|HISTORY OF MEDICINE
|Ahead of print
Important milestones for cancer at the Nobel prize
Ozgur Tanriverdi1, Muhammed Tasar2, Mustafa Yilmaz2, Melih Furkan Durak2, Selin Beyza Sezer2, Hatice Demir3, Muesser Ozcan3
1 Department of Medical Oncology; Bioethics Practice and Research Center, Mugla, Turkey
2 Bioethics Practice and Research Center, Mugla, Turkey
3 Bioethics Practice and Research Center; Department of History of Medicine and Ethics, Mugla Sitki Koçman University Faculty of Medicine, Mugla, Turkey
|Date of Submission||12-Nov-2019|
|Date of Decision||25-Mar-2020|
|Date of Acceptance||27-Mar-2020|
|Date of Web Publication||14-Sep-2020|
Department of Medical Oncology; Bioethics Practice and Research Center, Mugla
Source of Support: None, Conflict of Interest: None
The Nobel Prize, which is awarded annually, is open to everyone, regardless of nationality, race, belief or ideology, and winners are announced in October. We evaluated the history of the Nobel prizes for awards that have been awarded in fields related to cancer. The contents of the research and their contribution to oncology were determined and reviewed. There were nine awards directly related to cancer. Only studies thought to be groundbreaking in carcinogenesis and molecular treatment of cancer are included in this review.
Keywords: Cancer research, cancer, Nobel prize
| » Introduction|| |
The Nobel Prize is recognized as one of the most prestigious awards for intellectual achievement in the world, dedicated to the Swedish inventor and industrialist Alfred Bernhard Nobel. The award regulation was drafted in 1895 and focused on the idea that these awards would provide further development and incentives in many areas. On December 10, 1901, the fifth anniversary of Nobel's death, the first Nobel prizes were awarded in the fields of Physics, Chemistry, Physiology or Medicine, Literature, and Peace. The Nobel Prize, which is scheduled to be awarded annually, is open to everyone, regardless of nationality, race, belief or ideology, and winners are announced in October.
The awards associated with cancer were determined using search engines. The contents of the projects that received this award and also their contributions to the field of oncology were reviewed.
The first Nobel Prize in Physiology or Medicine was given in 1901 and was organized regularly except for 8 awards that could not be given until 2019 because the budget could not be allocated.,, The researches in the field of physiology or medicine were found to be mostly related to the pathogenesis or prevention of infectious, psychiatric, and cardiopulmonary diseases in the first 10 years or related to neuromuscular mechanisms.,, There were a total of 9 studies on cancer. The first Nobel Prize-winning research was the discovery of Spiroptera carcinoma in 1926.,, Others included hormone therapy in prostate cancer in 1966, the genetic material of tumor viruses in 1975, retroviral oncogenes in 1989, and human papillomavirus (HPV) in cervical cancer in 2008.,, Studies that shed light directly or indirectly on both carcinogenesis and cancer treatment, which received awards in different scientific fields, can be listed as follows: immunology research (1908), cell biology research (1910) and researches on cell biology, cell structure, DNA, RNA, intracellular signaling pathways and proteins, viral proteins, replication, telomerase and cell transport systems (1951). In the years after 1971, awarded research deals with programmed death and immune reactions, immunity, monoclonal antibodies and stem cell properties.,,, Similarly, although the first award in this field was given in 1901, the researches related to cancer and carcinogenesis were more limited. In 1957, it was determined that cell genetic material and related protein systems (especially ubiquitin) also came into prominence in the years following the award, which explored nucleotides and nucleotide co-enzymes. In 2015, Tomas Lindahl, Paul Modrich, and Aziz Sancar received the Chemistry Award with studies on nucleotide excision repair.,, In 2018, James P. Allison and Tasuku Honjo were given the Nobel Prize for their work based on immunotherapy [Table 1].,,,,,,,,,,,,,,
|Table 1: Nobel prizes directly associated with cancer,,,,,,,,,,,,,,|
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| » Milestones for Cancer at the Nobel Prize|| |
Only studies thought to be groundbreaking in carcinogenesis and molecular treatment of cancer are included in this review. Therefore, although they have important studies on cancer and have been nominated many times, researchers who have not received the Nobel Prize have not been included in this review. Two of these researchers, are Katsusaburo Yamagiwa and George Papanicolau. Papanicolau was a researcher who pioneered studies on the physiology and cytological features of the female reproductive system. Most of the studies related to cervical cancer have been concluded with the discovery of the Papanicolaou test, also known as Pap smear, which makes the early diagnosis of this cancer possible. In the first experimental study report presented by Yamagiwa and his assistant Ichikawa, the definitive histopathological process of folliculoepithelioma papillosum development is shown. Thus, they described the first experimental chemical carcinogenesis model based on human pathology after disruption in skin and newly developed and dilated blood vessels in rabbit ears. The studies carried out by these researchers have provided insight into many studies on carcinogenesis as well as cancer screening.
