Smallpox, Syphilis and Salvation

by Sheryl Persson

  Paul Ehrlich and Sahachiro Hata reported on the development of compound 606 and the success of their experiments at the Congress for Internal Medicine at Wiesbaden on 19 April 1910. Dr Schreiber of Magdeburg Hospital, who had been involved in the trials, gave an account of the first successful treatment of syphilitic patients at his hospital. When Ehrlich published his seminal paper, ‘Experimental Chemotherapy of Spirochaetal Diseases’, the medical world went into a frenzy. What Ehrlich had achieved was unprecedented and he was immediately bombarded with requests for the wonder drug.

  Salvarsan was registered with the patent office. Facilities at Georg Speyer Haus were geared up in order to make large quantities of the drug. The Hoechst Chemical Works began to build facilities for its manufacture but nevertheless for some time demand far exceeded supply. The success of this revolutionary drug spurred the expansion of the German pharmaceutical industry and Germany soon led the world in chemical and drug production. Within no time Salvarsan was being sold all over the world. Ehrlich received reports from as far away as the St Petersburg Hospital for Men in Russia that Salvarsan had completely cured patients and not one had relapsed.[41]

  In 1910 Salvarsan was heralded as a miracle cure for syphilis but Ehrlich insisted on keeping a close check on any irregularity that might arise from its use. It soon became apparent that the magic bullet was not as wondrous as first thought. The treatment was both expensive and painful. Initially Salvarsan was administered by injection but if the injection was not confined to the vein severe local pain resulted. Even when the drug was administered properly, it often caused necrosis, or tissue death, at the injection site. In some cases blood clots caused a swelling of the vein that could result in life-threatening infections. The side-effects were so severe for some patients that they died. Even worse, within a year, some patients who appeared to have been cured had relapsed.[42] The early elation had to be tempered and once again Ehrlich found himself facing powerful opponents, some of whom mounted a legal challenge to have Salvarsan banned.

  A court found in Salvarsan’s favour and Ehrlich was vindicated. The stress from the trial and the setbacks with his magic bullet left Ehrlich deeply troubled. Determined to find a safer and more effective compound than Salvarsan he returned to the laboratory and began testing again. The 914th arsenical substance, which was given the name Neosalvarsan, was found to be safer, more easily manufactured and, being more soluble, much less difficult for physicians to administer. Although it was not quite as active against the spirochaete, and therefore had less curative effect, it was still preferable to Salvarsan as a treatment.[43] Ehrlich, once again revealing the depths of his enormous intellectual talent and his commitment then devised a method of intravenous injection so that tissue damage and the danger of infection could be minimised and he ensured that the medical profession was instructed on its use.

  Paul Ehrlich had created his magic bullet, winning him praise and honours, but fame also put him in the firing line. He had to battle opposition and criticism before Salvarsan and Neosalvarsan were accepted, but opposition was not new to him. There were attacks from crackpots who accused him of trying to poison people, his reputation was sullied by his contemporaries who were motivated by professional jealousy and he also endured slurs that were anti-Semitic in nature.

  ***

  Salvarsan and Neosalvarsan were a first step only in a cure for syphilis, but they were miraculous compared to what had been on offer for syphilis sufferers in the past, and they gave hope for the discovery of better chemotherapeutic drugs in the future. In 1913 a doctor in the United States, Henry Pulsford, reported on the side-effects of Salvarsan and Neosalvarsan. Within six to eight hours of an injection, patients suffered nausea, vomiting, abdominal pain and diarrhoea. He attributed this reaction to the toxic effects of arsenic and the susceptibility of patients to varying doses of Salvarsan.[44] Pulsford warned about the risk of unnecessary deaths.

  Henry Wallhauser, another US physician, elaborated on Pulsford’s conclusion and recommended that Salvarsan be administered like other ‘dangerous remedies’ by giving small, repeated doses at varying intervals.[45] In 1914, Wallhauser grouped the deaths resulting from treatment with Salvarsan into two categories: degenerative and sudden. The latter category perplexed doctors. Patients would fall into a coma on the third or fourth day following injection. Wallhauser came to the conclusion that Salvarsan was safe in the early stages of syphilis, but as the disease progressed and damaged organs, patients could not cope with the toxicity of the arsenic.

