When I found out I was getting chemo I was curious to know what it was and how it worked. Prior to my treatment I picked up a booked called Understanding Chemotherapy. Published by Macmillan Cancer Support, it was aimed at people like me coming to chemo for the first time. It was clearly written, well-illustrated, and informative, but I wanted more. I wanted to get to the root of chemotherapy, to find out where it came from, when it started, how it developed. I started recording my impressions, keeping track of any side-effects, and Dini, my wife, put together a short video diary – vlogging a dead horse, as I thought at the time – after each session. But I wanted to step outside my own experience and try to understand the treatment by digging into its history. I believe in research as remedy and therapeutic practice. I used to joke about the healing power of footnotes. Some people might not want to know what’s happening to them but curiosity will kill me before cancer does. My impression of chemotherapy before my treatment started wasn’t a positive one. As far as I was aware, it roughed you up, then the cancer came back. That’s all I knew. I used to tell myself I’d refuse chemo if it was offered it. But when I found out that it would be the first line of defence in my battle against a cancer that was aggressive and advanced I changed my mind. Some people don’t like the military metaphor but I’m fine with it. I’m lucky as an academic to be able to access material that might be out of reach for others. I wanted to know exactly what form this treatment would take and how it would affect me. The first thing I learned was that chemotherapy has been around a long time and has a remarkable history. What follows is my attempt at a survey of this treatment from its origins to the present day.

Here’s a question. What do sleeping sickness (trypanosomiasis), malaria, syphilis, and mustard gas have in common? The answer is that they all lie at the tangled roots of chemotherapy. The earliest uses of chemotherapy were for sleeping sickness and syphilis. The story starts with founding figure Paul Ehrlich (1854-1915), a Polish-born German physician who did pioneering work in organic chemistry, immunology, oncology, haematology, pharmacology, and histology (the study of the microscopic anatomy of biological tissues).

Ehrlich’s thesis on “Contributions to the Theory and Practice of Histological Staining” earned him his doctorate at Leipzig University in 1878. Winner of the Nobel Prize in Physiology in 1908, Ehrlich is credited with coining the word ‘chemotherapy’ and defining its aim: “To be successful in chemotherapy we must search for substances which are fitted to annihilate the invading parasites with the least possible damage to the host organism.” Ehrlich approached his work like a cop trying to crack a case. Sir Henry Dale, Nobel Prizewinning pharmacologist and physiologist, said of Ehrlich’s personality: “I have heard him speak with enthusiasm […] of the Sherlock Holmes stories, and a portrait of Conan Doyle hung on his study wall; but that was because he prided himself on a supposed resemblance between Holmes’s detective methods and those of his own researches.”

Ehrlich’s interest in medicine and science began at an early age. During the school holidays, he mixed dye into the seeds fed to the family’s white pigeons. The birds were supposed to turn ‘a nice blue colour’. Instead, they died. Ehrlich persisted, and if pigeons were the earliest casualties of his search for a curative compound, then rabbits were also on the hit list. Ehrlich was ahead of his time in his interest in dyes as something that could be applied to living tissue as well as textiles. His PhD, completed in 1878, on selective staining of tissues was the basis of his future research. At this time chemotherapy was not considered as a treatment for cancer. Ehrlich’s research was directed towards a targeted treatment aimed at the destruction of harmful micro-organisms. Malaria was among the diseases he attempted to treat, but his breakthroughs came with the development of a single-dose treatment for Helicobacter pylori, and a treatment for syphilis in the form of a new compound called Salvarsan. The phrase, “magic bullet”, from the German “Zauberkugel”, was applied at this time to syphilis as a way of killing the parasite while preserving the host. The targeted treatment of cancer was still far off on the horizon. Ehrlich died in 1915, twenty years before the emergence of chemotherapy as a treatment for cancer, but his work laid the foundations for chemotherapy as we know it today.

