Smallpox, Syphilis and Salvation

by Sheryl Persson

  Globally, tetanus mortality dropped from between 20 to 50 deaths per million per annum between 1945 and 1950, to less than 0.16 per million in 1996.[43] War is certainly an ally of disease. Tetanus remains a problem in countries with very low rates of immunisation, as well as those that are at war or experiencing civil unrest where there are often high rates of injury.

  A very disturbing statistic is that in developing countries approximately 200,000 young babies and 30,000 mothers die each year from tetanus, which represents the second-highest cause of death by vaccine-preventable diseases. The true extent of the tetanus death toll is not really known. Eight countries account for about 73 per cent of neonatal tetanus deaths: Bangladesh, China, the Democratic Republic of the Congo, Ethiopia, India, Nigeria, Pakistan and Somalia. Many women live in rural areas in these countries and have little access to healthcare. Newborns and mothers die at home and neither the birth nor the death is reported. For this reason, tetanus is now often called the ‘silent killer’.

  In 1989 the World Health Assembly called for the elimination of neonatal tetanus worldwide. By necessity, the objective was redefined in 1993 to achieving less than one case of neonatal tetanus per 1000 live births in all at-risk countries by the year 2000. In 2000, 104 of the 161 developing countries that were targeted had achieved this. The result was accomplished by improving the immunisation rates of pregnant women—rates in the target population jumped from 4 per cent to 66 per cent in 1997—and by improving sanitary conditions during childbirth.[44] In 2006 a new campaign to provide up to 6 million tetanus vaccinations to protect vulnerable mothers and their new babies was launched by UNICEF because studies have shown that 100 per cent of children born to mothers who are vaccinated during pregnancy possess protective antibodies to tetanus.

  It was the discovery of Blood Serum Therapy by Emil von Behring and Shibasaburo Kitasato which led to the development of vaccines and cures for diphtheria and tetanus and also laid the foundations for the understanding of the body’s immune system. Their research into bacterial diseases at the end of the nineteenth century and the beginning of the twentieth also paved the way for the later development of penicillin and other antibiotics.

  Although they had parted company, in the Croonian Lecture delivered at the Royal Society of London on 22 March 1900, Professor Dr Paul Ehrlich, Director of the Royal Institute for Experimental Therapy, acknowledged that with ‘Behring’s remarkable discovery, that in the blood serum of animals immunised against diphtheria and tetanus, there were contained bodies which were able to specifically protect other animals against the toxines [ sic] of these diseases’, he had introduced an entirely new factor into the study of immunity and provided a promising prospect of immunising humankind against the majority of infectious diseases.[45]

  POSTSCRIPT

  On 4 December 1940, in the second year of World War II, the Philipps University at Marburg celebrated the 50th anniversary of the original publication of Emil von Behring’s discovery of Serum Therapy. Present at the ceremony were leaders of Adolf Hitler’s National Socialist Party, the elite from numerous German universities, many distinguished scientists and Behring’s friends, some of whom had travelled from other countries for the occasion.

  One of Behring’s sons participated in the ceremony but he was not greeted by any of the official speakers. The reason for this was that the Nazis had regarded Else von Behring as a ‘half-Jew’, because her mother came from a Jewish family. Fearing for her children, with the help of a number of friends Else had managed to have her six sons accepted by Hitler as ‘Aryans’. After her death in 1936, the Nazi party claimed Emil von Behring as an exemplification of national socialist ‘Germanic’ science. It was all part of Nazi propaganda.

  During the celebration at Marburg a new Behring Memorial was unveiled and at a two-day scientific meeting that followed, scientists discussed developments in immunology and the battle against infectious diseases. It is hard to imagine such enlightened discussion about medical discoveries to advance human health when we consider the progress of World War II and the medical experimentation that was conducted during the Nazi period.

  At the meeting, only the Danish researcher Thorvald Madsen, who had previously been chairman of the Health Organization of the League of Nations, dared to mention Emil von Behring’s personal and professional relationships with researchers from what had become enemy countries, including those at the Pasteur Institute in Paris. Courageously, Madsen also recalled how the brilliant Paul Ehrlich, despised by the Nazis because of his Jewish origin, had contributed significantly to Behring’s success.