  In Paris, Ernest Fourneau at the Pasteur Institute applied Ehrlich’s techniques to bismuth and created several antisyphilitic compounds to supplement the arsenicals. Some physicians used applications of mercury or bismuth ointments in conjunction with Salvarsan and Neosalvarsan.[46] It was trial and error and prior to World War II the medical profession accepted that while syphilis could be cured, it was a slow, painful and expensive process. Twenty to 40 injections over the course of a year were necessary. However, there was still optimism that the disease would eventually be eradicated.

  Salvarsan and Neosalvarsan remained the most effective drugs for treating syphilis until the advent of antibiotics in the 1940s. Without the discovery of Salvarsan the development of antibiotics and also sulfa drugs may not have happened when they did or perhaps not at all. Ehrlich’s work inspired other researchers including Alexander Fleming, the discoverer of penicillin. Fleming was one of the first doctors to administer Salvarsan in England and did so using Ehrlich’s new intravenous method.[47] Its success encouraged him to search for drugs that would treat and cure bacterial disease even though the consensus amongst the establishment was that vaccination research was the only way forward in the battle against micro-organisms.

  ***

  Paul Ehrlich lived for five years after the release of Salvarsan. In his personal life he was content despite what seemed to be recurrent turmoil in his professional life. Hedwig had supported him during the good times and the most trying. When World War I broke out Ehrlich was very distressed by the carnage, in the same way that his one-time friend, Emil von Behring, was. Neither of them lived to see the end of the war. Ehrlich never overcame nor did he understand the barrage of unwarranted and unscientific attacks that he endured over Salvarsan. The actions of his critics perturbed him and like-behaviour was not in his nature. Ehrlich’s motives were altruistic, his primary motivation being to advance science in order to cure disease. Ehrlich’s long career had revealed that, apart from diseases of the body there were also diseases of the soul—greed, hate and ignorance—which humankind seemed incapable of curing.

  Late in 1914 Paul Ehrlich suffered a stroke but recovered quickly. Apart from the bout of tuberculosis early in his life, he had enjoyed excellent health. However, at the age of 61 while on a holiday in Bad Homburg, he suffered a second, fatal stroke and died on 20 August 1915. Ehrlich had continued his research almost to the end of his life with his last project being an investigation of tumours. He was buried in the Jewish Cemetery in Frankfurt. An obituary in The Times in England acknowledged Ehrlich’s scientific and medical achievements, affirming that ‘the whole world is in his debt’.[48]

  Ehrlich’s indefatigable and obsessive nature, his kindness and modesty, his lifelong habit of eating little and smoking cigars incessantly, his insistence on repeating experiments before publishing results, and the respect and dedication of those who worked with him have been vividly captured in a biography entitled Paul Ehrlich als Mensch und Arbeiter, written by his secretary, Martha Marquardt.

  Paul Ehrlich’s place in the history of medicine rests not only on his cure for syphilis. His methods for staining bacteria were of great importance to the development of bacteriology. Through his demonstrations of the chemical reactions of dyes with living cells, haematology and later histology came into their own as sciences. Likewise his methods of assaying and standardising antitoxins are still the basis of immunology. He is credited with conceptualising the cell membrane recep
tor and was the first person to produce a chemical substance that had measurable chemotherapeutic effects, thus launching the age of chemotherapy. Ahead of his time, Ehrlich also theorised about a concept that he called ‘ horror autotoxicus’, which is what we now know as auto-immunity.[49] Paul Ehrlich’s was an extraordinary mind.

  Renowned and revered, Ehrlich was a member of no less than 81 academies and other learned bodies worldwide. His work was honoured with the bestowing of Orders in Germany, Russia, Japan, Spain, Romania, Serbia, Venezuela, Denmark and Norway. He won a plethora of prizes apart from the ultimate, the Nobel Prize. The Prussian government elected him to the highest rank of the Privy Medical Counsel in 1911 which came with the title of Excellency. As recently as 1996 a 200 Deutsche Mark banknote showing Paul Ehrlich was released into German currency. Hedwig Ehrlich also honoured her husband publicly when in 1929 she established the Paul Ehrlich Foundation in association with the Johann Wolfgang Goethe University in Frankfurt am Main. Each year the foundation awards the Paul Ehrlich and Ludwig Darmstaedter Prize, the most distinguished award for biomedical research in Germany.