One of Ehrlich’s early ideas was what he called ‘horror autotoxicus’: he argued that the body could never attack itself. Like Ehrlich’s other findings, this claim carried great weight, even when it ultimately proved untrue, but old theories die hard. When evidence mounted that the body could indeed attack itself, Ehrlich stuck fast to his original claim that this was an impossibility. According to Arthur M. Silverstein, “Ehrlich’s absolute dictum that autoimmune disease cannot occur would resound throughout the decades and prevent full acceptance of a growing reality”. Nonetheless, his ideas were crucial in providing the building blocks of modern methods for the treatment of cancer, as he was among the first to recognise the peculiarities of the disease.

In 1904, Ehrlich and his Japanese colleague, the distinguished bacteriologist Kiyoshi Shiga, investigated the use of dyes to treat trypanosomiasis, with mixed results. In 1910, Ehrlich developed an arsenical compound called salvarsan, the first targeted treatment of syphilis. Carl Browning, a medical student at the University of Glasgow, produced a study of chemotherapy for trypanosomiasis – aka “sleeping sickness” – as part of his MD thesis in 1908 in which he showed that Ehrlich’s treatment of a disease that had previously been fatal in animals with a ‘chemo-therapeutic agent’ was a game-changer. By 1912 chemotherapy was recognised as an emerging field.

The idea of “a magic bullet” persisted even after it became clear that there was no quick fix for any of the diseases to which chemotherapy was applied. But the phrase was hard to eradicate, and although its role in the search for a cure for syphilis was acknowledged, it soon became a byword for chemotherapy. A recent article on Ehrlich’s contribution to medicine, for example, speaks of his appointment in 1899 as director of Frankfurt’s Royal Institute of Experimental Therapy as a post that permitted him to pursue the “magic bullet”. One of the great ironies is that a phrase bound up with syphilis became indelibly associated with cancer, mainly because Hollywood produced a film in 1940 entitled Dr. Ehrlich’s Magic Bullet, starring Bucharest-born Edward G. Robinson. Playing Ehrlich came easily to Robinson, born Emanuel Goldenberg, because like Ehrich he had been on the receiving end of antisemitism, and proved to be a prominent anti-fascist in the period the film was made.

In 1941, Eric Boyland, a leading figure in molecular toxicology, stated: “Research on the chemotherapy of cancer is still in the stage of examining substances which inhibit tumour growth rather than cure it by causing complete disappearance of the tumour.” And the heels of chemotherapy turned slowly. In 1955, American clinical oncologist David A. Karnofsky cautioned against optimism around this new – or rather repurposed – treatment:

“Once cancer spreads beyond the site of origin, or when it appears initially as a disseminated disease, its subsequent and inexorable progression is determined largely by the biological characteristics of the disease in relation to the environmental situation provided by the host. The physician, in the past, has been frequently an interested but ineffectual observer, and this frustrating role has led to therapeutic discouragement and apathy. […] Only in recent years, beginning in the late 1930’s, were systematic efforts made to control the growth of certain forms of cancer by altering its physiological environment, and later, in the middle 1940’s, were drugs developed that temporarily restrained the growth of certain forms of neoplastic disease. Thus, in this brief period a new phase of cancer therapy was established-the search for drugs that could control, restrain, or destroy the growth of neoplastic cells wherever they existed in the body. A great deal of deliberate optimism was necessary to stimulate the growth of this field against the negativism that pervades any efforts to treat far-advanced or nonresectable cancer. Now a sound basic discipline of cancer chemotherapy is evolving.” Karnofsky, a non-smoker, died of lung cancer at the age of 55.