  CHAPTER 6

  MAGIC BULLETS

  PAUL EHRLICH, SERENDIPITY, SYPHILIS AND THE BEGINNING OF CHEMOTHERAPY

  It is unthinkable for a Frenchman to arrive at middle age without having syphilis and the Cross of the Legion of Honour.[1] André Gide

  In the first decades of the twentieth century the medical profession’s understanding of health and disease was expanding. Louis Pasteur’s Germ Theory of Disease had provided specific enemies for researchers to target and vaccines had been developed for some of humankind’s most vicious foes: smallpox, rabies, bubonic plague and cholera. With the emergence of immunisation and subsequent developments such as Emil von Behring’s Blood Serum Therapy, it had become established that antibodies could be produced in response to specific microbes—antibodies that were toxic only to those microbes, but harmless to the patient.

  This was the theoretical basis for the development of ‘designer’ drugs, drugs that target a specific pathogen. In the early 1900s the German bacteriologist and medical scientist Paul Ehrlich, who had worked with Emil von Behring, predicted the future of pharmaceutical research. After the introduction of Blood Serum Therapy he envisioned that chemists might soon be able to produce substances which he called ‘magic bullets’ that would have the capacity to target specific disease-causing agents. And it was Paul Ehrlich himself who set the designer drug revolution in motion when, in 1909, while he was looking for a cure for the microbial disease sleeping sickness, serendipitously discovered a cure for syphilis.

  The origins of syphilis have been a subject of much contentious debate. Some scientists suggest that syphilis—and the micro-organism that causes it, Treponema pallidum—existed in isolation in the New World and was brought back to Europe after Christopher Columbus discovered the Americas in 1492. The evidence for this is that an epidemic in Europe coincided with Columbus’ return in 1493. Some historians propose that the disease was carried by sailors who contracted it from indigenous people in the West Indies. Since war was common in Europe during this period, the constant movement of troops was a perfect conduit for spreading an epidemic. Historians who disagree with this theory point to ancient accounts in a range of sources from the Bible to Chinese documents which describe symptoms that seem consistent with late-stage syphilis. Because documentary evidence does not exist of illnesses compatible with syphilis amongst the indigenous peoples of the New World before European imperial expansion, other historians conclude that it was Europeans who brought the disease to the New World. A third view is that syphilis emerged in the Old World and the New World independently.[2] Wherever it came from, syphilis spread like wildfire throughout Europe during the 1600s.

  Confusion about its origin is reflected in the many names syphilis had prior to the one by which it is now known. The Italians called it the French disease, the name which had the widest currency. The French, refusing to lay claim to it, called syphilis the disease of Naples. The English used several names that implicated both the French and the Spanish among others. In the Middle East it was referred to as the European pustules. It was an international game of blame and name calling. The disease actually received its modern name from the Italian physician and poet Fracastoro. In 1530 he wrote about a shepherd suffering from ‘the great pox’ in his poem Syphilis, sive morbus gallicus.[3] The word ‘syphilis’, the name of the shepherd, was adopted by some physicians for the disease but it w
as not widely used until the nineteenth century.

  The descriptions of symptoms associated with syphilis written in the late fifteenth and early sixteenth centuries indicate that it was initially more rapacious than it is today. It was debilitating, spread rapidly and killed quickly. Known as the great pox, in contrast to smallpox, the pustules which developed on the body of the afflicted could be the size of large acorns and were described as dark green in colour and foul smelling.[4] Other symptoms included rashes, mouth ulcers, severe fevers and bone pains and in many cases death was the result.

  At the beginning of the twentieth century there were very few chemical treatments for the plethora of infectious diseases that humans endured and there was no cure for syphilis. For more than three centuries mercury, which was also used for ringworm, was the only treatment available for syphilis.[5] It was first used in the late fifteenth century and could be administered orally or rubbed onto the skin. The mercury induced heavy salivation, which was thought to remove the ‘bad humours’ that caused the illness. Hot vapour baths supposedly had the same effect and syphilitics were often plunged into scalding baths.[6] Treatment was more akin to torture. Often almost lethal doses of mercury were given, causing symptoms that were similar to those of the disease itself. Trained physicians were still using mercury in the mid nineteenth century for syphilitic patients.

