Cancer Research, History of

Michel Morange. Encyclopedia of Life Sciences: Supplementary Set. Volume 21. Wiley, 2007.

History of cancer research has always been closely linked with the history of biology. In particular, cancer research has been revitalized during the last two decades through the development and transformation of molecular biology.

Introduction

‘Biology and Cancer Research have developed together. Invariably, at each stage, the characteristics of the cancer cell have been ascribed to some defect in whatever branch of biology happens at the time to be fashionable and exciting.’ This quotation from John Cairns highlights the main difficulty encountered in writing a history of cancer research: it has occupied such an important place in the work of biologists—in particular during the last century-that its history generally coincides with the history of biology as a whole. Furthermore, cancer was the initial motivation behind many studies that led to developments unrelated to cancer. Finally a history of cancer research has to include a history of the different therapies used against cancer, since these therapies were based on rationales that had their origins in a specific vision of cancer.

Cancer was described and named first by Hippocrates, then by Galen, the Greek word ‘crab’ referring to the form of the tumour, with the blood vessels irradiating from it. It was initially considered to be the outcome of inflammation due to ‘black bile’. The history of cancer research is therefore extremely long, and it would be pointless to provide a chronological description of all the observations that have been made. Cancer research has continually swung between models viewing cancer as having an exogenous origin (of various kinds) or an endogenous origin, linked to some kind of organic degeneration. This oscillation was not specific to cancer research, but also concerned other diseases, including those we now know to be infectious diseases. Depending on the different theories and models, either the properties of cancer were explained by its origins or, on the other hand, cancer was viewed as a process relatively unrelated to the initial event that generated it.

For simplicity’s sake, cancer research will be assumed to have been non-existent prior to the advent of cell theory, apart from some very interesting epidemiological observations that will be described later. Three major steps in cancer research will be outlined. First, the view of cancer as due to cell proliferation, with the progressive characterization of the cancer cell during the nineteenth century. Thirdly, the present vision of cancer as a molecular disease, with the discovery of oncogenes and anti-oncogenes from the 1970s onwards. Between them, during the last decades of the nineteenth century and the first half of the twentieth century, the origin and mechanisms of cancer were sought for in the disciplines that developed at the time—microbiology, biochemistry, genetics, endocrinology, etc. The models that emerged have since been more or less integrated into the current molecular paradigm.

As far as therapy is concerned, the list of useless drugs used over the centuries would be too long—and too depressing—to report. Surgical ablation of the tumour, which was first employed at the end of the eighteenth century for breast cancer, became safe and more effective in parallel with the general development of surgery (in particular of anaesthesia and asepsis). It remained the only effective treatment until the beginning of the twentieth century.

Cancer as a Cellular Disease

The vision of cancer as a cellular disease developed rapidly, at the same time as the microscope was extensively used to study the organization of tissues and cell theory was elaborated. In the same year (1838) that Theodor Schwann proposed the cell theory, Johannes Müller, who was Schwann’s director, started his studies on the cell structure of tumours. The new vision was a reaction against the conceptions of Xavier Bichat and Rene´ Laënnec, who considered that cancer had its origin in tissues, and that cancer was thus both a local and a general disease. The conception of cancer as a cellular disease was further developed by Rudolf Virchow, a strong supporter of the theory of cell continuity and the popularizer of the famous aphorism ‘omnis cellula e cellula’ [every cell comes from another cell]. This new conception of cancer was responsible for the progressive unification of a range of diseases that were previously dispersed or poorly characterized: after much debate, leukaemias, described by John Hughes Bennett in 1845 and named by Rudolf Virchow, were recognized as cancer. The same was true for lymphomas, discovered by Thomas Hodgkin in 1832, and named in 1856. The steps leading to the progressive formation of a tumour were described by Wilhelm Waldeyer, who developed the very important idea that each type of tumour derives from the proliferation of one cell type. He was also among the first to distinguish between benign and malignant tumours. Jacob Henle hypothesized that metastases result from displaced cancerous cells. Using the definition of three cell layers that had been given recently by embryologists, carcinomas, tumours of epithelial origin, and sarcomas were distinguished. These numerous observations led to the development of histopathology (the study of the morphology of the cancerous cells), and through the determination of the origin and evolution of cancers, the possibility of a diagnosis and a prognosis. In practice, the development of histopathology was very slow, and became commonly used in cancer diagnosis only during the twentieth century. However, despite a general agreement on the cellular processes leading to tumour formation, scientists did not agree on the origin of tumours: Rudolf Virchow considere d that tumour development was the result of a local inflammation of the connective tissue, whereas in 1875 J. Cohnheim proposed that cancers came from cells that had been left aside during the development of the organism. In 1865 C. Thiersch proposed that cancer resulted from a disequilibrium in growth energy, an idea that was to develop during the first part of the twentieth century.