As recently as the 1960s, that is, in my lifetime, there was widespread scepticism in the medical community as to whether chemotherapy for cancer would be effective. Medical oncology was a fringe activity. The consensus was that cancer couldn’t be treated successfully in this way, and, as Vincent T. DeVita Jr and Edward Chu put it, “poison was the term in general use for anticancer drugs”. Resistance to chemotherapy within the medical establishment persisted. At Yale University innovative oncologist Paul Calabresi was frozen out due to his pioneering work with anticancer drugs, which was not popular with his colleagues. Again, as DeVita Jr and Chu observe: “It took plain old courage to be a chemotherapist in the 1960s and certainly the courage of the conviction that cancer would eventually succumb to drugs. Clearly, proof was necessary, and that proof would come in the form of the cure of patients with childhood acute leukemia and in adults with advanced Hodgkin’s disease.” A significant development in the USA was “the passage of the National Cancer Act of 1971 that launched the nation’s ever-controversial ‘war on cancer.’’’ This war on cancer was more than a magic bullet – it was a medical battlefield, and it remained so for decades to come.

By 2008, cancer researchers such as Vincent T. DeVita Jr and Edward Chu could look back on a century of chemotherapy:

“The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II–related programs, and the effects of drugs that evolved from them, that provided the impetus to establish in 1955 the national drug development effort known as the Cancer Chemotherapy National Service Center. The ability of combination chemotherapy to cure acute childhood leukemia and advanced Hodgkin’s disease in the 1960s and early 1970s overcame the prevailing pessimism about the ability of drugs to cure advanced cancers, facilitated the study of adjuvant chemotherapy, and helped foster the national cancer program. Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments.”

My first experience of four months of chemotherapy between November 2023 and March 2024 was far from traumatic. In fact it made me appreciate the health service we have in Scotland, the quality of care and the company of fellow patients – I won’t say “sufferers”, as that assumes too much. I shared a room with several others undergoing the same treatment and we talked, laughed, read, listened to music and swapped ideas about diet and exercise. The drug I was administered during that first course of treatment was Docetaxel. I’ve now embarked on a second course of chemotherapy, Cabazitaxel, that will take me through to  July if all goes according to plan. I know this is no magic bullet, but I welcome the opportunity to kill some cancer cells and buy some time. For me, understanding chemotherapy has been a form of therapy. I feel prepared.

REFERENCES

Anyone interested in the reading I did on the road to writing this piece can find most of the sources here:

Adrian Albert, Selective Toxicity: The Physico-Chemical Basis of Therapy, 7^th edition (London: Chapman & Hall, 1985; first published 1951).

Muhammad T. Amjad, Anusha Chidharla, and Anup Kasi, ‘Cancer Chemotherapy’, StatPearls. StatPearls Publishing, Treasure Island (FL); 2023. PMID: 33232037,

https://pubmed.ncbi.nlm.nih.gov/33232037/.

George Androutsos, ‘Paul Ehrlich (1854–1915): Founder of Chemotherapy and Pioneer of Haematology, Immunology and Oncology’, Journal of the Balkan Union of Oncology

9 (2004): 485-491.

Hans C. S. Aron, ‘Paul Ehrlich: His Contributions to Medicine: A Tribute at the Centennial of his Birthday’, Journal of the American Medical Association 154, 12 (1954): 969-972.

Julius M. Bernstein, ‘Chemotherapy’, in Applied Pathology (London: Published for The University of London Press by Hodder & Stoughton and Henry Frowde, 1913), 361-376.

Eric Boyland and Elinor Huntsman Mawson, ‘Experiments on the Chemotherapy of Cancer: The Effect of Aldehydes and Glucosides’, Biochemical Journal 32, 11 (1938): 1982-1987.

Eric Boyland, ‘Experiments on the Chemotherapy of Cancer: The Effect of Certain Antibacterial Substances and Related Compounds’, Biochemical Journal 32, 7 (1938): 1207-1213.

Eric Boyland, ‘Experiments on the Chemotherapy of Cancer: Further Experiments with Aldehydes and their Derivatives’, Biochemical Journal 34, 8-9 (1940): 1196-1201.

Eric Boyland, ‘Experiments on the Chemotherapy of Cancer: The Effect of Muscle Extract and Aliphatic Bases’, Biochemical Journal 35, 10-11 (1941): 1283-1288.

