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THE STORY OF CANCER: DOWN THE RABBIT-HOLE.

Byline: Nadir Hasan

From the earliest of times human beings have lived in awe of the forces of Nature and agonised over the (often) cruel edicts of Destiny and Fate. In the Quatrain quoted above the great Muslim poet and mathematician Omar Khayyam most eloquently refers to this very conundrum. Why is there so much sorrow pain and (from a bio-medical perspective) disease in this World of ours

The utterance: What did the Hand then of the Potter shake" from the lips' of a Pot of Clay sounds almost blasphemous. However should we not forgive this unfortunate Vessel of a more Ungainly Make" (abnormal / deformed / damaged) for its expression of this (apparently) sacrilegious sentiment In the same vein can a human being afflicted by some terrible disease not cry out in anguish at the (apparent) injustice of the Divine Hand in an attempt to find some semblance of meaning in apparent Chaos

At this stage we have to acknowledge that the Scientific Method is poorly equipped to answer these fundamental questions. Such grand matters which have been of ultimate concern to humanity Ethics Morality the Soul Spirituality Sacredness will always be the rightful realm of Religious Faith (Iman). Amen to that!

However to my mind Khayyam's symbolism reflects most acutely the most difficult and complex problem - confronting physicians/surgeons in general and oncologists/pathologists in particular of neoplastic disease (i.e. cancer) which truly represents the greatest challenge facing us!

Cancer" the most aptly described Emperor of all Maladies" has been the scourge of Mankind since records began. The earliest written description of human cancer appeared in ancient Egyptian manuscripts (papyri") dis- covered in the 19th century by Edwin Smith and George Ebers written between 1500 and 1600 BCE most likely referring to much more ancient records. It is believed that Imhotep the mythical physician of a bygone age (c. 26502600 BCE) may well have recorded the rst reference to breast cancer in one of these archaic documents.

Carroll L. Alice's Adventures in Wonderland. Gramercy Books NY 1995.

After the ancient Egyptian civilisation declined Greek medicine became preeminent especially with Great" Hip-pocrates of Kos (460- c.360BCE) whose approach to diagnosing diseases was based upon careful observations of his patients' signs and symptoms. Later on Galen (c.129c. 216) was Hippocrates' most prominent successor and propelled his legacy for nearly 15 centuries. Galen's prolic writings include 300 titles of which only about half have survived wholly or in part many destroyed in the re of the Temple of Peace (CE 191).

With the collapse of Greco-Roman civilization after the fall of Rome in CE 476 medical knowledge in the West-ern Roman Empire stagnated and many ancient medical writings were lost. Latin translations were not readily available and few scholars could read Greek. Yet Greek medical tradition remained alive and well in the Eastern Roman (Byzantine) Empire.

Islamic interest in Greek science and medicine during the Abbasid period led to translations of Galen's work into Arabic many of them by Syrian scholars. It has been written that a critical role was played by one Ja'far Ibn Barmak (minister of the Caliph of Bagdad) in the adoption of Greek thought by the Muslims (Arabs).

Islamic physician scholars and medical writers became preeminent in the early middle ages. The most illustri-ous and inuential in that era being:

Abu Bakr Muhammad Ibn Sazariya Razi also known as Rhazes (865-925)

Abu Ali al-Husayn ibn Abd Allah Ibn Sina known as Avicenna (980103)

Abu-Marwan Abd al-Malik ibn Zuhr or Avenzoar (10941 162) and

Ala-al-din abu Al-Hassan Ali ibn Abi- Hazm al-Qarshi al-Dimashqi or Ibn Al-Nas (12131288)

The Anatomy Canon of Avicenna a manuscript discovered in the Prussian State Library of Berlin is one of the marvels of Islamic medicine. In fact Ibn Sina was the rst scientist to understand the function of coronary circu-lation.