Johannes Andreas Grib Fibiger
Johannes Andreas Grib Fibiger was awarded the Nobel Prize in medicine in 1926 as a continuation of his work on stomach cancer dating back to 1914. It has been shown by the studies conducted by Fibiger that infectious agents may play a role in carcinogenesis for the first time in the world. As a result of this study, it has been determined that the lesions identified in the stomach in Fibiger mice are of infectious origin. It is stated that a nematode parasite called Gongylonema neoplasticum is responsible for these lesions.
In a histological experimental study in wild rats in 1907, a type of nematode was discovered in rats with epithelial hyperplasia and papilloma in their stomach. He argued that this nematode was different from all other known nematodes. Since he discovered that some of these papillomas were malignant and metastatic, these nematodes assumed a role in the pathogenesis of gastric cancer. He named these nematodes, temporarily, the Spiroptera carcinoma in 1914 and was identified by Ditlevsen University in 1918 under the name Gongylonema neoplasticum.,,,
Unfortunately, over time, experimental and molecular studies have shown that hyperplastic polyps do not develop as claimed by Fibiger and develop after a series of cellular structural disorders.,, As a result of the studies, it was determined that hyperplastic polyps developed as a result of chronic irritation and vitamin A deficiency and did not have a high-risk of malignancy as suggested by Fibiger.,, Nevertheless, it can be concluded that these discoveries that earned Fibiger the Nobel Prize gave important clues to the etiopathogenesis of cancer.
Otto Heinrich Warburg
In 1931, Otto Heinrich Warburg received the Nobel Prize in Physiology for his work on aerobic and anaerobic metabolic processes in cells. With this discovery as well as studies on the process of oxidation, it suggested the existence of new pathways in the fields of cellular metabolism and cellular respiration and paved the way for current studies.
In his previous years, he tried to investigate the vital processes of organisms by physical and chemical methods, which led to the discovery of the assimilation of carbon dioxide in plants, the chemical content of the respiratory ferment responsible for oxygen transfer, tumor metabolism, as well as active groups of hydrogen transfer enzymes of the flavin and nicotinamide.
Together with Seigo Minami, they published their first observations of changes in the metabolism of tumors, one of the most important discoveries of these previous years. In this study, the main result was observed that the tumors acidified Ringer's Solution (an isotonic saline solution containing 2.4 mMol NaHCO3) and chemically defined lactic acid in this acidified solution. To better interpret this result, Barcraft manometry was modified by Otto Warfung to measure slices of Flexner Jobling rat hepatoma. He then measured the amount of lactic acid produced from the increase in carbon dioxide formed during the 30-minute incubation. Interestingly, he found that tumor tissue causes the formation of lactate 70 times more than normal liver, kidney and heart tissue, and this phenomenon has survived to the present day as a Warburg effect.,,
Although these studies by Warburg have not been used directly in the treatment of cancer, it should be kept in mind that targeting molecular studies on tumor metabolism is still important today.