Probably the most important experimental consequence of this new cellular vision for cancer research was the first attempt at tumour transplantation by J. Doutrelepont in 1868, followed by M. Novinsky, A. Hanau and H. Morau, and many others. These early studies were not always reproducible. They also had varying objectives: some were aimed at discovering a pathogenic agent associated with the tumours (see below). Most of these studies confirmed the remarkable stability of the properties of cancerous cells, but nevertheless provided interesting clues about the parameters that affect the growth of transplanted tumours, and in particular the relationships between the donor—the organism from which the tumour comes—and the recipient—the organism into which the tumour is transplanted. It was also observed that pregnancy had an influence on tumour development. These early observations were developed in the first half of the twentieth century, opening a highly productive line of research on the role of the immune system and hormones in tumour development (it also led to the characterization of tissue antigens and the development of grafts).

Finally, tumour growth was interpreted as a Darwinian competition between normal and tumour cells. The vision of cancerous cells as cells that have escaped the control of the organism and act egoistically pervaded biological thought from the end of the nineteenth century, and is still very present in the current conceptions of cancer.

Cancer Research During the First Half of the Twentieth Century

Cancer caused by microorganisms?

The successes of Robert Koch’s and Louis Pasteur’s schools of microbiology, and the growing number of microbes shown to be involved in disease, led to the search for cancer-causing germs, despite the fact that cancer is clearly not a contagious disease. Many bacilli were described, as well as protozoa and yeasts. However, the criteria laid down by Koch to ascribe a given microbe a specific role in a pathology were never met, and such studies became rarer in the early years of the twentieth century. As early as 1903, viruses replaced bacteria as causative agents of cancer: involvement of viruses in cancer is another, more brilliant chapter of the history of cancer research.

Cancer as a dysregulation of metabolism

Otto Warburg, whose work on respiration was at the origin of modern biochemistry, was the first to pinpoint one central biochemical defect affecting cancer cells: they use the glycolytic pathway in conditions of high oxygen supply, whereas normal cells switch off this pathway, which is specifically associated with anaerobiosis. This regulation was known as the Pasteur effect, following its initial description by the founder of microbiology. Not only did Warburg provide strong experimental support for this observation by working on different types of tumours, he also made a model, linking this alteration of metabolism to the formation of cancer cells: for him, the initial event leading to cancer was an alteration of cellular respiration; the cell reacted and adapted to this change by increasing the activity of the glycolytic pathway. This pathway is much used by embryonic tissues, and this cellular adaptation was therefore parallel to the regression of the cancerous cell to a poorly differentiated state.

Otto Warburg remained firmly convinced by his theory, despite subsequent criticisms. Other biochemists put forward ideas that were more or less related to Warburg’s. Ephraim Racker suggested that the initial change in the cell involved acido-basic regulation rather than respiration. Albert Szent-Györgyi, who in 1937 received the Nobel Prize in Physiology or Medicine for his work on vitamin C, considered the cell—and proteins—as conductor, and cancer as an overall perturbation of this circulation of electrons. In the 1960s, his ideas were developed by Bernard Pullman. Linus Pauling’s campaign in favour of vitamin C treatment as a way to avoid cancer is a kind of degenerate product of this vision of cancer as a perturbation of oxidative metabolism. Interestingly, the perturbations of the energetic metabolism of cancerous cells have been confirmed since, but have yet to find a satisfactory explanation at the molecular level

Since protein synthesis is a very important part of cell metabolism, its modification was also thought to be involved in the origin of cancer. At the end of the 1940s, differences were initially noted between normal and cancerous cells, using the new radioactively labelled amino acids. However, these observations were not confirmed, and the scientists involved soon abandoned their initial aim: this research paved the way to understanding the mechanisms of protein synthesis, and the deciphering of the genetic code.