It was Avenzoar who rst described oesophageal and gastric cancer in his magnificent book Kitab al-Taysir fil-Mudawat wal-Tadbir (Practical Manual of Treatments and Diets) and proposed feeding enemas to keep alive pa-tients with stomach cancer. Like Hippocrates he insisted that prospective (student) surgeons should receive hands-on training before being allowed to operate on his own. By the end of the fourteenth century Avenzoar became well known in university circles at Padua Bologna and Montpellier where he was considered one of the greatest physicians of all time. Successive publication s of his Kitab al-Taysir and of translations ensured his inuence well into the seventeenth century.

Sadly the Mongol destruction of capital of the Abbasid Caliphate Baghdad in 1258 and the fall of Islamic Spain (Granada) marked the decline of Islamic Medicine. On reflection it almost seems as if a perfect storm' of unrelated tragic events conspired against the Glory of the Muslim world.

In Europe during the Middle-Dark Ages (500-1400 CE) there was a proliferation of Monasteries which become repositories of Arab- Greek medicine. An important figure of this era was Constantine Africanus (a Tunisian Tuni-sia was known Ifriqiya at that time) whose translations and annotations of Arabic (and Greek) medical texts made famous the Studium Hospitium (hospice/hospital) at Salerno (Italy). This was the beginning of an inuential and enduring phase of advances in knowledge with medical schools being established at Montpellier (1150) Bologna (1158) and Paris (1208). Later on during the (so-called) European Renaissance Andreas Vessalius (15141564) Ambroise ParACopyright (15101590) and Gabriele Fallopius (15231562) amongst others were significant figures in the development of scientific" medicine of that era.

However even in those early days cancer was known as an incurable deadly condition. Francois Le Dran (16851770) one of the best surgeons of his time postulated that cancer developed locally but spread through lymphatics becoming inoperable and fatal. Joseph Recamier (17741852) first coined the term metastasis" in 1829. Giovanni Battista Morgagni (16821771) wrote what is considered by many to be the first pathology text-book: De Sedibus et Causis Morborum per Anatomen Indigatis" (On the Seats and Causes of Diseases as In-vestigated by Anatomy) which defined a new era in the study of tumours (cancer). In 1713 Bernardino Ramazzini (16331714) of Padua made the important observation of a virtual absence of cervical cancer but higher inci-dence of breast cancer in Nuns related to married women an early astute observation of virus- and hormone- related carcinogenesis.

Further on an English Botanist John Hill (1716-1775) warned of the dangers to health of Tobacco. Percivall Pott (17141788) noted the increased incidence of scrotum cancer in chimney sweeps an important early observa-tion of chemical carcinogenesis. During that period several other important clinical associations were noted in-cluding recurrences distal to the original cancer multiple cancers in a single individual and families with a high incidence of cancer (by Jacques Mathieu Delpech (1772 1835) Gaspard Laurent Bayle (17741816) Pierre Paul Broca (1824 1880) James Paget (18141899) and Carl von Rokitansky (18041878)).

In 1839 Johannes Muller (18011858) published "On the ne structure and forms of morbid tumors" which remains a seminal publication in tumour pathology. Rudolf Virchow (18211902) is credited with being the Father' of Cellular pathology - the phrase omnis cellula e cellula" (every cell originates from another existing cell like it) is attributed to Virchow. However in his three-volume work Die Krankhaften Geschwulte Virchow had originally postulated that carcinomas originated from connective tissue cells and not from epithelium. Interestingly it was Robert Remak (18151865) who had first discovered that the origin of cells was by the division of pre-existing cells. Theodor Boveri (18621915) rst proposed a role for somatic mutations in cancer development based on his observations in sea urchins.

At this stage it interesting to note that even though the currently accepted concept of carcinogenesis posits a cellular origin' to tumours valid alternative models have been proposed which assign tissue' the fundamental focus in malignancy somewhat reminiscent of Virchow's original concepts!