Two important discoveries were made as a result of experimental studies by Peyton Rous. The first was that an indigenous chicken was observed from which the sarcoma cells were transferred to another poultry without any other means, and the second was that the tumor-inducing factor could be passed through a Berkefeld ultrafilter known to hold bacteria. The discovery of the Rous sarcoma virus, which is known to be a retrovirus, has shown that cancer is transmitted by a virus and that solid tumors are transplantable.,
After these studies, Richard E. Shope, a scientist who worked with Rous at the Rockefeller Institute in 1934, advised Rous to conduct a study on warts caused by an extremely effective virus known as the Shope papillomavirus (rabbit papillomavirus). When he confirmed to Rous that warts associated with this virus were benign tumors, he concluded that viral oncology was a mystery in itself.,, Over the next 30 years, Rous and colleagues have shown that benign tumors can progress to malignant carcinoma and that chemical carcinogens can interact with the virus. In this way, discoveries that constitute the building blocks for modern virology emerged. As a matter of fact, it is now known that around 20% of human cancers worldwide are particularly associated with viral etiology and preventive measures such as vaccines are reducing the risk of cancer.
After nearly 50 years, the longest “incubation period” of the Nobel Prize, Rous was awarded the Nobel Prize in Medicine in 1966 at the age of 87. The increase in the number of studies on viral oncology after Rous and the other Nobel prizes on this subject proved that studies by Rous are important paving stones in cancer science.
Charles Brenton Huggins
In 1941, Huggins established a definite relationship between hormones and prostate cancer, and the results of this study brought Huggins the Nobel Prize for antiandrogenic therapy. The basis of synthetic estrogen diethylstilbestrol causes significant regression in metastatic prostate cancer.,
Huggins' observation of treatment that reduces levels of acid phosphatase in tumor cells by castration or administration of estrogens in metastatic prostate cancer can be considered to help start the era of modern chemotherapy.,
Huggins discovered that castration or estrogen administration leads to glandular atrophy that can be reversed by androgen re-administration and deserves to be called the first person to use a systemic approach to treat prostate cancer.
David Baltimore, Renato Dulbecco, and Howard Martin Temin
In 1911, Peyton Rous had shown that viruses could cause leukemia and sarcoma in chickens. This discovery caused research on viral oncology and biology to be a curiosity., In the following years, the findings of the transformation into tumor cells of virus-induced changes in the growth characteristics of a normal cell have been facilitated due to the fact that cell cultivation methods are more useful under laboratory conditions in parallel with advances in molecular biology technology.,, In studies by Renato Dulbecco, the effect of a relatively simple generated DNA tumor virus on cells grown under laboratory conditions was investigated. As a result of these studies, it was determined that viral replication either caused the disruption of the cells as a result of the release of newly produced virus particles or caused the transformation of the cells., No virus particles were produced by these transformed cells. Following this observation, another important question about viral oncology and biology came up. The question was whether a virus caused the transformation of cells and then disappeared, or whether the genetic material of the virus would remain in these transformed cells.,, It had been shown by Dulbecco et al. that the genetic material of the virus can be introduced into the genetic material of transformed cells using molecular biology techniques, and as a result, it has been accepted as a starting point for answers to these important questions.,
In addition to these studies, studies conducted by Howard Temin since the late 1950s had been concerned with tumor viruses containing RNA, that is, alternative types of genetic material.,,, The idea that the genetic information of an RNA virus capable of transforming can be copied into DNA and integrated into the genetic material of the cells was investigated by Temin.,,, Moreover, the most important discovery in molecular biology and viral oncology with the studies shed by the theory put forward by Temin can be considered to be the definition of reverse transcriptase enzyme in 1970 by Temin and David Baltimore., This enzyme is a specific enzyme capable of extracting a DNA copy from RNA in RNA tumor virus particles, and more specifically, the discovery of this enzyme has shown that replication of RNA tumor viruses most likely involves an information transfer via DNA.,,,,
J. Michael Bishop and Harold E. Varmus
In 1970, J. Michael Bishop and Harold E. Varmus developed a DNA probe to study the Rous sarcoma virus, which is known to cause cancer in chickens. At the end of this study, this DNA probe has been reported to be effective not only in detecting a cancer-related gene called “src” but also in showing that the carcinogen gene in this virus is found in normal cells.,,