Hormones and cancer

The discovery by Antoine Lacassagne in 1932 that the injection of oestrogen in male mice induced the formation of mammary tumours led to many studies on the effects of hormones, particularly sexual hormones, in tumour development. It was subsequently shown that some forms of breast or prostate cancer responded to hormone treatment (later involving hormone analogues). The fact that Lacassagne’s discovery was made at a time when hormones were being given a major role in physiology and in embryology was surely not a concidence.

Cancer and the environment

The hypothesis that cancer could result from the action of compounds present in the environment is not new. In 1775, Percivall Pott showed that scrotal cancer was relatively frequent in chimney sweeps who began work as boys. In 1879, it was observed that lung cancer affected coal miners. Aniline dye was also shown to induce the formation of bladder cancer in workers in the chemical industry. Experiments performed in 1915 on rabbits showed that these animals developed tumours when their ears were painted with coal tar. In the late 1920s, E. Kennaway isolated polycyclic aromatic hydrocarbons from coal tar and demonstrated their carcinogenic power. X-rays were known to have a carcinogenic effect, and radium was also shown to be responsible for tumours. The carcinogenic effect of radiation and radioactive compounds was widely confirmed by medical studies following the atomic bombs dropped on Hiroshima and Nagasaki at the end of World War II. Fears immediately rose as to the potentially deleterious effects of atomic tests on the environment.

The role of cigarette smoke in inducing lung cancer was officially established by two epidemiological studies, one in England in 1962, the second in the United States two years later. In fact, the link between smoking and lung cancer had long been suspected—the first anti-tobacco campaign was launched in the 1930s by Nazi politicians in Germany. In the 1950s and 1960s, more and more compounds produced by the chemical industry, such as asbestos, were shown to be potentially oncogenic.

Genetics and cancer

The idea that genes were involved in cancer was proposed by Lucien Cuénot in 1908, soon after the rediscovery of Mendel’s laws in 1900. At the same time, Theodor Boveri correlated the modifications in cell division of cancerous cells with chromosomal alterations that could be observed in these cells. In the 1920s Hermann Muller showed that X-rays, which had previously been observed to both cure and induce cancer, were mutagenic. This supported the idea that gene mutations were at the origin of cancer.

However, apart from rare, familial forms of cancers which were described in the twentieth century, observations in human populations do not support a simple genetic model of cancer. The extensive work of Clarence C. Little at the Jackson Memorial Laboratory showed that different pure strains of mice could have very different rates of cancer. In particular, he isolated one strain with an exceptionally high susceptibility to breast cancer. However, further studies by John Bittner in the 1950s showed that these tumours resulted from the transmission of a virus through the mothers’ milk. In addition to a general distrust of the eugenic ideas that underlay the use of pure strains of mice, this result led to a shift in favour of the viral origin of cancer, a theory that was in direct competition with the genetic theory of cancer. Despite these ambiguous results, the hypothesis that cancer has its roots in somatic mutations occurring during the life of the organism became relatively well established, as more and more carcinogenic compounds isolated from the environment were shown to be mutagenic, either spontaneously or following their transformation by the organism.

Cancer and viruses

At the same time, the role of viruses in inducing cancer was taken more and more seriously. The first observations suggesting that viruses were involved in tumour formation were made by Amédée Borrel at the Pasteur Institute (Paris) in 1903. This was a logical development of previous research on the involvement of microbes in tumour formation. In 1908, Vilhelm Ellermann and Oluf Bang showed that leukaemia could be transmitted in the chicken by an ultrafiltrating agent, and Peyton Rous obtained the same result for a sarcoma. Similar results were obtained in rabbits and in mice for breast cancer, and further work on leukaemia in mice was carried out by Ludwig Gross in the 1950s. Many RNA viruses (‘retroviruses’) were isolated from such studies. In the 1970s, the Epstein-Barr virus was the first virus to be shown responsible for a (rare) form of human cancer.

