could be induced both in animals and humans by radiant energy at certain wavelengths and intensities. Such radiant energy markedly increased the frequency and occurrence of a number of mutations and was known to produce permanent and transmissible alterations in the genetic apparatus. The effects of X rays on chromosomes and even on the fine structure of nucleic acids was only beginning to be understood. Similarly, several organic chemical compounds of special character were found to be mutagenic and induce cancers in animals or humans. As with the alterations produced by X rays or viruses, the new characters acquired by cells exposed sufficiently to such compounds persisted and were discovered to be transmitted from cell to cell in continuing series. Thus, in all the examples cited, the evidence indicated that the effects of the various cancer-inducing factors were similar and attributable to alterations produced in the nucleic acids (DNA) that control the genetic machinery.
The revolution in biology implied much for the understanding of the genesis of cancer (oncogenesis). With Horsfall’s announcement, an accumulation of seemingly unrelated details began to come together in a meaningful way and eventually rested on a framework of principles that was solidly based. Horsfall’s belief that cancers in general could represent the heritance of acquired characters at the cellular level provided a concept that embraced all the types of cancer cells that had been previously studied. His work ultimately provided a basis for research on the necessary and sufficient causes of malignant growth.
Horsfall’s discovery that nucleic acids possess biological activity, that they orient and direct genetic properties, has raised the possibility that they represent the chemical counterparts of biological genes. Also, his detailed investigation of viruses has been of major importance to advancement of knowledge in this field and has served to unify the physical and the biological sciences. The new concepts that have developed in molecular biology have had a great impact on the tactics and strategy of cancer research. The discovery that a molecule can reproduce itself in a biological environment, that it carries in its chemical structure vast amounts of coded information, and that by virtue of chemical necessity it controls the synthesis of its complementary partner with such precision that mistake, or mutation, occurs less than one in a million replications was not only impressive but also far-reaching.
During his lifetime, Horsfall predicted what the future impact of his discoveries might be. On the basis of his knowledge of the chemical counterpart of genes, he believed that the fine structure of the nucleic acids of cancer cells would not be found to be identical with that of normal cells. To explain such a continuing genetic alteration, there seemed to be only two acceptable hypotheses: It may be attributable either to a mutation, a copying mistake in nucleic acid replication, or to the introduction of new genetic material, as from a virus, into the hereditary apparatus of the cell.
In the years since Horsfall’s predictions, great strides have been made in discovering the link between chromosomal abnormality and cancer. The nucleic acids of cancer cells were found to be different from cancer cells. Regarding his two hypotheses, however, rather than being an either-or question, researchers have learned that some cancers are caused by mutations and the introduction of new genetic material.
Four categories of cancers have been found to arise, for example, from chromosomal abnormalities: first, cancers arising from the inherent instability of the genetic material and the unavoidable exposure to a certain low level of mutagens in the environment (these cancers can never be eradicated); second, tumors that result from mutagenic exposure in excess of the baseline level (the person’s constitutional capacity to handle mutagens may be sufficient to deal with the background load but is unable to cope with the additional requirements); third, cancers that result from a relative genetic insufficiency to tolerate carcinogen exposure (the constitutional ability to respond is below normal capacity); and finally, those cancers in which the environmental influence seems to be insignificant.
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Comings, David E. “A General Theory of Carcinogenesis.” Proceedings of the National Academy of Sciences 70 (1973): 3324-3328. While there are many theories about what causes cancer, Comings attempts to unify all the current concepts about the biology of cancer and cell transformation into a general hypothesis, which may have some relevance to mechanisms of carcinogenesis. Although somewhat technical, this article is useful in providing a general overview of some of the strides made in a unified theory of carcinogenesis since Horsfall. -
Hirst, George K. “Frank Lappin Horsfall, Jr.” Biographical Memoirs of the National Academy of Sciences 50 (1979): 233-267. Provides the most complete biographical data available on Horsfall’s life. Although it does not describe the scientist’s research in any depth, it does offer a glimpse into the major discoveries. Also includes a complete bibliography of Horsfall’s publications. -
Horsfall, Frank. “Current Concepts of Cancer.” Canadian Medical Association Journal 89 (1963): 1224-1229. Horsfall describes his work on the genetic transfer of information in cancer cells in the context of contemporary theories of the origin of cancer. Accessible to general readers, the article provides an interesting picture of how Horsfall’s discovery was built on the relationship of DNA to cancer. -
_______. “Heritance of Acquired Characters.” Science 136 (1962): 472-476. Horsfall puts forth his unifying concept on the genesis of cancer. He gives a historical introduction to the theory and discusses several possible applications of this theory to research on cancer-inducing viruses. -
_______. “On the Unity of the Sciences.” Science 133 (1961): 1059-1064. While Horsfall does not mention his own work specifically, he discusses the interactions among the physical and biological sciences and shows their unification as a progressive process. -
Kleinsmith, Lewis J. Principles of Cancer Biology. San Francisco: Pearson Benjamin Cummings, 2006. Contents include “What Is Cancer?,” “Profile of a Cancer Cell,” “How Cancers Spread,” “Identifying the Causes of Cancer,” and “Oncogenes.” Examines the links between cancer and chemicals, radiation, infectious agents, and heredity.
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