In 1989, the Nobel Prize in Physiology or Medicine was awarded to J. Michael Bishop and Harold E. Varmus for shedding light on further studies on tumor growth mechanisms and demonstrating that carcinogenesis is based on a genetic basis by exploring the cellular origin of retroviral oncogenes.,
Harald zur Hausen
In 2008, the Nobel Prize in Physiology or Medicine was awarded to two different studies. Half of this award was given to Harald zur Hausen for discovering HPVs causing cervical cancer, while the other half was presented to Françoise Barré-Sinoussi and Luc Montagnier for the discovery of the human immunodeficiency virus.,,
After previous advances in viral oncology, the demonstration of the role of HPV in the etiopathogenesis of cervical cancer by Harald zur Hausen should be considered an important paving stone not only for molecular oncology but also for clinical oncology. As a result of this long-lasting study, significant progress has been achieved in preventive oncology, and women have been protected by vaccination for cervical cancer.,
The basis of his study was the idea that a viral DNA material integrated into the genomes of the tumor cell containing an oncogenic virus could also be present. With this hypothesis, he first discovered the new HPV-DNA in cervical cancer biopsies and in 1983 discovered the type of tumorigenic HPV16. Later, in 1984, he cloned HPV16 and 18 of the patients with cervical cancer. As a result, the basis of the vaccine developed against cervical cancer was laid.,,
Tomas Lindahl, Paul Modrich, and Aziz Sancar
The main focus of interest by these three researchers was how DNA has a repair mechanism to protect itself against any damage. With this curiosity, while Tomas Lindahl and Sancar were investigating nucleotide excision repair in humans, Paul Modrich showed how the cell corrects errors that occur when DNA is replicated during cell division.,,
As a result of these studies, Tomas Lindahl, Paul Modrich, and Aziz Sancar received the Nobel Prize in biochemistry in 2015 for the information they provided on DNA repair mechanisms. These studies not only shed light on carcinogenesis but also led to the discovery of important predictive and prognostic factors in cancer treatment.[15-17,37]
When we recall the basic information, it is clear that in the double helix of DNA, cytosine mates with guanine, but when the amino group disappears, the damaged adenine remains the same, and if this defect cannot be repaired, a mutation also occurs when the next DNA is copied. Lindahl described a bacterial enzyme that removes damaged cytosine residues and reduces the frequency of errors during DNA replication by a thousand times, assuming that the cell needs some protection against this repair defect. Paul Modrich showed that these methyl groups can act as signs that help a specific restriction enzyme to cut the DNA strip in the right place.,, It is now known that congenital disorders in noncompliance repair in clinical oncology cause an inherited variant of colon cancer.
Parallel to these studies, “nucleotide excision repair”, also known as a mechanism used by most cells to repair ultraviolet (UV) damage, was mapped by Aziz Sancar.,
Studies by Aziz Sancar have discovered how to repair UV-associated DNA damage using a bacterium that produces photolyase enzymes and functions in the dark system. They used three UV-sensitive bacterial species carrying three different genetic mutations: uvrA, uvrB, and uvrC. Moreover, by defining the dark system, it was able to identify, isolate, and characterize enzymes encoded by the uvrA, uvrB, and uvrC genes. In groundbreaking in vitro experiments, these enzymes showed that they were able to detect UV damage and then cut one on each side of the damaged fragment in the DNA chain., These results actually shed light on the carcinogenesis associated with DNA repair mechanism disorder, which is now clearly known in many cancers.
James P. Allison and Tasuku Honjo
After realizing the mechanism that releases the brake of the immune system and the cause of immune cells attacking tumors, James P. Allison examined a protein known to act as an immune system brake. In parallel, Tasuku Honjo also discovered a protein on immune cells, and after a detailed study of the function of that protein, it revealed that this protein also functions as a brake with a different mechanism of action.,,
In the 1990s, James P. Allison studied CTLA-4, a T-cell protein, and developed an antibody that could bind to CTLA-4 and inhibit its function after observing that CTLA-4 acts as a brake in T-cells. In an experimental study at the end of 1994, it was shown to treat cancer by inhibiting immune braking and antitumor T-cell activity with this antibody to cancer mice.,
In 1992, Tasuku Honjo discovered PD-1, another protein that functions as a T-cell brake and is no different from CTLA-4 expressed on the surface of T cells.,
As a result of the discoveries of both scientists, advances in the field of oncological pharmacology have gained momentum and today, significant survival times of immunotherapy have been achieved in many solid tumors, especially malignant melanoma, renal cell carcinoma, and lung cancer.