A confused situation

At the beginning of the 1970s, cancer research was totally confused. Although there were strong arguments in favour of somatic mutations induced by environmental factors being at the origin of cancer, some viruses had been clearly shown to be oncogenic, at least in animals

On the therapeutic front, surgery remained the major treatment. For breast cancer, which was the focus of major campaigns in the USA after World War II, surgery, on the basis of early diagnosis, was considered to be appropriate, despite the absence of any real experimental support. The conservative or non-conservative nature of the surgery was still a matter of debate. Radiotherapy was also used in cancer therapy. At the end of the nineteenth and the beginning of the twentieth century, newly discovered X-rays and radioactive compounds (radium) were soon used to treat cancer. As early as 1906, proliferating tumour cells were shown to be more sensitive to radiation than normal cells. Treatment could be targeted on the tumours—for instance by implanting needles containing radium directly inside the tumour. Simultaneously, statistical studies in all the developed countries reached the same conclusion: cancer mortality was increasing abruptly. These fears, together with the new therapeutic hopes, stimulated the formation of special centres and hospitals for cancer therapy in the early years of the twentieth century. Continual progress was made in the nature of the radiation used, and the way it was delivered to the diseased tissues. By the 1940s, cobalt progressively replaced other treatments in beam therapy. After World War II, radiation sources became increasingly complex, fully justifying the existence of specialized centres for curing cancer. These developments went hand in hand with the rise of professional societies and philanthropic associations, such as the American Cancer Society, which became increasingly influential in cancer research, in particular after World War II. Following the success of penicillin, systematic screening was used after World War II to search for similar compounds that would be active against cancer cells. The rise of chemotherapy was reinforced by the parallel development of a trial culture, with randomization, double-blind tests and statistical analysis. Apart from the sexual hormone analogues, which were used for the treatment of some forms of breast or prostate cancer, all other treatments were nonspecific, aimed simply at killing rapidly dividing tumour cells.

During the 1970s, cancer rates were rising again, partly due to changes in the environment, but mainly due to increases in longevity and the disappearance or decline of other diseases. As a result, cancer became of increasing concern for western societies. In 1971, President Nixon launched the US campaign against cancer—the American Cancer Act. The aim was to attack cancer with a similar effort in terms of money and human resources as had been used for the Apollo programme to put a man on the moon. It was decided to focus on the isolation of viruses that might be involved in human cancers. Many studies had already described oncogenic viruses in animals. If a virus were to be isolated from human tumours, precedent suggested it would be possible to develop a vaccine against it: in 1970, the first vaccine against a virus responsible for a lymphoma (Marek’s disease) in chickens had been developed.

The results of this ‘crusade’ were mixed. Some commentators argued that it was a ‘medical Vietnam’, i.e. a disaster for the US cancer research. A more balanced view would be that the studies carried out did not discover a ‘magic bullet’ against cancer, nor did they find the elusive viruses which might have been responsible for the major forms of human cancers. However, this research was very important because it led to the new molecular vision of cancer which emerged during this period.

Cancer as a Molecular Disease

The elaboration of a new consensus vision of cancer

From the beginning of the 1980s, a new vision of cancer appeared, centring on the role of a family of genes—oncogenes—which were rapidly joined by the anti-oncogenes—or tumour suppressor genes. Modifications in the expression or function of these genes were thought to be responsible for cell transformation, and tumour formation.

As seen earlier, this new vision replaced not one, but many different models of cancer, which were all partially conflicting. In contrast, whatever their preference for one or another of these models, cancer specialists had accepted that cancer was a dysregulation, leading to a de-differentiation of cells. These characteristics of the cancer cell played a minor role in the new oncogene model.

Some historians of science have suggested that the new model of cancer was the direct consequence of the entrance of molecular biologists into the field, and of the use of the new technology of genetic engineering. While it is true that studying genetic modifications that might be responsible for cancer was one of molecular biologists’ objectives, the nature of the genes involved, and the way their modifications explain cancer, was not. The development of the new model between 1976 and 1984 was simply the consequence of a rapid succession of discoveries.

A series of discoveries

In 1976, Dominique Stehelin, Peter Vogt, Harold Varmus and Michael Bishop discovered that the transforming gene present in the oncogenic Rous sarcoma virus was in fact quite similar to a normal gene present in avian cells. For a while, there was some confusion over what the experiment meant: did the avian genome contain silent retroviruses analogous to the oncogenic Rous sarcoma virus? This possibility had been put forward by Robert Huebner and George Todaro, who had proposed in 1969 that tumour formation resulted from the activation of silent retroviruses present within every genome. This model was directly inspired by research on lysogeny in bacteria.

The hypothesis was abandoned, however. The gene present in non-infected avian cells turned out not to be a part of a retrovirus: it was a normal gene, which had been highly conserved during evolution. When similar studies were carried out on the numerous oncogenic viruses that had already been characterized, in every example, the transforming gene present in these viruses was found to be homologous to a normal gene, present in non-infected cells, which was not a part of an endogenous retrovirus.

