Training Of Cancer Researchers, The

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Jose Russo

• Publisher: WSPC
• Year: 2017
• ISBN:
  9789813203167
• Topic: Medicine
• Subtopic: Oncology

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Advances in cancer research have grown exponentially in recent decades. What we now know about the disease owes a lot to breakthroughs in science and technology. Cancer researchers have had to solve increasingly difficult problems with methods that were unimaginable just a few years ago, and new generations of researchers have to be trained to face these challenges.

One important aspect of their training is the framing of social, economic and cultural changes of the human population. Despite having state-of-the-art technology and specializations, researchers are still required to think faster than ever before, making new discoveries fit the practical situation of each type of cancer. This book discusses a number of topics that address these challenges and the origins of cancer research from a cultural and historical perspective.

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Chapter 1

The Original Idea as the Main Driver in Cancer Research

1.1.The Importance of the Individual Mind

In 1946, Dr. Stanley P. Reimann, director of The Research Institute in Philadelphia (presently the Fox Chase Cancer Center–Temple Health), delivered a speech at the third annual meeting of the American-Soviet Medical Society in New York City. He stated, “Some people say that the day of the lone experimenter with a rabbit in one hand and a hypodermic syringe in the other is over. It may well be that the field is still open for the lone experimenter to make discoveries”. There is no doubt that both views still have supporters. However, when we study the trend for human endeavors in the sciences, and particularly in cancer research, we observe fewer single-investigator studies and more often the teamwork of a few collaborators — e.g., a paper published in the journal Genes Genomes Genetics names 1014 authors with more than 900 undergraduate students among them. Although some questioned whether every person made enough of a contribution to be credited as an author, the paper’s senior author, Dr. Sarah Elgin, at Washington University in St. Louis, Missouri, said, “large collaborations with correspondingly large author lists have become a fact of life in genomic research. Putting together the efforts of many people allows you to do good projects”.

Yet how will the new generation of leading cancer researchers emerge in this environment where the research endeavor has progressed from the individual effort to the institutional product? And how will national groups address the need for international collaborations between different research teams? How true is Reimann’s observation today? A study published few years ago (Adams, 2011) showed that “about 75% of the research output of China, Brazil, India and South Korea remains entirely domestic. The total volume of papers from these four countries has increased 20-fold — from fewer than 15,000 papers annually in 1981 to more than 300,000 papers in 2011. For established economies after the mid-1990s, the domestic research output of the United Kingdom (47,500 papers per year), Germany (45,000 papers) and France (30,000 papers) levelled off while international collaboration in these countries increased more than ten-fold. The author of this article (Adams, 2011) concluded that exceptional research groups share ideas, resources and outcomes. For example, the most frequent international partners of the University of Cambridge, UK, are the Max Planck institutes in Germany, the Massachusetts Institute of Technology and Harvard University, both in Cambridge; the California Institute of Technology in Pasadena; the University of California, Berkeley; and the universities of Toronto, Heidelberg and Tokyo. Harvard’s frequent international partners are Imperial College London, University College London, the Max Planck institutes, the Karolinska Institute in Stockholm and the universities of Cambridge, Toronto and Geneva. The conclusion is that internationally co-authored papers are more highly cited because the authors are more likely to be doing excellent research”. The counterpart of this is that many outstanding scientists in developing countries will be left out.

All these data can be demoralizing for those who aspire to be cancer researchers and occupy the mind with questions of individual versus teamwork versus large collaborations and whether or not to be part of a larger whole as opposed to being the driver in the research process. Therefore, the main question is: what has been the driving force in cancer research (as well as for all the sciences) to get us where we are today? And the simple answer is that the research idea germinates in the mind of a single individual most of the time and it is the idea that counts. At the end, the great triumphs of science have resulted from the determination to follow an individual’s idea, as with Marie Curie’s discovery of radium or Isaac Newton’s discovery of gravitational law (Russo, 2010). It required the industrious and clear mind of Rudolf Virchow to start a systematic review of pathological lesions as demonstrated in the Handbook of Special Pathology and Therapeutics in 1847. In this book, Virchow clarified his views on cellular pathology at a critical time. In the early period of pathology, many disease processes were still poorly understood. Many prominent pathologists believed that pathological changes occurred due to an imbalance in the blood of substances, such as fibrin and albumin, which created a “blastema” that formed abnormal cells leading to disease. Virchow, together with Robert Remak (Titford, 2010), categorically stated that cells were derived from other cells, and therefore, pathological cells were also derived from other pathological cells. This innovative concept was later expanded in his Cellular Pathology, followed by a three-volume series on tumors in 1863.

Virchow’s greatest achievements were in microscopic pathology. Virchow was not the first to study diseased tissues microscopically, but he was the first to recommend a systemic microscopic study of tissues. Likewise, Virchow recommended a complete autopsy; in contrast, previous pathologists only studied specific tissues and organs as directed by clinicians. Virchow established the relationship between cancer and inflammation. He also suggested that chronic inflammation influenced tumor development. Balkwill and Mantovani metaphorically summarized Virchow’s idea: “If genetic damage is the match that lights the fire of cancer, inflammation provides the fuel that feeds the flames” (Balkwill and Mantovani, 2001). The importance of inflammation and immunosurveillance for tumor progression is one of the current accepted concepts in cancer (Hanahan and Weinberg, 2011).