Interest in a possible bacterial or parasitic link to cancer was rst raised in the 17th and 18th centuries. Between the 1880s and the 1920s there was a huge effort to find cancer-causing micro- organisms. In fact Andreas Grib Fibiger (1867 1928) was awarded the 1926 Nobel Prize in Physiology or Medicine for his discovery of the cancer causing nematode' Spiroptera carcinoma. Although such early studies were later found to be inaccurate the ba-sic concepts of infectious' aetiology of cancer have in fact found support in at least some cases. Peyton Rous (18791970) demonstrated the viral origin of cancer in chickens and was awarded the 1966 Nobel Prize for Physiology or Medicine for this discovery. Today the association of Helicobacter pylori and gastric cancer is well established.

Also the International Agency for Research on Cancer (IARC) has classified the following viruses as group 1 human carcinogens: Epstein-Barr virus (EBV) hepatitis B virus (HBV) hepatitis C virus (HCV) Kaposi's sarcoma herpes virus (KSHV) human immunodeficiency virus type-1 (HIV-1) human T cell lymphotrophic virus type-1 (HTLV-1) and human papillomavirus (HPV).

At this stage is worth mentioning that the original hypothesis of bacteriological basis of cancer left a more pervasive and counterproductive parallel with infectious diseases: that cancer cells like bacteria are foreign invaders that must be eradicated at all costs!

Thus at beginning of the 20th century there was much controversy regarding the mechanism of carcinogenesis. In 1903 an editorial in the British Medical Journal stated: . few things even in medicine have ever been so tangled as the views which are held by different people on the origin and cause of cancer'' (Plimmer HG. Chair of Comparative Pathology Imperial College of Science and Technology 1917-1918; Fellow of the Royal Society 1910; President of the Royal Microscopical Society 1911-1912).

During the 1940s onwards researchers continued the search for the cause of cancer with much urgency. One important development was the proposal of the theory chemical carcinogenesis in three stages: initiation promotion and latency. Chemical substances such as oils tar petroleum rubber products were conclusively shown to be carcinogens in experimental animals. It was also discovered that laboratory animals on a diet of Brazilian groundnuts developed liver tumours. Aflatoxin the responsible chemical agent was identified and traced to contamination of the nuts by a fungus Aspergillus flavus.

In the 1960s nitrosamines and a number of other compounds were added to the long list of organ-specific car-cinogens in experimental animals. These discoveries were followed by experimental confirmation that exogenous oestrogen is capable of inducing mammary carcinoma in several different species of laboratory animals.

The 1953 discovery of the three-dimensional structure of DNA by Watson and Crick (aided by Rosalyn Franklin's X-ray diffraction studies) was crucial in establishing the concept of DNA damage as the cause of cancer. However it was a German surgeon and cancer researcher Karl- Heinrich Bauer who in 1928 (by observing mutations in plants and animals) had first proposed idea that cancers were likely caused by mutations.

At this point we may recall that it was the German biologist Theodore Boveri who in 1914 first proposed that tumours arise from chromosomal abnormalities. The (somatic) mutation theory' (SMT) of cancer evolved slowly during early years of the last century (1918-1930). Over the ensuing decades this concept became increasingly accepted and became the basis of intense biomedical research with innumerable publications in the literature. In short the SMT posits that cancer is the result of progressive accumulation of random mutations and increased deregulation of key molecular pathways.

For clarity it may be useful to the revisit the genetic' basis of separating different types of human cancers: First there are tumours that are inherited through the germline of the carriers - they represent about 5% of the total in-cidence of human cancers. There is consensus about the mutational origin of these inherited cancers.

Second are sporadic" tumours that represent 95% of all clinical cancers putatively the result of a variety of chemical physical and biological (environmental) agents. It is these sporadic' cancers which have been the target of the long War on Cancer' declared by US President Richard Nixon way back in 1971.

Over the past two decades there has been an explosive growth in scientific knowledge of the bio-molecular fac-tors involved in carcinogenesis. The enormous development of genetics biochemistry and molecular biology during the twentieth century made possible the emergence of the big scientic-technological revolution of recombinant DNA. In turn this made possible new and accelerated advancements associated with (so-called) Omics'' and bioinformatics allowing for high throughput and high content analysis of biological data.