  There was money to be made from the afflicted in a time when superstition prevailed and there was little understanding of disease. The unscrupulous touted fantastic remedies. In 1858William Earl claimed that treatment with mercury could be supplanted by his new method which he called an ‘Anti Detersive Essence’, a complete cure which, he said, needed no recourse to deleterious drugs or chemicals.[7]

  The method of transmission, through sexual intercourse, made syphilis a taboo topic. The desperate fell victim to claims that went unchallenged partly because of strict attitudes in Victorian times towards sexuality and the human body. In an age when chair and table legs were covered with fabric skirts to preserve modesty and decorum, open discussions of venereal disease were unlikely to happen.

  Until the 1800s, gonorrhoea and syphilis were assumed to be different types of the same disease. In 1837 the French scientist Philippe Ricord, as a result of carrying out experiments on syphilitic chancres, or lesions, discovered that they were in fact two specific diseases. Ricord also discovered that syphilis goes through three distinct stages of infection: primary syphilis, secondary syphilis and tertiary syphilis. At the time Ricord was studying the disease it was common for syphilitics to experience a period of latency, in which no symptoms are visible.[8]

  Two discoveries made it possible for Paul Ehrlich to find a ‘magic bullet’ to aim at syphilis. In 1905 in Berlin, Professors Fritz Schaudinn and Erich Hoffmann discovered the cause of syphilis, the spirochaete Treponema pallidum.They isolated this pale, corkscrew-shaped organism in serum from a lesion of secondary syphilis. In addition, Schaudinn and Hoffmann believed there was a relationship between spirochaetes and trypanasomes, the microorganism that causes sleeping sickness (an inflammation of the brain causing extreme weakness and drowsiness).[9] The following year the first serologic procedure for diagnosing syphilis (a laboratory test carried out on blood serum to detect antibodies associated with a disease) was invented by a group of researchers that included August von Wasserman, Albert Neisser and Carl Bruck.[10]

  ***

  By the beginning of the twentieth century syphilis and the symptoms associated with the various stages of the disease were better understood. While sexually transmitted, it can also pass from mother to child in utero, in which case it is called congenital syphilis. The course of the disease is long. With primary syphilis, the chancres form at the point of contact, usually on the genitals, but they can appear almost anywhere on the body. Some can be so small that they may go unnoticed. If the chancres do not become infected, they heal without treatment within a month or two. Primary syphilis lasts for ten to 50 days.

  While the chancres are healing, the second stage begins. Secondary syphilis starts with the appearance of a rash at six weeks to six months after infection. Bones and joints often become painful and the circulatory system can be affected, causing heart palpitations. These symptoms can be accompanied by fevers, indigestion and headaches. Sometimes lesions develop into moist ulcers (including open sores in the mouth) that are actually teeming with the spirochaetes.

  People suffering from syphilis experience a period of latency that lasts anywhere from a few weeks to 30 years. During that time all symptoms disappear until the third stage, tertiary syphilis, begins. Tumours, which are characteristic of late syphilis, begin to appear because of the concentration of spirochaetes in the body’s tissues. This is the most acute stage of the disease which can lead to death because the cardiovascular and central nervous systems are compromised. At this stage the disease can also cause a softening of brain tissue resulting in progressive paralysis and insanity.[11]

  Syphilis was a dreaded disease, one of many that had wrought immeasurable damage and brought misery to the human race for centuries, virtually unchecked by any drug or therapy. It was via a circuitous route, however, that syphilis came under the scrutiny of Paul Ehrlich. Although his initial intention was to find a cure for sleeping sickness, what transpired was not uncommon when it came to early medical breakthroughs. While following a pre-determined path to find a cure for one disease, the seeker would take a sudden and unintended detour.