In 1914, Theodor Boveri, a disciple of Virchow’s, pointed out the role of the chromosomes’ constitution of the cell, specifically noting that kariological disorder is initiated by abnormalities of mitosis and that centriolar malfunction might sometimes be involved. Yet his work has only recently been rescued by our increased understanding of the role of genes in cancer (Harris, 2008). Boveri postulated that malignant tumors are clonal outgrowths and that their ability to multiply exponentially is the hallmark of the neoplastic process. These pivotal ideas developed by a single individual are the cornerstone of the genetic theory of cancer.

Another individual who changed our way of thinking in the neurosciences was Santiago Ramón y Cajal, whose ideas pioneered investigations of the microscopic structure of the brain. His unique drawings illustrating the delicate arborizations of brain cells — which he painstakingly extracted from his own histological preparations — allowed him to provide an understanding of the nervous system that is still a source of inspiration for the new cadre of researchers in that field. He discovered the axonal growth cone and demonstrated experimentally that the relationship between nerve cells was not continuous, but contiguous. This provided definitive evidence for what would later be known as the “neuron doctrine”, which displaced the concept of reticular theory that was widely accepted in his time.

It is also true that new ideas are often inspired by the environment that the scientist works in, such as a mentor or a reading that stimulates the individual to think in a different direction. For example, Levi-Montalcini read an article by Viktor Hamburger that indicated that when the growing limbs of chick embryos were cut off, the resultant atrophy in the neuronal cell clusters intended to innervate them was due to the loss of an “inductive factor” from the absent limbs. Hamburger suggested that this factor was necessary for the growth and differentiation of the neural precursor cells. Levi-Montalcini repeated this experiment and concluded instead that the neuronal death resulted from the absence of a growth-promoting substance that resulted to be the neural growth factor (Bradshaw, 2013). Again in this example, it is initiative and individual interpretation that make the final mark.

The significant collaboration of more than one mind is also well documented, like in Nirenberg and Matthaei’s discovery that RNA, rather than DNA, programmed the synthesis of proteins (Caskey, 2011). These initial discoveries paved the way for finally deciphering the genetic code, making possible the spectacular era of DNA sequencing, recombinant DNA technology and genome projects that followed.

In the same line of thinking, Siekevitz and Zamecnik obtained the definitive data on protein biosynthesis through the use of a cell-free (in vitro) system, thus revealing the enzymatic activation of amino acids, the ribosome as the site of peptide-bond formation and the existence of transfer RNA (Pederson and Paul, 2009). In other collaborative situations, one is the main investigator and one makes the crucial observations. This is the case of Elizabeth Carswell and Barbara Williamson who were working in the laboratory of Lloyd J. Old. They noted that tumors of mice turned black, which eventually led to the identification of the cytokine, tumor necrosis factor (which is involved in tumor regression) (Sharma and Allison, 2012).

Another good demonstration of the idea of an individual behind important discoveries is the work of Philip Lawley, which laid the foundation that cancer is a genetic disease. He provided the first convincing evidence that DNA is the key target for chemicals that cause cancer, and identified a major DNA-repair mechanism that counteracts the assault of carcinogens on DNA (Venitt and Phillips, 2012). He studied the physicochemical properties of DNA (before its double-helical structure was revealed by James Watson and Francis Crick). Lawley demonstrated that alkylating agents could bond covalently with DNA to produce stable adducts, a radical idea at a time when it was believed that such interactions were weak or reversible and that proteins were the crucial target of carcinogens. Lawley went on to show how point mutations are induced when potent alkylating mutagens, such as N-methyl-N-nitrosourea, react with those atoms in DNA that determine base pairing during DNA replication. Point mutations are now known to occur frequently in a variety of human cancer genes.

I cannot emphasize enough the importance of the individual idea and work, which have generated pivotal changes in our understanding of cancer. I could continue enumerating hundreds of cases that support this point but that would transform this chapter into a biographical compendium.