| » Conclusions|| |
In conclusion, we have presented, in brief, highlights of the Nobel prize winning researchers and studies that have been directly linked to the field of oncology.
We certify that all of our affiliations with or without financial involvement, within the past 5 years and foreseeable future and, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, and royalties).
The study was approved by the institutional Clinic Research Ethics Committee and the study was performed in accordance with the declaration of Helsinki.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Gros C. An empirical study of the per capita
yield of science Nobel prizes: Is the US era coming to an end? R Soc Open Sci 2018;5:180167.
Tan SY, Tatsumura Y. George Papanicolaou (1883-1962): Discoverer of the Pap smear. Singapore Med J 2015;56:586-7.
Bartholomew JR. Katsusaburo Yamagiwa's Nobel candidacy: physiology or medicine in the 1920s. In: Historical Studies in the Nobel Archives. The Prize in Science and Medicine. Tokyo: Universal Academy Press, 2002, p. 107-31.
Raju TN. The Nobel chronicles. 1926: Johannes Andreas Grib Fibiger (1867-1928). Lancet 1998;352:1635.
Petithory JC, Theodorides J, Brumpt L. A challenged Nobel prize: Johannes Fibiger, 1926. Hist Sci Med 1997;31:87-95 (Article in French).
Clemmesen J. Johannes Fibiger: Gongylonema and vitamin A in carcinogenesis. Acta Pathol Microbiol Scand Suppl 1978;270:1-13.
Stolt CM, Klein G, Jansson AT. An analysis of a wrong Nobel Prize- Johannes Fibiger, 1926: A study in Nobel archives. Emerg Infect Dis 2013;19:660-3.
Schwartz L, Supuran CT, Alfarouk KO. The Warburg effect and the hallmarks of cancer. Anticancer Agents Med Chem 2017;17:164-70.
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703-7.
Weiss RA, Vogt PK. 100 years of Rous sarcoma virus. J Exp Med 2011;208:2351-5.
Noyes WF. Studies on the shope rabbit Papilloma virus. II. The location of infective virus in papillomas of the conttontail rabbit. J Exp Med 1959;109:423-8.
Vogt PK. Oncogenes and the revolution in cancer research. Homage to Hidesaburo Hanafusa (1929-2009). Genes Cancer 2010;1:6-11.
Bister K. Discovery of oncogenes: The advent of molecular cancer research. Proc Natl Acad Sci USA 2015;112:15259-60.
Weiss RA. On viruses, discovery, and recognition. Cell 2008;135:983-6.
Dehm SM, Bonham K. SRC gene expression in human cancer: The role of transcriptional activation. Biochem Cell Biol 2004;82:263-74.
Munnolli SS, Pujar SM, Kademani BS. Scientometric portrait of Nobel laureate Harald zur Hausen. Annals of Library and Information Studies 2011;58:71-8.
Patel C, Brotherton JML, Pillsbury A, Jayasinghe S, Donovan B, Macartney K, et al.
The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent? Euro Surveill 2018; 41: doi: 10.2807/1560-7917. ES.2018.23.41.1700737.
Cleaver JE. Profile of Tomas Lindahl, Paul Modrich, and Aziz Sancar, 2015 Nobel laureates in chemistry. Proc Natl Acad Sci USA 2016;113:242-5.
Guo ZS. The 2018 Nobel prize in medicine goes to cancer immunotherapy (editorial for BMC Cancer). BMC Cancer 2018;18:1086.
Bullement A, Latimer NR, Gorrod HB. Survival extrapolation in cancer immunotherapy: A validation-based case study. Value in Health 2019;22:276-83.