The real breakthrough came when these genes were shown to be involved in oncogenesis using a totally different experimental approach in a completely different situation. In a study aimed at following the fate of oncogenic viruses after their entry into recipient cells, Robert Weinberg’s group cut the DNA of these transformed cells, and showed that some of these DNA fragments—those containing the virus following its integration in the genome—were able to transform normal recipient cells. The surprise came when the experiment was done on cancerous cells, produced by a chemical carcinogen: the result was identical. The gene responsible for transformation was rapidly isolated and shown to be identical to one of the genes that had previously been shown to have been hijacked by the oncogenic viruses. Point mutations in the coding part of the gene had transformed a normal gene into an oncogene: these mutations did not alter the regulation of the expression of the gene, but rather its functional properties.

In a few months, the same genes were demonstrated to be responsible for cell transformation in three other situations, which at a first glance appeared to be very different. Some oncogenic retroviruses contain no transforming gene: it was discovered that these retroviruses integrate into the genome close to some of the oncogenic genes that had been characterized in previous studies, and activate their expression. Other cancers, such as leukaemias, are associated with chromosome translocation. As seen earlier, at the beginning of the twentieth century, Theodor Boveri proposed that such effects might cause cancer. It was discovered that the translocation points corresponded precisely to the position of previously characterized oncogenes, and that their expression increased following translocation: translocation stimulates gene expression by placing the oncogene under the control of strong promoters (or enhancers) of transcription. Finally, in some cancers, there is an amplification of some parts of the genome: once again, the amplified sequences corresponded to the same oncogenes.

This limited family of genes, the oncogenes, seemed to be involved in all the forms of known tumours: spontaneous or chemically induced, produced by a viral infection or associated with chromosomal rearrangements. Their functions, which emerged ‘directly’ from sequencing, were particularly revealing: these genes code for growth factors, growth factor receptors, proteins involved in intracellular signal transduction, or proteins interacting with DNA to stimulate cell division. The discovery that oncogenes code for components of intracellular signalling pathways took place at the same time as these pathways and their molecular targets were described.

The rapid pace of these discoveries, the fact that different experimental approaches showed that the same small group of genes was involved in cancer, and that a molecular description provided an immediate clue as to their function—they participate in the signalling pathways which adapt cell division to the needs of the organism—all these characteristics explain the rapid success of the new oncogene theory of cancer. The new model integrated previous visions and models of cancer: a cancer could be due to mutations, to chromosomal rearrangements as well as to infection by oncogenic viruses. In fact, prior to the arrival of the new oncogene vision, the only viruses that had been proved to be oncogenic were responsible for some rare forms of cancer in animals and humans. Subsequently, the hepatitis B and papilloma viruses have been shown to cause common forms of human cancers, hepatocarcinoma and cervical cancer, respectively.

However, in one respect these oncogenes did not agree with previous results: the mutations were dominant. The relative rarity of tumours compared with the high frequency of mutations, and studies of familial forms of cancers such as retinoblastoma, suggested that somatic mutations leading to cancer would be recessive. The first ‘anti-oncogene’ or tumour suppressor gene was isolated in 1986 by Robert Weinberg’s group: it is involved in the familial forms of retinoblastoma. Interestingly, it was soon found that DNA tumour viruses, which do not harbour oncogenic genes in their genomes, transform by inhibiting the activity of cellular anti-oncogenes. The first anti-oncogenes to be described were also shown to participate in the control of cell division. The description of a limited number of genes raised the legitimate hope that diagnostic precision could improve rapidly, and even that new drugs aimed at inhibiting the action of the proteins encoded by these genes might be forthcoming.

The difficulties faced by the new model

Fifteen years have passed since these observations, and the hope that these oncogenes and anti-oncogenes might be used in diagnosis, and as the targets of drug action, has only partially been fulfilled. BRCA1 and BRCA2 genes are widely used for estimating the risks of breast cancer, and there are promising new anticancer drugs which act by inhibiting the tyrosine kinase activity of an oncogene that is specifically activated in certain forms of cancer. However, apart from these rare examples, the therapeutic benefits of the massive amount of research on oncogenes and antioncogenes is low. Gene therapy essays are still in their infancy. This is rather disappointing, given the high hopes, and the effort that has been expanded over the last two decades.