On the other hand all this new and sophisticated technology for the massive acquisition of biological data ap-pears to have widened the gap between the deluge' of biological data available and the (very) limited amount of actual new (actionable) knowledge. At the turn of the millennium biologists faced for the rst time the challenge of what to do with these new data which are being massively acquired at a rate much faster than that required for their processing

Thus as we approach 2015 the Story of Cancer continues to unfold with even more intricate plots and unex-pected twists. In fact the current leaders of the field appear to be as confused as anyone else. One of the Godfathers' of the current SMT paradigm' of cancer biology- oncology Dr Robert Weinberg (co-author of the highly influential Hallmarks of Cancer" paper) wrote a leading edge essay in the prestigious scientific journal CELL in March this year (Cell. 2014; 157: 267271). The article makes difficult reading to quote: how and why a cancer cell behaves as it does is still far beyond our reach the data that we now generate overwhelm our abilities of interpretation ... we lack the conceptual paradigms and computational strategies for dealing with this complexity . (etc) .. "

Thus as we cautiously journey down the Rabbit-hole in search of that elusive White Rabbit (the cure for cancer) - it appears that this long winding tunnel has lead us to a cul-de-sac a dead end. What next Should we re-trace our path back Or attempt an alternative route Or simply give up

It appears that the resolution to the current impasse in the understanding of malignant tumours (cancer) may lie in an honest revaluation of the technique we have used (path we have followed') for the past many many years in our attempts to find an answer to this most difficult problem.

The Reductionist Method of dissecting biological systems into their constituent parts has been effective in ex-plaining the chemical basis of numerous living processes. However it is becoming increasingly obvious that this approach has reached its limits especially with reference to the major challenges we face in medicine today: chronic (autoimmune/degenerative) diseases and cancer.

How can we catch (or tame) the White Rabbit

But that my friends is a Story for another day . Carroll L. Alice's Adventures in Wonderland. Gramercy Books NY 1995.

Further Reading and Selected Bibliography

Fritzgerald E. Rubaiyat of Omar Khayyam (Oxford World's Classics) Oxford University Press 2009.

Mukherjee S. The Emperor of All Maladies: A Biography of Cancer. Sribner: NY 2010.

Ghalioungui P. Magic and Medical Science in Ancient Egypt Barnes and Noble: NY 1965.

Nunn JF. Ancient Egyptian Medicine University of Oklahoma Press 1996.

Gourevitch D. Reinventing Hippocrates. Bull Hist Med. 2003; 77: 1418 19.

Maynard J. The Light of Alexandria. Sciartmedia.com 2005.

O'Leary and De Lacy. How Greek science passed to the Arabs. Routledge and Kegan Paul London 1949.

Hunt J. The pursuit of learning in the Islamic World 6102000 McFarland 2005.

Haddad SI. Arabian contributions to medicine. Ann Med History 1936; 3: 6072.

Burnett and Jacquart (Eds). Constantine the African and Ali ibn al- 'Abbas al-Magusi (Studies in Ancient Medicine Vol 10) Brill Academic Publ. Leiden 1994.

Peter D. Revolutionizing the Sciences: European Knowledge and Its Ambitions 1500-1700. Princeton: Princeton UP 2001.

Ross and McLauglin (Eds). Ambroise ParACopyright "A Surgeon in the Field" (The Portable Renaissance Reader). Viking Pen-guin New York 1981.

Wolff J. The Science of cancerous disease from earliest times to the present. Science History Publications Canton MA 1989.

Ventura HO. Giovanni Battista Morgagni and the foundation of modern medicine. Clin Cardiol. 2000; 23: 792794.

Franco G. Ramazzini and workers' health. The Lancet. 1999; 354 (9181): 858-861.

Dobson J. 'Percivall Pott' - Annals of The Royal College of Surgeons of England vol. 50 pp. 546; 1972.

http://www.history-of-the-microscope.org / historyof-the- microscope-who-invented-the-microscope.php. (accessed October 2014)

Anderson CT. Robert Remak and the multinucleated cell: eliminating a barrier to the acceptance of cell division. Bull Hist Med. 1986; 60: 523 43.