  In 2001 members of the Nobel Foundation looked back over the previous century at the list of people who were considered to have brought the greatest benefit to humankind. Rolf Luft, a physician and scientist who had been chair of the Nobel Committee for Medicine and Physiology, placed Paul Ehrlich at the very top because of what he had achieved both through experimentation and because of his creativity as a theorist.[50]

  The Institute for Experimental Therapy in Frankfurt which Ehrlich set up and directed, now bears his name, the Paul Ehrlich Institute, and the address is Paul Ehrlich Strasse. When the Jewish persecution by the Nazis began in the 1930s, the name was removed but has since been restored. The institute, now operated by the Ministry of Health, oversees the control and testing of vaccines. Strehlen, Ehrlich’s birthplace, was renamed Ehrlichstadt by the Polish authorities after World War II.

  EHRLICH’S INFLUENCE EXTENDS TO CANCER TREATMENT

  Paul Ehrlich’s legacy is perpetual. A scientific symposium to commemorate the 150th anniversary of his birth and to honour his historic contribution to medical research was held in March 2004 in Frankfurt. Among the institutions that organised the symposium, Combating Pathogens and Cancer, were the Paul Ehrlich Institute, Georg Speyer Haus, the Paul Ehrlich Foundation and the Paul Ehrlich Society for Chemotherapy.

  The title of the symposium reflects the fact that the human species is in a constant tug-of-war for survival with micro-organisms and disease. In 1945, when penicillin became widely available as an accepted treatment for syphilis coupled with public health measures, the fight against the ‘great pockes’ appeared to have been won. As it transpired, however, new strains of the spirochaete Treponema pallidum developed resistance to penicillin and other antibiotics, as have other diseases, due to the overuse of these drugs. Since the 1950s the incidence of sexually transmitted diseases has been on the rise.

  The World Health Organization reports approximately 12 million cases of syphilis each year. In the same way that AIDS is having an impact on other re-emerging diseases, there is a two- to five-fold increased risk of acquiring HIV infection if syphilis is present. It is to be lamented that in the 21st century approximately 500,000 infants, most of them in the developing world, are being born each year with congenital syphilis.

  New campaigns against syphilis are ongoing and although Ehrlich may have hoped for more with Salvarsan, he may never have envisioned just how far-reaching the repercussions of his discovery of ‘magic bullets’ would be. For most of us living in economically advanced countries, because of the phenomenal developments in medicine that took place in the twentieth century, the fear of catching and dying from infectious diseases has diminished. Smallpox, bubonic plague, polio, diphtheria and their ilk are no longer the threat they once were and the names of the diseases themselves are hardly ever spoken in non-medical circles. Today, the diagnosis which engenders most fear is cancer. Since vaccination has been used to control the contagious diseases that were once universal scourges, cancer has taken their place and is now one of the leading causes of death in developed countries.

  Again Paul Ehrlich’s legacy can be seen around us in the 21st century. He developed the first chemotherapeutic drug and one of the main treatments for cancer remains chemotherapy. Cancer can be viewed either as the collective name of more than 100 different conditions, or one condition with many different target sites in the body. It is the uncontrolled growth and spread of cells that can affect almost any tissue.[51] Lung, colorectal and stomach cancer are among the five most common cancers in the world for both men and women. Among men, lung and stomach cancer are the most common cancers, and for women it is breast and cervical cancer. More than 11 million people are diagnosed with cancer every year and cancer kills 7 million people annually, amounting to 12.5 per cent of all deaths worldwide. It is estimated that there will be 16 million new cases every year by 2020.[52]

  New magic bullets have extended the reach of Paul Ehrlich’s imagination, most particularly in the realm of chemotherapy. Behind the chemotheraperutic revolution was Ehrlich’s seminal idea that scientists could make chemical compounds that could target specific disease agents and that a toxin for that organism could then be delivered along with the agent of selectivity without harming the person afflicted with the disease. This conviction guided many scientists to follow Ehrlich’s creativity in chemistry in their search for new chemical therapies such as antimalarials, sulfonamides, antihistamines and ataraxic drugs (drugs that relieve anxiety), and drugs that they would eventually aim directly at cancer.[53] The discovery that certain toxic chemicals are able to cure specific cancers ranks as one of the greatest in modern medicine.