Eric Boyland, ‘Chemical Carcinogenesis and Experimental Chemotherapy of Cancer’, The Yale Journal of Biology and Medicine 20, 4 (1948): 321-341.

Carl H. Browning, ‘Chemo-Therapy in Trypanosome Infections: An Experimental Study’, Journal of Pathology and Bacteriology 12, 2 (1908): 166-190.

Carl H. Browning, ‘Chemotherapy’, in A System of Bacteriology in Relation to Medicine, Volume 6 (London: H. M. Stationery Office, 1929), pp. 501-516.

John Cairns, Peter Boyle and Emil Frei, ‘Cancer Chemotherapy’, Science 220, 4594 (1983): 252, 254, 256.

‘Chemotherapy and Cancer’, The British Medical Journal 1, 4039 (1938): 1216.

Henry Dale, ‘Paul Ehrlich’, British Medical Journal 1, 4863 (1954): 659-663.

Henry Dale, ‘Introduction’, in F. Himmelweit (ed.), The Collected Papers of Paul Ehrlich, 4 vols., Volume III: Chemotherapy (London: Pergamon Press, 1960), 1-8.

Luke Demaitre, ‘Medieval Notions of Cancer: Malignancy and Metaphor’, Bulletin of the History of Medicine 72, 4 (1998): 609-637.

Vincent T. DeVita Jr and Edward Chu, ‘A History of Cancer Chemotherapy’, Cancer Research 68, 21 (2008): 8643-8653.

Emil Frei, ‘Cancer Chemotherapy’ [Reply to Cairns and Boyle], Science 220, 4594 (1983): 254, 256.

Iago Galdston, ‘Some Notes on the Early History of Chemotherapy’, Bulletin of the History of Medicine 8, 6 (1940): 806-818.

Iago Galdston, ‘Ehrlich, Biologist of Deep and Inspired Vision’, The Scientific Monthly 79, 6 (1954): 395-399.

Carlos Gamio, ‘Of Rabbits and Men: The Tale of Paul Ehrlich’, Microessays 2016: Science Communication in Action: 6-11. A collection of short articles about microbiology written for the general public by Microbiology, Virology and Parasitology students from the University of Glasgow, https://www.gla.ac.uk/media/Media510620smxx.pdf#page=6

Gian Franco Gensini, Andrea Alberto Conti, and Donatella Lippi, ‘The Contributions of Paul Ehrlich to Infectious Disease’, Journal of Infection 54, 3 (2007): 221-224.

Susan Gubar, ‘In the Chemo Colony’, Critical Inquiry 37, 4 (2011): 652-670.

Chris Hoy, All That Matters, written with Matt Majendie (London: Hodder & Stoughton, 2024).

Venita Jay, ‘Paul Ehrlich: A Portrait in History’, Archives of Pathology & Laboratory Medicine 125, 6 (2001): 725-725.

David A. Karnofsky, and Joseph H. Burchenal, ‘Present Status of Clinical Cancer Chemotherapy’, The American Journal of Medicine 8, 6 (1950): 767-788.

David A. Karnofsky, ‘Chemotherapy of Cancer’, CA: A Cancer Journal for Clinicians 5, 5 (1955): 165-173.

Stefan H. E. Kaufmann, ‘Paul Ehrlich: Founder of Chemotherapy’, Nature Reviews Drug Discovery 7, 5 (2008): 373-373.

Perrin H. Long, ‘Paul Ehrlich and Modern Chemotherapy’, Bulletin of the New York Academy of Medicine 28, 5 (1952): 344-346.

Audre Lorde, A Burst of Light: Essays (Ann Arbor, Michigan: Firebrand Books, 1988).

Macmillan Cancer Support, Understanding Chemotherapy (2022), https://cdn.macmillan.org.uk/dfsmedia/1a6f23537f7f4519bb0cf14c45b2a629/9153-10061/mac11619-e16-chemotherapy?ga=2.224655770.1079658837.1705659312-2146784877.1705659312.