  ***

  Paul Ehrlich was born into a prosperous Jewish family on 14 March 1854 at Strehlen in Upper Silesia in German East Prussia, an area now in Poland. He was the only son of Ismar Ehrlich, a lottery-office keeper, and Rosa Weigert. Paul’s parents were keen for their son to be well educated and when he was ten Paul was sent to preparatory school at Breslau and went on to attend a number of universities between 1872 and 1878.

  At eighteen Paul Ehrlich entered the University of Breslau to study natural sciences but soon transferred to Strasbourg University to study medicine. He also spent some time at Freiburg University.[12] As a young student Ehrlich already had interests that he wished to pursue and he began to conduct experiments to test the concept that certain cells seemed to have an affinity for certain chemicals. This was Paul Ehrlich’s particular preoccupation.

  At Breslau University, Ehrlich studied under the physiologist Heidenhain and the pathologist Cohnheim. Cohnheim’s assistant was Ehrlich’s older cousin, Karl Weigert, and it was Weigert who introduced Ehrlich to aniline dyes.[13] At the time that Ehrlich was a student, the German dye industry was thriving and new aniline dyes, which had been discovered in 1853, were being used by researchers for tissue staining to enhance the normally colourless tissue sections. Joseph von Gehrlach had shown that nerve tissues could be stained with natural dyes and had used gold chloride or carmine to stain his tissue samples, popularising the method among his contemporaries. With the invention of chemical dyes a greater array of stains became available.[14]

  Ehrlich continued his medical studies at the University of Leipzig where he was able to expand the range of his research with aniline dyes. Ehrlich had also developed an interest in the body’s reaction to chemicals. He found that different cells held different dyes and he used this knowledge to develop effective staining techniques to study bacterial and other tissues. Amongst his fellow students Ehrlich enjoyed a certain notoriety and he was remembered as the man with blue, yellow, red and green fingers.[15]

  At the age of 24 Ehrlich was awarded his medical degree and as was to be expected his dissertation was on the theory and practice of staining animal tissues, with the title being, ‘Contributions to the Theory and Practice of Histological Staining’. In it he laid down a basic principle that was to pervade his work: that pharmacological activity is based on the affinity of molecules of living matter for various chemical substances when brought into relationship with them.[16] This assumption would come to underpin the foundation of chemotherapy.

  After gra
duating in 1878 Ehrlich was appointed as an assistant to Professor Friedrich von Frerichs at the medical clinic of Charité Hospital in Berlin. Frerichs recognised Ehrlich’s talent and made it possible for him to continue his work with dyes and tissue staining rather than practise clinical medicine even though he was given the position of Senior House Physician. In his research on the reactions of dyes on living cells, Ehrlich gradually developed the fundamental concept that to understand biological processes it would be necessary to describe them in chemical terms.

  While still a student, Ehrlich had begun to prepare papers for publication on the morphology of blood, an extension of his work with tissue staining, and had published his first paper on the effects of aniline dyes on living cells. Ehrlich was able to differentiate the elements of blood by colour analysis and this work on the staining of granules in blood cells laid the foundation for another medical discipline, haematology. We tend to forget or are unaware that there are so many specialist areas within medicine that once did not exist because the requisite knowledge was unknown. The discoveries were cumulative. Without an understanding of blood, how much less medicine would be able to do for humans today.

  In 1882, after being present at the Physiological Society in Berlin where Robert Koch announced that he had isolated the tubercle bacillus, Ehrlich developed his new method of staining it which Koch then adopted. The method proved to be of decisive importance in finding a way to diagnose tuberculosis. Subsequent modifications to Ehrlich’s method were introduced by two scientists who gave their names to the Ziehl–Neelson (ZN) stain which is used today to detect Mycobacterium tuberculosis.[17] An even more sensitive diagnostic test was announced in South Africa in 2002 at the Medical Research Council’s Molecular and Cellular Biology Centre. Less time-consuming than the ZN stain, the new test can pick up the disease in patients who have very low counts of bacilli which are not detectable with a ZN stain. It was the work of Ehrlich that made possible the development of Gram’s method by Danish scientist Hans Christian Gram (see Chapter Five).