  Cancer has always been with us. Over the centuries there have been many theories about its cause. One theory was that cancer was a poison that spread slowly through the body. Cancer was also once believed to be contagious. With the widespread use of the microscope in the eighteenth century, it was discovered that the ‘cancer poison’ spread from the primary tumour through the lymph nodes to other sites. In the late 1800s the knowledge that the body was made up of various tissues that in turn were made up of millions of cells marked the beginning of cellular pathology and put an end to old theories about chemical imbalances in the body causing cancer.

  Before Joseph Lister introduced his methods of asepsis, the use of surgery to treat cancer had poor results due to problems with infection. With improved surgical hygiene in the nineteenth century the survival statistics went up and surgical removal of tumours became the primary treatment for cancer. Soon after, however, as medical advances began to accelerate, multi-disciplinary approaches to cancer treatment were introduced. The first effective non-surgical cancer treatment became available soon after Marie Curie discovered radiation in 1898.

  The era of chemotherapy began in earnest in the 1940s. In the United States, Gertrude Elion and George Hitchings introduced ‘rational drug design’ to target specific cancers, a new version of the magic bullet.[54] Early spectacular successes in the 1960s made it seem that cancer would be curable with a new range of chemotherapeutic drugs. Not so, and the cancer puzzle is still being solved one piece at a time and chemotherapy is one piece in that puzzle.

  In Ehrlich’s time, chemotherapy meant the use of chemical substances to treat disease. Today, chemotherapy refers primarily to cytoxic (literally ‘cell destroying’) drugs that are used to destroy cancer cells by interfering with cell division in various ways, such as the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, which means that chemotherapy has the potential to harm healthy tissue. Nowadays, in addition to surgery, radiotherapy and chemotherapy, cancer can be treated with immunotherapy, or a combination of all these methods.

  The concept of a magic bullet as Paul Ehrlich envisioned it was fully realised according to th
e scientific world with the invention of monoclonal antibodies. These work by targeting tumour-specific antigens, thus enhancing the host’s immune response to tumour cells to which the agent attaches itself. The process of producing monoclonal antibodies was invented by Georges Köhler, César Milstein and Niels Kaj Jerne in 1975.

  It is difficult to get one’s mind around the complexity of cell structure, DNA, auto-immunity and chemical compounds. The research that has gone into discovering and understanding the complexities of cancer cells, then developing drugs to stop them from reproducing, is almost unfathomable to the scientifically untrained and the science behind the development of cancer-curing, chemotherapeutic drugs is becoming increasingly more complex. By understanding the mechanism of a cancer at the genetic level, the most basic inner workings of the cell, scientists are endeavouring to tailor new medicines to inhibit a cancer growth with a precision not previously possible.[55] And beyond this, the aim is to replace abnormal genes with normal ones, so cells regain their normal function. The quest to find ‘magic bullets’ continues.

  Medical breakthroughs are reported on an almost daily basis in the print and visual media. Only time will tell if these breakthroughs will be significantly measurable and eventually change the world. At the beginning of September 2006 a vaccine to protect women against cervical cancer was launched in Australia. It was developed in the 1990s by a Scottish-born Australian, Professor Ian Frazer, a contemporary medical pioneer, his research partner Dr Jian Zhou and their colleagues at the University of Queensland. Final trials of the vaccine, known as Gardasil, showed it to be 100 per cent effective against the most common strains of human papilloma virus (HPV) which causes an estimated 70 per cent of cervical cancers.[56] Around 300,000 women die from cervical cancer annually, the second-biggest cancer killer of women.