Virchow R. Die Cellularpathologie 4th ed. Berlin: Hirschwald 1871.

Harris H. Concerning the Origin of Malignant Tumours by Theodor Boveri. J Cell Sci. 2008; 121 (suppl 1): 184.

Stolley PD and Lasky T. Johannes Fibiger and His Nobel Prize for the Hypothesis That a Worm Causes Stomach Cancer. Ann Intern Med. 116: 765-76. 1992.

Rubin H. The early history of tumor virology: Rous RIF and RAV. Proc Natl Acad Sci USA. 2011; 108: 14389-9.

Marshall B Adams PC. Helicobacter pylori: A Nobel pursuit Can J Gastroenterol. 2008; 22: 895896.

Chen Hsu. Epidemiology of virus infection and human cancer. Recent Results Cancer Res 193: 11-32. 2014.

Plimmer HG. The parasitic theory of cancer. Br Med J. 1903; 2: 1511-15.

Berenblum I. The mechanism of carcinogenesis: a study of the significance of carcinogenic action and related phenomena. Cancer Res. 1941; 1: 807-814.

Friedenwald WF Rous P. The initiating and promoting elements in tumor production. An analysis of the effects of tar benzpyrene and methylcholanthrene on rabbit skin. J Exp Med. 1944; 80: 101-120.

Hartwell JL. Survey of compounds which have been tested for carcinogenic activity. Washington DC: National Cancer Institute; 1951.

Lancaster et al. Toxicity associated with certain samples of groundnuts. Nature. 1961; 192: 1095-1096.

Ghadially FN Roy S. Experimentally produced synovial sarcomas. Cancer. 1966; 19: 1901-1908.

Cutts JH and Noble RL. Estrone-induced mammary tumors in the rat. Induction and behavior of tumor. Cancer Res. 1969; 24: 1116-23.

Watson JD and Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953; 171(4356): 737738.

Bauer KH. Mutationstheorie der Geschwulst-Entstehung. Berlin: Julius Springer Verlag; 1928.

Wright NA. Boveri at 100: cancer evolution from preneoplasia to malignancy. J Pathol. 2014; 234: 146-151.

Weinberg RA. In Retrospect: The chromosome trail. Nature. 2008; 453: 725.

Edler L and Kopp-Schneider A. Origins of the mutational origin of cancer. Int J Epidemiol. 2005; 34: 11681170.

McCombs RS McCombs RP. A hypothesis on the causation of cancer. Science. 1930; 72: 423424.

Ashley DJB: The two hit" and multiple hit" theories of carcinogenesis. Br J Cancer. 1969; 23: 313328.

Knudson A: Mutation and cancer: statistical study in Retinoblastoma. Proc Natl Acad Sci USA. 1971; 68(4): 82023.

Fearon ER Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61: 759767.

Nixon R. Remarks on signing the National Cancer Act of 1971.

Nixon R (1971) Annual message to the congress on the state of the union.

Michor et al. Dynamics of cancer progression" Nature Reviews Cancer. 2004; 4: 197-205.

Hanahan D Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57 70.

Vogelstein B Kinzler KW: Cancer genes and the pathways they control. Nat Med. 2004; 10: 789799.

Hanahan D Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646674.

Ranea et al. (2010) Finding the dark matter'' in human and yeast protein network prediction and modelling. PLoS Comput Biol 6:e1000945

Witzany G Baluska F. Life's code script does not code itself: The machine metaphor for living organisms is out-dated. EMBO Rep. 2012; 13: 10541056.

Baker SG Kramer BS. Paradoxes in carcinogenesis: new opportunities for research directions. BMC Cancer. 2007; 7: article 151.

Weinberg RA. Coming full circle-from endless complexity to simplicity and back again. Cell. 2014; 157: 267271.

Carroll L. Alice's Adventures in Wonderland. Gramercy Books NY 1995.
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