William Martindale, The Extra Pharmacopoeia, revised by W. Harrison Martindale and W.W. Westcott, 2 vols. (London: H. K. Lewis and Company, 1912).

Denis R. Miller, ‘A Tribute to Sidney Farber – The Father of Modern Chemotherapy’, British Journal of Haematology 134, 1 (2006): 20-26.

John Parascandola, ‘The Theoretical Basis of Paul Ehrlich’s Chemotherapy’, Journal of the History of Medicine and Allied Sciences 36, 1 (1981): 19-43.

Anna Piro, Antonio Tagarelli, Giuseppe Tagarelli, Paolo Lagonia & Aldo Quattrone, ‘Paul Ehrlich: The Nobel Prize in Physiology or Medicine 1908’, International Reviews of Immunology 27, 1-2 (2008): 1-17.

Steven Riethmiller, ‘Erlich, Bertheim and Atoxyl: The Origins of Modern Chemotherapy’, Bulletin for the History of Chemistry 23 (1999): 28-33.

Steven Riethmiller, ‘From Atoxyl to Salvarsan: Searching for the Magic Bullet’, Chemotherapy 51 (2005): 234-242.

John M. Riddle, ‘Ancient and Medieval Chemotherapy for Cancer’, Isis 76, 3 (1985): 319-330.

Bartolomeo Ruspini, Ruspini’s Styptic (Manchester: Butterworth & Co., 1884).

Arthur M. Silverstein, ‘Autoimmunity Versus Horror Autotoxicus: The Struggle for Recognition’, Nature immunology 2, 4 (2001): 279-281.

Arthur M. Silverstein, ‘Paul Ehrlich, Archives and the History of Immunology’, Nature Immunology 6 (2005): 639.

Susan L. Smith, ‘Mustard Gas and American Race‐Based Human Experimentation in World War II’, The Journal of Law, Medicine & Ethics 36, 3 (2008): 517-521.

Susan L. Smith, ‘War! What is it good for? Mustard Gas Medicine’, Canadian Medical Association Journal 189, 8 (2017): E321-E322.

Susan Sontag, Illness as Metaphor (New York: Farrar, Strauss and Giroux, 1978).

Fritz Stern, ‘Paul Ehrlich: The Founder of Chemotherapy’, Angewandte Chemie International Edition 43, 33 (2004): 4254-4261.

Alfred W. Stewart, Chemistry and its Borderland (London: Longmans, Green, and Co, 1914).

Michael Stolberg, ‘Metaphors and Images of Cancer in Early Modern Europe’, Bulletin of the History of Medicine 88, 1 (2014): 48-74.

Owsei Temkin, ‘In Commemoration of the Hundredth Anniversary of the Birth of Paul Ehrlich: The Era of Paul Ehrlich’, Bulletin of the New York Academy of Medicine 30, 12 (1954): 958-967.

B. T. Terry, Chemo-Therapeutic Trypanosome Studies with Special Reference to the Immunity Following Cure (New York: The Rockefeller Institute for Medical Research, 1911).

Peter Valent, Bernd Groner, Udo Schumacher, Giulio Superti-Furga, Meinrad Busslinger, Robert Kralovics, Christoph Zielinski et al, ‘Paul Ehrlich (1854-1915) and his Contributions to the Foundation and Birth of Translational Medicine’, Journal of Innate Immunity 8, 2 (2016): 111-120.

K. J. Williams, ‘The Introduction of ‘Chemotherapy’ Using Arsphenamine – The First Magic Bullet’, Journal of the Royal Society of Medicine 102, 8 (2009): 343-348.

Bernhard Witkop, ‘Paul Ehrlich and His Magic Bullets, Revisited’, Proceedings of the American Philosophical Society143, 4 (1999): 540-557.