1.2.The Challenges Ahead for Developing the Driving Idea

Next I would like to examine the challenges that the new cadre of cancer researchers will need to face in order to develop the driving idea for solving the problems of cancer. What we know thus far is that by the time most cancers are detected, at least one tumor has grown to contain a billion cells which, by mutation and natural selection, have become altered in ways that allow them to escape the body’s safeguard mechanisms. Cancer cells are constantly changing and altering the genes controlling the normal process of growing. In 1900, the leading causes of death in the United States were pneumonia, influenza, and tuberculosis; a century later, they are heart disease and cancer. More than 40 years since “war” was declared on cancer, 15% of deaths worldwide are attributable to cancer. In The Emperor of All Maladies, a beautiful book written by Mukherjee (2010), there is a thorough description of the history of cancer. In the nineteenth and early twentieth centuries, cancer was defined by the demonstration of invasion and metastases, based on gross findings at surgery or autopsy. Although histopathologic examination of tumors — focusing on tissue changes — became possible with greater and greater resolution over time, the definition of cancer remained the same and prognostication based on histopathologic analyses of tumor biopsies and resection specimens was still not possible. When the concepts of tumor grading and staging were discovered in the 1920s and 1930s, histopathology could finally provide prognostic information, fostering the tumor staging and eventually the cancer biomarker fields. Analyzing such factors as the tumor histologic pattern, degree of nuclear pleomorphism, number of mitoses, presence of inflammatory response, blood vessel invasion, lymph node involvement, and the presence of hormone receptors (Bloom and Richardson, 1957; Bloom et al., 1970; Russo et al., 1987), attempts have been made to identify patients at high risk of early disease recurrence and thus more effectively target aggressive auxiliary chemotherapy and intensive follow-up protocols. However, many cancers having similar histologic patterns differ markedly in their recurrence behavior, which affects a patient’s survival. In the case of breast cancer it was obvious that single morphologic or biologic characteristics were insufficient to predict the biologic behavior of a tumor; therefore, a combination of various criteria was necessary to accurately identify subpopulations of patients, such as breast cancer sufferers at increased risk of recurrence or shortened survival. For example, after the publication of the new genomic classification of breast cancer in 2006 (Sørlie et al., 2006), several adaptations, compiling a variety of representative genes, have been introduced in the practice of oncology. Among these adaptations is the Oncotype Dx, which contains a 21-gene expression signature (Mamounas et al., 2010). This study comprises female breast cancer patients that are estrogen receptor positive (ER+) and lymph node negative (LN–). The Oncotype was developed from a formalin-fixed paraffin-embedded tissue (FFPE) assay to predict distant recurrence of ER+ breast cancer and originally selected 250 candidate genes to test on National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 trials. At the end they refined a 16+5 gene panel that could reliably predict recurrence (Mamounas et al., 2010). The Mammaprint contains a 70-gene expression signature and the major trial in 2002 comprised women younger than 61 years, T1-T2, N0 disease (Van’t Veer et al., 2002; Van de Vijver et al., 2002) The Prosigna from Nanostring contains a 50-gene expression signature plus five control genes and represents the old PAM50 assay. The PAM, or prediction analysis of microarrays, recapitulated the microarray classifier using RT-PCR-based PAM50 assay in comparison to standard clinical molecular markers. The major trial was in 2013 using a stage I–III cancer population and cleared by the Federal Drug Administration (FDA) in 2013. The PAM50 gene signature has been transferred to a novel and robust method for mRNA quantification (Van de Vijver et al., 2002). This method works well in FFPE, does not rely on amplification of nucleic acids, and is intended for using kits in local labs with the proper instruments. The PAM50 expressions results are used to calculate a risk of recurrence score (ROR) and thus identify low-, intermediate-, and high-risk groups. The score is based on the intrinsic subtype and pathologic characteristics, with special weight given to a set of proliferation-associated genes. PAM50 correlates well with the Oncotype and the use of the four immunocytochemistry parameters (ER, PR, Her2, and ki67) (Dowsett et al., 2013).

What we know for the diagnosis and prognosis of breast cancer, as described above, can be easily applied to other solid tumors and leukemias. Our knowledge and understanding of cancer is greater than a decade ago and we have a better perspective on the role of certain specific mutations in clue genes implicated in the disease. We also have many approved cancer drugs, some of which specifically target mutations in those genes. Oncologists are also getting better in the diagnosis as well as the initial treatment of the disease. Unfortunately, there are still many relevant challenges to face, such as drug resistance, tumor metastasis, the role of microenvironment, the immune response, the cancer-drug delivery system, and other areas that will be discussed in the next portion of this chapter and that need to be better understood by the new cadre of cancer researchers.

1.2.1.Drug resistance

Any cancer is a complex bio system that changes each time its cells divide. Thus the drugs that are used to kill cancers change not only the cancer cell but the whole microenvironment of the tumor. The selective pressure induced by the treatment activates protein pumps that work to get rid of the drug by changing the DNA repair of the cells or activating new signal transduction pathways. Ultimately the cancers create a resistance to the drugs that are supposed to kill them. The field of drug resistance is the new frontier in cancer research. Currently researchers are trying to understand at the molecular level what makes the cancer cell resistant to treatment that is intended to kill...

Table of contents

• Cover Page
• Title
• Copyright
• Dedication
• Preface
• Acknowledgments
• About the Author
• Contents
• Chapter 1: The Original Idea as the Main Driver in Cancer Research
• Chapter 2: Trends in Scientific Discovery
• Chapter 3: The Communality of Science in Cancer Research
• Chapter 4: The Economic Basis of Cancer Research
• Chapter 5: Is Politics Part of the Cancer Research Affair?
• Chapter 6: The Role of Society in the Training of Cancer Researchers
• Chapter 7: The Perception of Cancer Research by the Public
• Chapter 8: Measuring Scientific Innovation in Cancer Research
• Chapter 9: The Past and Present of Academic Research
• Chapter 10: What the Future of Cancer Research Will Look Like
• Index