The main limit to understanding, and the problem involved in applying our knowledge to diagnosis and cure, is the overwhelming complexity that has been revealed. The number of oncogenes and tumour suppressor genes has grown steadily since the middle of the 1980s. At the same time our knowledge of the intracellular signalling pathways that control cell division has improved immensely. But disappointingly, despite all these efforts, nobody understands exactly why only certain links and nodes in these very complex pathways and networks are affected in cancer, why some genes encoding their components are mutation hot spots. Something in the regulation and functioning of these pathways and networks is obviously missing. A full understanding of these networks and their dysfunctions will probably come only when the components have been sufficiently characterized for their functioning to be modelled.

The number of categories of genes, the mutations of which are involved in tumour formation, has also increased. As well as oncogenes, which activate cell division permanently, and anti-oncogenes, which inhibit it, there are genes involved in the control of cell death or apoptosis. Apoptosis enables the organism to eliminate abnormal cells, in particular cells that have accumulated mutations and that might be prone to transformation. The inactivation of genes involved in DNA repair can also contribute to cell transformation. Other genes are also involved in the increased ability of tumour cells to attract blood vessels in order to increase their metabolic supply, or to digest the barriers that prevent their diffusion in the organism (‘metastasis’). Recently, mutations have been found which do not directly affect the tumour, but which influence the surrounding tissues and create an environment more favourable to its growth and diffusion.

The molecular description of cancer has become increasingly complex. Apart from a specific form of intestinal tumour, in which the steps leading to transformation have been fully described, in the case of most tumours the genes involved are simply not known. Furthermore, no general rules have emerged from the data we have to hand. This is merely the molecular confirmation of previous observations which showed that each type of tumour has specific characteristics that distinguish it from other tumours. Cancer results from stochastic events (mutations) and from the selection among these mutations of those that provide the cancerous cell the best conditions for growth. Each cancer is unique, with its own developmental history.

Hopes in a new, global approach

This situation explains why the post-genomic era is seen as a source of a new understanding of cancer. The general idea behind these new approaches is that the order that exists in the living world will only be revealed through a global view of its functioning. The cancer cell not only is a cell in which a given gene has been altered, but also a cell that has reached a new functional state, a new equilibrium. In a cancerous cell, many genes have their activity altered as a consequence of the initial mutations in the oncogenes and anti-oncogenes. This new pattern of gene expression is closely linked to the properties of the cancer cell. It can provide clues as to its future evolution, and therefore help prognosis

This new approach to cancer has been stimulated by the development of new tools, such as DNA chips—microarrays—which make it possible in a single experiment to estimate the activity of tens of thousands of genes. Initial results from post-genomic approaches to cancer seem promising. Not only can these experiments distinguish different types of tumours by the analysis of molecular data and confirm diagnoses made by more traditional methods, such as histopathology, but some poorly characterized forms of cancers have been shown to have specific molecular profiles, associated with very different prognoses.

On the basis of the preliminary data, we can imagine that, in a few years, cancer diagnosis will be a precise, automatic process, leading to a precise therapeutic protocol. In addition, the new functional state corresponding to the cancer will be modelled. Using this model, it will be possible to predict which links in the network need to be targeted to restore a normal functional state.

Whether such therapeutic hopes will in fact be fulfilled remains open. Whatever the answer, the new vision of cancer which has already emerged from these studies is different from the early oncogenic model. The alteration of oncogenes and anti-oncogenes is still thought to be an important initial event in oncogenesis, but the piecemeal approach is not considered as sufficient to understand the new properties of the cancerous cell. The new models are reminiscent of the models proposed sixty years ago by the geneticist Conrad Waddington to explain differentiation. Interestingly, recent studies also point again to a similarity between the functional state of a cancerous cell, and the successive functional states that occur during differentiation and development.

Conclusion

Cancer, the dread disease, has always frightened people. Many metaphors have been used to describe the disease and its evolution. ‘Wars’ against cancer have always been lost, and premature hopes have been systematically dashed. This explains why people suffering from cancer regularly turn to quacks and charlatans. The more our knowledge progresses, the more it appears that cancer is intimately linked to life. We will not be able to understand cancer without fully understanding the functioning of cells and organisms. Retrospectively, this explains why research on cancer had such an impact on our understanding of the most fundamental characteristics of organisms, and why the history of cancer research is so closely linked to the history of biology itself.